Journal articles on the topic 'Boston. Massachusetts General Hospital. Ward 4'

In 1996, the dominant (43%) strain of vancomycin-resistant enterococci (VRE; type A) at Massachusetts General Hospital was identified at Brigham and Women’s Hospital (BWH). To characterize the epidemiology of infection with type A isolates of VRE at BWH, we collected demographic and clinical data for all patients from whom VRE were isolated from a clinical specimen through September 1996. The first clinical isolates from all BWH patients from whom VRE were isolated were typed by pulsed-field gel electrophoresis ofSmaI digests of chromosomal DNA. Among patients hospitalized after the first patient at BWH infected with a type A isolate of VRE was identified, exposures were compared between patients who acquired type A isolates of VRE and those who acquired other types of VRE. Isolates from 99 patients identified to have acquired VRE were most commonly from blood (n = 27), urine (n = 19), or wounds (n = 19). Three months after the index patient arrived at BWH and at a time when ≥12 types of strains of VRE were present, type A isolates of VRE became dominant; 39 of 75 (52%) of the study cohort had acquired type A isolates of VRE. We found no association between the acquisition of type A isolates of VRE and transfer from another institution or temporal overlap by service, ward, or floor with patients known to have acquired type A isolates of VRE. By multivariate analysis, only residence in the medical intensive care unit (adjusted odds ratio [OR], 3.2; 95% confidence interval [CI], 1.4 to 107) and the receipt of two or more antibiotics per patient-day (adjusted OR, 12.2; 95% CI, 1.2 to 9.0) were associated with the acquisition of strain A. This strain of VRE, dominant at two Boston hospitals, was associated with intensity of antibiotic exposures (i.e., two or more antibiotics per patient-day). We hypothesize that this strain may have unidentified properties providing a mechanism favoring its spread and dominance over other extant isolates, and further studies are needed to define these properties.

IntroductionIntegrating palliative care (PC) early in the illness course for patients with serious cancers improves their outcomes and is recommended by national organisations such as the American Society of Clinical Oncology. However, monthly visits with PC clinicians from the time of diagnosis can be challenging to implement due to the lack of specialty-trained PC clinicians and resources. Therefore, we developed a stepped care model to triage PC service based on patients’ needs.Methods and analysisWe are conducting a non-blinded, randomised trial to evaluate the non-inferiority of a stepped PC model compared with an early integrated PC model for improving patients’ quality of life (QOL) at 24 weeks (primary outcome). Patients assigned to early integrated PC meet with PC every 4 weeks throughout their illness. Patients assigned to stepped PC have PC visits only at clinically significant points in their illness (eg, cancer progression) unless their QOL decreases, at which time they are ‘stepped up’ and meet with PC every 4 weeks throughout the remainder of their illness. Secondary aims include assessing whether stepped PC is non-inferior to early integrated PC regarding patient-clinician communication about end of life care and length of stay on hospice as well as comparing resource utilisation. Patients are recruited from the Massachusetts General Hospital Cancer Center, Boston, Massachusetts; Duke Cancer Center, Durham, North Carolina and University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania. The target sample size is 510 patients.Ethics and disseminationThe study is funded by the National Cancer Institute, approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board and will be reported in accordance with the Consolidated Standards of Reporting Trials statement. We will disseminate results through professional society meetings, peer-reviewed publications and presentations to patient organisations.Trial registration numberNCT03337399.

Abstract Homozygous deletion of CDKN2A is an important predictor of poor prognosis in patients with IDH-mutant gliomas. The updated 2021 WHO classification now recognizes this alteration as sufficient for the designation of an astrocytoma, IDH-mutant, WHO Grade 4, which otherwise requires histological observation of necrosis or microvascular proliferation. While overall survival patterns associated with CDKN2A deletion have been well-described, we sought to characterize progression-free survival (PFS) in this patient population. Across three institutions (Massachusetts General Hospital, Boston; University Hospital Heidelberg, Heidelberg; TU Dresden, Dresden), we identified 48 patients with IDH-mutant gliomas in which CDKN2A deletion was detected at the time of diagnosis, followed for a median of 15.2 years. The average age of the cohort is 35 years, with 60% of the patients identified as male. Most patient received immediate treatment after surgery, with 81% of the cohort undergoing radiation therapy and 73% receiving chemotherapy. Based on RANO criteria, the median progression-free survival of this patient population is 2.8 years (95% CI 1.4 – 3.3 years) and median overall survival is 4.3 years (95% CI 2.1 – 6.6 years). A positive T2/FLAIR mismatch sign or lack of contrast enhancement on MRI at the time of diagnosis are both associated with improved PFS in univariate regression analysis. For comparison, we identified a control cohort of 51 patients with astrocytoma, IDH-mutant, grade 4 without CDKN2A deletion from MGH, achieving grade 4 by histologic criteria. Demographics were similar to the CDKN2A-deleted cohort, with median age (37 years) and percentage of male patients (60%). Notably, however, PFS for the grade 4, CDKN2A-intact, IDH-mutant glioma comparison group is estimated at 5.9 years (95% CI 3.3 – 7.9 years). Overall, these data reinforce the accelerated disease course associated with deletion of CDKN2A in IDH-mutant gliomas, providing an important reference for clinical trial design.

9502 Background: To evaluate the efficacy of 12 weeks of Stanford V chemotherapy (prednisone, vinblastine, doxorubicine, nitrogen mustard, etoposide, vincristine, and bleomycin) without routine growth factor support plus response-adapted low-dose, involved-field radiotherapy (IFRT) in children and adolescents with unfavorable risk Hodgkin lymphoma (HL). Methods: Multi-institutional (St. Jude Children’s Research Hospital, Stanford University, Children’s Hospital Boston, Massachusetts General Hospital and Maine Children’s Hospital) clinical trial. One hundred forty-one patients with clinical stages IIB (n=43), IIIB (n=19), IVA (n=27), and IVB (n=52) HL were treated with 12 weeks of Stanford V chemotherapy and low dose IFRT between June 2002 and May 2011. Involved nodal sites in complete remission (CR, defined as > 75% shrinkage of the original tumor and PET negative) after 8 weeks of Stanford V received 15 Gy IFRT; those sites that achieved only partial response received 25.5 Gy IFRT after completion of all 12 weeks of chemotherapy. Results: With a median follow-up of 4.6 years, the 3-year overall and event-free survival (EFS) are 97% (SE=2%) and 79% (SE=4%) respectively. There was no significant difference in EFS by stage (IIB vs. IIIB vs. IV; P=0.84). Ten patients developed progessive disease and 18 relapsed, while 5 have died (1 after relapse in an accident and 4 of refractory disease). Most common toxicities were grade 3 hematologic with 234 episodes of neutropenia in 101 patients (72%) and 85 episodes of anemia in 52 patients (37%); Fever and neutropenia occurred 13 times in 12 patients (9%). Conclusions: Risk-adapted, combined-modality therapy using 12 weeks of Stanford V chemotherapy plus IFRT is well tolerated in this population with manageable acute toxicities. Overall survival is comparable to other more intense chemotherapy regimens. Future high-risk front line therapies may consider a Stanford V backbone with targeted intensification and further tailoring of radiation therapy.

ImportancePatients with unmet health-related social needs are at high risk for preventable health care utilization. Prior interventions to identify health-related social needs and provide navigation services with community resources have not taken place in pharmacy settings.ObjectiveTo evaluate an enhancement of pharmacy care to reduce hospital admissions and emergency department (ED) visits among primary care patients in a Medicaid accountable care organization (ACO).Design, Setting, and ParticipantsThis nonrandomized controlled trial was conducted from May 1, 2019, through March 4, 2021, with 1 year of follow-up. Study allocation was determined by odd or even medical record number. The study was performed at a general internal medicine practice at a large safety-net hospital in Boston, Massachusetts. Patients who qualified for the hospital’s pharmacy care program (aged 18-64 years and within the third to tenth percentile for health care utilization and cost among Medicaid ACO membership) who attended a visit with a primary care clinician were eligible. Of 770 eligible patients, 577 were approached, 127 declined, and 86 could not be contacted.InterventionsPatients in the control group received usual pharmacy care focused on medication adherence. Patients in the intervention group received enhanced pharmacy care with an additional focus on identification of and intervention for health-related social needs. The intervention took place for 1 year.Main Outcomes and MeasuresThe primary outcome was inpatient hospital admissions and ED visits (composite outcome) in the 12 months after enrollment during the intervention period.ResultsAmong 364 allocated patients (mean [SD] age, 50.1 [10.1] years; 216 women [59.3%]), 35 were Hispanic of any race (9.6%) and 214 were non-Hispanic Black (58.8%). All participants were included in the intention-to-treat analysis. In analyses controlling for baseline hospital admissions and ED visits the year prior to enrollment, the enhanced pharmacy care group was not associated with the odds of having any hospital admission or ED visit (adjusted odds ratio, 0.62 [95% CI, 0.23-1.62]; P = .32) among all patients and was not associated with the visit rates among those with any visit (adjusted rate ratio, 0.93 [95% CI, 0.71-1.22]; P = .62) relative to the usual pharmacy care group in the year following enrollment.Conclusions and RelevanceThe findings of this nonrandomized controlled trial suggest that inpatient and ED utilization among Medicaid ACO members at a safety-net hospital was not significantly different between groups at 1-year follow-up.Trial RegistrationClinicalTrials.gov Identifier: NCT03919084

Background Individuals with opioid use disorder (OUD) have a high prevalence of smoking and frequently experience unmet social determinants of health (SDOH), which may be barriers to smoking cessation. Hospitalization is an opportunity to encourage smoking cessation. Unfortunately, many clinicians do not provide tobacco treatment to support the maintenance of cessation achieved during hospitalization. Interventions are required to support these high-risk individuals after hospital discharge. Objective This study aimed to test the feasibility and acceptability of a 28-day SMS text messaging program tailored to individuals with OUD, which provides smoking cessation support and addresses unmet SDOH needs. Methods From July to December 2019, we enrolled 25 individuals who were hospitalized with tobacco dependence and OUD at our large safety net hospital. The SMS text messaging program was initiated during hospitalization and continued for 28 days. Participants were enrolled in either the ready to quit within 30 days or the not ready to quit within 30 days program based on their readiness to quit. Automated SMS text messages were sent twice daily for 4 weeks. The topics included health and cost benefits of quitting, both general and opioid specific (16 messages); managing mood and stress (8 messages); motivation, coping strategies, and encouragement (18 messages); addressing medication misconceptions (5 messages); links to resources to address substance use (2 messages providing links to the Massachusetts Substance Use Helpline and Boston Medical Center resources), tobacco dependence (1 message providing a link to the Massachusetts Quitline), and unmet SDOH needs (6 messages assessing SDOH needs with links to resources if unmet SDOH needs were identified). Questionnaires and interviews were conducted at baseline and at 2 and 4 weeks after enrollment. Results The participants were 56% (14/25) female, 36% (9/25) African American, 92% (23/25) unemployed, and 96% (24/25) Medicaid insured. Approximately 84% (21/25) activated the program, and none of the participants unsubscribed. Approximately 57% (12/21) completed either the 2- or 4-week questionnaires. Program satisfaction was high (overall mean 6.7, SD 0.8, range 1-7). Many perceived that the SMS text messaging program provided social support, companionship, and motivation to stop smoking. Messages about the health benefits of quitting were well received, whereas messages on how quitting cigarettes may prevent relapse from other substances had mixed views, highlighting the importance of tailoring interventions to patient preferences. Conclusions SMS text messaging to promote smoking cessation and address SDOH needs may be an effective tool for improving quit rates and health outcomes in individuals with tobacco dependence and OUD. Our study adds to the growing body of evidence that SMS text messaging approaches are feasible and acceptable for providing tobacco treatment to all individuals who smoke, even among low-income populations who have OUD and are not ready to quit.

ABSTRACT Background One of the most important mainstays in disaster management is preparedness. In partnership with the International Trauma & Disaster Institute, Massachusetts General Hospital, Boston, and the Panamerican Trauma Society (PTS), the Brazilian Society of Integrated Assistance to the Traumatized (SBAIT) has been promoting, for the last 4 years, education and training through the “Advanced Disaster Medical Response” (ADMR) course for health care providers. The aim of this study is to evaluate the impact of the ADMR course on medical staff learning. Materials and methods Between 2011 and 2014, 23 ADMR courses (each of 8 hours duration) were conducted in Brazil. Attendees answered a pretest and posttest survey to evaluate their experience in disaster medicine and acquired knowledge during the course. Each test consisted of the same 10 objective questions, resulting in a score of 0 to 10. Attendees had to do both tests in order to qualify for a course certificate. Results In 4 years, 1,398 students participated in the courses. Participants were predominantly physicians and medical students of the male gender. Posttest scores were significantly higher than those of the pretests: 9 (±1.22) and 7 (±1.67) respectively, representing an increase of 34.1% in acquired knowledge. Students with prior experience in disaster medical response (p<0.05) or participation in multiple-casualty simulations (p<0.05) or theoretical training (p<0.05) scored better on pretests than those without similar experience. For every kind of prior experience, posttest scores were higher than pretests (p<0.05). Conclusion The ADMR course is an effective learning tool for medical personnel and health care providers, increasing knowledge of disaster medical response. How to cite this article Simões RL, Dorigatti AE, Pereira BM, Calderan TRA, Briggs SM, Fraga GP. Education on Advanced Disaster Medical Response: Initial Experience in Brazil. Panam J Trauma Crit Care Emerg Surg 2016;5(2):76-82.

Context.—Testing for high-risk human papillomavirus (HR-HPV) in head and neck squamous cell carcinomas (HNSCCs) is important for both prognostication and clinical management. Several testing platforms are available for HR-HPV; however, effective alternative automated approaches are needed. Objective.—To assess the performance of the automated Roche cobas 4800 HPV real-time polymerase chain reaction-based system on formalin-fixed, paraffin-embedded HNSCC specimens and compare results with standard methods of in situ hybridization (ISH) and p16 immunohistochemistry. Design.—Formalin-fixed, paraffin-embedded samples of HNSCC were collected from archival specimens in the Department of Pathology, Massachusetts General Hospital (Boston), and prepared using the automated system by deparaffinization and dehydration followed by tissue lysis. Samples were integrated into routine cervical cytology testing runs by cobas. Corresponding formalin-fixed, paraffin-embedded samples were evaluated for HR-HPV by ISH and p16 by immunohistochemistry. Discrepant cases were adjudicated by polymerase chain reaction. Results.—Sixty-two HNSCC samples were analyzed using the automated cobas system, ISH, and immunohistochemistry. Fifty-two percent (n = 32 of 62) of formalin-fixed, paraffin-embedded tumors were positive for HR-HPV by cobas. Eighty-eight percent (n = 28 of 32) of cases were the HPV 16 subtype and 12% (n = 4 of 32) were other HR-HPV subtypes. Corresponding testing with ISH was concordant in 92% (n = 57 of 62) of cases. Compared with the adjudication polymerase chain reaction standard, there were 3 false-positive cases by cobas. Conclusions.—Concordance in HNSCC HR-HPV status between cobas and ISH was more than 90%. The cobas demonstrated a sensitivity of 100% and a specificity of 91% for detection of HR-HPV. Advantages favoring cobas include its automation, cost efficiency, objective results, and ease of performance.

ImportanceAdoption of primary care interventions to reduce childhood obesity is limited. Progress in reducing obesity prevalence and eliminating disparities can be achieved by implementing effective childhood obesity management interventions in primary care settings.ObjectiveTo examine the extent to which implementation strategies supported the uptake of research evidence and implementation of the Connect for Health pediatric weight management program.Design, Setting, and ParticipantsThis quality improvement study took place at 3 geographically and demographically diverse health care organizations with substantially high numbers of children living in low-income communities in Denver, Colorado; Boston, Massachusetts; and Greenville, South Carolina, from November 2019 to April 2022. Participants included pediatric primary care clinicians and staff and families with children aged 2 to 12 years with a body mass index (BMI) in the 85th percentile or higher.ExposuresPediatric weight management program with clinician-facing tools (ie, clinical decision support tools) and family-facing tools (ie, educational handouts, text messaging program, community resource guide) along with implementation strategies (ie, training and feedback, technical assistance, virtual learning community, aligning with hospital performance metrics) to support the uptake.Main Outcomes and MeasuresPrimary outcomes were constructs from the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) Framework examined through parent, clinician, and leadership surveys and electronic health record data to understand the number of children screened and identified, use of the clinical decision support tools, program acceptability, fidelity to the intervention and implementation strategies, and program sustainability.ResultsThe program screened and identified 18 333 children across 3 organizations (Denver Health, 8480 children [46.3%]; mean [SD] age, 7.97 [3.31] years; 3863 [45.5%] female; Massachusetts General Hospital (MGH), 6190 children [33.8%]; mean [SD] age, 7.49 [3.19] years; 2920 [47.2%] female; Prisma Health, 3663 children [20.0%]; mean [SD] age, 7.33 [3.15] years; 1692 [46.2%] female) as having an elevated BMI. The actionable flagging system was used for 8718 children (48%). The reach was equitable, with 7843 children (92.4%) from Denver Health, 4071 children (65.8%) from MGH, and 1720 children (47%) from Prisma Health being from racially and ethnically minoritized groups. The sites had high fidelity to the program and 6 implementation strategies, with 4 strategies (67%) used consistently at Denver Health, 6 (100%) at MGH, and 5 (83%) at Prisma Health. A high program acceptability was found across the 3 health care organizations; for example, the mean (SD) Acceptability of Intervention Measure score was 3.72 (0.84) at Denver Health, 3.82 (0.86) at MGH, and 4.28 (0.68) at Prisma Health. The implementation strategies were associated with 7091 (39%) uses of the clinical decision support tool. The mean (SD) program sustainability scores were 4.46 (1.61) at Denver Health, 5.63 (1.28) at MGH, and 5.54 (0.92) at Prisma Health.Conclusions and RelevanceThese findings suggest that by understanding what strategies enable the adoption of scalable and implementation-ready programs by other health care organizations, it is feasible to improve the screening, identification, and management of children with overweight or obesity and mitigate existing disparities.

ImportanceReproductive genetic carrier screening can be performed prior to or during pregnancy to assess a reproductive couple’s risk of having a child with a recessively inherited disorder. Although professional societies endorse preconception screening as preferable to prenatal screening to allow for greater reproductive choice, implementation of preconception screening is challenging.ObjectiveTo determine how carrier screening timing varies by multilevel factors associated with health care delivery including patient, clinician, and location across a large integrated health care system.Design, Setting, and ParticipantsThis cross-sectional study used a mixed-methods approach including (1) quantitative analysis of multilevel factors associated with the timing of reproductive carrier screening and (2) qualitative analyses of data from interviews conducted with clinicians ordering carrier screenings. The setting was the Mass General Brigham, a large integrated health care system in the greater Boston, Massachusetts area. Participants included adult female patients who completed reproductive carrier screening performed by Myriad Women’s Health between October 1, 2018, to September 30, 2019.ExposuresSite of care (ordering clinical location and hospital affiliate), ordering clinician specialty, and patient characteristics, including age at date of test collection, self-reported race and ethnicity, primary insurance payor, and number of comorbidities.Main Outcomes and MeasuresThe primary outcome was the timing of carrier screening (preconception vs prenatal). A series of 4 multilevel logistic regression models were fitted to measure the relative contribution of site, clinician, and patient-level factors on the timing of screening. Interviews with ordering clinicians (N = 9) were analyzed using a framework approach to explore barriers to preconception screening.ResultsAmong 6509 adult female patients who completed carrier screenings, 770 (12%) were Asian, 352 (5%) were Hispanic, 640 (10%) were non-Hispanic Black, 3844 (59%) were non-Hispanic White, 858 (13%) were other or multiple races and ethnicities, and 2611 (40%) were aged 31 to 35 years; 4701 (63%) had prenatal screening and 2438 (37%) had preconception screening; screenings were ordered by 161 distinct clinicians across 32 clinical locations affiliated with 4 hospitals. In model 1, adjusted for hospital (fixed effect), clinic and clinician (random effects), 49% of the variability in timing was associated with clinician-level effects (intraclass correlation coefficient [ICC], 0.49) and 28% was associated with clinic-level effects (ICC, 0.28). Clinician specialty explained the greatest amount of variation in screening timing. Interviewed clinicians (N = 9) supported preconception screening but cited several barriers to offering population-based preconception screening.Conclusions and RelevanceIn this cross-sectional study, multilevel factors were associated with carrier screening timing. These findings suggest that increasing access to preconception screening may involve engaging specific medical specialties.

ImportanceThe hybrid ophthalmology telemedicine model asynchronously pairs an imaging appointment by a technician with a subsequent virtual appointment by a clinician. Although it has been mentioned in several studies as an alternative to standard in-person care during the COVID-19 pandemic, outcomes of this alternative clinical care model remain to be evaluated.ObjectiveTo investigate the outcomes associated with the hybrid ophthalmology telemedicine model during the COVID-19 pandemic for nonurgent and nonprocedural ophthalmological care.Design, Setting, and ParticipantsRetrospective, cross-sectional study of all hybrid visits scheduled during the year 2020 in a single academic, hospital-based eye clinic in Boston, Massachusetts. All hybrid ophthalmology telemedicine visits completed in the year 2020 by opthalmologists and optometrists were included. Data were analyzed from January to December 2020.ExposuresHybrid telemedicine clinical encounters.Main Outcomes and MeasuresFour outcome metrics were calculated: (1) need for subsequent procedure visit, (2) medication change, (3) nonurgent, and (4) urgent consultation with another eye clinician. Adverse outcomes were defined as irreversible vision loss and the need for additional in-person evaluation to reach a management decision.ResultsFrom April 9 to December 30, 2020, 889 patients (506 female patients [56.9%]; mean [SD] age, 62.1 [14.5] years; age range, 13-98 years) completed 940 hybrid visits. The most common visit indications were glaucoma (424 visits [45.1%]) and retinal diseases (499 visits [53.1%]). A total of 25 visits (2.7%) led to a procedure, 22 visits (2.3%) led to a change in medication, and 44 visits (4.7%) were referred for nonurgent consultation with another subspecialty with no instances of urgent referrals. Sixteen patients (1.7%) were referred to the on-call clinician for a same-day emergency in-person visit or recommended for a subsequent standard in-person visit to reach a management decision. There were no cases of irreversible vision loss following a hybrid visit.Conclusions and RelevanceThese findings suggest that with the appropriate patient selection and clinical setting, the hybrid ophthalmology telemedicine model may be a good alternative to standard in-person visits, particularly for patients with glaucoma and retinal diseases.

Background: Travel screening can facilitate the identification of patients at risk for emerging infectious diseases, such as Middle East respiratory syndrome (MERS). A travel navigator with associated decision support through a best practice advisory (BPA) was implemented in an electronic health record to build upon the CDC identify-isolate-inform framework. Compliance with documentation of travel history, symptom screening when appropriate, and isolation of suspect MERS patients were assessed. Methods: Adult and pediatric emergency department encounters at the Massachusetts General Hospital, a 1,035-bed, tertiary-care, academic health center in Boston, Massachusetts, from August 2018 to October 2019, were included. We categorized an encounter as adherent to initial travel screening if providers answered foreign, domestic, or no travel to the screen. Encounters were defined as nonadherent if they were recorded as unknown or if an answer was not selected. Adherence to completion of data entry for the subgroup of patients with documented foreign travel was further assessed for region- and country-level specification, completion of symptom screen, and response to the MERS BPA (Fig. 1). Results: In total, 127,866 encounters were included, of which 105,593 (83%) were adherent to initial travel screening. Among 4,498 encounters with documented foreign travel, 2,970 (66%) specified the region of travel, and 710 (16%) selected a country of travel from the listing. Moreover, 214 encounters had documented travel to the Middle East. Selection of Middle East or 1 of the 13 countries identified by the CDC as at risk for MERS triggered symptom screening for fever and cough, which was performed in 139 encounters (65%). Of these, 95 encounters documented absence of fever and cough, 15 documented fever and cough, 12 documented a cough alone, and 17 documented a fever alone through reporting or obtaining vitals. The MERS BPA was triggered in 37 encounters; 10 patients were ordered for isolation using the BPA. Of these, 4 patients met CDC criteria for a MERS patient under investigation and were tested; all were negative. Conclusions: Initial screening to document foreign travel is completed at a high rate; however, use of the travel navigator to specify region and country, key components necessary to prompt clinicians for symptom screening, are documented in a minority of encounters. Future interventions are needed to improve region and country capture and appropriate symptom screening, with isolation when appropriate.Funding: NoneDisclosures: None

BACKGROUND Endoscopic evaluation in diagnosing and managing ulcerative colitis (UC) is becoming increasingly important. Several endoscopic scoring systems have been established, including the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score and Mayo Endoscopic Subscore (MES). Furthermore, the Toronto Inflammatory Bowel Disease Global Endoscopic Reporting (TIGER) score for UC has recently been proposed; however, its clinical value remains unclear. AIM To investigate the clinical value of the TIGER score in UC by comparing it with the UCEIS score and MES. METHODS This retrospective study included 166 patients with UC who underwent total colonoscopy between January 2017 and March 2023 at the Affiliated Hospital of Qingdao University (Qingdao, China). We retrospectively analysed endoscopic scores, laboratory and clinical data, treatment, and readmissions within 1 year. Spearman’s rank correlation coefficient, receiver operating characteristic curve, and univariate and multivariable logistic regression analyses were performed using IBM SPSS Statistics for Windows, version 26.0 (IBM Corp., Armonk, NY, United States) and GraphPad Prism version 9.0.0 for Windows (GraphPad Software, Boston, Massachusetts, United States). RESULTS The TIGER score significantly correlated with the UCEIS score and MES (r = 0.721, 0.626, both P < 0.001), showed good differentiating values for clinical severity among mild, moderate, and severe UC [8 (4–112.75) vs 210 (109–219) vs 328 (219–426), all P < 0.001], and exhibited predictive value in diagnosing patients with severe UC [area under the curve (AUC) = 0.897, P < 0.001]. Additionally, the TIGER (r = 0.639, 0,551, 0.488, 0.376, all P < 0.001) and UCEIS scores (r = 0.622, 0,540, 0.494, and 0.375, all P < 0.001) showed stronger correlations with laboratory and clinical parameters, including C-reactive protein, erythrocyte sedimentation rate, length of hospitalisation, and hospitalisation costs, than MES (r = 0.509, 0,351, 0.339, and 0.270, all P < 0.001). The TIGER score showed the best predictability for patients' recent advanced treatment, including systemic corticosteroids, biologics, or immunomodulators (AUC = 0.848, P < 0.001) and 1-year readmission (AUC = 0.700, P < 0.001) compared with the UCEIS score (AUC = 0.762, P < 0.001; 0.627, P < 0.05) and MES (AUC = 0.684, P < 0.001; 0.578, P = 0.132). Furthermore, a TIGER score of ≥ 317 was identified as an independent risk factor for advanced UC treatment (P = 0.011). CONCLUSION The TIGER score may be superior to the UCIES score and MES in improving the accuracy of clinical disease severity assessment, guiding therapeutic decision-making, and predicting short-term prognosis.

Abstract OBJECTIVE Posterior circulation aneurysms can be difficult lesions to treat surgically, and they have potential for high morbidity and mortality, particularly in elderly patients or those in poor neurological condition. In an effort to improve outcomes, our combined neurosurgical and neuroendovascular unit has used both surgical clipping and endovascular coiling techniques to treat posterior circulation aneurysms. Patients considered at high risk for surgery were managed with endovascular treatment. METHODS From 1990 to 1998, 197 posterior circulation aneurysms in 189 patients were treated in our combined neurovascular unit. Of these aneurysms, 128 were ruptured, 63 were unruptured, and 6 had a distant history of rupture in patients who came to our center for delayed or repeat treatment. A total of 132 aneurysms were treated with surgical clipping (85 ruptured, 46 unruptured, and 1 with distant history of rupture) and 65 aneurysms were treated with endovascular coiling (43 ruptured, 17 unruptured, and 5 with distant history of rupture). Dissecting aneurysms of the vertebral or posteroinferior cerebellar arteries or aneurysms treated with proximal (Hunterian) occlusion were excluded from this analysis. Surgical risk was assessed using a previously described system (Massachusetts General Hospital [MGH] grade), which incorporates age, Hunt and Hess grade, size of lesion, and Fisher grade. RESULTS Overall clinical outcomes at 1 year of follow-up were 77.2% excellent or good, 10.2% fair, 4.1% poor, and 8.6% dead. Surgical treatment resulted in 95.6% complete aneurysm occlusion and 4.4% with residual aneurysm after surgical treatment, whereas endovascular treatment resulted in 32.3% complete occlusion, 26.2% with residual aneurysm, and 41.5% with partial occlusion. In most cases, however, treatment with Guglielmi detachable coils (Boston Scientific/Target, Fremont, CA) was performed for palliation rather than complete radiographic occlusion. Outcome was closely associated with MGH grade with either treatment modality. Excellent/good outcomes were achieved in 96, 92.3, 82.9, 46.2, and 0% of surgically treated patients with MGH Grades of 0, 1, 2, 3, and 4, respectively. In comparison, excellent/good outcomes were achieved in 100, 84.2, 61.9, 0, and 50% of endovascularly treated patients with MGH Grades of 0, 1, 2, 3, and 4, respectively. CONCLUSION A combined surgical and endovascular approach to posterior circulation aneurysms can achieve good outcomes in high-risk surgical patients treated by use of coiling techniques.

1065 Background: The GATA3 gene encodes for a transcription factor (TF) that plays a pivotal role in the development of breast tissue. Breast tumors with lower GATA3 expression have worse prognosis compared to tumors with higher expression. However, the consequences of somatic GATA3 mutations ( GATA3mut) on clinical outcomes in metastatic breast cancer (MBC) remain poorly understood. Further, GATA3 TF interferes with FOXA1 and ER to enhance transcription of ER-responsive genes, but the role of GATA3mut in altering downstream transcriptional activity and its effects on response to anti-estrogens remains unclear. Methods: We retrospectively identified ctDNA next-generation sequencing results from 101 ER+/HER2- patients with MBC treated with either selective estrogen receptor degraders (SERDs) alone or a combination of SERDs and CDK4/6 inhibitors at Massachusetts General Hospital (Boston, MA) and Northwestern University (Chicago, IL). Associations between GATA3mut, patient and tumor characteristics, and prior treatments were assessed using logistic regression. Clinical outcomes were estimated through Cox proportional hazards regression. Results: GATA3mut were observed in 13 patients (13%), each with a single GATA3 variant. These mutations were detected in exon 4 (M294K), exon 5 that includes Zn-finger-2 motif (T327fs, R331fs, N334K, D336fs, c.925-3_925-2del splice acceptor variant), and exon 6 (K358fs, P409fs, M416fs, G431fs, M439fs, V440fs). All mutations except for M294K were insertion/deletion frameshift mutations that result in either elongation or truncation of the protein, potentially with heterogenous downstream effects. GATA3mut were the only detectable alteration in 4 patients. The most commonly co-occurring mutations with GATA3mut were ESR1mut in 7/13 (53.8%) and PIK3CAmut in 6/13 (46%) patients. Presence of GATA3mut was associated with prior exposure to chemotherapy (OR = 1.09, 95%CI [1.01 - 1.10], p = 0.03). Patients with GATA3mut tumors had shorter PFS compared to GATA3wild tumors (4.1 vs. 6.7 months, in both univariate and multivariate analysis controlled for presence of ESR1mut: HR = 2.22 95%CI [1.12 – 4.38], p = 0.02). OS was also significantly shorter in patients harboring GATA3mut compared to GATA3wild (14.1 vs. 27.1 months, multivariate analysis: HR = 2.30 95%CI [1.04 – 5.11], p = 0.04). Conclusions: GATA3mut in breast cancer tend to be grouped within exons 5 and 6, and they likely contribute to acquired resistance to endocrine-based therapies in MBC. Our study showed that patients with GATA3mut ER+ MBC have worse prognosis compared to those who were GATA3wild. Larger studies are needed to further stratify and ascertain functional effects of different GATA3 mutations and explore GATA3 gene or its translational product as a possible druggable target.

ImportanceAspirin may reduce severity of metabolic dysfunction–associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown.ObjectiveTo test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD.Design, Setting, and ParticipantsThis 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023.InterventionsParticipants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months.Main Outcomes and MeasuresThe primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified.ResultsAmong 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was −6.6% with aspirin vs 3.6% with placebo (difference, −10.2% [95% CI, −27.7% to −2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (−8.8 vs 30.0 percentage points; mean difference, −38.8 percentage points [95% CI, −66.7 to −10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (−2.7% vs 0.9%; mean difference, −3.7% [95% CI, −6.1% to −1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (−11.7 vs 15.7 percentage points; mean difference, −27.3 percentage points [95% CI, −45.2 to −9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn.Conclusions and RelevanceIn this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings.Trial RegistrationClinicalTrials.gov Identifier: NCT04031729

433 Background: Prior randomized controlled trials (RCT) comparing bladder preservation to radical cystectomy (RC) for muscle invasive bladder cancer (MIBC) closed early due to lack of accrual. Given that no future RCTs are foreseen, and in the absence of level 1 data, we aimed to provide the best evidence possible on outcomes of matched cohorts comparing trimodality therapy (TMT, maximal transurethral resection of bladder tumor followed by concurrent chemoradiation) to RC in order to guide management. Methods: This retrospective analysis included 703 patients with MIBC clinical stage T2-T3/4aN0M0 MIBC urothelial carcinoma of the bladder, 421 RC and 282 TMT who would have been eligible for both TMT or RC, treated at the Massachusetts General Hospital, Boston; Princess Margaret Cancer Centre, Toronto; and University of Southern California, Los Angeles between 2005-2017. To compare homogeneous cohorts, all patients included in this analysis had solitary tumors < 7 cm, no or unilateral hydronephrosis, and no multifocal carcinoma in situ. Treatment propensity scores were estimated using logistic regression, and patients were matched 3:1 with replacement. Covariates included age, sex, clinical T stage, hydronephrosis, (neo)adjuvant chemotherapy, body mass index, smoking history, and ECOG status. Overall survival (OS) was estimated with adjusted Cox models; cancer-specific survival (CSS), distant failure-free survival, pelvic nodal failure-free survival and metastasis-free survival (combined distant and pelvic nodal failure) were estimated with adjusted competing risk models. Our primary endpoint of interest was metastasis-free survival. The analysis was performed as intent-to-treat. Results: The 3:1 matched cohort comprised of 1,116 patients (834 RC vs 282 TMT). After matching, age (71.3 vs 71.6), cT2 clinical stage (88 vs 90%), presence of hydronephrosis (12 vs 10%), and use of (neo)adjuvant chemotherapy (60 vs 65%) were similar between RC and TMT cohorts. Salvage cystectomy was performed in 38 patients (13%) treated by TMT. At 5 years, metastasis-free (73 vs 78%, p = 0.07), distant failure-free (78 vs 82%, p = 0.14), and pelvic nodal failure-free (96 vs 94%, p = 0.33) survival were not statistically different between RC and TMT, whereas CSS and OS favored TMT (78 vs 85%, p = 0.02; 70 vs 78%, p < 0.001). Outcomes for RC and TMT were not different among centers. Final pT stage in the RC patients was: pT0 14%, pT1 7%, pT2 29%, pT3/4 42% and N+ 24%. Peri RC mortality was 2.1% and median number of nodes removed was 40. NMIBC recurrence occurred in 57/278 (20.5%) TMT patients. Conclusions: This large multi-institutional contemporary study provides the best evidence to date, in the absence of randomized trials, supporting TMT for select patients with MIBC. Oncologic outcomes seem to be equivalent between TMT and RC, affirming the position that TMT should be offered as an effective alternative.

Abstract On June 15, 2018, the first checkpoint inhibitor (CPI) was approved by the CFDA and will be commercially available in China by fall. It is anticipated more CPIs will be approved in the near future. In contrast, six CPIs have been approved in the U.S. for various diseases and stages since 2014. Consequently, PD-1/PD-L1 clinical trials have become the most active area of clinical research in China. Using ClinicalTrials.gov with the criteria of "recruiting/active/interventional", I analyzed opened trials in China; I compiled data and cross-checked with domestic public domain information in China (http://www.chictr.org.cn/). As of July 8, 2018, a total of 134 protocols were identified in PD-1 (112 as China sites [CN], 22 as multi-regional clinical trials [MRCT]), 36 protocols in PD-L1 (9 CN, 27 MRCT) and 13 protocols in anti-CTLA-4 (ipilimumab) (4 CN, 9 MRCT) categories covering both malignant hematology and solid tumors over 20 different disease types. Trials of FDA approved agents in China include nivolumab (n=21), atezolizumab (19), pembrolizumab (12), Durvalumab (10), avelumab (2) and ipilimumab (13). They are predominantly MRCT and in combination with chemotherapy, second CPI or a targeted agent. Trials of domestic PD-1 agents are essentially conducted only in China, with exception of SHR-1210 and BGB-A317 which are also registered for ex-china trials. The majority of early phase trials (>95%) are conducted by a short list of centers in Beijing, Shanghai, and Guangdong, and Zhejiang. Among domestic PD-1 trials, 36 combine PD-1 with various cell therapy technologies, including CAR-T, DC, PD-1 knockout T cells, or CSR T cells; this indicates such combinations are an area of active investigation. The number of registered trials for each PD-1 biologic agent are SHR-1210 (n=34), JS001 (15), BGB-A317 (8), GB226 (2) and IBI308 (1). PD-L1 trials have essentially the same broad disease indications as PD-1 agents, and are open for advanced solid tumors. The number of PD-L1 trials is fewer than for PD-1 agents, including Atezolizumab (n=19), Durvalumab (10), Avelumab (2), KN035 (2), CS1001 (2), and SHR-1316 (1). While majority of CPI trials in China are designed for a single category of cancer, 30% of PD-1 trials, 20% of PD-L1 trials and 7% of ipilimumab trials are opened to advanced solid tumors including lymphoma. In addition, there are more than 20 PD-(L) 1 inhibitors that are in various stages of clinical development in China. In reality, patients in China have been obtaining CPI agents for cancer treatment outside of clinical trials from overseas. Patients who meet clinical trial eligibility criteria might not represent real world population for efficacy and adverse events. After the first CFDA approved nivolumab, which has a very specific label indication (advanced stage lung cancer after failing platin-based regimen) and other CPIs to be approved soon, the off-label use of these CPI agents could be widespread for various advanced stage cancers. Judging from the multiple FDA-approved indications of CPIs, the potential demand in China could reach millions of cases. Currently, there are policies to limit total formulary drug expense in public hospitals, so with the high cost of these medications, hospitals may not be able to provide timely treatment to necessary patients, which could create wait list issue. For care providers, the complexity of managing immune-related adverse events (irAE) and recognizing phenomenon such as pseudo-progression, poses critical need for systemic training and education for physicians, nurses, and patients as well. It is crucial for policy makers, medical societies, and hospitals to implement policies, and treatment guidelines for all immuno-oncology drugs according to the best evidence-based practice to meet potential demand and safe guard societal and patient benefits. In collaboration with Massachusetts General Hospital (Boston, USA), the Cancer Center of Jiahui International Hospital (Shanghai, China) has developed comprehensive clinical pathways and practice guidelines locally in China in order to deliver safe, effective and patient-centered care. We have implemented telemedicine to support multidisciplinary care models to manage treatment criteria and treatment complications. Going forward, post-market clinical studies will be conducted for data collection and in collaboration with pharmaceutical companies. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a rare type of lymphoma that is often aggressive with poor survival. The majority of cases cluster in regions with high rates of endemic human T-lymphotropic virus type 1 (HTLV-1) because chronic infection is necessary for the development of ATLL. ATLL is rare in the US, with most cases occurring in immigrants from endemic regions. Although treatment data exist from Japan, some of the agents evaluated are not available in the US. Because of limited prospective data in the US, there is no well-defined standard of care. Brentuximab vedotin (BV) is a CD30-targeting antibody-drug conjugate that has been shown to be effective even in lymphomas with very low CD30 expression (Jagadeesh, JCO, 2019). Studies have shown 36% to 50% of ATLL cases will express CD30. CD30 may be associated with worse survival in acute ATLL, making it an important therapeutic target. BV has been studied in combination with a CHP (cyclophosphamide, doxorubicin, prednisone) backbone for the treatment of CD30 expressing PTCL. ATLL patients were eligible for the study, but only 7 patients were enrolled (Horwitz, Lancet, 2019). BV-CHEP has been studied in CD30 expressing PTCL and was shown to be safe and effective (Herrera, Blood, 2019). No ATLL patients were enrolled prior to the preliminary report. We developed a prospective, multicenter pilot study evaluating BV in combination with cyclophosphamide, doxorubicin, etoposide, and prednisone (BV-CHEP) for the treatment of ATLL. We report the interim safety and efficacy analysis of the first 8 patients treated on this study. Methods: Adult patients from 5 centers (UNC Chapel Hill, Boston Medical Center, Massachusetts General Hospital, Beth Israel Deaconess Medical Center, and Moffitt Cancer Center at Memorial Healthcare System) were enrolled from October 2017 until present. Newly diagnosed ATLL cases were eligible, including the acute, lymphomatous and chronic unfavorable subtypes. Patients did not have to express CD30 to be enrolled on the study. Patients could go on to frontline consolidation with allogeneic stem cell transplant per provider preference at any time after 2 cycles of BV-CHEP. Transplant-ineligible patients completed a total of 6 cycles of BV-CHEP and those who expressed CD30 were eligible for BV maintenance, whereas those without CD30 expression entered follow-up. Patients could receive prephase steroids and/or 1 cycle of CHOP-equivalent chemotherapy prior to enrollment. Prior antiviral therapy was allowed. Patients were treated with standard dosing every 21 days: BV 1.8 mg/kg on day 1, cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, etoposide 100 mg/m2 days 1-3, and prednisone 100mg days 1-5. All patients received GCSF support. The primary endpoint was complete response (CR) by PET-CT after at least 2 cycles of therapy per adapted Lugano and ATLL criteria. Secondary endpoints were safety, overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: 8 patients were enrolled and were evaluable for interim safety and efficacy analysis. All patients were HTLV-1 positive; 4 of 8 (50%) were acute type and 4 of 8 were the lymphomatous type. 4 of 8 patients had CD30 expression. The median age was 56 (range 38 to 68) and 7 of 8 (87.5%) were female. 6 of 8 patients identified as Black (Antigua and Barbuda N=1, Haiti N=4, US N=1), 1 identified as Asian (Japan) and 1 patient identified as Hispanic (Colombia). All patients were advanced stage (7 of 8 stage IV; 1 stage III). Five of 8 patients completed at least 4 cycles of treatment (median 4 cycles; range 2 to 6). After at least 2 cycles of BV-CHEP, 4 of 8 patients achieved a CR (50%). An additional 2 patients achieved a PR, for an ORR of 75%. The median PFS was 196 days (Fig.1) and the median OS was not reached (Fig.2). When CD30 expressing patients (N=4) were compared to non-expressing patients (N=4), there was no significant difference in median PFS or OS. The regimen was well-tolerated with grade 3 mucositis occurring in 3 patients, grade 3 hypertension in 2 patients, and grade 3 rash in 1 patient. No patients had to come off study due to toxicity. Three patients received consolidation allogeneic transplant. No patients received maintenance BV. Conclusions: In this interim analysis, BV-CHEP chemotherapy was safe and effective in the treatment of aggressive ATLL. We look forward to reporting the final results once the study completes accrual. Figure 1 Figure 1. Disclosures Dittus: BeiGene: Other: Advisory Board; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding. Sandoval-Sus: SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board; BMS: Other: Advisory Board, Speakers Bureau. Sloan: Stemline: Honoraria; Abbvie: Honoraria; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacosmos: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Brentuximab vedotin will be used in CD30- ATLL patients.

Abstract Radiation Therapy Toxicities and Survival Outcomes in Monoallelic ATM Variant Carriers with Non-Metastatic Breast Cancer: A Retrospective Analysis Rayan Bensenane1 MD, Arnaud Beddok1,2,3 MD, Nadine Andrieu4 PhD, Fabienne Lesueur4 PhD, Eve Cavaciuti 4 MSc, Dorothee Le Gal4 MSc, Eon-Marchais Severine4 PhD, Dominique Stoppa Lyonnet 5MD PhD, Youlia Kirova1 MD 1. Institut Curie, PSL Research University, Radiation Oncology Department, Paris/Saint-Cloud/Orsay, France. 2. Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, 125 Nashua St., Boston, MA, 02114, USA 3. Institut Curie, PSL Research University, University Paris Saclay, Inserm LITO U1288 Orsay, France 4. Inserm, U900, Institut Curie, PSL Research University, Mines ParisTech, Paris, France 5.Department of Genetics, Institut Curie; Inserm U830, Institut Curie; Paris-Cité University Abstract (characters: 2952; max 3400 characters, not include spaces) Background: The Ataxia-Telangiectasia Mutated (ATM) gene, involved in the repair of DNA double-strand breaks, can contribute to radiosensitivity when a bi-allelic variant is present and lead to Ataxia-Telangiectasia syndrome. Moreover, monoallelic ATM pathologic variant (PV) carriers, especially women, has an estimated occurrence rate of 0.5-1% globally and face a 2 to 3-fold increased risk of developing breast cancer. Despite evidence of in vitro radiosensitivity in cells derived from monoallelic variant carriers, there is a dearth of patient studies examining the risk of radiation-induced toxicity. This study aims to explore radiation therapy (RT) toxicities in non-metastatic breast cancer women carrying a germline monoallelic ATM variant, compared to non-carriers. Methods: A retrospective study was conducted on patients treated at Institut Curie, Paris from 1999 to 2014 and participating to CoF-AT (a French national study) and GENESIS database. ATM variant screenings encompassed both PV and non-PV, with toxicities evaluated using CTCAE v.5. Variants were classified as pathogenic, variant of unknown significance (VUS), or benign. Follow-up started from age/date at breast cancer to acute, late toxicities, disease recurrence or last news. Survival and toxicity comparisons were made using Kaplan-Meier survival analysis and Chi-square tests, respectively, with a significance level of α set at 0.05. Results: Among 50 patients, nine were ATM variant carriers (3 PV/5 VUS/1 benign), and 41 were non-carriers. Most patients had no smoking history (68%), and invasive ductal carcinoma was the predominant diagnosis (82%). The majority underwent breast-conservative surgery (80%), and the dominant RT techniques were 3D-Conformational Radiation Therapy (70%) and Isocentric Lateral Decubitus (30%). The median RT dose was 50 Gy over an average period of 36.5 days. With a median follow-up of 12 years post-diagnosis, no significant difference in acute dermatitis, esophagitis, lymphedema, cutaneous fibrosis, telangiectasia, or heart disease was observed between the groups. Analysis of overall survival (OS) showed a 5-year OS of 98%, decreasing to 89% at 10 years. For ATM variant carriers, the OS at 5, 10, and 15 years was 100%, 89%, and 89%, respectively, similar to non-carriers. Kaplan-Meier analysis revealed no significant differences in 5, 10, and 15-year overall survival, progression-free survival, local failure-specific survival, and contralateral breast cancer rates between the groups. Conclusion: In non-metastatic breast cancer patients, monoallelic ATM variant carrier status does not significantly influence acute or late RT toxicities and survival outcomes. These findings, derived from a small cohort, highlight the need for prospective studies for further validation. Table: Acute and Late Toxicities Post-Radiation Therapy in Monoallelic ATM Variant Carriers vs Non-Carriers Citation Format: Rebecca Zasloff, Samantha Thomas, Kendra Parrish, Astrid Botty van de Bruele, Gayle DiLalla, Maggie DiNome, Laura Rosenberger, Hannah Woriax, E Shelley Hwang, Jennifer Plichta, Akiko Chiba. Racial/Ethnic Disparities in Rates of Pathological Complete Response and Survival in Patients with Inflammatory Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-10-01.

Abstract Radiation Therapy Toxicities and Survival Outcomes in Monoallelic ATM Variant Carriers with Non-Metastatic Breast Cancer: A Retrospective Analysis Rayan Bensenane1 MD, Arnaud Beddok1,2,3 MD, Nadine Andrieu4 PhD, Fabienne Lesueur4 PhD, Eve Cavaciuti 4 MSc, Dorothee Le Gal4 MSc, Eon-Marchais Severine4 PhD, Dominique Stoppa Lyonnet 5MD PhD, Youlia Kirova1 MD 1. Institut Curie, PSL Research University, Radiation Oncology Department, Paris/Saint-Cloud/Orsay, France. 2. Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, 125 Nashua St., Boston, MA, 02114, USA 3. Institut Curie, PSL Research University, University Paris Saclay, Inserm LITO U1288 Orsay, France 4. Inserm, U900, Institut Curie, PSL Research University, Mines ParisTech, Paris, France Abstract (characters: 2952; max 3400 characters, not include spaces) Background: The Ataxia-Telangiectasia Mutated (ATM) gene, involved in the repair of DNA double-strand breaks, can contribute to radiosensitivity when a bi-allelic variant is present and lead to Ataxia-Telangiectasia syndrome. Moreover, monoallelic ATM pathologic variant (PV) carriers, especially women, has an estimated occurrence rate of 0.5-1% globally and face a 2 to 3-fold increased risk of developing breast cancer. Despite evidence of in vitro radiosensitivity in cells derived from monoallelic variant carriers, there is a dearth of patient studies examining the risk of radiation-induced toxicity. This study aims to explore radiation therapy (RT) toxicities in non-metastatic breast cancer women carrying a germline monoallelic ATM variant, compared to non-carriers. Methods: A retrospective study was conducted on patients treated at Institut Curie, Paris from 1999 to 2014 and participating to CoF-AT (a French national study) and GENESIS database. ATM variant screenings encompassed both PV and non-PV, with toxicities evaluated using CTCAE v.5. Variants were classified as pathogenic, variant of unknown significance (VUS), or benign. Follow-up started from age/date at breast cancer to acute, late toxicities, disease recurrence or last news. Survival and toxicity comparisons were made using Kaplan-Meier survival analysis and Chi-square tests, respectively, with a significance level of α set at 0.05. Results: Among 50 patients, nine were ATM variant carriers (3 PV/5 VUS/1 benign), and 41 were non-carriers. Most patients had no smoking history (68%), and invasive ductal carcinoma was the predominant diagnosis (82%). The majority underwent breast-conservative surgery (80%), and the dominant RT techniques were 3D-Conformational Radiation Therapy (70%) and Isocentric Lateral Decubitus (30%). The median RT dose was 50 Gy over an average period of 36.5 days. With a median follow-up of 12 years post-diagnosis, no significant difference in acute dermatitis, esophagitis, lymphedema, cutaneous fibrosis, telangiectasia, or heart disease was observed between the groups. Analysis of overall survival (OS) showed a 5-year OS of 98%, decreasing to 89% at 10 years. For ATM variant carriers, the OS at 5, 10, and 15 years was 100%, 89%, and 89%, respectively, similar to non-carriers. Kaplan-Meier analysis revealed no significant differences in 5, 10, and 15-year overall survival, progression-free survival, local failure-specific survival, and contralateral breast cancer rates between the groups. Conclusion: In non-metastatic breast cancer patients, monoallelic ATM variant carrier status does not significantly influence acute or late RT toxicities and survival outcomes. These findings, derived from a small cohort, highlight the need for prospective studies for further validation. Table: Acute and Late Toxicities Post-Radiation Therapy in Monoallelic ATM Variant Carriers vs Non-Carriers * Pearson/Chi2 test ; NS: non significant at α=0.05; ATM +/+: wild type for ATM; ATM +/- : ATM monoallelic germline variant carrier Citation Format: Rayan BENSENANE, Youlia Kirova, Arnaud BEDDOK, Andine ANDRIEU, Fabienne Lesueur, Eve CAVACIUTI, Dorothée Le GAL, Severine EON-MARCHAIS, Dominique STOPPA LYONNET. Radiation Therapy Toxicities and Survival Outcomes in Monoallelic ATM Variant Carriers with Non-Metastatic Breast Cancer: A Retrospective Analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-22-05.

Abstract Background: Endocrine therapy with CDK 4/6 inhibitors (ET/CDK4/6i) represents the 1st line therapy for ER+/HER2- ABC. While majority of patients derive clinical benefit with combination therapy, a subset have refractory disease with progression within 6 months. However, predictive biomarkers for rapid progression are lacking. In this study, we evaluated genomic profiles associated with rapid disease progression on ET/CDK4/6i. Methods: We identified 77 patients who received 1st line ET/CDK4/6i combination therapy (AI or SERD with one of the 3 approved CDK4/6is) and had ctDNA analysis performed via plasma based genotyping utilizing the commercially available Guardant360 assay at three sites: Washington University in St. Louis, MO, Northwestern University (Chicago, IL), and Massachusetts General Hospital (Boston, MA). We aimed to look at the differences in patient characteristics and genomic profiles of the tumors assessed from baseline ctDNA specimens between the patients with rapid progression (time to progression TTP&lt;=6 months) vs others. In particular, we focused on growth factor receptors (FGFR, EGFR) given that previous studies have shown that activation of FGFR1 and EGFR signaling may be implicated in resistance to endocrine based therapy in breast cancer. Time to progression was estimated by using Cox regression. Variable associations were estimated via logistic regression. Results: In the combined cohort, FGFR1 amplification (FGFR1amp) was detected in 15/77 patients (19.5%). FGFR1amp was seen in 5/10 (50%) of patients with rapid progression, consistent with existing knowledge that FGFR1amp contributes to resistance to CDK4/6i and/or ET. Presence of FGFR1amp was independently associated with shorter TTP (11.2 vs. 34.7 months, HR=3.14, p=0.02). EGFR mutations (EGFRmut) were detected in 8/77 (10.4%) patients, 3 of which were found among patients with rapid progression and another 5 among those with TTP&lt;=15 months. Presence of EGFRmut was also associated with shorter TTP (8.5 vs. 31.7 months, HR=6.50, p&lt;0.001) in multivariable analysis. Of the 4 patients with shortest TTP (&lt;3 months) 3 harbored both FGFR1amp and EGFRmut. In another 3 patients we observed FGFR1amp and co-activation of genes implicated in G1/S phase cell cycle transition, suggesting that FGFR1 amplified cells may require a co-activating downstream event that ultimately, via multiple pathway cross-talk, renders them resistant to ET/CDK4/6 inhibition. Patients with FGFR1 amplified tumors were younger compared to those without FGFR1amp (54.3 vs. 62.7 years, p=0.04). Presence of FGFR1amp was associated with presence of liver (p=0.01) but not bone or lung metastases which could be one of the explanations why patients with higher liver tumor burden are more resistant to ET/CDK4/6i inhibition. PIK3CA and TP53 gene mutations in our cohort were frequent (found in 41% and 30% of the patients, respectively) but were independently not associated with TTP (PIK3CAmut+ HR=1.31, p=0.55, TP53mut+ HR=0.67, p=0.36). ESR1 mutations were rarely encountered (9%) as the cohort had only been exposed to adjuvant endocrine therapy. Conclusions: These findings highlight how ctDNA can be used for patient stratification prior to initiation of first line of therapy in ER+/HER2- ABC since it is evident that not all patients derive the same benefit from ET/CDK4/6i. Certain genomic alterations, particularly in FGFR1, EGFR, and G1/S phase cell cycle transition are associated with rapid progression to 1st line ET/CDK4/6i therapy, and highlight the need for clinical trials investigating combination/novel therapies for this subgroup of patients with HR+/HER2- ABC. Our findings are hypothesis-generating and require further exploration in larger datasets. Citation Format: Marko Velimirovic, Lorenzo Gerratana, Andrew A Davis, Whitney L Hensing, Katherine Clifton, Ami N Shah, Paolo D'Amico, Charles S Dai, Elyssa N Denault, Cynthia X Ma, Seth A Wander, Dejan Juric, Massimo Cristofanilli, Bruce A Chabner, Aditya Bardia. Genomic predictors of rapid progression to first line endocrine and CDK4/6 inhibitor combination therapy in patients with estrogen receptor positive (ER+) HER-2 negative (HER2-) advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-07-02.

Abstract Background: High throughput genomic technologies such as NGS are enhancing the ability to dynamically characterize MBC but their role in describing biological evolution of multiple mutations together remains unclear. ESR1 and PIK3CA are central mutations related to the biology and druggability of hormone-receptor positive, HER2 negative (luminal-like) MBC. The aim of this study was to explore the interplay between oncogenic pathway alterations and ESR1 and PIK3CA codon variants on the impact and clinical phenotype of luminal-like MBC. Methods: The study retrospectively analyzed a multi-institutional cohort comprising 1047 MBC patients (pts) characterized for ctDNA through NGS before treatment start at Northwestern University (Chicago, IL), Massachusetts General Hospital (Boston, MA) and Washington University in St. Louis between 2015-2020. The analysis was then focused on luminal-like MBC. Pathway classification was defined based on previous work (Sanchez-Vega F et al, Cell. 2018) (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Single nucleotide variations (SNVs) were annotated for their oncogenicity through OncoKB and ClinVar. Only pathogenic variants were included in the models. Associations among, pathway classification, and ESR1/PIK3CA codon variants were explored through stepwise logistic regression. Overall survival (OS) was tested through Cox regression. Results: The luminal-like cohort comprised 702 pts. ESR1 mutations were detected in 166 pts (24%) and PIK3CA in 214 pts (31%). The most common ESR1 gene mutations were found in codons 537 (31%), 538 (21%), 536 (8%) and 380 (7%), while alterations in codons 1047 (38%), 545 (25%), and 542 (20%) were the most common for PIK3CA. Other pathogenic SNVs were observed in 33% and 17% of pts for ESR1 and PIK3CA, respectively with the former being polyclonal. SNVs alterations were mainly observed in the PI3K (35%), P53 (32%), ER (28%), RAS (8%), RTK (8%) and cell cycle (5%) pathways, while copy number variations (CNVs) were detected in the RTK (15%), cell cycle (11%), MYC (7%) PI3K (6%) and RAF (5%) pathways. ESR1 537 variants were associated with alterations in the ER and WNT pathways, 538 with cell cycle, 380 with P53 and ER, 536 with RTK. PIK3CA 1047 variants were associated with alterations in the RTK and P53 pathways, 542 with RTK, RAS and RAF, E545 with PI3K, RAS, cell cycle and P53. 1047 and 542 were also associated with CNVs in the PI3K pathway. Independent prognostic factors in terms of OS were ESR1 537/380 codon variants (HR 1.94 P = 0.001 and HR 2.29 P = 0.047), SNVs in the RAS, cell cycle, and P53 pathways (HR 1.74 P = 0.003 HR 1.84 P = 0.009 and HR 1.56 P &lt; 0.001) and CNVs in the cell cycle pathway (HR 1.96 P &lt; 0.001). Conclusions: This study demonstrated how ESR1 and PIK3CA codon variants, together with alterations in specific oncogenic pathways, can differentially impact the biology and clinical phenotype of luminal-like MBC. As novel endocrine therapy agents such as selective estrogen receptor degraders (SERDs) and PI3K inhibitors are being developed, these results highlight the pivotal role of ctDNA NGS to describe tumor evolution and optimize clinical decision making. Odds Ratio95% Confidence IntervalPESR1 Y537ER SNVs3.341.487.530.004WNT SNVs6.251.4127.740.016ESR1 D538cell cycle SNVs5.221.7915.230.003ESR1 E380P53 SNVs4.801.4116.310.012ER SNVs5.331.3321.400.018ESR1 L536RTK CNVs4.511.1517.690.031PIK3CA H1047RTK SNVs3.751.708.290.001P53 SNVs2.611.584.34&lt; 0.001PI3K CNVs6.082.4515.08&lt; 0.001PIK3CA E542RTK SNVs5.001.9412.880.001RAS SNVs3.651.369.770.01RAF SNVs6.011.0733.870.042PI3K CNVs6.302.2917.36&lt; 0.001PIK3CA E545PI3K SNVs2.881.276.530.011RAS SNVs2.871.186.980.02cell cycle SNVs3.071.088.740.035NRF2 SNVs21.431.29356.520.033P53 SNVs3.752.046.89&lt; 0.001 Citation Format: Lorenzo Gerratana, Andrew A Davis, Marko Velimirovic, Katherine Clifton, Whitney L Hensing, Ami N Shah, Charles S Dai, Carolina Reduzzi, Paolo D’Amico, Qiang Zhang, Firas Wehbe, Seth Wander, William J Gradishar, Amir Behdad, Fabio Puglisi, Cynthia X Ma, Aditya Bardia, Massimo Cristofanilli. Exploring the interplay among ESR1/PIK3CA codon variants, oncogenic pathway alterations and clinical phenotype of metastatic breast cancer (MBC) through circulating tumor DNA (ctDNA) next-generation sequencing (NGS) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD6-08.

Abstract Introduction: Approximately 40-50% of breast cancers are characterized by low HER2 expression (HER2-low), defined as immunohistochemistry (IHC) 1+ or 2+ and HER2 fluorescence in situ hybridization (FISH) unamplified, encompassing a large and heterogeneous subgroup that may confer benefit from novel HER2 directed therapies. Circulating tumor DNA (ctDNA) has emerged as a minimally invasive technique to detect cancer-specific gene aberrations. Genetic alterations in ctDNA of HER2-low MBC have not been well described, and we hypothesized that HER2-low MBC may have a distinct genomic profile, beyond standard histopathologic features. Methods: This retrospective cohort study included patients with MBC treated at Washington University in St. Louis, Northwestern University (Chicago, IL) and Massachusetts General Hospital (Boston, MA) who had undergone ctDNA analysis during the course of treatment using the commercially available Guardant360® assay. HER2 expression was evaluated by IHC/FISH according to ASCO/CAP guidelines on metastatic tissue biopsies (or primary breast tumor tissue if a metastatic site biopsy was not available). Tumors were classified as HER2-low (IHC 1+ or 2+/FISH negative), HER2-0 (IHC 0) or HER2-positive (IHC 3+ or IHC 2+/FISH amplified). Clinicopathologic characteristics and ctDNA genetic alterations for HER2-low MBC were described and compared with the HER2-0 and HER2-positive subgroups. Chi-square and Fisher’s exact tests were used for categorical variables. Logistical regression was performed for multivariable analyses. Results: A total of 991 patients with MBC were analyzed, including 160 (16.1%) HER2-positive, 351 (35.4%) HER2-0, and 480 (48.4%) HER2-low MBC. The majority (89.2%) of HER2-low MBC were estrogen-receptor positive (ER+). Compared with HER2-0 MBC, HER2-low MBC had a significantly higher incidence of PIK3CA mutations (OR 1.54, p=0.027). PDGFRA and MYC amplifications were also more common among HER2-low MBC (2.3% vs 0.28% and 8.1% vs 4.6%, respectively), although not significantly associated with this subtype in multivariable analysis. Within the ER+ MBC cohort, those with HER2-low also had higher rates of PIK3CA mutations (OR 1.66, p=0.012) and MYC amplification (OR 2.29, p=0.034), as compared to HER2-0. Compared with HER2-positive, HER2-low MBC had significantly lower rates of ERBB2 alterations (OR 0.26, p=0.0076 for ERBB2 mutations and OR 0.022, p&lt;0.001 for ERBB2 amplification). ESR1, AKT1, and RB1 mutations were more common in HER2-low compared with HER2-positive MBC (14.0% vs 6.9%; 3.1% vs none; 3.1% vs none, respectively), but were not significant in multivariable analysis. Conclusions: Among patients with ER+ MBC, HER-low had a higher incidence of PIK3CA mutations and MYC amplification compared to HER2-0 MBC, and both of these alterations have been implicated as mechanisms of endocrine resistance. We did not demonstrate a high incidence of ERBB2 alterations in patients with HER2-low MBC. To our knowledge, this is the first study to describe genetic alterations detected by ctDNA in patients with HER2-low MBC. Given the emergence of novel HER2-targeted antibody drug conjugates with clinical activity in HER2-low MBC, these findings may guide combination treatment strategies and patient selection for future studies. Further studies are needed to confirm whether HER2-low MBC represents a truly unique biologic subtype. Citation Format: Whitney L Hensing, Lorenzo Gerratana, Katherine Clifton, Marko Velimirovic, Ami Shah, Paolo D'Amico, Carolina Reduzzi, Qiang Zhang, Charles S Dai, Nusayba A Bagegni, Mateusz Opyrchal, Foluso O Ademuyiwa, Bose Ron, Amir Behdad, Cynthia X Ma, Aditya Bardia, Massimo Cristofanilli, Andrew A Davis. Genetic alterations detected by circulating tumor DNA (ctDNA) in HER2-low metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-01-01.

Background: Idiopathic hypereosinophilia and hypereosinophilic syndrome (HES) comprise a rare, heterogeneous group of hematologic disorders characterized by the overproduction of eosinophils leading to tissue eosinophilic infiltration and damage. Hypereosinophilia can be primary - due to a clonal or malignant process - or secondary to a non-clonal process. Primary eosinophilia can be accompanied by clonal markers, such as in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA/B, FGFR1 or PCM1-JAK2, genetic mutations or chromosomal abnormalities leading to a diagnosis of chronic eosinophilic leukemia. Without easily identifiable clonal markers, a diagnosis of idiopathic HES is made after secondary causes are excluded. Thrombotic complications in clonal eosinophilic disorders have been described in case reports but the prevalence of thrombosis has not been extensively studied. We hypothesized that HES is associated with an increased thrombotic risk compared to the general population. Additionally, given the known increased thrombotic risk in patients with clonal hematopoiesis of indeterminate potential, we also hypothesized that the risk of thrombosis is greatest in HES patients with evidence of an underlying clonal process. Methods: Using an institutional database, we retrospectively analyzed 44 patients with HES who had undergone molecular testing with a DNA based next generation sequencing (NGS) assay (Heme SnapShot) and an RNA based NGS assay (Heme fusion) as part of their work up for HES at Massachusetts General Hospital from 2016 to 2020. Patients with secondary eosinophilia were excluded. We used Fisher's exact test to compare rates of thrombotic events or death between patients with and without molecular aberration. Relative risk and corresponding 95% CI was estimated by fitting a log-binomial regression model. Results: Among the 44 patients analyzed, 16 (36.4%) had a molecular aberration detected on NGS. Of the patients with molecular aberrations detected, 4 (25%) had PGFRA, PGFRB, or FGFR1 fusions. Other pathogenic mutations were as follows - 1 (6.3%) JAK2 mutation, 3 (18.8%) TET2, 1 (6.3%) DNMT3A and 9 (56.4%) had mutations in other genes. White blood cell count, absolute eosinophil count, hematocrit, platelet count, tryptase and vitamin B12 levels at diagnosis of HES were similar between the two groups. After a median follow-up time of 29 months (IQR 19.3, 52), 9 (20.5%) of all HES patients had a thrombotic event after diagnosis of HES (4 venous and 5 arterial) with a median time to first thrombotic event of 14.0 months (IQR 3.5, 28.0). HES patients with a molecular aberration had increased number of thrombotic events compared to HES patients with no molecular aberrations, 37.5% versus 10.7% respectively (p = 0.053, risk ratio 3.5, 95% CI 1.01 - 12.12). Three patients with molecular aberrations died versus 1 patient with no molecular aberrations (p = 0.129, risk ratio 5.25, 95% CI 0.59 - 46.36). Among patients with at least 12 months of follow-up (n = 40, 14 with and 26 without molecular aberrations), the one-year cumulative incidence of thrombotic events was 42.9% in patients with molecular aberrations vs 11.5% without (p = 0.044, RR 3.7 95% CI 1.2-12.0). HES patients who had thrombotic events had an increased risk of death compared to those without thrombotic events (p = 0.0226, RR 11.7, 95% CI 1.8 - 75.2). Conclusions: Thrombotic complications are common in the current study of patients with HES and are associated with an increased risk of death. Although our patient cohort was small, presence of molecular aberrations had increased rates of thrombotic events and mortality, suggesting an area of further study including possible therapeutic trials. Figure 1 Disclosures Brunner: Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Al-Samkari:Argenx: Consultancy; Amgen: Research Funding; Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Rigel: Consultancy. Rosovsky:Bristol-Myers Squibb, Janssen: Research Funding; Bristol-Myers Squibb, Dova, Janssen, Portola: Consultancy. Fathi:PTC Therapeutics: Consultancy; Takeda: Consultancy; TrovaGene: Consultancy; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Astellas: Consultancy; Novartis: Consultancy; NewLink Genetics: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Trillium: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy; Kura: Consultancy; Boston Biomedical: Consultancy; Blue Print Oncology: Consultancy; AbbVie: Consultancy; Agios: Consultancy, Research Funding; Amphivena: Consultancy, Honoraria. Weitzman:Abbvie: Consultancy. Hobbs:Incyte: Research Funding; Bayer: Research Funding; Novartis: Honoraria; Celgene/BMS: Honoraria; Merck: Research Funding; Constellation: Honoraria, Research Funding; Jazz: Honoraria.

Background: Adolescent and young adult (AYA) patients (pts) with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. These regimens, which rely heavily on corticosteroids and asparaginase (asp), are known to increase the risk of osteonecrosis (ON). In children older than 10 years (yrs), reported rates of symptomatic ON range from 5-25% (Mattano JCO 2000, Mattano Lancet Onc 2012, Toft Eur J Haematol 2016, Larsen JCO 2016). In adults, the frequency of ON and fractures (fx) are not well described including among those treated on pediatric regimens. In the recently reported C10403 trial (Stock Blood 2019), a 4% rate of ON was reported among patients aged 17-39 yrs. Here, we describe the orthopedic toxicities of AYA pts treated on sequential Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols. Methods: Pts aged 1-50 yrs were treated on four sequential multi-center DFCI ALL Consortium protocols between 2000 and 2018. Additional pts treated as per these protocols at DFCI, Massachusetts General Hospital (MGH), and Boston Children's Hospital (BCH) were identified by chart review. Earlier pts were enrolled on parallel Pediatric 00-001 (2000-2004) and Adult 01-175 (2002-2008) trials while later pts were enrolled on parallel Pediatric 05-001 (2005-2011) and Adult 06-254 (2007-2011) trials. Protocol 00-001 randomized pts between dexamethasone (dex) and prednisone (pred) during consolidation, while the other three trials used dex (all trials used pred during induction). Both 00-001 and 01-175 used native E.Coli asp, while later protocols (05-001, 06-254) used PEG asp for some (05-001, randomized) or all (06-254) pts. All pts were intended to receive 30 weeks of asp during consolidation. Pts aged 15-50 yrs were included in this study. Orthopedic toxicities were extracted from case report forms for trial pts and by chart review for those not on trial. Additional chart review was performed on all pts treated at DFCI, MGH, and BCH to identify surgical events. All pts were combined in the modeling based on the treatment backbone. The 5-yr cumulative incidences (CIs) of ON and fx were estimated and compared using the Gray test. Univariate and multivariable competing risk regression models were constructed with death as a competing risk. Results: A total of 367 pts with a median age of 23 yrs (68% &lt; 30 yrs) were identified. The majority (61%) of pts were male and the median BMI was 24.5 kg/m2 (46% overweight or obese). The median follow-up for pts remaining alive was 5 yrs (range, 0.01-14.1). In total, 60 pts experienced ON (5-yr CI 17%, [95% CI 13-22]) and 40 pts experienced fx (5-yr CI 12%, [8-15]). The median time to develop ON was 1.6 yrs (range, 0.5-7.7). The median time to fx was 1.4 yrs (range, 0.2-5.2). Pts &lt; 30 yrs were significantly more likely to be diagnosed with ON (21%, [16-27]) compared to those aged 30-50 yrs (8%, [4-14], univariate HR 2.77 [1.35-5.65]; p=0.005). Pts treated on PEG-asp based protocols were significantly more likely to be diagnosed with ON (5-yr CI 24% [18-30]) compared to those treated on earlier trials with native E.coli asp (5-yr CI 5% [2-10], HR 5.28 [95% CI 2.24-12.48], p&lt;0.001). These results remained statistically significant in multivariate analysis including treatment backbone, age, BMI, and sex. BMI and sex were not associated with orthopedic toxicity, although there was a trend toward fewer fx in male pts (HR 0.55, [0.29-1.02]). Of the 54 ONs for which adequate information was available, surgery was performed in 25 (46%) and total joint replacement in 18 (33%). Of the 9 fx with adequate information, 3 (33%) required surgery. Conclusions: In a large cohort of AYA ALL pts aged 15-50 yrs treated on a pediatric regimen, orthopedic toxicities were common (17% for ON, 12% for fx at 5 yrs). Younger pts (&lt; 30 yrs) experienced higher rates of ON, as well as pts treated on later-generation PEG-asp protocols which combined dex and PEG asp. Increased rates of orthopedic toxicity in later generation protocols may be driven by the pharmacokinetic drug interaction between PEG asp and dex, leading to higher dex exposure (Yan JCO 2008, Panetta Clin Pharmacol Ther 2009). Increased awareness may be useful in early identification of orthopedic toxicities. Future efforts should focus on further understanding the pathophysiology and risk factors for orthopedic toxicity in ALL AYA regimens and developing prophylactic interventions. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board. Brunner:Acceleron Pharma Inc.: Consultancy; Biogen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Forty Seven, Inc: Consultancy; Jazz Pharma: Consultancy; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Xcenda: Consultancy; GSK: Research Funding; Janssen: Research Funding; Astra Zeneca: Research Funding. DeAngelo:Blueprint Medicines Corporation: Consultancy, Research Funding; Forty-Seven: Consultancy; Jazz: Consultancy; Incyte Corporation: Consultancy; Novartis: Consultancy, Research Funding; Shire: Consultancy; Takeda: Consultancy; Abbvie: Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy; Autolos: Consultancy; Agios: Consultancy; Pfizer: Consultancy.

Abstract Background:Invasive lobular carcinoma (ILC) is the second most common histology of breast cancer, accounting for approximately 10-15% of cases. Prior studies have demonstrated that loss of E-cadherin, as well as alterations in tissue including CDH1, FOXA1, TBX3 and PTEN loss, that were more commonly observed in Luminal A ILC, while GATA3 was more commonly observed in invasive ductal carcinoma (IDC) (Ciriello et al., Cell 2015). However, data regarding the characterization of circulating tumor DNA (ctDNA) in patients (pts) with metastatic ILC are limited. We hypothesized that there would be distinct mutational profiles between pts with metastatic ILC and IDC that could be characterized using ctDNA. Methods:This retrospective cohort study included de-identified clinical, pathological, and ctDNA data from pts with metastatic breast cancer (MBC) combined under a data use agreement and approved by the institutional review boards of three sites: Washington University in St. Louis (MO), Northwestern University (Chicago, IL), and Massachusetts General Hospital (Boston, MA). All pts included in the study had ctDNA testing per standard of care with plasma-based genotyping performed by Guardant360 (Redwood City, CA) between 2015-2020. Histological classification (ILC vs. IDC) was defined based on review of pathology reports from the primary tumor or from breast biopsies of de novo MBC, and additional clinical and pathological variables were obtained via electronic medical record review. Single nucleotide variants (SNVs) were annotated using OncoKB and ClinVar and only pathogenic variants were included. Mutational profiles were compared across histologic subtypes using Fisher’s exact test to assess differences in alteration frequency across subtypes. Multivariable analysis was performed. Results:A total of 994 pts with MBC underwent ctDNA testing and were included in the analysis. 10.7% of pts had ILC (N=106) and 89.3% had IDC (N=888). 89.4% of ILC cases were categorized as hormone-receptor positive (HR+) compared with 67.1% of IDC cases. Pts with ILC had a lower frequency of triple-negative (6.7% vs. 17.7%) and HER2 positive (3.9% vs. 15.2%) breast cancer compared with IDC. Pts with ILC had a significantly higher number of pathogenic SNVs compared with IDC (mean 4.45 vs. 2.77; P=0.0037). In contrast, pts with ILC had a significantly lower number of copy number alterations as compared to pts with IDC (mean 0.40 vs. 1.03; P=0.0017). No differences were observed in mutant allele frequency between pts with ILC and IDC. The 5 most common alterations observed in pts with ILC were the following: PIK3CA, TP53, ESR1, ERBB2, and ARID1A. Alterations in AR, BRAF, CDH1, ERBB2, FGFR2, IDH2, KRAS, NF1, PIK3CA, SMAD4, and TERT were significantly higher in ILC than IDC (all P&lt;0.05). In contrast, mutations in GATA3, and amplifications in ERBB2 and MYC were significantly more common in pts with IDC (all P&lt;0.05). In multivariable analysis, mutations in BRAF, CDH1, ERBB2, IDH2, TERT remained significantly higher in ILC, while amplification of MYC was significantly higher in IDC (all P&lt;0.05). After restricting the analysis to pts with HR+ HER2 negative MBC, the following genes were significant in multivariate analysis: CDH1 and ERBB2 for pts with ILC and MYC amplification for pts with IDC (all P&lt;0.05). Discussion:In this large, multi-institutional dataset, pts with metastatic ILC were characterized by a significantly higher number of SNVs in ctDNA compared to pts with IDC, suggesting higher mutational burden. We report several alterations that were significantly different in ILC vs. IDC. These results demonstrate the ctDNA profile of pts with ILC, and future studies should explore serial plasma-based genotyping to track ILC evolution to develop targeted precision medicine based therapeutic approaches for this unique subset of pts with MBC. Citation Format: Andrew A Davis, Lorenzo Gerratana, Katherine Clifton, Marko Velimirovic, Whitney L Hensing, Ami N Shah, Paolo D’Amico, Carolina Reduzzi, Qiang Zhang, Charles S Dai, Elyssa N Denault, Nusayba A Bagegni, Mateusz Opyrchal, Foluso O Ademuyiwa, Ron Bose, William J Gradishar, Amir Behdad, Cynthia X Ma, Aditya Bardia, Massimo Cristofanilli. Circulating tumor DNA characterization of invasive lobular carcinoma in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD14-04.

Characterization of molecular alterations in acute myeloid leukemia (AML) has led to development of targeted therapies, including FLT3 and IDH1/2 inhibitors. Maintenance therapy following hematopoietic cell transplantation (HCT) has shown substantial promise. Enasidenib (ENA), a selective IDH2 inhibitor, was associated with impressive rates of response in relapsed/refractory (R/R) AML and is now FDA-approved for this indication. We sought to assess the tolerability and define the maximum tolerated dose (MTD) of ENA as maintenance following HCT for IDH2-mutated myeloid malignancy. HCT-eligible patients (pts) ≥ 18 years with AML in remission, or myelodysplastic syndrome (MDS) with &lt;5% marrow blasts, were enrolled. There were no restrictions on conditioning or donor type. A 2-step registration process was utilized; 1 before HCT and 1 before ENA initiation. Before HCT, pts were required to have normal organ and recovered marrow function (neutrophils &gt; 1000/µL and platelets &gt; 50000/µL). Those with prior HCT, active disease, QTc ≥450ms, and active infections were excluded. ENA was initiated between day 30 and 90 after HCT, at which time the following were required: chimerism ≥70% of donor origin among blood/marrow cells, no acute graft versus host disease (aGVHD) requiring ≥0.5mg/kg/day prednisone or equivalent, and no relapse. ENA was taken orally (po) daily (qd) in 28-day cycles. The period for dose-limiting toxicity (DLT) evaluation was the first cycle, escalation to successive levels was guided by DLT incidence, and 2 levels (50mg,100mg) were studied. Following establishment of MTD or recommended phase 2 dose (RP2D), 10 pts would be enrolled in an expansion cohort. Pts were monitored for relapse and toxicity and continued until disease progression, intolerable toxicity, or receipt of 12 cycles. Nineteen pts have been registered prior to HCT at 3 sites, Massachusetts General Hospital, Dana Farber Cancer Institute, and Johns Hopkins Hospital. Three pts could not initiate ENA following HCT; 2 due to logistic challenges of the COVID pandemic and 1 due to relapse. The remaining 16 pts initiated ENA treatment. The median age was 61 years (range 31-76); 12 (75%) were male, and 13 (81%) were Caucasian. Fourteen (88%) had AML, of which 6 were AML with MDS related changes and 2 had antecedent myeloproliferative neoplasm. Two pts (13%) had MDS. Among these 16 pts, 9 (56%) had IDH2 R140, and 5 (25%) had IDH2 R172 mutations. IDH2 subtype data was unavailable for 2 pts. Of 15 pts with available data from time of diagnosis, 11 (73%) had intermediate-risk and 4 (27%) had adverse-risk cytogenetics. Among these 15 pts, common concurrent mutations were DNMT3A (47%), SRSF2 (33%), and RUNX1 (33%). Eleven AML pts (85%) received intensive versus non-intensive therapies (15%) prior to HCT, and among all pts, 7 (44%) had received ENA prior to HCT. HCT data was available for all 16 pts; 4 pts (25%) received myeloablative, and 12 (75%) received reduced-intensity conditioning. Nine pts (56%) had a matched unrelated, 6 (38%) had haploidentical, and 1 (6%) had a matched related donor HCT. Three pts were enrolled at the 50mg dose level, 6 pts at 100mg, and after no DLTs were detected, the remaining were enrolled in an expansion cohort at 100mg qd. Median follow-up (F/U) for surviving patients is currently 11.7 months (range 1.5-18.9). 2 pts (13%) have relapsed during F/U, at 96 and 364 days post HCT. Additional ≥grade (G) 3 toxicities detected during treatment, possibly or probably related to ENA, included neutropenia, anemia, and bilirubinemia. Six pts (38%) required dose interruptions lasting a median 19 days (range 7-25), 4 required a dose reduction to 50mg, and 1 stopped treatment due to G3 bilirubinemia. In total, 3 pts (18%) discontinued study treatment, 1 for aforementioned G3 bilirubinemia, 1 to pursue a GVHD trial, and 1 for relapse. Six pts have completed the 12-month f/u without relapse, and 7 remain on study. 15 of 16 pts remain alive. Thus far, 3 pts have experienced ≥ G2 aGVHD, and 4 had moderate chronic GVHD. Serial measurement of 2HG is being conducted on samples, and these will be reported. Enasidenib is well-tolerated as post-HCT maintenance therapy for myeloid malignancy at the RP2D of 100mg qd. No DLTs have been detected, and a low rate of post-HCT relapse has been identified to date, although longer f/u is needed. Larger, randomized studies of ENA in the post-SCT setting would determine the true efficacy of this agent as maintenance therapy. Disclosures Fathi: Blueprint: Consultancy; Jazz: Consultancy; Amgen: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Takeda: Consultancy, Research Funding; Boston Biomedical: Consultancy; Amphivena: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Forty Seven: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy. Soiffer:Gilead: Consultancy; Novartis: Consultancy; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; VOR Biopharma: Consultancy; alexion: Consultancy; Rheos Therapeutics: Consultancy; Cugene: Consultancy; Precision Bioscience: Consultancy; Be the Match/ National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Consultancy. Levis:Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria. Mims:Novartis: Speakers Bureau; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Agios: Consultancy; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Abbvie: Membership on an entity's Board of Directors or advisory committees. Devine:Magenta Therapeutics: Consultancy. Defilipp:Incyte: Research Funding; Regimmune: Research Funding; Syndax Pharmaceuticals: Consultancy. Spitzer:Jazz Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Frigault:Celgene: Consultancy; Arcellx: Consultancy; Novartis: Consultancy, Research Funding; Gilead/Kite: Consultancy, Research Funding. Amrein:Amgen: Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding. Hobbs:Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding; Constellation: Honoraria, Research Funding; Jazz: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria. Brunner:Janssen: Research Funding; Acceleron Pharma Inc.: Consultancy; GSK: Research Funding; Xcenda: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz Pharma: Consultancy; Forty Seven, Inc: Consultancy; Celgene/BMS: Consultancy, Research Funding; Biogen: Consultancy; Astra Zeneca: Research Funding. Narayan:Genentech: Other: Prior Spouse employment within 24 months and prior spouse equity divested within past 24 months; Takeda: Other: Prior Spouse employment within 24 months; Sanofi-Genzyme: Other: Current Spouse employment . Chen:AbbVie: Other: Data and Safety Monitoring Board Member; Incyte Corporation: Consultancy; Takeda: Consultancy; Actinium: Other: Data and Safety Monitoring Board Member; Equillium: Other: Data and Safety Monitoring Board Member; Magenta: Consultancy; Kiadis: Consultancy. OffLabel Disclosure: Enasidenib as post-transplant maintenance therapy

The cardiac surgery is the youngest surgical specialty that has emerged in the early period of the 20th century. Surprisingly, however, it is also the first surgical specialty that seems to be the first to disappear in a way or another in the second half of the 21st century. Even if the optimists consider this will never happen, it is expected that cardiac surgery will suffer a radical metamorphosis, which makes the realists say that this field of surgery will actually disappear.Before the beginning of the 20th century, the surgeons around the world have been convinced that human heart is untouchable. Remarkable surgeons of the 19th century like Theodor Billroth – the founder of the Viennese school of surgery- said in 1863 that “ Any surgeon that dares to perform surgery on the heart will fail and will lose the appreciation of his colleagues” [1]. This statement reveals the general opinion of that time, that the human heart is the center of the soul, of life itself and therefore it should never be touched. Considering this, Sharman stated in 1902 in „The American Journal of Medical Association” : “even though the heart lies at a few centimeters beneath the skin, it took 2400 years for surgery to reach this distance” [2].Ironically, the same year that English surgeon Stephan Paget stated that “probably the human heart is boundary that nature set for any kind of surgery -1896- was also the year when Ludwig Rehn, a German surgeon from Frankfurt, managed to successfully repair a right ventricular wound, signing the birth certificate of the cardiac surgery [3]. Since then the myth that the human heart can’t be touched by surgeons vanished and the sacred center of the heart has been opened…Two distinct periods of cardiac surgery can be identified over the next 100 years. The first period is the so called “surgery on a closed heart”, before the invention of extracorporeal circulation. In this heroic period, the first interventions that involved the pericardium were performed.In the first years of the 20th century, Alexis Carell imagined the experimental basis of cardio-vascular surgery. He invented the vascular sutures, demonstrated the possibility of organ transplantation and imagined coronary surgery. As recognition of his fundamental work he received the Nobel prize for medicine and physiology in 1912. Although he never performed surgery on humans, Alexis Carell remains to this day the first surgeon in history that was awarded with this prestigious prize [4].Surgery of the pericardium started in 1920 with Ludwig Rehn and Ferdinand Sauerbruch [5]. The first surgical approach of the aortic valve was realized by Theodor Tyffier in Paris in 1912 [6]. He succeeded to enlarge an aortic stenosis through a purse on the anterior wall of the aorta. In 1923, in Boston, USA, Elliot Cuttler realized the first instrumental mitral valve valvulotomy on a 12 year old girl [7]. Using a specially modified forceps, and the apex of the left ventricle as the initial approach, he managed to successfully open the mitral valve commissures and then to close the incision on the left ventricle. The first digital mitral valve commissurotomy through the left appendage was performed in 1925 by Sir Henry Soutar[8]. Catastrophic results ( 90% mortality) lead surgeons to abandon this procedure for the next 25 years. In 1948, Charles P. Bailey (Philadelphia), Dwight E. Harken (Boston) and Russell Brock (London) realized the first successful mitral valve commissurotomy [9,10].The first ligature of patent arterial duct was performed by Robert Edward Gross. This procedure took place at Harvard Medical School and Children’s Hospital from Boston, Massachusetts, in 1938 [11].Palliative treatment of the Fallot tetralogy started with the first systemic-pulmonary shunt,realized by Alfred Blalock in 1944 at John Hopkins Hospital [12]. The idea of subclavio-pulmonaryanastomosis was born with the contribution of Hellen Taussig, founder of pediatric cardiology.Treatment of aortic coarctation was independently realized by Edward Gross and Clarance Crafoord in 1945. Both surgeons managed to excised the diseased segment of the aorta and then performed an end to end anastomosis of the aorta [13].Sir Thomas Holmes-Sellors in 1947 and Russel Brock in 1948 realized the first pulmonary valvevalvulotomy [10].In our country, professor Nicolae Hortolomei was the first to perform surgery on the heart atColtea Hospital. He legated a patent arterial duct, excised an aortic coarctation and successfullyrealized in 1953 a digitally mitral valve commissurotomy [14].The second period of cardiac surgery began with the developing of the extracorporeal circulation.This technology allowed stopping the heart and keeping the patient alive, using a device thatmanage to circulate and oxygenate the blood. This ensemble composed of a pomp and anoxygenator was called “the extracorporeal circulation machine” and made possible the future development of “open cardiac surgery”.In 1946 Wilfred G. Bigelow (Toronto, Canada ), demonstrated the role of hypothermia inincreasing the tissue resistance to hypoxemia. This concept is fundamental in the development of extracorporeal circulation [15]. The first procedure on an open heart was realized by John Lewis from University of Minnesota, Mineapolis USA, on 2 september 1952. He used profund hypotermia and occlusion of the caval veins, without using extracorporeal circulation. Using this technique he closed an interatrial septal defect in a 6 year old boy. Time was his biggest limitation, because the heart could not be stoped for more than 8-10 minutes.On 6 may 1953, John H. Gibbon realised the first open heart surgery using an extracorporealcirculation machine [16]. He succesfully closed and interatrial septal deffect on an 18 years old girl.Unfortunatly he lost the following 4 patients, and he decided to abandon this king of surgery after20 years of research.A year later, on the 26th of March 1954 at „University of Minesotta” from Mineapolis USA, C.Walton Lillehei closed an inteventricluar septal defect on a child using the so called “crossedcirculation technique”. In this procedure, he connected the patient’s circulaton to his fathercirculation, trying to repoduce the fetal circulation [17]. Using this technique he operated 45patients, being the first surgeon that closed ventricular septal defects, corrected the commonatrioventricular canal and treated the Fallot tetralogy. Finding a compatible match for the “cross circulation” was the biggest limit of this technique. This method was untill the developement of liver and renal transplant, the only kind of surgery that could reach 200% mortality rate and was abandoned later due to ethical considerations.Starting from 1955, John Kirkling (Mayo Clinic), used the extracorporeal circulation machine(pomp - oxigenator) [18]. He used the Mayo-Gibbon-IBM type, and this technology began to beused all over the world.In Romania, the first surgical procedure on the heart using an extracorporeal circulation machinewas realized in 1961 at Fundeni Hospital (Bucharest). A remarkable team composed of professor Voinea Marinescu and professor Dan Setlacec, closed an atrial septal defect on an 18 years old boy.The extracorporeal machine was handled by Marian Ionescu, and the anesthesia was managed by professor George Litarczek. The patient is still living.Surgery of the cardiac valves started in 1960 when Albert Starr realized the first mitral valvereplacement [19].Without a doubt coronary artery bypass grafting is the most widly spread type of cardiac surgery.Initially introduced by Michael DeBakey and later perfected by Renee Favaloro in 1960, thisprocedure remains one of the most frequent and best studied type of surgery in medicine [20].A crucial moment in the history of cardiac surgery is represented by the first cardiac transplanton human performed by Christian Barnard in 1967[21]. This achievement consecrate cardiacsurgery as a high performace field and made the cardiac surgen a public figure. In this moment, thelove story between cardiac surgery and media started. Most probably the majority of active cardiac surgeons of this generation owe Christiaan Barnard their option for choosing this field and this medical specialty her huge succes.It is considered that the maximum moment of cardiac surgery is the year 1986 when worldwide over 2000 procedures on the open heart were performed daily.But new discoveries started to appear in the cardiovascular field. In the 70s percutaneous procedures were invented. Andreas Gruntzig realized in 1977 the first coronary angioplasty and coronary stents were implanted in 1986 by Puel and Sigwart. Development on interventional cardiology was exponential and nowadays at the European Association of Cardiothoracic Surgery simposium about the future of cardiac surgery, 90% of the cardiac surgeons stated that they would prefer the coronary stent over coronar artery bypass grafting surgery if they would have to choose as patients.Starting with 2003 when was realised the first transcatheter aortic valve implantation (TAVI), the exclusive field of cardiac valve surgery is partialy claimed by interventional cardiology [23].The field of aortic anevrisms and acute dissections falls from cardiac surgery also to interventional cardiology after the developement of endoaortic stent grafts [24,25].As a consequence the number of coronary artery bypass grating procedures falls 28% between 1997 and 2004 in the USA. Meanwhile coronary percutaneos procedures rises with 121% [24,28]. Also it is possible that for the first time in history, the number of cardiac surgeons will decrease untill 2020 [24.28].But cardiac surgery extends in to new fields in order to survive. For exemple, one of the future aspect is the treatment of cardiac insuffiency. It is estimated that over 5 milion americans have cardiac insuffiency [26] and cardiac transplantation is the solution for these patients. Unfortunately, the number of donors falls, and this is no longer an effective solution. Multiple devices are designed in order to help the heart, ranging from univentricular asist devices to artificial hearts. This devices can act as a bridge to cardiac transplantation or they can be the solution for patients that are not eligible for cardiac transplantation.Surgical treatment of atrial fibrilation remains a solid options for patients with this disease which have a high risk of emboly or progression to cardiac insufficiency [27].The field of corection of congenital cardiac malformations lessens because of early diagnostic and possibility to end the pregnancy. But there are surgical treatments for children that are born with complex congenital heart malformations with optimal results.The development of minimally invasive techniques, robotics and hybrid ones represents the response of cardiac surgery to interventional cardiology.Apparently, cardiac surgery and interventional cardiology are merging. More and more patients are heald in hybrind operating rooms, using hybrid techniques. The concept of “heart teams” emerges- a team made of cardiologists, cardiac surgeons and cardiac anesthesiologists. Probably, in the future will exist only a cardiologist-cardiac surgeon or a cardiac surgeon-cardiologist, either way a specialist in cardiovascular medicine.The conclusion isn’t pessimistic. As long as there will be patients, doctors will be needed. It remains to be seen if they will be surgeons, interventional cardiologists or just cardiologists.Certainly, general anesthesia, opeaning the mediastinum through median sternotomy using an electic saw and circulating the patients blood through the extracorporeal circulation machine, not to mention stopping the heart, isn’t the future.But introducing needls in arteries, wires in the aorta and pen sprins into the coronary isn’t also the future.Without a doubt, the future belongs to physicians that will cure cardiovascular disease with pills or even better just with advices...

Abstract STUDY QUESTION Are epididymosomes implicated in protein transfer from the epididymis to spermatozoa? SUMMARY ANSWER We characterized the contribution of epididymal secretions to the sperm proteome and demonstrated that sperm acquire epididymal proteins through epididymosomes. WHAT IS KNOWN ALREADY Testicular sperm are immature cells unable to fertilize an oocyte. After leaving the testis, sperm transit along the epididymis to acquire motility and fertilizing abilities. It is well known that marked changes in the sperm proteome profile occur during epididymal maturation. Since the sperm is a transcriptional and translational inert cell, previous studies have shown that sperm incorporate proteins, RNA and lipids from extracellular vesicles (EVs), released by epithelial cells lining the male reproductive tract. STUDY DESIGN, SIZE, DURATION We examined the contribution of the epididymis to the post-testicular maturation of spermatozoa, via the production of EVs named epididymosomes, released by epididymal epithelial cells. An integrative analysis using both human and mouse data was performed to identify sperm proteins with a potential epididymis-derived origin. Testes and epididymides from adult humans (n = 9) and adult mice (n = 3) were used to experimentally validate the tissue localization of four selected proteins using high-resolution confocal microscopy. Mouse epididymal sperm were co-incubated with carboxyfluorescein succinimidyl ester (CFSE)-labeled epididymosomes (n = 4 mice), and visualized using high-resolution confocal microscopy. PARTICIPANTS/MATERIALS, SETTING, METHODS Adult (12-week-old) C57BL/CBAF1 wild-type male mice and adult humans were used for validation purposes. Testes and epididymides from both mice and humans were obtained and processed for immunofluorescence. Mouse epididymal sperm and mouse epididymosomes were obtained from the epididymal cauda segment. Fluorescent epididymosomes were obtained after labeling the epididymal vesicles with CFSE dye followed by epididymosome isolation using a density cushion. Immunofluorescence was performed following co-incubation of sperm with epididymosomes in vitro. High-resolution confocal microscopy and 3D image reconstruction were used to visualize protein localization and sperm-epididymosomes interactions. MAIN RESULTS AND THE ROLE OF CHANCE Through in silico analysis, we first identified 25 sperm proteins with a putative epididymal origin that were conserved in both human and mouse spermatozoa. From those, the epididymal origin of four sperm proteins (SLC27A2, EDDM3B, KRT19 and WFDC8) was validated by high-resolution confocal microscopy. SLC27A2, EDDM3B, KRT19 and WFDC8 were all detected in epithelial cells lining the human and mouse epididymis, and absent from human and mouse seminiferous tubules. We found region-specific expression patterns of these proteins throughout the mouse epididymides. In addition, while EDDM3B, KRT19 and WFDC8 were detected in both epididymal principal and clear cells (CCs), SLC27A2 was exclusively expressed in CCs. Finally, we showed that CFSE-fluorescently labeled epididymosomes interact with sperm in vitro and about 12–36% of the epididymosomes contain the targeted sperm proteins with an epididymal origin. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION The human and mouse sample size was limited and our results were descriptive. The analyses of epididymal sperm and epididymosomes were solely performed in the mouse model due to the difficulties in obtaining epididymal luminal fluid human samples. Alternatively, human ejaculated sperm and seminal EVs could not be used because ejaculated sperm have already contacted with the fluids secreted by the male accessory sex glands, and seminal EVs contain other EVs in addition to epididymosomes, such as the abundant prostate-derived EVs. WIDER IMPLICATIONS OF THE FINDINGS Our findings indicate that epididymosomes are capable of providing spermatozoa with a new set of epididymis-derived proteins that could modulate the sperm proteome and, subsequently, participate in the post-testicular maturation of sperm cells. Additionally, our data provide further evidence of the novel role of epididymal CCs in epididymosome production. Identifying mechanisms by which sperm mature to acquire their fertilization potential would, ultimately, lead to a better understanding of male reproductive health and may help to identify potential therapeutic strategies to improve male infertility. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Spanish Ministry of Economy and Competitiveness (Ministerio de Economía y Competividad; fondos FEDER ‘una manera de hacer Europa’ PI13/00699 and PI16/00346 to R.O.; and Sara Borrell Postdoctoral Fellowship, Acción Estratégica en Salud, CD17/00109 to J.C.), by National Institutes of Health (grants HD040793 and HD069623 to S.B., grant HD104672-01 to M.A.B.), by the Spanish Ministry of Education, Culture and Sports (Ministerio de Educación, Cultura y Deporte para la Formación de Profesorado Universitario, FPU15/02306 to F.B.), by a Lalor Foundation Fellowship (to F.B. and M.A.B.), by the Government of Catalonia (Generalitat de Catalunya, pla estratègic de recerca i innovació en salut, PERIS 2016-2020, SLT002/16/00337 to M.J.), by Fundació Universitària Agustí Pedro i Pons (to F.B.), and by the American Society for Biochemistry and Molecular Biology (PROLAB Award from ASBMB/IUBMB/PABMB to F.B.). Confocal microscopy and transmission electron microscopy was performed in the Microscopy Core facility of the Massachusetts General Hospital (MGH) Center for Systems Biology/Program in Membrane Biology which receives support from Boston Area Diabetes and Endocrinology Research Center (BADERC) award DK57521 and Center for the Study of Inflammatory Bowel Disease grant DK43351. The Zeiss LSM800 microscope was acquired using an NIH Shared Instrumentation Grant S10-OD-021577-01. The authors have no conflicts of interest to declare.

Characterization of pathogenic alterations in acute myeloid leukemia (AML) has led to development of promising targeted therapies, including FLT3 (FLT3i) and IDH1/2 inhibitors (IDHi), with several approved for use; midostaurin (MIDO), gilteritinib, enasidenib (ENA), and ivosidenib (IVO). A proportion of patients (pts) have concurrentFLT3andIDHmutations at diagnosis or develop a second mutation during therapy.FLT3mutations, in particular, are associated with poor response rates to IDHi therapy, and treatment-emergentFLT3mutations also appear to confer therapeutic resistance to these agents. There is therefore growing interest to study combined therapies that target multiple pathways, but the clinical experience with combined IDHi and FLT3i therapy has not yet been reported. We performed a retrospective data collection and analysis at 5 institutions (Massachusetts General Hospital, University of Pennsylvania, Johns Hopkins University, University of California San Francisco, and MD Anderson). Using de-identified information from institutional databases, pts treated with concurrent IDHi and FLT3i were identified. Collected data included demographic data, date of initial diagnosis, number of prior therapies, prior hematopoietic cell transplant (HCT), prior targeted therapy, type ofIDHandFLT3mutation, concurrent mutations and cytogenetics, duration of concurrent therapy, therapy-related toxicity, best response, toxicities, and vital status. We identified 12 pts who received concurrent IDHi and FLT3i therapy, 11 of which had relapsed/refractory (R/R) AML. Median age was 57 (range 31-84) and 9 (75%) were male. 7 (58%) were Caucasian, 3 (25%) African American, and 2 (17%) Asian. All pts had intermediate-risk cytogenetics.IDH1R132 mutations were detected in 3 (25%), andIDH2R140 mutations in 9 (75%) pts. OneIDH2mutation arose at relapse. All pts hadFLT3-ITDmutations, and for 3 (38%), this mutation was known to have emerged at relapse. Common concurrent mutations includedDNMT3A(75%) andNPM1(58%). Median number of prior lines of therapy was 2 (range 0-6), and 4 pts (33%) had underwent prior HCT. Six pts (50%) had received FLT3i monotherapy in a prior line of treatment; 4 sorafenib, 1 gilteritinib, 1 MIDO, and 1 with FF-10101 (one pt had 2 prior lines of FLT3i). Six pts were initiated on concurrent therapy in simultaneous fashion, and the remainder were sequential; 2 pts (17%) were on IDHi therapy to which the FLT3i was added, and 4 (33%) had been on FLT3i with subsequent IDHi addition. Four pts (33%) received concurrent gilteritinib and ENA, 3 (25%) received gilteritinib and IVO, 3 (25%) received sorafenib and ENA, and 2 (17%) MIDO and ENA. Three pts received hypomethylating therapy concurrent with combined FLT3i/IDHi therapy; 2 received azacitidine (AZA) with ENA/MIDO, and 1 received AZA with ENA/gilteritinib. Pts were on concurrent therapy for a median of 75 days (range 9-343). Two pts had rash attributable to sorafenib, leading to temporary treatment pause in one and discontinuation in the other. No other toxicities were thought to be related to concurrent treatment. Four pts (33%) achieved CR or CRi (2 CR, 2 CRi), all with persistence of molecular residual disease (MRD). The median duration of remission for these pts was 310 days (range 85-326), and 3 have since relapsed. One pt experienced MLFS, 1 had peripheral blast reduction and 1 had improvement in platelets. An additional pt had MRD(+) CR (byNPM1PCR) on gilteritinib prior to addition of ENA, and then achieved MRD(-) CR with dual therapy. The 4 remaining pts did not respond to concurrent treatment. Two pts (17%) were effectively bridged to HCT following dual therapy. Five pts (42%) remain alive. In this retrospective analysis, a notable proportion of pts benefitted from concurrent FLT3i and IDHi therapy. Composite remission rate was 33%, and overall response rate (CR+CRi+MLFS) was 42% among a largely R/R patient cohort, the majority of whom had received IDHi or FLT3i monotherapy in a prior line of treatment. An additional pt in MRD(+) CR cleared MRD following concurrent treatment. Concurrent therapy appeared to be largely well-tolerated. These response rates are particularly intriguing, given the presence ofFLT3/ITDmutations, alterations thought to confer resistance to IDHi monotherapy. Larger, prospective studies are needed to fully assess the promise of concurrent FLT3i and IDHi therapy in co-mutated pts with AML. Disclosures Fathi: Amphivena:Consultancy;Astellas:Consultancy;Trillium:Consultancy;Amgen:Consultancy;Seattle Genetics:Consultancy, Research Funding;Abbvie:Consultancy;Pfizer:Consultancy;Newlink Genetics:Consultancy;Forty Seven:Consultancy;Trovagene:Consultancy;Kite:Consultancy;BMS/Celgene:Consultancy, Research Funding;Novartis:Consultancy;Daiichi Sankyo:Consultancy;Kura Oncology:Consultancy;Blueprint:Consultancy;PTC Therapeutics:Consultancy;Agios:Consultancy, Research Funding;Takeda:Consultancy, Research Funding;Jazz:Consultancy;Boston Biomedical:Consultancy.Perl:Arog Pharmaceuticals Inc:Other: uncompensated consulting, travel costs for meetings;Astellas:Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding;AbbVie Inc:Consultancy, Honoraria, Other, Research Funding;Syndax:Consultancy, Honoraria;Takeda:Honoraria, Other: Travel costs for meeting;Leukemia & Lymphoma Society, Beat AML:Consultancy;Novartis:Honoraria, Other, Research Funding;Actinium Pharmaceuticals Inc:Consultancy, Honoraria, Research Funding;Daiichi Sankyo:Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding;FUJIFILM Pharmaceuticals USA, Inc:Research Funding;New Link Genetics:Honoraria, Other;Bayer HealthCare Pharmaceuticals:Research Funding;Biomed Valley Discoveries:Research Funding;Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company:Consultancy, Honoraria, Other;Jazz:Honoraria, Other;Agios:Consultancy, Honoraria, Other;FORMA Therapeutics:Consultancy, Honoraria, Other.Levis:Menarini:Honoraria;Amgen:Honoraria;FujiFilm:Honoraria, Research Funding;Daiichi-Sankyo:Honoraria;Astellas:Honoraria, Research Funding.Smith:Daiichi Sanyko:Consultancy, Honoraria;Abbvie:Other: Research Support, Research Funding;FujiFilm:Other: Research support, Research Funding;Astellas Pharma:Honoraria, Other: Research Support, Research Funding;Revolution Medicines:Other: Research Support, Research Funding;Sanofi:Honoraria.Brunner:Forty-Seven Inc:Membership on an entity's Board of Directors or advisory committees;AstraZeneca:Research Funding;Takeda:Research Funding;Celgene:Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis:Research Funding;Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees.Amrein:Amgen:Research Funding;AstraZeneca:Consultancy, Research Funding;Takeda:Research Funding.Hobbs:Merck:Research Funding;Constellation:Honoraria, Research Funding;Incyte:Research Funding;Bayer:Research Funding;Celgene/BMS:Honoraria;Novartis:Honoraria;Jazz:Honoraria.Narayan:Sanofi-Genzyme:Other: Current Spouse employment ;Takeda:Other: Prior Spouse employment within 24 months;Genentech:Other: Prior Spouse employment within 24 months and prior spouse equity divested within past 24 months.Daver:Pfizer:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Karyopharm:Research Funding;Servier:Research Funding;Daiichi Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Genentech:Research Funding;AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Astellas:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Novimmune:Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Amgen:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Trovagene:Research Funding;Fate Therapeutics:Research Funding;ImmunoGen:Research Funding;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Jazz:Consultancy, Membership on an entity's Board of Directors or advisory committees;Trillium:Consultancy, Membership on an entity's Board of Directors or advisory committees;Syndax:Consultancy, Membership on an entity's Board of Directors or advisory committees;Amgen:Consultancy, Membership on an entity's Board of Directors or advisory committees;KITE:Consultancy, Membership on an entity's Board of Directors or advisory committees;Agios:Consultancy, Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.DiNardo:Calithera:Research Funding;Celgene:Consultancy, Honoraria, Research Funding;Agios:Consultancy, Honoraria, Research Funding;Syros:Honoraria;Daiichi Sankyo:Consultancy, Honoraria, Research Funding;Notable Labs:Membership on an entity's Board of Directors or advisory committees;Jazz:Honoraria;ImmuneOnc:Honoraria;Takeda:Honoraria;MedImmune:Honoraria;Novartis:Consultancy;AbbVie:Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Midostaurin for relapsed/refractory AML Sorafenib for relapsed/refractory AML

Background: Allogeneic hematopoietic cell transplant (HCT) is a potentially curative approach for eligible patients with acute myeloid leukemia (AML). The 5-year overall survival (OS) for AML patients (pts) following HCT is approximately 40-50%. However, data regarding outcomes for pts with certain molecular subtypes of AML are lacking. Of particular interest are post-HCT outcomes of pts with targetable mutations such as FLT3, IDH1, or IDH2, given the potential role of maintenance targeted therapy in the post-HCT setting. We conducted a retrospective, multi-institutional study describing outcomes for IDH1- or IDH2-mutated AML pts following HCT. Methods: We performed retrospective data collection, using institutional databases, at three academic sites (Massachusetts General Hospital, Dana Farber Cancer Institute, and Ohio State University). We identified pts &gt;18 years of age with a diagnosis of IDH1- or IDH2-mutated AML who underwent allogeneic HCT from 2010 to 2019. Data collected included pt age, sex, mutational and cytogenetic profile, treatment received prior to HCT, marrow response prior to HCT, stem cell source, HCT conditioning regimen, graft-versus-host disease (GVHD) prophylaxis, and time of relapse, death, or last known follow-up. IDH mutational status was assessed using next generation sequencing prior to HCT. Time to event endpoints are analyzed using the Kaplan Meier method for OS and progression-free survival (PFS), or the Gray method in a competing risk setting for time to relapse and non-relapse mortality (NRM). Proportional hazard cox models and competing risk regression models were used to test difference between groups while adjusting for other covariates. Results: In total, 117 pts with IDH1- or IDH2-mutated AML who received allogeneic HCT were identified. An IDH1 mutation was identified in 35 patients (pts) while an IDH2 mutation was found in 81 pts (Table 1). One pt had both IDH1 and IDH2 mutations and he was not included in subsequent univariate and multivariate analyses. The most commonly co-occurring mutations among all patients were DNMT3A (35%), NPM1 (32%), FLT3-ITD (14%), ASXL1 (10%), and TP53 (3%). 50 pts (43%) were &gt;65 years old (range 27-74), and 60 (51%) were male. 12 pts (10%) had favorable-risk, 70 pts (60%) had intermediate-risk, and 21 pts (18%) had adverse-risk AML by ELN cytogenetic criteria; data were unavailable for 14 patients (12%). 112 pts (96%) achieved CR/CRi prior to HCT. 76 pts (65%) received reduced intensity and 40 (34%) underwent myeloablative conditioning (Table 1); data were unavailable for 1 patient (0.9%). 36 pts (31%) received an IDH inhibitor before HCT and 3 (2.6%) received an IDH inhibitor as maintenance therapy after HCT. Following HCT, 18 pts (15%) experienced grade 2-4 acute GVHD and 44 (38%) experienced chronic GVHD requiring systemic treatment. With a median follow-up of 23 months for surviving pts, the 1-year PFS and OS for the IDH1-mutated cohort was 74% (95% CI 55%-85%) and 76% (95% CI 58%-87%), respectively, and the 2-year PFS and OS was 55% (95% CI 35%-71%) and 73% (95% CI 55%-85%), respectively (Figure 1). With a median follow-up of 26 months for surviving pts, the 1-year PFS and OS for the IDH2-mutated cohort was 58% (95% CI 47%-68%) and 72% (95% CI 61%-81%), respectively, and the 2-year PFS and OS was 52% (95% CI 40%-63%) and 60% (95% CI 48%-70%), respectively (Figure 1). The 2-year cumulative incidence of relapse and NRM was 36.1% (95% CI 19.0%-53.6%) and 9.1% (95% CI 2.2%-22.0%), respectively, for the IDH1-mutated cohort, and 29.8% (95% CI 19.9%-40.4%) and 18.0% (95% CI 10.3%-27.3%), respectively, for the IDH2-mutated cohort. On multivariate analysis of OS, there was no statistically significant association with older age, higher-risk disease, absence of pre-HCT CR/CRi, use of reduced intensity conditioning, or IDH mutation. Conclusion: This is the first multi-institutional retrospective study to characterize outcomes of IDH1- or IDH2-mutated AML patients undergoing allogeneic HCT. We report important benchmarks of relapse, disease-free, and overall survival that will inform interpretation of ongoing and future clinical trials investigating the benefit of maintenance IDH1 and IDH2 inhibitor therapy in the post-HCT setting. Disclosures Eisfeld: Karyopharm: Current Employment, Current equity holder in publicly-traded company; Vigeo Therapeutics: Consultancy. Mims:Novartis: Speakers Bureau; Agios: Consultancy; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Abbvie: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Jones:Pharmacyclics LLC, an AbbVie Company: Patents & Royalties: and other intellectual property, Research Funding. Cutler:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medsenic: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Consultancy, Membership on an entity's Board of Directors or advisory committees. Koreth:Amgen: Consultancy; Moderna Therapeutics: Consultancy; Biolojic Design Inc: Consultancy; EMD Serono: Consultancy; Equillium: Consultancy; Clinigen: Other; Miltenyi: Other: Research Support; BMS: Other: Research Support; Cugene: Membership on an entity's Board of Directors or advisory committees; Therakos: Membership on an entity's Board of Directors or advisory committees; Regeneron: Other: Research Support. Defilipp:Incyte: Research Funding; Regimmune: Research Funding; Syndax Pharmaceuticals: Consultancy. Soiffer:Celgene: Membership on an entity's Board of Directors or advisory committees; Rheos Therapeutics: Consultancy; Juno: Membership on an entity's Board of Directors or advisory committees; alexion: Consultancy; Be the Match/ National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Cugene: Consultancy; Precision Bioscience: Consultancy; Kiadis: Membership on an entity's Board of Directors or advisory committees; VOR Biopharma: Consultancy; Mana Therapeutics: Consultancy; Novartis: Consultancy. Chen:AbbVie: Other: Data and Safety Monitoring Board Member; Equillium: Other: Data and Safety Monitoring Board Member; Takeda: Consultancy; Incyte Corporation: Consultancy; Magenta: Consultancy; Kiadis: Consultancy; Actinium: Other: Data and Safety Monitoring Board Member. Fathi:PTC Therapeutics: Consultancy; Daiichi Sankyo: Consultancy; Abbvie: Consultancy; Takeda: Consultancy, Research Funding; Trillium: Consultancy; Forty Seven: Consultancy; Novartis: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Boston Biomedical: Consultancy; Kura Oncology: Consultancy; Blueprint: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Newlink Genetics: Consultancy; Agios: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy.

This plenary session began with a focus on cutting edge research into the role of the immune system in atherosclerotic cardiovascular disease (ASCVD). Firstly, Chiara Giannerelli, New York University (NYU) Langone Health and NYU Grossman School of Medicine, New York, USA, emphasised the value of deep phenotyping of atherosclerotic disease to understand the immune mechanisms involved in cardiovascular (CV) risk. She presented data demonstrating an enrichment of phenotypically distinct cluster of differentiation (CD) 4+ and CD8+ T cells in advanced atherosclerotic plaque compared with paired blood and explained how this data can be used to identify drugs with the potential to be repurposed to reduce CV risk. Secondly, Eicke Latz, Institute of Innate Immunity, University of Bonn, Germany, presented data from his research team that begins to explain how the Western diet might lead to chronic inflammation and atherogenesis, implicating cholesterol crystals and short-chain sphingomyelins in the reprogramming of granulocyte-monocyte precursor cells (GMP) in this process. The arguments for greater use of imaging and molecular biomarkers in clinical practice were presented by Wolfgang Koenig, German Heart Center Munich, Technical University of Munich, Germany, who speculated that the assessment of CV risk in the future is likely to harness big data and machine learning to achieve accurate risk assessment in individual patients. Finally, Amit Khera, Massachusetts General Hospital, Boston, USA, covered the role of genetic factors in the prediction of CV disease (CVD), explaining that a combination of traditional risk factors and polygenic scoring techniques provides the most accurate estimation of CVD risk.

ImportanceStevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a severe hypersensitivity reaction. Identifying a culprit drug is critical for patient care, yet identification is based on clinical judgment. Data are limited on the accuracy in or approach to identifying a culprit drug.ObjectiveTo evaluate patient allergy list outcomes, current approaches in identifying culprit drugs, and potential methods of improving culprit drug identification.Design, Setting, and ParticipantsThis retrospective cohort study spanned 18 years (January 2000 to July 2018), was conducted at Brigham and Women’s Hospital and Massachusetts General Hospital (Boston), and included patients with clinically and histologically confirmed cases of SJS/TEN overlap and TEN.Main Outcomes and MeasuresThis study descriptively analyzed potential culprits to SJS/TEN, patients’ allergy lists, and currently used approaches that led to those lists. It then tested the theoretical contribution of incorporating various parameters to allergy list outcomes.ResultsOf 48 patients (29 women [60.4%]; 4 Asian [8.3%], 6 Black [12.5%], 5 Hispanic [10.4%], and 25 White [52.1%] individuals; median age, 40 years [range, 1-82 years]), the mean (SD) number of drugs taken per patient at disease onset was 6.5 (4.7). Physicians labeled 17 patients as allergic to a single culprit drug. Comparatively, 104 drugs were added to allergy lists across all patients. Physicians’ approaches relied largely on heuristic identification of high-notoriety drugs and the timing of drug exposure. Use of a vetted database for drug risk improved sensitivity. Algorithm for Drug Causality for Epidermal Necrolysis scoring was discordant in 28 cases, labeling an additional 9 drugs missed by physicians and clearing 43 drugs labeled as allergens by physicians. Human leukocyte antigen testing could have potentially affected 20 cases. Consideration of infection as a culprit was limited.Conclusions and RelevanceThe results of this cohort study suggest that currently used approaches to identify culprit drugs in SJS/TEN are associated with overlabeling patients allergic to likely nonculprit drugs and less commonly missed possible culprit drugs. Incorporation of a systematized unbiased approach could potentially improve culprit drug identification, although ultimately a diagnostic test is necessary.

Abstract James Clark White, a chemist, botanist and eminent dermatologist, was a born to a shipbuilder in Boston in 1833 and from a young age was fascinated by the natural world around him. White proceeded to study medicine at Harvard and spent a further year at the University of Vienna. He was taught by renowned dermatologists, including Ferdinand Von Hebra, whose detailed drawings and lectures in dermatology were pivotal to White’s interest in the field. White’s varied background in both chemistry and botany translated into his prolific academic work on environmental dermatoses. His famous Dermatitis Venenata: An Account of External Irritants Upon the Skin was the first to provide a collective resource of contact dermatitis, before the pathogenesis of these conditions was truly understood. Another instrumental piece, ‘A case of keratosis (ichthyosis) follicularis’ is now recognized as the first description of Darier disease, which was subsequently named Darier–White disease. White authored eight books and over 100 original articles that covered many areas of cutaneous disease. White returned to Massachusetts General Hospital where, after spending a few years in general practice, he devoted his career to skin disease. He developed the dermatology department into a centre of excellence and was ultimately appointed the first chair of dermatology. A founding member of the American Dermatology Society, and twice its chairman, he progressed to become the first full professor of dermatology in the USA. White spearheaded dermatological education at Harvard, extending the specialty training from 2 to 4 years and introduced an exit examination for residents. White is regarded as part of the vanguard that elevated American dermatology to European standards in the late nineteenth century. In his personal time, White was ardent collector of fine wines and china. He devoted much time reading and listing species of birds and plants that he encountered around his residence in Belfast, Maine. He died in September 1916. His family also had distinguished careers, including his son Charles J. White, who took over his practice to also become a professor of dermatology at Harvard Medical School; and a grandson, also named James C. White, a professor of neurosurgery at the same institution. Almost two centuries after his birth, White’s lifelong dedication to dermatology has produced many works that remain relevant and inspire the dermatologists of today.

INTRODUCTION Radiomics has been proven effective for the characterisation of primary prostate cancer (PCa).1,2 However, the limited interpretability of the proposed models represents one of the major limitations in this field.3,4 This study investigated 68Ga-prostate-specific membrane antigen (PSMA) PET radiomics for the prediction of post-surgical International Society of Urological Pathology (ISUP) grade in patients with primary PCa, ensuring model interpretability. MATERIALS AND METHODS Forty-seven patients with PCa were examined with 68Ga-PSMA PET at the authors’ institution. Those patients were enrolled in this study prior to radical prostatectomy. Images were acquired using either PET/MRI or PET/CT. ISUP grade was available at both biopsy and radical prostatectomy for all patients. A radiologist manually segmented the whole prostate on PET images using the co-registered CT or MRI for anatomical localisation on 3D Slicer software (Brigham and Women’s Hospital, Boston, Massachusetts, USA).5 The whole prostate was used as volume of interest (VOI) to avoid the limitations of radiomics for small volumes.6 VOIs were normalised, resampled, and discretised. A total of 103 image biomarker standardisation initiative-compliant, radiomic features (RF) were extracted using PyRadiomics (Python Software Foundation, Beaverton, Oregon, USA).7 RFs were harmonised with the ComBat method8 to control for the scanner effect, and selected using the minimum redundancy maximum relevance algorithm. Combinations of the four most relevant RFs were used to train 12 radiomics machine learning models for the prediction of post-surgical ISUP ≥4 versus ISUP <4 that were validated by five-fold repeated stratified cross-validation. To ensure that results were not driven by spurious associations, two ad hoc control models were generated. The first one Creative Commons Attribution-Non Commercial 4.0 ● April 2023 ● Urology 37 EAU 2023 • Abstract had SUVmax and VOI volume as input (radiomics baseline), while the other was made by setting to zero all voxel values prior features extraction (PET zeros). Balanced accuracy, sensitivity, specificity, and positive and negative predictive values were collected. The performance of the best developed model was compared with that of ISUP grade biopsy. RESULTS ISUP grade at biopsy was upgraded in 9 out of 47 patients after prostatectomy, resulting in a balanced accuracy of 85.9%; sensitivity of 71.9%; specificity of 100.0%; positive predicted value of 100.0%; and negative predictive value of 62.5%. The best performing radiomic model yielded a balanced accuracy of 87.6%; sensitivity of 88.6%; specificity of 86.7%; positive predicted value of 94.0%; and negative predicted value of 82.5%. All radiomic models trained with at least two RFs (grey level size zone matrix; zone entropy and shape; least axis length) outperformed the control models. Conversely, no significant differences were found for radiomic models trained with two or more RFs (Mann–Whitney U test; p>0.05). See Table 1 for a detailed report of all the generated models’ performance. CONCLUSION These findings support the role of 68Ga-PSMA PET radiomics for the accurate and non-invasive prediction of post-surgical ISUP grade. Future multicentre studies will be needed to establish with certainty the accuracy and reproducibility of the radiomic signature proposed here.

Photo by Sharon McCutcheon on Unsplash ABSTRACT COVID-19 highlighted a disproportionate impact upon marginalized communities that needs to be addressed. Specifically, a focus on equity rather than equality would better address and prevent the disparities seen in COVID-19. A distributive justice framework can provide this great benefit but will succeed only if the medical community engages in outreach, anti-racism measures, and listens to communities in need. INTRODUCTION COVID-19 disproportionately impacted communities of color and lower socioeconomic status, sparking political discussion about existing inequities in the US.[1] Some states amended their guidelines for allocating resources, including vaccines, to provide care for marginalized communities experiencing these inequities, but there has been no clear consensus on which guidelines states should amend or how they should be ethically grounded. In part, this is because traditional justice theories do not acknowledge the deep-seated institutional and interpersonal discrimination embedded in our medical system. Therefore, a revamped distributive justice approach that accounts for these shortcomings is needed to guide healthcare decision-making now and into the post-COVID era. BACKGROUND Three terms – health disparity, health inequities, and health equity – help frame the issue. A health disparity is defined as any difference between populations in terms of disease incidence or adverse health events, such as morbidity or mortality. In contrast, health inequities are health disparities due to avoidable systematic structures rooted in racial, social, and economic injustice.[2] For example, current data demonstrate that Black, Latino, Indigenous Americans, and those living in poverty suffer higher morbidity and mortality rates from COVID-19.[3] Finally, health equity is the opportunity for anyone to attain his or her full health potential without interference from systematic structures and factors that generate health inequities, including race, socioeconomic status, gender, ethnicity, religion, sexual orientation, or geography.[4] ANALYSIS Health inequities for people of color with COVID-19 have led to critiques of states that do not account for race in their resource allocation guidelines.[5] For example, the Massachusetts Department of Public Health revised its COVID-19 guidelines regarding resource allocation to patients with the best chance of short-term survival.[6] Critics have argued that this change addresses neither preexisting structural inequities nor provider bias that may have led to comorbidities and increased vulnerability to COVID-19. By failing to address race specifically, they argue the policy will perpetuate poorer outcomes in already marginalized groups. As the inequities in COVID-19 outcomes continue to be uncovered and the data continue to prove that marginalized communities suffered disproportionately, we, as healthcare providers, must reconsider our role in addressing the injustices. Our actions must be ethically grounded in the concept of justice. l. Primary Theories of Justice The principle of justice in medical ethics relates to how we ought to treat people and allocate resources. Multiple theories have emerged to explain how justice should be implemented, with three of the most prominent being egalitarianism, utilitarianism, and distributive. This paper argues that distributive justice is the best framework for remedying past actions and enacting systemic changes that may persistently prevent injustices. An egalitarian approach to justice states all individuals are equal and, therefore, should have identical access to resources. In the allocation of resources, an egalitarian approach would support a strict distribution of equal value regardless of one’s attributes or characteristics. Putting this theory into practice would place a premium on guidelines based upon first-come, first-served basis or random selection.[7] However, the egalitarian approach taken in the UK continues to worsen health inequities due to institutional and structural discrimination.[8] A utilitarian approach to justice emphasizes maximizing overall benefits and achieving the greatest good for the greatest number of people. When resources are limited, the utilitarian principle historically guides decision-making. In contrast to the egalitarian focus on equal distribution, utilitarianism focuses on managing distributions to maximize numerical outcomes. During the COVID-19 pandemic, guidelines for allocating resources had utilitarian goals like saving the most lives, which may prioritize the youthful and those deemed productive in society, followed by the elderly and the very ill. It is important to reconsider using utilitarian approaches as the default in the post-COVID healthcare community. These approaches fail to address past inequity, sacrificing the marginalized in their emphasis on the greatest amount of good rather than the type of good. Finally, a distributive approach to justice mandates resources should be allocated in a manner that does not infringe individual liberties to those with the greatest need. Proposed by John Rawls in a Theory of Justice, this approach requires accounting for societal inequality, a factor absent from egalitarianism and utilitarianism.[9] Naomi Zack elaborates how distributive justice can be applied to healthcare, outlining why racism is a social determinant of health that must be acknowledged and addressed.[10] Until there are parallel health opportunities and better alignment of outcomes among different social and racial groups, the underlying systemic social and economic variables that are driving the disparities must be fixed. As a society and as healthcare providers, we should be striving to address the factors that perpetuate health inequities. While genetics and other variables influence health, the data show proportionately more exposure, more cases, and more deaths in the Black American and Hispanic populations. Preexisting conditions and general health disparities are signs of health inequity that increased vulnerability. Distributive justice as a theoretical and applied framework can be applied to preventable conditions that increase vulnerability and can justify systemic changes to prevent further bias in the medical community. During a pandemic, egalitarian and utilitarian approaches to justice are prioritized by policymakers and health systems. Yet, as COVID-19 has demonstrated, they further perpetuate the death and morbidity of populations that face discrimination. These outcomes are due to policies and guidelines that overall benefit white communities over communities of color. Historically, US policy that looks to distribute resources equally (focusing on equal access instead of outcomes), in a color-blind manner, has further perpetuated poor outcomes for marginalized communities.[11] ll. Historical and Ongoing Disparities Across socio-demographic groups, the medical system exacerbates historical and current inequities. Members of marginalized races,[12] women,[13] LGBTQ people,[14] and poor people[15] experience trauma caused by discrimination, marginalization, and failure to access high-quality public and private goods. Through the unequal treatment of marginalized communities, these historic traumas continue. In the US, people of color do not receive equal and fair medical treatment. A meta-analysis found that Hispanics and Black Americans were significantly undertreated for pain compared to their white counterparts over the last 20 years.[16] This is partly due to provider bias. Through interviewing medical trainees, a study by the National Academy of Science found that half of medical students and residents harbored racist beliefs such as “Black people’s nerve endings are less sensitive than white people’s” or “Black people’s skin is thicker than white people’s skin.”[17] More than 3,000 Indigenous American women were coerced, threatened, and deliberately misinformed to ensure cooperation in forced sterilization.[18] Hispanic people have less support in seeking medical care, in receiving culturally appropriate care, and they suffer from the medical community’s lack of resources to address language barriers.[19] In the US, patients of different sexes do not receive the same quality of healthcare. Despite having greater health needs, middle-aged and older women are more likely to have fewer hospital stays and fewer physician visits compared to men of similar demographics and health risk profiles.[20] In the field of critical care, women are less likely to be admitted to the ICU, less likely to receive interventions such as mechanical ventilation, and more likely to die compared to their male ICU counterparts.[21] In the US, patients of different socioeconomic statuses do not receive the same quality of healthcare. Low-income patients are more likely to have higher rates of infant mortality, chronic disease, and a shorter life span.[22] This is partly due to the insurance-based discrimination in the medical community.[23] One in three deaths of those experiencing homelessness could have been prevented by timely and effective medical care. An individual experiencing homelessness has a life expectancy that is decades shorter than that of the average American.[24] lll. Action Needed: Policy Reform While steps need to be taken to provide equitable care in the current pandemic, including the allocation of vaccines, they may not address the historical failures of health policy, hospital policy, and clinical care to eliminate bias and ensure equal treatment of patients. According to an applied distributive justice framework, inequities must be corrected. Rather than focusing primarily on fair resource allocation, medicine must be actively anti-racist, anti-sexist, anti-transphobic, and anti-discriminatory. Evidence has shown that the health inequities caused by COVID-19 are smaller in regions that have addressed racial wealth gaps through forms of reparations.[25] Distributive justice calls for making up for the past using tools of allocation as well as tools to remedy persistent problems. For example, Brigham and Women’s Hospital in Boston, MA, began “Healing ARC,” a pilot initiative that involves acknowledgement, redress, and closure on an institutional level.[26] Acknowledgement entails informing patients about disparities at the hospital, claiming responsibility, and incorporating community ideas for redress. Redress involves a preferential admission option for Black and Hispanic patients to specialty services, especially cardiovascular services, rather than general medicine. Closure requires that community and patient stakeholders work together to ensure that a new system is in place that will continue to prioritize equity. Of note, redress could take the form of cash transfers, discounted or free care, taxes on nonprofit hospitals that exclude patients of color,[27] or race-explicit protocol changes (such as those being instituted by Brigham and Women’s Hospital that admit patients historically denied access to certain forms of medical care). In New York, for instance, the New York State Bar Association drafted the COVID-19 resolutions to ensure that emergency regulations and guidelines do not discriminate against communities of color, and even mandate that diverse patient populations be included in clinical trials.[28] Also, physicians must listen to individuals from marginalized communities to identify needs and ensure that community members take part in decision-making. The solution is not to simply build new health centers in communities of color, as this may lead to tiers of care. Rather, local communities should have a chance to impact existing hospital policy and should also use their political participation to further their healthcare interests. Distributive justice does not seek to disenfranchise groups that hold power in the system. It aims to transform the system so that those in power do not continue to obtain unfair benefits at the expense of others. The framework accounts for unjust historical oppression and current injustices in our system to provide equitable outcomes to all who access the system. In this vein, we can begin to address the flagrant disparities between communities that have always – and continue to – exist in healthcare today.[29] CONCLUSION As equality focuses on access, it currently fails to do justice. Instead of outcomes, it is time to focus on equity. A focus on equity rather than equality would better address and prevent the disparities seen in COVID-19. A distributive justice framework can gain traction in clinical decision-making guidelines and system-level reallocation of resources but will succeed only if the medical community engages in outreach, anti-racism measures, and listens to communities in need. There should be an emphasis on implementing a distributive justice framework that treats all patients equitably, accounts for historical harm, and focuses on transparency in allocation and public health decision-making. [1] APM Research Lab Staff. 2020. “The Color of Coronavirus: COVID-19 Deaths by Race and Ethnicity in the U.S.” APM Research Lab. https://www.apmresearchlab.org/covid/deaths-by-race. [2] Bharmal, N., K. P. Derose, M. Felician, and M. M. Weden. 2015. “Understanding the Upstream Social Determinants of Health.” California: RAND Corporation 1-18. https://www.rand.org/pubs/working_papers/WR1096.html. [3] Yancy, C. W. 2020. “COVID-19 and African Americans.” JAMA. 323 (19): 1891-2. https://doi.org/10.1001/jama.2020.6548; Centers for Disease Control and Prevention. 2020. “COVID-19 in Racial and Ethnic Health Disparities.” Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/community/health-equity/racial-ethnic-disparities/index.html. [4] Braveman, P., E. Arkin, T. Orleans, D. Proctor, and A. Plough. 2017. “What is Health Equity?” Robert Wood Johnson Foundation. https://www.rwjf.org/en/library/research/2017/05/what-is-health-equity-.html. [5] Bedinger, M. 2020 Apr 22. “After Uproar, Mass. Revises Guidelines on Who Gets an ICU Bed or Ventilator Amid COVID-19 Surge.” Wbur. https://www.wbur.org/commonhealth/2020/04/20/mass-guidelines-ventilator-covid-coronavirus; Wigglesworth, A. 2020 May 11. “Institutional Racism, Inequity Fuel High Minority Death Toll from Coronavirus, L.A. Officials Say.” Los Angeles Times. https://www.latimes.com/california/story/2020-05-11/institutional-racism-inequity-high-minority-death-toll-coronavirus. [6] Executive Office of Health and Human Services Department of Public Health. 2020 Oct 20. “Crises Standards of Care Planning and Guidance for the COVID-19 Pandemic.” Commonwealth of Massachusetts. https://www.mass.gov/doc/crisis-standards-of-care-planning-guidance-for-the-covid-19-pandemic. [7] Emanuel, E. J., G. Persad, R. Upshur, et al. 2020. “Fair Allocation of Scarce Medical Resources in the Time of Covid-19. New England Journal of Medicine 382: 2049-55. https://doi.org/10.1056/NEJMsb2005114. [8] Salway, S., G. Mir, D. Turner, G. T. Ellison, L. Carter, and K. Gerrish. 2016. “Obstacles to "Race Equality" in the English National Health Service: Insights from the Healthcare Commissioning Arena.” Social Science and Medicine 152: 102-110. https://doi.org/10.1016/j.socscimed.2016.01.031. [9] Rawls, J. A Theory of Justice (Revised Edition) (Cambridge, MA: Belknap Press of Harvard University Press, 1999). [10] Zack, N. Applicative Justice: A Pragmatic Empirical Approach to Racial Injustice (New York: The Rowman & Littlefield Publishing Group, 2016). [11] Charatz-Litt, C. 1992. “A Chronicle of Racism: The Effects of the White Medical Community on Black Health.” Journal of the National Medical Association 84 (8): 717-25. http://hdl.handle.net/10822/857182. [12] Washington, H. A. Medical Apartheid: The Dark History of Medical Experimentation on Black Americans from Colonial Times to the Present (New York: Doubleday, 2006). [13] d'Oliveira, A. F., S. G. Diniz, and L. B. Schraiber. 2002. “Violence Against Women in Health-care Institutions: An Emerging Problem.” Lancet. 359 (9318): 1681-5. https://doi.org/10.1016/S0140-6736(02)08592-6. [14] Hafeez, H., M. Zeshan, M. A. Tahir, N. Jahan, and S. Naveed. 2017. “Health Care Disparities Among Lesbian, Gay, Bisexual, and Transgender Youth: A Literature Review. Cureus 9 (4): e1184. https://doi.org/10.7759/cureus.1184; Drescher, J., A. Schwartz, F. Casoy, et al. 2016. “The Growing Regulation of Conversion Therapy.” Journal of Medical Regulation 102 (2): 7-12. https://doi.org/10.30770/2572-1852-102.2.7; Stroumsa, D. 2014. “The State of Transgender Health Care: Policy, Law, and Medical Frameworks.” American Journal of Public Health. 104 (3): e31-8. https://doi.org/10.2105/AJPH.2013.301789. [15] Stepanikova, I., and G. R. Oates. 2017. “Perceived Discrimination and Privilege in Health Care: The Role of Socioeconomic Status and Race.” American Journal of Preventative Medicine. 52 (1s1): S86-s94. https://doi.org/10.1016/j.amepre.2016.09.024; Swartz, K. “Health Care for the Poor: For Whom, What Care, and Whose Responsibility?” In Cancian, M., and S. Danziger (Eds.). Changing Poverty, Changing Policies (New York: Russell Sage Foundation Press, 2009), 69-74. [16] Meghani, S. H., E. Byun, and R. M. Gallagher. 2012. “Time to Take Stock: A Meta-analysis and Systematic Review of Analgesic Treatment Disparities for Pain in the United States.” Pain Medicine 13 (2): 150-74. https://doi.org/10.1111/j.1526-4637.2011.01310.x; Williams, D. R., and T. D. Rucker. 2000. “Understanding and Addressing Racial Disparities in Health Care.” Health Care Financing Review 21 (4): 75-90. https://scholar.harvard.edu/davidrwilliams/dwilliam/publications/understanding-and-addressing-racial-disparities-health. [17] Hoffman, K. M., S. Trawalter, J. R. Axt, and M. N. Oliver. 2016. “Racial Bias in Pain assessment and treatment recommendations, and false beliefs about biological Differences Between Blacks and Whites.” PNAS 113 (16): 4296-4301. https://doi.org/10.1073/pnas.1516047113. [18] Pacheco, C. M., S. M. Daley, T. Brown, M. Filipp, K. A. Greiner, and C. M. Daley. 2013. “Moving Forward: Breaking the Cycle of Mistrust Between American Indians and Researchers.” American Journal of Public Health. 103 (12): 2152-9. https://doi.org/10.2105/AJPH.2013.301480. [19] Velasco-Mondragon, E., A. Jimenez, A. G. Palladino-Davis, D. Davis, and J. A. Escamilla-Cejudo. 2016. “Hispanic Health in the USA: A Scoping Review of the Literature.” Public Health Reviews 37:31. https://doi.org/10.1186/s40985-016-0043-2. [20] Cameron, K. A., J. Song, L. M. Manheim, and D. D. Dunlop. 2010. “Gender Disparities in Health and Healthcare Use Among Older Adults.” Journal of Women’s Health (Larchmt) 19 (9): 1643-50. https://doi.org/10.1089/jwh.2009.1701. [21] Bierman, A. S. 2007. “Sex Matters: Gender Disparities in Quality and Outcomes of Care. Canadian Medical Association Journal 177 (12): 1520-1. https://doi.org/10.1503/cmaj.071541; Fowler, R. A., S. Sabur, P. Li, et al. 2007. “Sex-and Age-based Differences in the Delivery and Outcomes of Critical Care. Canadian Medical Association Journal 177 (12): 1513-9. https://doi.org/10.1503/cmaj.071112. [22] McLaughlin, D. K., and C. S. Stokes. 2002. “Income Inequality and Mortality in US Counties: Does Minority Racial Concentration Matter?” American Journal of Public Health 92 (1): 99-104. https://doi.org/.10.2105/ajph.92.1.99; Shea, S., J. Lima, A. Diez-Roux, N. W. Jorgensen, and R. L. McClelland. 2016. “Socioeconomic Status and Poor Health Outcome at 10 years of Follow-up in the Multi-ethnic Study of Atherosclerosis.” PLoS One 11 (11): e0165651. https://doi.org/10.1371/journal.pone.0165651. [23] Han, X., K. T. Call, J. K. Pintor, G. Alarcon-Espinoza, and A. B. Simon. 2015. “Reports of Insurance-based Discrimination in Health care and its Association with Access to Care.” American Journal of Public Health 105 Suppl 3 (Suppl 3): S517-25. https://doi.org/10.2105/AJPH.2015.302668. [24] Aldridge, R. W., D. Menezes, D. Lewer, et al. 2019. “Causes of Death Among Homeless People: A Population-based Cross-sectional Study of Linked Hospitalization and Mortality Data in England.” Wellcome Open Research 4:49. https://doi.org/10.12688/wellcomeopenres.15151.1. [25] Richardson, E. T., M. M. Malik, W. A. Darity Jr., et al. 2021. “Reparations for Black American Descendants of Persons Enslaved in the U.S. and their Potential Impact on SARS-CoV-2 Transmission.” Social Science and Medicine 276: 113741. https://doi.org/10.1016/j.socscimed.2021.113741. [26] Wispelwey, B., and M. Morse. 2021. “An Antiracist Agenda for Medicine.” Boston Review. http://bostonreview.net/science-nature-race/bram-wispelwey-michelle-morse-antiracist-agenda-medicine. [27] Johnson, S. F., A. Ojo, and H. J. Warraich. 2021. “Academic Health Centers’ Antiracism Strategies Must Extend to their Business Practices.” Annals of Internal Medicine 174 (2): 254-5. https://doi.org/10.7326/M20-6203; Golub, M., N. Calman, C. Ruddock, et al. 2011. “A Community Mobilizes to End Medical Apartheid.” Progress in Community Health Partnerships: Research, Education, and Action 5 (3): 317-25. https://doi.org/10.1353/cpr.2011.0041. [28] New York State Bar Association. 2020. “New York State Bar Association House of Delegates: Revised COVID-19 Resolutions.” https://nysba.org/app/uploads/2020/10/Final-Health-Law-Section-COVID-19-Resolutions_10-8-20-1-1.pdf. [29] Egede, L. E. 2006. “Race, Ethnicity, Culture, and Disparities in Health Care.” Journal of General Internal Medicine 21 (6): 667-669. https://doi.org/10.1111%2Fj.1525-1497.2006.0512.x

Photo ID 129550171© Katarzyna Bialasiewicz|Dreamstime.com INTRODUCTION One night in 2016, I fell sound asleep, then awoke to painkiller-induced, nightmarish hallucinations in the ICU. Despite being unable to identify myself or surroundings, I can clearly remember the discordant beeping of hospital monitors, acrid smell of saline wash, and taste of sickly sweet orange amoxicillin syrup. I was unaware that, the morning after I’d fallen asleep, I’d skied off an unmarked 30-foot cliff, breaking my legs, jaw, eye socket and nose, rupturing my right ear canal, and shattering nearly all of my teeth. Over the years that followed, I was fortunate enough to receive care from skilled, compassionate physicians. This not only allowed me to return to ski racing, but to dream of becoming a surgeon. Having grown older and thus more aware throughout my years as a pediatric patient, I’ve developed a nuanced understanding of what treatment made me feel heard. In fact, I found the most radically varying aspect of my care to be the degree to which I was addressed as a conscious, capable individual versus an extension of my parents. This is unsurprising as the proper amount of authority lended to pediatric patients persists as highly disputed in bioethics. Over the course of this paper, several perspectives will be considered in order to evaluate the current position of the pediatric patient in medical decision-making. First, the ambiguity of maturity and reactions to pediatric autonomy will be considered through the Mature Minor Doctrine, especially important in the refusal of life-saving therapies. Next, the need for improved pain management, rooted in the misalignment of experienced and perceived pain in pediatric patients. Finally, this paper will prove, through the lenses of communitarianism and mosaic decision-making, the need for a more nuanced approach to pediatric care that structurally accounts for the patient’s voice without neglecting their place within a greater network. Therefore, there exists a great need for a more direct, balanced integration of pediatric patients’ as well as revisiting prevailing notions of where pediatric patients stand in relation to reason and experience. ANALYSIS To begin, Fleischman’s Pediatric Ethics opens with an exploration of what makes pediatric bioethics distinct.[1] Fleischman quickly runs into the most problematic of principles in the treatment of pediatric patients– autonomy. The ethical ambiguity of the degree of autonomy to offer pediatric patients and at what point in their lives is a central point of conflict. Many in favor of expanded authority point to the neurobiological similarity between young adults and late teenagers.[2] Furthermore, while parents are treated as natural decision-makers for their children, there are several cases of minors facing pressure to undergo medical treatment against their wishes.[3],[4] In response to these concerns, the Mature Minor Doctrine was created, a common law exception to the parental consent requirement. The doctrine allows a minor “to refuse or consent to medical treatment if [they possess] sufficient maturity to understand and appreciate the benefits and risks of the proposed medical treatment.”[5] The doctrine has spurred extensive and impassioned bioethical discourse, especially in relation to the refusal of life-saving therapies. In “Health Care Decisionmaking by Children'', Ross draws a clear distinction between the notion of competence, often cited in psychological justifications of the Mature Minor Doctrine, and sound judgment.[6] Her points against child liberationists can be simplified as follows: (a) children need time to develop virtues that preserve their life-time autonomy versus their present-day autonomy, (b) pediatric patients possess “limited world experience and so [their] decisions are not part of a well-conceived life plan,”[7] and (c) it serves parents and children alike for parents to make decisions in line with their view of a good life. I find all three points convincing, but each of them to be uniquely rooted in this same, critical lack of experience possessed by pediatric patients. I can attest to this. There were times where I suffered so desperately that I longed for relief by any means. I even told my mother that I was content only hearing out of one ear, willing to do anything to prevent another surgery. Now, I am fearful to imagine a world where, at my lowest, I had full autonomy. Hence, the broad aversion to expanded pediatric autonomy is largely rooted in potential misuse, especially in the possibility of a unilateral, misinformed decision in favor of death via refusal of life-sustaining therapy.[8],[9] Yet, one might argue, the desire for death has concrete rationale beyond lack of life experience— pain and suffering. As Foley describes, “The public's fear of pain and the media's portrayal that physician-assisted suicide and euthanasia are the only reliable options for pain relief… demand that health care delivery systems commit their efforts to improve pain relief at an institutional level.”[10] Indeed, the issue of insufficient pain management is all too common in pediatrics. One study comparing postoperative pain assessments surveyed 307 patients, 207 of whom were verbal. Across the board, nurses’ pain estimations produced significantly lower pain scores than parents and children, and were consistently closer to estimated pain scores of independent observers.[11] In another study, a total of 356 nurses across 22 Japanese PICUs were surveyed, and despite possessing a median of 4 years of experience, a mere 32.6% expressed confidence in their ability to accurately assess pain.[12] It is alarming and telling that even in verbal pediatric patients, pain is significantly underestimated by medical personnel, reflecting a real gap in pediatric patient-professional communication. I can, again, personally attest to this. In the children’s ward, I was offered only Tylenol for severe nerve pain in my legs that kept me awake most nights. Relatedly, the spirited debate in response to the Mature Minor Doctrine is somewhat disproportionate. Despite the suggestion of various commentators that the law broadly recognizes the doctrine or that states are trending in its direction, only eight states have adopted a mature minor exception, and even these states condition this authority greatly.[13] With this in mind, a crucial issue is illuminated– an aversion to the pediatric patient voice altogether. As Flesichman writes, “Children should be informed about the nature of their condition, the proposed treatment plan, and the expected outcome… appropriate to their developmental levels.”[14] Hence, it is vital to curtail pediatric autonomy in complex and life-threatening choices, but it is worth seriously considering that the current landscape might excessively minimize or avoid pediatric patients’ expression, merely serving to inform them rather than account for their voice. The experience that pediatric patients do possess, in the form of knowing their body, past medical experiences, and thus present pain-related needs, is systemically underrepresented. This is a pressing issue. Before considering expansion of the pediatric voice, though, it is first important to consider the manner in which the patient’s capacity is further complicated by their role within a larger community. It is worthwhile explicitly mentioning communitarianism, a prevailing school of thought in modern bioethics, defined by Callahan as “a way of… assum[ing] that human beings are social animals… and whose lives are lived out within deeply penetrating social, political, and cultural institutions and practices.”[15] Pediatric patients present a uniquely communitarian case as the perspectives of parents and the needs of patients’ families are vital considerations in offering care. The pediatric patient’s role in a larger family unit and community should be kept in focus so long as the well-being of the patient isn’t compromised, such as in potentially life-threatening religious preferences, as the obligation of the physician is, first and foremost, to the patient. Nonetheless, the status quo demands a more thoughtful and structural accounting of the pediatric voice to ensure that they feel heard and empowered in complex decision-making and regular care alike. Hence, it is necessary to develop and evaluate clinical models and frameworks that directly account for the pediatric voice, that integrate pediatric patients’ input as continuous, regular, and required elements of treatment. For instance, there may be promise in a model similar to that of mosaic decision-making, a means of restoring the capacity of reemergent patients following brain injury. Rather than enabling complete surrogate authority, the model would enable a pediatric patient’s emergent voice to be accommodated but to not “speak beyond its range and capabilities” via group deliberation between surrogate and patient, a medical professional, and a patient advocate.[16] Opting for such a model would enable the active involvement of pediatric input without excessively empowering the patient in a manner that neglects their communitarian role and lack of experience. CONCLUSION In the heated response to the largely unenforced mature minor doctrine, one finds the invaluable and lacking factor of experience in pediatric patients, especially in decisions to withdraw or refuse life-sustaining medical treatments. In this same response, however, one finds a sharp aversion to the pediatric voice, reflected in pervasive under-medication. Deficits in pain management must be addressed to more effectively treat discomfort, an effort bolstered by a more structural accounting of the pediatric voice and thus pain-related needs. Finally, frameworks that regularly involve the pediatric patient perspective while valuing their communitarian importance and lacking experience, such as the mosaic model, hold real promise moving forward. - [1] Fleischman, Alan. Pediatric Ethics: Protecting the Interests of Children. (Oxford: Oxford University Press, September, 2016), p. 1-16. [2] Coleman, Doriane & Rosoff, Philip. “The Legal Authority of Mature Minors to Consent to General Medical Treatment.” (Itasca: American Journal of Pediatrics, March 2013), p. 1. [3] Hawkins, Susan. “Protecting the Rights and Interests of Competent Minors in Litigated Medical Treatment Disputes.” (New York: Fordham Law Review, March 1996), p. 1. [4] Derish, Melinda & Heuvel, Kathleen. “Mature Minors Should Have the Right to Refuse Life-Sustaining Medical Treatment.” (Boston: The Journal of Law, Medicine & Ethics, January 2021), p. 1-14. [5] Derish, Melinda & Heuvel, Kathleen. “Mature Minors Should Have the Right to Refuse Life-Sustaining Medical Treatment.” p. 7. [6] Ross, Lainie. “Health Care Decisionmaking by Children. Is It in Their Best Interest?” (Garrison: The Hastings Center Report, November-December 1997), p. 1-5. [7] Ross. “Health Care Decisionmaking by Children''. p. 5. [8] Penkower, Jessica. “The Potential Right of Chronically Ill Adolescents to Refuse Life-Saving Medical Treatment - Fatal Misuse of the Mature Minor Doctrine.” (Chicago: DePaul Law Review, 1996), p. 1-8. [9] Burk, Josh. “Mature Minors, Medical Choice, and the Constitutional Right to Martyrdom.” (Charlottesville: Virginia Law Review, September 2016), p. 1-15. [10] Foley, Kathleen. “Pain Relief Into Practice: Rhetoric Without Reform.” (Alexandria: Journal of Clinical Oncology, 1995), p. 1-3 [11] Hla et. al. “Perception of Pediatric Pain: A Comparison of Postoperative Pain Assessments Between Child, Parent, Nurse, and Independent Observer.” (Melbourne: Pediatric Anesthesia. 2014) p. 1-5. [12] Tsuboi et. al. “Nurses' perception of pediatric pain and pain assessment in the Japanese PICU.” (Tokyo: Pediatrics International, February 2023), p. 1-3, 10-12. [13] Coleman, Doriane & Rosoff, Philip. “The Legal Authority of Mature Minors”. p. 1-3. [14] Fleischman, Alan. Pediatric Ethics. p. 115. [15] Callahan, Daniel. “Principlism and communitarianism.” (Garrison: The Hastings Center Report, October 2003), p. 2. [16] Fins, Joseph. “Mosaic Decisionmaking and Reemergent Agency after Severe Brain Injury”. (Cambridge: Cambridge University Press, September 2017), p. 6.

Introduction Utopia has always been countercultural, and ever since technological progress has allowed, utopia has been using alternative media to promote and strengthen its underpinning ideals. In this article, I am seeking to clarify the connections between counterculture and alternative media in utopian contexts to demonstrate their reciprocity, then draw together these threads through reference to a well-known figure of the Rainbow Region–Rusty Miller. His trajectory from iconic surfer and Aquarian reporter to mediator for utopian politics and ideals in the Rainbow Region encompasses in a single identity the three elements underpinning this study. In concluding, I will turn to Rusty’s Byron Guide, questioning its classification as alternative or mainstream media, and whether Byron Bay is represented as countercultural and utopian in this long-running and ongoing publication. Counterculture and Alternative Media in Utopian Contexts Counterculture is an umbrella that enfolds utopia, among many other genres and practices. It has been most often situated in the 1960s and 1970s as a new form of social movement embodying youth resistance to the technocratic mainstream and its norms of gender, sexuality, politics, music, and language (Roszak). Many scholars of counterculture underscore its utopian impulses both in the projection of better societies where the social goals are achieved, and in the withdrawal from mainstream society into intentional communities (Yinger 194-6; McKay 5; Berger). Before exploring further the connections between counterculture and alternative media, I want to define the scope of countercultural utopian contexts in general, and the Rainbow Region in particular. Utopia is a neologism created by Sir Thomas More almost 500 years ago to designate the island community that demonstrates order, harmony, justice, hope and desire in the right balance so that it seems like an ideal land. This imaginary place described in Utopia (1516) as a counterpoint to the social, political and religious shortcomings of contemporary 16th century British society, has attracted accusations of heresy (Molner), and been used as a pejorative term, an insult to denigrate political projects that seem farfetched or subversive, especially during the 19th century. Almost every study of utopian theory, literature and practice points to a dissatisfaction with the status quo, which inspires writers, politicians, architects, artists, individuals and communities to rail against it (see for example Davis, Moylan, Suvin, Levitas, Jameson). Kingsley Widmer’s book Counterings: Utopian Dialectics in Contemporary Contexts reiterates what many scholars have stated when he writes that utopias should be understood in terms of what they are countering. Lyman Tower Sargent defines utopia as “a non-existent society described in considerable detail and normally located in time and space” and utopianism as “social dreaming” (9), to which I would add that both indicate an improvement on the alternatives, and may indeed be striving to represent the best place imaginable. Utopian contexts, by extension, are those situations where the “social dreaming” is enhanced through human agency, good governance, just laws, education, and work, rather than being a divinely ordained state of nature (Schaer et al). In this way, utopian contexts are explicitly countercultural through their very conception, as human agency is required and their emphasis is on social change. These modes of resistance against dominant paradigms are most evident in attempts to realise textual projections of a better society in countercultural communal experiments. Almost immediately after its publication, More’s Utopia became the model for Bishop Vasco de Quiroga’s communitarian hospital-town Santa Fe de la Laguna in Michoacan, Mexico, established in the 1530s as a counterculture to the oppressive enslavement and massacres of the Purhépecha people by Nuno Guzmán (Green). The countercultural thrust of the 1960s and 1970s provided many utopian contexts, perhaps most readily identifiable as the intentional communities that spawned and flourished, especially in the United States, the United Kingdom, Australia, and New Zealand (Metcalf, Shared Lives). They were often inspired by texts such as Charles A. Reich’s The Greening of America (1970) and Ernest Callenbach’s Ecotopia (1975), and this convergence of textual practices and alternative lifestyles can be seen in the development of Australia’s own Rainbow Region. Located in northern New South Wales, the geographical area of the Northern Rivers that has come to be known as the Rainbow Region encompasses Byron Bay, Nimbin, Mullumbimby, Bangalow, Clunes, Dunoon, Federal, with Lismore as the region’s largest town. But more evocative than these place names are the “rivers and creeks, vivid green hills, fruit and nut farms […] bounded by subtropical beaches and rainforest mountains” (Wilson 1). Utopian by nature, and recognised as such by the indigenous Bundjalung people who inhabited it before the white settlers, whalers and dairy farmers moved in, the Rainbow Region became utopian through culture–or indeed counterculture–during the 1973 Aquarius Festival in Nimbin when the hippies of Mullumbimby and the surfers of Byron Bay were joined by up to 10,000 people seeking alternative ways of being in the world. When the party was over, many Aquarians stayed on to form intentional communities in the beautiful region, like Tuntable Falls, Nimbin’s first and largest such cooperative (Metcalf, From Utopian Dreaming to Communal Reality 74-83). In utopian contexts, from the Renaissance to the 1970s and beyond, counterculture has underpinned and alternative media has circulated the aims and ideals of the communities of resistance. The early utopian context of the Anabaptist movement has been dubbed as countercultural by Sigrun Haude: “During the reign of the Münster (1534-5) Anabaptists erected not only a religious but also a social and political counterculture to the existing order” (240). And it was this Protestant Reformation that John Downing calls the first real media war, with conflicting movements using pamphlets produced on the new technology of the Gutenberg press to disseminate their ideas (144). What is striking here is the confluence of ideas and practices at this time–countercultural ideals are articulated, published, and disseminated, printing presses make this possible, and utopian activists realise how mass media can be used and abused, exploited and censored. Twentieth century countercultural movements drew on the lessons learnt from historical uprising and revolutions, understanding the importance of getting the word out through their own forms of media which, given the subversive nature of the messages, were essentially alternative, according to the criteria proposed by Chris Atton: alternative media may be understood as a radical challenge to the professionalized and institutionalized practices of the mainstream media. Alternative media privileges a journalism that is closely wedded to notions of social responsibility, replacing an ideology of “objectivity” with overt advocacy and oppositional practices. Its practices emphasize first person, eyewitness accounts by participants; a reworking of the populist approaches of tabloid newspapers to recover a “radical popular” style of reporting; collective and antihierarchical forms of organization which eschew demarcation and specialization–and which importantly suggest an inclusive, radical form of civic journalism. (267) Nick Couldry goes further to point out the utopian processes required to identify agencies of change, including alternative media, which he defines as “practices of symbolic production which contest (in some way) media power itself–that is, the concentration of symbolic power in media institutions” (25). Alternative media’s orientation towards oppositional and contestatory practices demonstrates clear parallels between its ambitions and those of counterculture in utopian contexts. From the 1960s onwards, the upsurge in alternative newspaper numbers is commensurate with the blossoming of the counterculture and increased utopian contexts; Susan Forde describes it thus: “a huge resurgence in the popularity of publications throughout the ‘counter-culture’ days of the 1960s and 1970s” (“Monitoring the Establishment”, 114). The nexus of counterculture and alternative media in such utopian contexts is documented in texts like Roger Streitmatter’s Voices of Revolution and Bob Osterlag’s People’s Movements, People’s Press. Like the utopian newspapers that came out of 18th and 19th century intentional communities, many of the new alternative press served to educate, socialise, promote and represent the special interests of the founders and followers of the countercultural movements, often focusing on the philosophy and ideals underpinning these communities rather than the everyday events (see also Frobert). The radical press in Australia was also gaining ground, with OZ in Australia from 1963-1969, and then from 1967-1973 in London. Magazines launched by Philip Frazer like The Digger, Go-Set, Revolution and High Times, and university student newspapers were the main avenues for youth and alternative expression on the Vietnam war and conscription, gay and lesbian rights, racism, feminism and ecological activism (Forde, Challenging the News; Cock & Perry). Nimbin 1973: Rusty Miller and The Byron Express The 1973 Aquarius Festival of counterculture in Nimbin (12-23 May) was a utopian context that had an alternative media life of its own before it arrived in the Rainbow Region–in student publications like Tharnuka and newsletters distributed via the Aquarius Foundation. There were other voices that announced the coming of the Aquarius Festival to Nimbin and reported on its impact, like The Digger from Melbourne and the local paper, The Northern Star. During the Festival, the Nimbin Good Times first appeared as the daily bulletin and continues today with the original masthead drawn by the Festival’s co-organiser, Graeme Dunstan. Some interesting work has been done on this area, ranging from general studies of the Rainbow Region (Wilson; Munro-Clark) to articles analysing its alternative press (Ward & van Vuuren; Martin & Ellis), but to date, there has been no focus on the Rainbow Region’s first alternative newspaper, The Byron Express. Co-edited by Rusty Miller and David Guthrie, this paper presented and mediated the aims and desires of the Aquarian movement. Though short-lived, as only 7 issues were published from 15 February 1973 to September 1973, The Byron Express left a permanent printed vestige of the Aquarian counterculture movement’s activism and ideals from an independent regional perspective. Miller’s credentials for starting up the newspaper are clear–he has always been a trailblazer, mixing “smarts” with surfing and environmental politics. After graduating from a Bachelor of Arts in history from San Diego State College, he first set foot in Byron Bay during his two semesters with the inaugural Chapman College affiliated University of the Seven Seas in 1965-6. Returning to his hometown of Encinitas, he co-founded the Surf Research accessory company with legendary Californian surfer Mike Doyle, and launched Waxmate, the first specially formulated surf wax in 1967 (Davis, Witzig & James; Warshaw 217), selling his interest in the business soon after to spend a couple of years “living the counterculture life on the Hawaiian Island of Kauai” (Davis, Witzig & James), before heading back to Byron Bay via Bells Beach in 1970 (Miller & Shantz) and Sydney, where he worked as an advertising salesman and writer with Tracks surfing magazine (Martin & Ellis). In 1971, he was one of the first to ride the now famous waves of Uluwatu in Bali, and is captured with Steven Cooney in the iconic publicity image for Albe Falzon’s 1971 film, Morning Of The Earth. The champion surfer from the US knew a thing or two about counterculture, alternative media, advertising and business when he found his new utopian context in Byron Bay. Miller and Guthrie’s front-page editorial of the inaugural issue of The Byron Express, published on 15 February 1973, with the byline “for a higher shire”, expressed the countercultural (cl)aims of the publication. Land use, property development and the lack of concern that some people in Byron had for their impact on the environment and people of the region were a prime target: With this first issue of the Byron Express, we hope to explain that the area is badly in need of a focal point. The transitions of present are vast and moving fast. The land is being sold and resold. Lots of money is coming into the area in the way of developments […] caravan parts, hotels, businesses and real estate. Many of the trips incoming are not exactly “concerned” as to what long term effect such developments might have on the environment and its people. We hope to serve as a focus of concern and service, a centre for expression and reflection. We would ask your contributions in vocal and written form. We are ready for some sock it to ya criticism… and hope you would grab us upon the street to tell us how you feel…The mission of this alternative newspaper is thereby defined by the need for a “focal point” that inscribes the voices of the community in a freely accessible narrative, recorded in print for posterity. Although this first issue contains no mention of the Aquarius Festival, there were already rumours circulating about it, as organisers Graeme Dunstan and Johnny Allen had been up to Main Arm, Mullumbimby and Nimbin on reconnaissance missions beginning in September 1972. Instead, there was an article on “Mullumbimby Man–Close to the Land” by Nicholas Shand, who would go on to found the community-based weekly newspaper The Echo in 1986, then called The Brunswick Valley Echo and still going strong. Another by Bob McTavish asked whether there could be a better form of government; there was a surf story, and a soul food section with a recipe for honey meade entitled “Do you want to get out of it on 10 cents a bottle?” The second issue continues in much the same vein. It is not until the third issue comes out on 17 March 1973 that the Aquarius Festival is mentioned in a skinny half column on page four. And it’s not particularly promising: Arrived at Nimbin, sleepy hamlet… Office in disused R.S.L. rooms, met a couple of guys recently arrived, said nothing was being done. “Only women here, you know–no drive”. Met Joanne and Vi, both unable to say anything to be reported… Graham Dunstan (codenamed Superfest) and John Allen nowhere in sight. Allen off on trip overseas. Dunstan due back in a couple of weeks. 10 weeks to go till “they” all come… and to what… nobody is quite sure. This progress report provides a fascinating contemporary insight into the tensions–between the local surfies and hippies on one hand, and the incoming students on the other–around the organisation of the Aquarius Festival. There is an unbridled barb at the sexist comments made by the guys, implicit criticism of the absent organisers, obvious skepticism about whether anyone will actually come to the festival, and wonderment at what it will be like. Reading between the lines, we might find a feeling of resentment about not being privy to new developments in their own backyard. The final lines of the article are non-committal “Anyway, let’s see what eventuates when the Chiefs return.” It seems that all has been resolved by the fifth issue of 11 May, which is almost entirely dedicated to the Aquarius Festival with the front page headline “Welcome to the New Age”. But there is still an undertone of slight suspicion at what the newcomers to the area might mean in terms of property development: The goal is improving your fellow man’s mind and nourishment in concert with your own; competition to improve your day and the quality of the day for society. Meanwhile, what is the first thing one thinks about when he enters Byron and the area? The physical environment is so magnificent and all encompassing that it can actually hold a man’s breath back a few seconds. Then a man says, “Wow, this land is so beautiful that one could make a quid here.” And from that moment the natural aura and spells are broken and the mind lapses into speculative equations, sales projections and future interest payments. There is plenty of “love” though, in this article: “The gathering at Nimbin is the most spectacular demonstration of the faith people have in a belief that is possible (and possible just because they want it to be) to live in love, through love together.” The following article signed by Rusty Miller “A Town Together” is equally focused on love: “See what you could offer the spirit at Nimbin. It might introduce you to a style that could lead to LOVE.” The centre spread features photos: the obligatory nudes, tents, and back to nature activities, like planting and woodworking. With a text box of “random comments” including one from a Lismore executive: ‘I took my wife and kids out there last weekend and we had such a good time. Seems pretty organized and the town was loaded with love. Heard there is some hepatitis about and rumours of VD. Everyone happy.” And another from a land speculator (surely the prime target of Miller’s wrath): “Saw guys kissing girls on the street, so sweet, bought 200 acres right outside of town, it’s going to be valuable out there some day.” The interview with Johnny Allen as the centrepiece includes some pertinent commentary on the media and reveals a well-founded suspicion of the mediatisation of the Aquarius Festival: We have tried to avoid the media actually. But we haven’t succeeded in doing so. Part of the basic idea is that we don’t need to be sold. All the down town press can do is try and interpret you. And by doing that it automatically places it in the wrong sort of context. So we’ve tried to keep it to people writing about the festival to people who will be involved in it. It’s an involvement festival. Coopting The Byron Express as an “involved” party effects a fundamental shift from an external reporting newspaper to a kind of proponent or even propaganda for the Aquarius festival and its ideas, like so many utopian newspapers had done before. It is therefore perhaps inevitable that The Byron Express should disappear very soon after the Aquarius festival. Fiona Martin and Rhonda Ellis explain that Rusty Miller stopped producing the paper because he “found the production schedule exhausting and his readership too small to attract consistent advertising” (5). At any rate, there were only two more issues, one in June–with some follow up reporting of the festival–and another in September 1973, which was almost entirely devoted to environmentally focused features, including an interview with Kath Walker (Oodgeroo Noonuccal). Byron Bay 2013: Thirty Years of Rusty’s Byron Guide What Rusty did next is fairly well known locally–surfing and teaching people how to surf and a bit of writing. When major local employer Walkers slaughterhouse closed in 1983, he and his wife, social geographer Tricia Shantz, were asked by the local council to help promote Byron Bay as a tourist destination, writing the first Byron guide in 1983-4. Incorporating essays by local personalities and dedicated visitors, the Byron guide perpetuates the ideal of environmental awareness, spiritual experimentation, and respect for the land and sea. Recent contributors have included philosopher Peter Singer, political journalist Kerry O’Brien, and writer John Ralston Saul, and Miller and Shantz always have an essay in there themselves. “People, Politics and Culture” is the new byline for the 2013 edition. And Miller’s opening essay mediates the same utopian desires and environmental community messages that he espoused from the beginning of The Byron Express: The name Byron Bay represents something that we constantly try to articulate. If one was to dream up a menu of situations and conditions to compose a utopia, Australia would be the model of the nation-state and Byron would have many elements of the actual place one might wish to live for the rest of their lives. But of course there is always the danger of excesses in tropical paradises especially when they become famous destinations. Australia is being held to ransom for the ideology that we should be slaves to money and growth at the cost of a degraded and polluted physical and social environment. Byron at least was/is a refuge against this profusion of the so-called real-world perception that holds profit over environment as the way we must choose for our future. Even when writing for a much more commercial medium, Miller retains the countercultural utopian spirit that was crystallised in the Aquarius festival of 1973, and which remains relevant to many of those living in and visiting the Rainbow Region. Miller’s ethos moves beyond the alternative movements and communities to infiltrate travel writing and tourism initiatives in the area today, as evidenced in the Rusty’s Byron Guide essays. By presenting more radical discourses for a mainstream public, Miller together with Shantz have built on the participatory role that he played in launching the region’s first alternative newspaper in 1973 that became albeit briefly the equivalent of a countercultural utopian gazette. Now, he and Shantz effectively play the same role, producing a kind of countercultural form of utopian media for Byron Bay that corresponds to exactly the same criteria mentioned above. Through their free publication, they aim to educate, socialise, promote and represent the special interests of the founders and followers of the Rainbow Region, focusing on the philosophy and ideals underpinning these communities rather than the everyday events. The Byron Bay that Miller and Shantz promote is resolutely utopian, and certainly countercultural if compared to other free publications like The Book, a new shopping guide, or mainstream media elsewhere. Despite this new competition, they are planning the next edition for 2015 with essays to make people think, talk, and understand the region’s issues, so perhaps the counterculture is still holding its own against the mainstream. References Atton, Chris. “What Is ‘Alternative’ Journalism?” Journalism: Theory, Practice, Criticism 4.3 (2003): 267-72. Berger, Bennett M. The Survival of a Counterculture: Ideological Work and Everyday Life among Rural Communards. New Brunswick: Transaction Publishers, 2004. Cock, Peter H., & Paul F. Perry. “Australia's Alternative Media.” Media Information Australia 6 (1977): 4-13. 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