Добірка наукової літератури з теми "Lance et Adams"

3530 Background: IMA910 is a novel cancer vaccine consisting of 10 class I and 3 class II tumor-associated peptides (TUMAPs), naturally presented on HLA molecules of CRC. Vaccine-induced immune responses are associated with prolonged OS of renal cell carcinoma pts treated with IMA901, a multi-peptide vaccine identified by the same antigen discovery platform. Methods: 92 HLA-A*02+ aCRC pts with stable or responding disease after 12 weeks of first-line oxaliplatin-based therapy were enrolled in this phase I/II trial. After immunomodulation with cyclophosphamide (300 mg/m2) to reduce regulatory T cells, pts were immunized intradermally (up to 16 vaccinations) with IMA910 in combination with GM-CSF without (cohort 1; n=66) or with (cohort 2; n=26) topically applied imiquimod. Safety and PFS data was recently presented [Mayer et al., ASCO-GI 2012]. OS of IMA910 pts was compared to matched pts from arm C (intermittent chemotherapy) of the COIN trial [Adams et al., Lancet Oncology 2011]. Matching was performed in a prospectively defined, fully blinded fashion based on a propensity score involving all available prognostic factors. T-cell responses to individual IMA910 peptides were analyzed by HLA multimer and intracellular cytokine assays. Results: At a median follow up of 1.7 yrs, OS of IMA910 vaccinated pts was significantly longer in comparison to 1:1 matched HLA-A*02+ COIN pts (HR 0.675, 95% CI 0.458-0.995, p=0.047; 1 yr OS: 69% vs 55%; 2 yr OS: 40% vs 24%). Multi-TUMAP responders (≥2 CD8+ and ≥2 CD4+ vaccine-induced T cells) had a significantly longer OS (HR 0.45, p=0.04) compared to matched COIN pts while non-multi-TUMAP responders showed similar OS compared to matched COIN pts (HR 0.76, p=0.22). Conclusions: OS of IMA910 pts was significantly longer in comparison to matched COIN pts with separation of survival curves at ~9 months and increasing OS difference over time. Multi-TUMAP immune responders had a significantly longer OS compared to non-multi-TUMAP responders and compared to matched COIN pts. These clinical and immune response data strongly suggest clinical activity of IMA910 in 1st line CRC pts and warrant further development.

Abstract Purpose: This group has previously worked on Radiosensitivity Index (RSI),1,2 which has been clinically validated in 1919 patients across multiple cohorts.3 The Linear Quadratic (LQ) model is a widely accepted model used to prescribe radiation dose and fractionation. We hypothesize that clonogenic data can be fitted to the linear quadratic equation to predict α and β based on gene expression. Here we introduce a novel genomic model (gLQ) developed in cell lines to estimate the α and β parameters in cell lines. Methods: We analyzed public data on 494 irradiated clonogenic cell lines,4 considering Survival Fraction (SF) at known radiation dosages (2-10 Gy, i.e., SF2 through SF10) and fractions to calculate “ground truth” α and β using RAD-ADAPT software.5 Ground truth α and β were aligned to publically available Affymetrix U133 2.0 plus microarray and RNA seq data. Normalization was performed by Robust Multi-array average and RSEM respectively. 90% of the 494 cell line data (n=444) was used to train the model, while 10% (n=50) was left untouched. To narrow the data on 18,468 genes for each cell line to a smaller set of representative genes, we used a combination of clustering analysis, feature selection using Max-min Markov Blanket, and evaluating the functionality of selected features as they relate to radiosensitivity and cancer.6 Limiting the genes used as inputs in the machine-trained regression improved model training time. Machine learning, specifically Bayesian Ridge Regression, was utilized to identify relationships between calculated α and β and the representative gene expression profile for each cell line. 598 genes were selected for the α model, and 1198 genes were selected for the β model. These models were then locked down and tested on the 50 untouched validation cell lines. Results: Calculated ground truth α and β had a strong fit (R2=0.94). The resulting trained, locked-down model predicted α and β values for the remaining unseen 10% of the cell lines as a separate validation cohort with R2 values of 0.8809 and 0.8175, respectively. Conclusions: This suggests that genomic data can be used to effectively predict cellular radiosensitivity. References: 1.Torres-Roca JF. A molecular assay of tumor radiosensitivity: a roadmap towards biology-based personalized radiation therapy. Per Med. 2012;9(5):547-557. doi:10.2217/pme.12.55 2.Eschrich SA, Pramana J, Zhang H, et al. A gene expression model of intrinsic tumor radiosensitivity: prediction of response and prognosis after chemoradiation. Int J Radiat Oncol Biol Phys. 2009;75(2):489-496. doi:10.1016/j.ijrobp.2009.06.014 3.Scott JG, Sedor G, Ellsworth P, et al. Pan-cancer prediction of radiotherapy benefit using genomic-adjusted radiation dose (GARD): a cohort-based pooled analysis. Lancet Oncol. 2021;22(9):1221-1229. doi:10.1016/S1470-2045(21)00347-8 4.Yard, B., Adams, D., Chie, E. et al. "A genetic basis for the variation in the vulnerability of cancer to DNA damage," Nat Commun, 7, 11428 (2016) 5.https://bmsr.usc.edu/software/rad-adapt 6.https://academic.oup.com/bioinformatics Citation Format: Benjamin M Honan, Jeffrey S. Peacock. A genomic model to predict cellular radiosensitivity. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P042.

The pandemic of COVID-19 has afflicted every individual and has initiated a cascade of directly or indirectly involved events in precipitating mental health issues. The human species is a wanderer and hunter-gatherer by nature, and physical social distancing and nationwide lockdown have confined an individual to physical isolation. The present review article was conceived to address psychosocial and other issues and their aetiology related to the current pandemic of COVID-19. The elderly age group has most suffered the wrath of SARS-CoV-2, and social isolation as a preventive measure may further induce mental health issues. Animal model studies have demonstrated an inappropriate interacting endogenous neurotransmitter milieu of dopamine, serotonin, glutamate, and opioids, induced by social isolation that could probably lead to observable phenomena of deviant psychosocial behavior. Conflicting and manipulated information related to COVID-19 on social media has also been recognized as a global threat. Psychological stress during the current pandemic in frontline health care workers, migrant workers, children, and adolescents is also a serious concern. Mental health issues in the current situation could also be induced by being quarantined, uncertainty in business, jobs, economy, hampered academic activities, increased screen time on social media, and domestic violence incidences. The gravity of mental health issues associated with the pandemic of COVID-19 should be identified at the earliest. Mental health organization dedicated to current and future pandemics should be established along with Government policies addressing psychological issues to prevent and treat mental health issues need to be developed. References World Health Organization (WHO) Coronavirus Disease (COVID-19) Dashboard. 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Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study. Lancet Infect Dis. 2020; 20:689-96. https://doi.org/10.1016/S1473-3099(20)30198-5. Dalton L, Rapa E, Stein A. Protecting the psychological health of through effective communication about COVID-19. Lancet Child Adolesc Health. 2020;4(5):346-347. https://doi.org/10.1016/S2352-4642(20)30097-3. Centre for Disease Control. Helping Children Cope with Emergencies. Available at: https://www.cdc.gov/childrenindisasters/helping-children-cope.html [Accessed on 25 August 2020]. Liu JJ, Bao Y, Huang X, Shi J, Lu L. Mental health considerations for children quarantined because of COVID-19. Lancet Child & Adolesc Health. 2020; 4(5):347-349. https://doi.org/10.1016/S2352-4642(20)30096-1. Sprang G, Silman M. Posttraumatic Stress Disorder in Parents and Youth After Health-Related Disasters. Disaster Med Public Health Prep. 2013;7(1):105-110. https://doi.org/10.1017/dmp.2013.22. Rehman U, Shahnawaz MG, Khan NH, Kharshiing KD, Khursheed M, Gupta K, et al. Depression, Anxiety and Stress Among Indians in Times of Covid-19 Lockdown. Community Ment Health J. 2020:1-7. https://doi.org/10.1007/s10597-020-00664-x. Cao W, Fang Z, Hou, Han M, Xu X, Dong J, et al. The psychological impact of the COVID-19 epidemic on college students in China. Psychiatry Research. 2020; 287:112934. https://doi.org/10.1016/j.psychres.2020.112934. Wang C, Zhao H. The Impact of COVID-19 on Anxiety in Chinese University Students. Front Psychol. 2020; 11:1168. https://dx.doi.org/10.3389%2Ffpsyg.2020.01168. Kang L, Li Y, Hu S, Chen M, Yang C, Yang BX, et al. The mental health of medical workers in Wuhan, China dealing with the 2019 novel coronavirus. Lancet Psychiatry 2020;7(3): e14. https://doi.org/10.1016/s2215-0366(20)30047-x. Lai J, Ma S, Wang Y, Cai Z, Hu J, Wei N, et al. Factors associated with mental health outcomes among health care workers exposed to coronavirus disease 2019. JAMA Netw Open 2020;3(3): e203976. https://doi.org/10.1001/jamanetworkopen.2020.3976. Lancee WJ, Maunder RG, Goldbloom DS, Coauthors for the Impact of SARS Study. Prevalence of psychiatric disorders among Toronto hospital workers one to two years after the SARS outbreak. Psychiatr Serv. 2008;59(1):91-95. https://dx.doi.org/10.1176%2Fps.2008.59.1.91. Tam CWC, Pang EPF, Lam LCW, Chiu HFK. Severe acute respiratory syndrome (SARS) in Hongkong in 2003: Stress and psychological impact among frontline healthcare workers. Psychol Med. 2004;34 (7):1197-1204. https://doi.org/10.1017/s0033291704002247. Lee SM, Kang WS, Cho A-R, Kim T, Park JK. Psychological impact of the 2015 MERS outbreak on hospital workers and quarantined hemodialysis patients. Compr Psychiatry. 2018; 87:123-127. https://dx.doi.org/10.1016%2Fj.comppsych.2018.10.003. Koh D, Meng KL, Chia SE, Ko SM, Qian F, Ng V, et al. Risk perception and impact of severe acute respiratory syndrome (SARS) on work and personal lives of healthcare workers in Singapore: What can we learn? Med Care. 2005;43(7):676-682. https://doi.org/10.1097/01.mlr.0000167181.36730.cc. Verma S, Mythily S, Chan YH, Deslypere JP, Teo EK, Chong SA. Post-SARS psychological morbidity and stigma among general practitioners and traditional Chinese medicine practitioners in Singapore. Ann Acad Med Singap. 2004; 33(6):743e8. Yeung J, Gupta S. Doctors evicted from their homes in India as fear spreads amid coronavirus lockdown. CNN World. 2020. Available at: https://edition.cnn.com/2020/03/25/asia/india-coronavirus-doctors-discrimination-intl-hnk/index.html. [Accessed on 24 August 2020] Violence Against Women and Girls: the Shadow Pandemic. UN Women. 2020. May 3, 2020. Available at: https://www.unwomen.org/en/news/stories/2020/4/statement-ed-phumzile-violence-against-women-during-pandemic. [Accessed on 24 August 2020]. Gearhart S, Patron MP, Hammond TA, Goldberg DW, Klein A, Horney JA. The impact of natural disasters on domestic violence: an analysis of reports of simple assault in Florida (1999–2007). Violence Gend. 2018;5(2):87–92. https://doi.org/10.1089/vio.2017.0077. Sahoo S, Rani S, Parveen S, Pal Singh A, Mehra A, Chakrabarti S, et al. Self-harm and COVID-19 pandemic: An emerging concern – A report of 2 cases from India. Asian J Psychiatr 2020; 51:102104. https://dx.doi.org/10.1016%2Fj.ajp.2020.102104. Ghosh A, Khitiz MT, Pandiyan S, Roub F, Grover S. Multiple suicide attempts in an individual with opioid dependence: Unintended harm of lockdown during the COVID-19 outbreak? Indian J Psychiatry 2020; [In Press]. The Economic Times. 11 Coronavirus suspects flee from a hospital in Maharashtra. March 16 2020. Available at: https://economictimes.indiatimes.com/news/politics-and-nation/11-coronavirus-suspects-flee-from-a-hospital-in-maharashtra/videoshow/74644936.cms?from=mdr. [Accessed on 23 August 2020]. Xiang Y, Yang Y, Li W, Zhang L, Zhang Q, Cheung T, et al. Timely mental health care for the 2019 novel coronavirus outbreak is urgently needed. The Lancet Psychiatry 2020;(3):228–229. https://doi.org/10.1016/S2215-0366(20)30046-8. Van Bortel T, Basnayake A, Wurie F, Jambai M, Koroma A, Muana A, et al. Psychosocial effects of an Ebola outbreak at individual, community and international levels. Bull World Health Organ. 2016;94(3):210–214. https://dx.doi.org/10.2471%2FBLT.15.158543. Kumar A, Nayar KR. COVID 19 and its mental health consequences. Journal of Mental Health. 2020; ahead of print:1-2. https://doi.org/10.1080/09638237.2020.1757052. Gupta R, Grover S, Basu A, Krishnan V, Tripathi A, Subramanyam A, et al. Changes in sleep pattern and sleep quality during COVID-19 lockdown. Indian J Psychiatry. 2020; 62(4):370-8. https://doi.org/10.4103/psychiatry.indianjpsychiatry_523_20. Duan L, Zhu G. Psychological interventions for people affected by the COVID-19 epidemic. Lancet Psychiatry. 2020;7(4): P300-302. https://doi.org/10.1016/S2215-0366(20)30073-0. Dubey S, Biswas P, Ghosh R, Chatterjee S, Dubey MJ, Chatterjee S et al. Psychosocial impact of COVID-19. Diabetes Metab Syndr. 2020; 14(5): 779–788. https://dx.doi.org/10.1016%2Fj.dsx.2020.05.035. Wright R. The world's largest coronavirus lockdown is having a dramatic impact on pollution in India. CNN World; 2020. Available at: https://edition.cnn.com/2020/03/31/asia/coronavirus-lockdown-impact-pollution-india-intl-hnk/index.html. [Accessed on 23 August 2020] Foster O. ‘Lockdown made me Realise What’s Important’: Meet the Families Reconnecting Remotely. The Guardian; 2020. Available at: https://www.theguardian.com/keep-connected/2020/apr/23/lockdown-made-me-realise-whats-important-meet-the-families-reconnecting-remotely. (Accessed on 23 August 2020) Bilefsky D, Yeginsu C. 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Background: Clinical and analytical data on patients suffering from coronavirus disease-2019 (COVID-19) indicate that endothelial damage plays a key role in the pathophysiology of the disease and is responsible for the pulmonary complications and the thrombotic microangiopathy affecting multiple organs, which contribute directly to mortality (Ackerman et al. N Engl J Med 2020). Detection of biomarkers of endothelial injury in circulating blood may provide critical diagnostic and prognostic information on the disease course (Goshua et al. Lancet Haematology 2020). Endothelial injury is also a cornerstone of pathobiology in other septic and potentially life-threatening inflammatory syndromes. Objectives: To identify circulating markers of endothelial damage in COVID-19 patients, and compare their levels with those observed in other septic syndromes. Methods: Plasma samples from non-critically ill patients with confirmed COVID-19 pneumonia (positive nasopharyngeal swab and confirmatory radiological chest imaging) requiring admission (n=42) were collected during the first 36h of hospitalization. Endothelial damage was evaluated by measuring in plasma: i) markers of endothelial function and activation (sVCAM-1, VWF, ADAMTS-13 activity, Protein C and α2-antiplasmin as a marker of fibrinolysis); ii) heparan sulfate (HS) levels, as indicators of endothelial glycocalyx degradation and loss of endothelial barrier function; and iii) C5b9 deposits on endothelial cells in culture, and soluble C5b9 (sC5b9) levels, to measure complement activation. Circulating dsDNA was analyzed as an indicator of the presence of neutrophil extracellular traps (NETs). ELISA tests were used for sVCAM-1, Protein C, HS, and sC5b9 levels. ADAMTS-13 activity was evaluated by FRETS. VWF, Protein C, and α2-antiplasmin were measured at the Atellica COAG 360 (Siemens Healthineers). C5b9 deposits were assessed by immunofluorescence and dsDNA levels by Quant-iT PicoGreen assay kit. Results were compared with those obtained in healthy donors (controls, n=45), and patients with non-infectious systemic inflammatory response syndrome (NI-SIRS, n=8) and septic shock (SS, n=8). Results: Levels of sVCAM-1 were significantly higher in COVID-19 patients vs. controls, NI-SIRS and SS (159±12 vs. 79±4, 57±8 and 80±10 ng/mL, respectively, p<0.005) (Mean±SDM). VWF was elevated in COVID-19 patients vs. controls (240±26 vs. 96±5%, p<0.001), with similar values in NI-SIRS (271±40%), and significantly reduced vs. SS (476±43%, p<0.001). HS levels in COVID-19 patients were twice those detected in controls (1669±174 vs. 839±36 ng/mL, p=0.001), but they did not differ from those in NI-SIRS (1372±368 ng/mL), and were significantly lower than in SS (3677±880 ng/mL, p<0.001 vs COVID-19). Regarding complement activation, deposits of C5b9 on endothelial cells were significantly increased vs. controls (2-fold, p<0.01), with no notable differences vs. NI-SIRS (3±1-fold) and significantly lower than in SS (8±2-fold, p<0.001). Remarkably, sC5b9 levels were much more elevated in COVID-19 patients (1064±120 vs. 204±11 ng/mL, p<0.001), and no significant differences were observed vs. NI-SIRS (902±160 ng/mL) or SS (958±180 ng/mL). Also of note, presence of NETs was significantly elevated in the plasma of COVID-19 patients vs. controls (16±1.3 vs. 2±0.3 ng/ml, p<0.001), but similar to NI-SIRS (19±5 ng/mL) and clearly inferior to SS (33±6 ng/mL, p<0.001) (Figure). Importantly and in contrast, ADAMTS-13 activity, Protein C, and α2-antiplasmin values were within the normal range in COVID-19 patients. Conclusions: Our data clearly demonstrate the presence of endothelial stress products in the circulating blood of non-critically ill COVID-19 patients. These biomarkers of endothelial injury are suggestive indicators of different aspects of the disease: specifically, release of acute phase reactants, degradation of the endothelial cell glycocalyx, and activation of the complement system. Furthermore, this profile of biomarkers in COVID-19 appears specific, with a differential behavior in comparison with septic shock, in which endothelial damage is also known to be critical. Additional studies are needed to validate these biomarkers as diagnostic and prognostic tools of the endothelial complications in COVID-19 patients, both in early disease and later, as well as supporting specific forms of therapeutic intervention. Figure Disclosures Carreras: Jazz Pharmaceuticals: Research Funding, Speakers Bureau; German Jose´ Carreras Leukaemia Foundation: Research Funding. Carlo-Stella:Boehringer Ingelheim and Sanofi: Consultancy; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Moraleda:Sandoz: Consultancy, Other: Travel Expenses; Novartis: Consultancy, Other: Travel Expenses; Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Takeda: Consultancy, Other: Travel Expenses. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Diaz-Ricart:German Jose Carreras Leukaemia Foundation: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding.

Since December 2019, the COVID-19 pandemic has led to significant mortality in the world. Based on epidemiological data from China, 20% or more of COVID-19 patients had cardiovascular comorbidities. Life-threatening complications due to COVID-19 can develop in these patients. Meanwhile, the risk of complications may be higher in patients with heart failure (HF), who usually have older people and more comorbidities. COVID-19 can lead to myocardial injury and disease exacerbation in HF patients due to a cytokine storm-related hyper-inflammation syndrome.1 Hence, most studies only addressed the prevalence of the cardiovascular disease among COVID-19 patients and less specifically the prevalence of HF. A study in China found that 23% of COVID-19 patients had HF, of which 52% died.2 On the other hand, it has been suggested that COVID-19 may cause heart damage due to the specific condition of HF patients and the characteristics of this syndrome.3 Therefore, it is important to pay attention to the cardiovascular consequences of COVID-19. Despite, the effect of different drug therapies on the outcomes of COVID-19 patients with HF, management of potential interactions between cardiovascular and COVID-19 medication regimens among patients with HF remains an important and challenging clinical issue. In the early pandemic, antiviral drugs such as hydroxychloroquine were widely used to manage COVID-19 infection. Chloroquine and hydroxychloroquine are potassium channel blockers that can prolong QTc and play a role in sudden cardiac death. This process becomes especially dangerous when combined with other treatments, including the QTc prolonging azithromycin and lopinavir/ritonavir. Therefore, HF patients may be at particular risk for sudden cardiac death. In addition, in advanced treatments of HF patients, interactions may occur between COVID-19 and the cardiovascular medication regimen. For example, patients with left ventricular assist devices (LVAD) are usually treated with anticoagulation drugs such as warfarin. Warfarin is a vitamin k antagonist that can interact with some antiviral drugs in the treatment of COVID-19.4 Previous evidences have shown that chloroquine and hydroxychloroquine interactions with cardiovascular drugs such as digoxin and antiarrhythmic drugs are associated with the possibility of HF, QT prolongation, and cardiac arrhythmias.5,6 On the other hand, Remdesivir, which is made to treat Ebola, has shown little potential effect against SARS-CoV-2. Despite the lack of interaction of Remdesivir with HF drugs, it has been suggested that patients receiving Remdesivir be closely monitored due to the risk of QT prolongation and electrolyte disturbances. 1 In sum, previous evidence regarding the potential interactions between cardiovascular and COVID-19 medication regimens among patients with HF are limited and no strong evidence is available. Therefore, further studies are needed to identify these interactions. Given the increasing incidence of COVID-19 in HF patients, it is essential to better understand the interactions between this disease and SARS-CoV-2 in order to manage these patients. Also, a multidisciplinary approach including members of the HF team may lead to better management of HF patients in this pandemic. References Zhang Y, Coats AJ, Zheng Z, Adamo M, Ambrosio G, Anker SD, et al. Management of heart failure patients with COVID‐19: a joint position paper of the Chinese Heart Failure Association & National Heart Failure Committee and the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2020;22(6):941-56. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62. Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential effects of coronaviruses on the cardiovascular system: a review. JAMA Cardiol. 2020;5(7):831-40. Bader F, Manla Y, Atallah B, Starling RC. Heart failure and COVID-19. Heart Fail Rev. 2021;26(1):1-10. Chorin E, Wadhwani L, Magnani S, Dai M, Shulman E, Nadeau-Routhier C, et al. QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin. Heart Rhythm. 2020;17(9):1425-33. Mercuro NJ, Yen CF, Shim DJ, Maher TR, McCoy CM, Zimetbaum PJ, et al. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(9):1036-41.

Abstract Background: Palbociclib might be less effective than ribociclib in HR+/HER2- and HER2-enriched BC. This hypothesis is currently being tested in the HARMONIA prospective phase III clinical trial (NCT05207709). Here, we evaluated the downstream biological effects of both drugs using cell lines and patient tumor samples. Methods: Three HR+ BC cell lines (i.e., MCF7, T47D and BT474) were treated at 2 different dose levels of palbociclib or ribociclib (i.e., 100 nM and 500 nM) +/- fulvestrant (1 nM) for 72 hours (h). PAM50 gene signatures were determined on the nCounter, as well as phosphorylation of RB (p-RB) by Western Blot and senescence-associated β-galactosidase activity by FACS. In vitro experiments were performed in triplicates. PAM50 gene signatures were obtained from 49 paired baseline versus week-2 samples and 49 paired baseline versus surgery samples of the CORALLEEN phase II study (Prat, Lancet Oncol. 2020), which treated 49 women with PAM50 Luminal B HR+/HER2- early BC with neoadjuvant ribociclib (600 mg daily) plus endocrine therapy (ET). PAM50 signature scores were also evaluated in publicly available data from 23 paired baseline versus week-2 samples and 16 paired baseline versus surgery samples of the NEOPALANA phase II trial (Ma, Clin Cancer Res. 2017) which treated 50 patients with HR+/HER2- early BC with palbociclib (125 mg daily) plus anastrozole. Changes in PAM50 signatures upon CDK4/6i were determined by paired t-tests and significant analysis of microarray (SAM). Results: Across all cell lines, both palbociclib and ribociclib statistically significantly reduced p-RB at 72h with both doses (i.e., 100 and 500 nM) compared to non-treated cells (p< 0.001). Senescence was also observed at 72h with both doses. Both drugs +/- ET significantly increased the Luminal A signature and decreased Luminal B and proliferation signatures with both doses. However, the HER2-enriched signature was only significantly reduced when both CDK4/6 inhibitors were given at 500 nM. In tumor samples from the CORALLEEN and NEOPALANA phase II studies, a similar change in PAM50 biology was observed with both drugs, namely an increase in Luminal A signature and a decrease in Luminal B and proliferation signatures after 2 weeks of treatment and at surgery. At 2 weeks of treatment, the HER2-enriched signature was significantly decreased in both studies with ribociclib (p< 0.001) and palbociclib (p< 0.001). However, the decrease in the HER2-enriched signature was only observed in surgical samples of patients treated with ribociclib (p< 0.001), but not palbociclib (p=0.194). A difference in sample size could explain this result. Nevertheless, in CORALLEEN, the median number of days between the last dose of ribociclib and surgery was 13.1 days (range: 1-78). In NEOPALANA, the median number of days between the last dose of palbociclib and surgery was 29 days (range: 8-49), except for 8 patients who received additional 10-12 days of palbociclib immediately before surgery (Ma, Clin Cancer Res. 2017). In patients who underwent surgery at 8 days or before, the HER2-enriched signature was significantly decreased for both ribociclib (p< 0.001) and palbociclib (p=0.013). Interestingly, in patients that underwent surgery after >8 days from the last dose, a significant reduction of the HER2-enriched signature was only observed with ribociclib (p< 0.001), but not with palbociclib (p=0.500). Conclusions: Both palbociclib and ribociclib have similar effects on PAM50 biology when given at the same dose. However, in clinical practice, palbociclib is given at a lower dose than ribociclib, and although HER2-enriched signature is significantly decreased in tumors after 2 weeks of CDK4/6i+ET, this effect is only maintained at later time points with ribociclib, indicating a dose-dependent efficacy of CDK4/6i in this biologically aggressive subtype. Citation Format: Natàlia Lorman-Carbó, Olga Martínez-Sáez, Aranzazu Fernandez-Martinez, Patricia Galván, Nuria Chic, Barbara Adamo, Maria Vidal, Montserrat Muñoz, Charles M. Perou, Joaquín Gavilá, Tomás Pascual, Aleix Prat, Fara Brasó-Maristany. Dissecting the biological activity of different CDK4/6 inhibitors (CDK4/6i) in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-16.

Abstract Introduction: Daratumumab (DARA) is a human CD38-targeting monoclonal antibody that induces deep clinical responses in MM pts through multifaceted mechanisms of action (MOA) including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis and induction of apoptosis. Flow cytometry analysis revealed a previously unknown immunomodulatory role of DARA, via T-cell induction expansion, T-cell activity enhancement, and reduction of immune suppressive cell populations including CD38+ myeloid-derived suppressor cells, CD38+ regulatory T cells (TRegs), and CD38+ regulatory B cells (BRegs). Next-generation mass cytometry (CyTOF), which allows high parameter evaluation of the immune system, was used to assess the effects of DARA alone or in combination on a more comprehensive profile of immune cell subpopulations. Methods: Relapsed/refractory MM pt samples from a subset of single agent studies; SIRIUS (32 pts; whole blood [WB] only; Lonial S et al. The Lancet, 2016) and GEN501 (5 pts; WB and bone marrow [BM], Lokhorst HM et al. NEJM, 2015) along with GEN503, a study of DARA plus lenalidomide and dexamethasone (9 pts; WB and BM; Plesner T et al. ASH 2015) were analyzed. Fluorochrome or metal-conjugated antibody panel stained samples were evaluated by flow cytometry or cytometry by time-of-flight (CyTOF®) platforms, respectively. FACS analyses were performed and analyzed by FACS Canto II flow cytometers and FACSDiva software. For CyTOF analysis, events were clustered by phenotype by a spanning tree progression of density normalized events (SPADE) algorithm, and each cluster was associated with an immune population via Cytobank® software. Differential analysis of population fractions and marker intensity, over time and between response groups, derived raw P values from t-tests and single cell level bootstrap adjusted P values corrected for multiple dependent hypothesis testing. Results were visualized using SPADE trees (Figure) and Radviz projections, a new method that allows for the comparison of populations and conditions while preserving the relation to original dimensions. Results: Flow cytometry and high-dimensional CyTOF analyses confirmed previous findings including higher CD38 expression on plasma cells compared with other immune populations of natural killer (NK), monocytes, B and T cells, and depletion of both plasma cells and NK cells upon DARA treatment. Interestingly, while NK cells were significantly reduced with DARA treatment, remaining active NK cells (CD16+CD56dim) demonstrated increased expression of activation markers CD69, CD25 and CD137 while also decreasing granzyme B and increasing naive marker CD27. Though functionality tests weren't performed, the ability to evaluate several markers simultaneously suggests these cells possess limited cytotoxicity. Additionally, these studies indicated depletion of CD38 positive immune suppressive subsets of Tregs and Bregs. CD38+ basophil reductions occurred independent of response and may provide insight to short-lived infusion related reactions. Several observations within the T-cell compartment were indicative of a DARA-mediated adaptive response in both WB and BM samples. T cells displayed increases in total numbers and shifted towards higher CD8:CD4 and effector:naïve ratios after 2 months of DARA treatment. Responders had higher expression levels of several activation markers including CD69 and HLA-DR along with increased production of cytolytic enzyme granzyme B in CD8+ T cells following DARA treatment. Interestingly, in the GEN503 sample set, pts who achieved a complete response presented with a distinct BM CD4 T-cell phenotype of high granzyme B positivity versus those that achieved a partial response or very good partial response. This observation suggests pts with an active immune phenotype may achieve deeper responses to DARA in combination with standard of care agents lenalidomide and dexamethasone. Conclusion: CyTOF analysis of pt samples from both single agent and combination DARA studies agree with flow cytometry and support the pharmacodynamics and immune modulatory MOA of DARA while providing additional insight into changes in T-cell subtypes and activation status. Future CyTOF analyses of clinical samples from phase 3 combination studies aim to confirm these observations and expand the understanding of the MOA of DARA. Disclosures Adams: Janssen Research & Development, LLC: Employment. Stevenaert:Janssen: Employment. Van der Borght:Janssen: Employment. Casneuf:Janssen R&D, Beerse, Belgium: Employment; Johnson & Johnson: Equity Ownership. Smets:Janssen: Employment. Bald:Janssen: Employment. Abraham:Janssen: Employment. Ceulemans:Janssen: Employment. Vanhoof:Janssen: Employment; Johnson & Johnson: Equity Ownership. Ahmadi:Janssen: Employment. Usmani:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array: Research Funding; BioPharma: Research Funding; Pharmacyclics: Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees; Skyline: Membership on an entity's Board of Directors or advisory committees. Plesner:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lonial:Janssen: Consultancy; BMS: Consultancy; Merck: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Onyx: Consultancy; Onyx: Consultancy; Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy. Lokhorst:Genmab: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mutis:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Research Funding; Celgene: Research Funding. van de Donk:Janssen: Research Funding; BMS: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Sasser:Janssen Pharmaceuticals R&D: Employment; Johnson & Johnson: Equity Ownership.

Background:The efficacy and safety of the interleukin-17 inhibitor ixekizumab (IXE) for the treatment of radiographic (r-) and non-radiographic (nr-) axial spondyloarthritis (axSpA) has been shown for up to 52 weeks.1-2Objectives:To study the efficacy and safety of ixekizumab in the treatment of patients with r- and nr-axSpA for up to 116 weeks.Methods:COAST-Y (NCT03129100) is the 2-year extension of the COAST-V, -W, and -X trials. Patients continued with the dose received at the end of the originating trial at Week 52, either with 80 mg IXE every 4 weeks (Q4W) or every 2 weeks (Q2W). Patients who had been assigned to adalimumab or placebo were re-randomized to IXE Q4W or Q2W at Week 16 in COAST-V and -W. Patients who had received placebo for 52 weeks in COAST-X were switched to IXE Q4W in COAST-Y. Patients who switched from placebo or adalimumab treatment to IXE (COAST-V, -W, or -X) or from IXE Q4W to open-label IXE Q2W (COAST-X) during the originating studies were analyzed separately from patients continuously treated with IXE. Standardized efficacy measures were used (Table 1). Missing data were handled by non-responder imputation for categorical data and modified baseline observation carried forward for continuous data. Safety data were analyzed for all patients who received ≥1 dose of IXE.Table 1.Demographic and efficacy results for patients continuously treated with IXE for 116 weeksIXE Q4W N=157IXE Q2W N=195Demographics Age42.7 (13.0)41.8 (11.2) Male (n, [%])124 (79.0)132 (67.7) Baseline ASDAS3.92 (0.80)3.95 (0.76) Baseline BASDAI7.07 (1.26)7.18 (1.35) Baseline BASFI6.57 (1.76)6.74 (1.86) Baseline BASMI4.08 (1.46)3.97 (1.52) Baseline SF-36 PCS33.90 (7.27)33.26 (6.88)Outcome measureResponse (n, [%])Week 52Week 116Week 52Week 116 ASDAS <2.175 (47.8)69 (43.9)88 (45.1)96 (49.2) ASAS partial remission34 (21.7)31 (19.7)35 (17.9)39 (20.0) ASAS4082 (52.2)89 (56.7)99 (50.8)108 (55.4) BASDAI5078 (49.7)75 (47.8)83 (42.6)99 (50.8)Change from baseline ASDAS-1.64 (1.05)-1.60 (1.15)-1.63 (1.03)-1.78 (1.04) BASFI-2.88 (2.31)-2.76 (2.39)-2.83 (2.38)-3.15 (2.34) BASMI-0.57 (0.95)-0.57 (0.93)-0.53 (0.92)-0.60 (1.00) SF-36 PCS9.03 (8.62)8.43 (8.70)8.87 (7.57)9.86 (8.45)Data are mean (SD) unless otherwise noted. Non-responder imputation was used for categorical variables, and modified baseline observation carried forward for continuous variables.Results:Of the 773 patients enrolled in COAST-Y, 86.0% completed Week 116 of treatment (52 weeks of one of the originating trials and 64 weeks of COAST-Y). Among the patients continuously treated with IXE for 116 weeks (IXE Q4W: N=157; IXE Q2W: N=195), 46.9% achieved low disease activity (ASDAS <2.1), and 19.9% achieved ASAS partial remission at 116 weeks (Table 1; Figure 1). In comparison to baseline, 56.0% achieved ASAS40 (Table 1). The mean change from baseline at Week 116 was –1.70 for ASDAS, –2.98 for BASFI, and 9.22 for SF-36 Physical Component Summary (Table 1). Similar observed responses were achieved between the patients continuously treated with IXE and patients initially treated with placebo or adalimumab. For the 932 patients in the safety population, no new safety signals were identified.Conclusion:Ixekizumab treatment led to consistent and sustained long-term improvements in disease activity and quality of life in patients with r- and nr-axSpA, with no new safety signals after up to 2 years of treatment.References:[1]Dougados, et al. Ann Rheum Dis 2020;79:176-185.[2]Deodhar, et al. Lancet 2020; 395:53-64.Disclosure of Interests:Juergen Braun Speakers bureau: Abbvie, Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Eli Lilly and Company, Medac, MSD, Mundipharma, Novartis, Pfizer, Roche, Sanofi-Aventis, and UCB, Consultant of: Abbvie, Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Eli Lilly and Company, Medac, MSD, Mundipharma, Novartis, Pfizer, Roche, Sanofi-Aventis, and UCB, Grant/research support from: Abbvie, Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Eli Lilly and Company, Medac, MSD, Mundipharma, Novartis, Pfizer, Roche, Sanofi-Aventis, and UCB, Uta Kiltz Speakers bureau: AbbVie, Hexal, MSD, Novartis, Pfizer, Roche, and UCB, Consultant of: AbbVie, Biocad, Eli Lilly and Company, Grünenthal, Hexal, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Biogen, Hexal, Novartis, and Pfizer, Atul Deodhar Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Giliad, GlaxoSmith & Kline, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmith & Kline, Novartis, Pfizer, and UCB, Tetsuya Tomita Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Eisai, Eli Lilly and Company, Janssen, Mitsubishi Tanabe, Novartis, Takeda, Pfizer, Consultant of: AbbVie, Astellas, Bristol-Myers Squibb, Eisai, Eli Lilly and Company, Janssen, Mitsubishi Tanabe, Novartis, Takeda, Pfizer, Maxime Dougados Consultant of: AbbVie, BMS, Eli Lilly and Company, Merck, Novartis, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, BMS, Eli Lilly and Company, Merck, Novartis, Pfizer, Roche, and UCB, Rebecca Bolce Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, David Sandoval Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, David Adams Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Chen-Yen Lin Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Jessica A. Walsh Consultant of: AbbVie, Amgen, Eli Lilly and Company, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Merck, and Pfizer

Le syndrome de Lance-Adams est une pathologie neurologie chronique très handicapante rencontrée chez les survivants d'anoxie cérébrale. Il est caractérisé essentiellement par des myoclonies positives, d'action, multifocales ou généralisées, et des myoclonies négatives. Les mécanismes sous-tendant les myoclonies de cette pathologie sont peu connus. De multiples hypothèses ont été proposées depuis la description initiale de ce syndrome. L'étude multimodale d'une large cohorte de patients avec un syndrome de Lance-Adams a montré que les myoclonies sont générées dans le cortex cérébral, en particulier le cortex moteur (ou sensorimoteur). L'observation de l'histoire clinique de certains patients a par ailleurs permis de proposer, avec succès, une nouvelle approche thérapeutique par électroconvulsivothérapies à une patiente pharmacorésistante. Une revue extensive de la littérature a permis de faire émerger une vue d'ensemble et intégrée de cette pathologie et de mieux délimiter le profil de patients. Enfin, nous avons essayé, par différentes approches, de développer un nouveau modèle murin de myoclonies post-anoxiques, sans succès. Une amélioration de cette préparation expérimentale permettrait la réalisation de multiples explorations, notamment immunohistochimiques et électrophysiologiques, afin de mieux comprendre les mécanismes cellulaires et de réseaux à l'origine des myoclonies du syndrome de Lance-Adams
Lance-Adams syndrome is a post-anoxic disabling chronic neurological disorder. The main clinical features are action-induced multifocal or generalized positive myoclonus, and negative myoclonus. The underlying mechanisms of this disorder are poorly understood. Multiple hypotheses have been proposed since the initial description of this syndrome. The multimodal analysis of a large cohort of patients with Lance-Adams syndrome demonstrated that myoclonus originates in the cerebral cortex, particularly in the motor (or sensorimotor) cortex. Additionally, careful observation of the natural history of patients led to the successful proposal of a new therapeutic approach using electroconvulsive therapy in a pharmacoresistant patient. An extensive literature review provided an integrated overview of this pathology and helped better define the patient profile. Lastly, through various approaches, we attempted to develop a new murine model of post-anoxic myoclonus, without success. An improvement in this experimental preparation would allow for multiple explorations, particularly immunohistochemical and electrophysiological studies, to better understand the cellular and network mechanisms underlying the myoclonus in Lance-Adams syndrome