Articles de revues : « Trial pre-clinico »

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Chaudhary, Nayan, Ciara Mecalfe et Marc Hafner. « Abstract P5-13-03 : Real-world clinico-genomic data reveal differences in genomic landscape associated with CDK4/6 inhibitors in HR+/HER2- breast cancer ». Cancer Research 83, n^o 5_Supplement (1 mars 2023) : P5–13–03—P5–13–03. http://dx.doi.org/10.1158/1538-7445.sabcs22-p5-13-03.

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Abstract Purpose: Studies based on data from routine clinical practice (real-world data, RWD) benefit from larger patient numbers and are more representative of patient diversity than clinical trial studies. When combined with comprehensive genomic profiling (CGP), RWD may uncover the impact of therapies and patient characteristics on tumor genomic landscape. Here we aimed at assessing the feasibility of using RWD to identify changes in the prevalence of genomic alterations upon treatment and proposed a methodology to address RWD inherent caveats. Experimental Design: To explore associations between tumor genomics and treatment chosen by physicians, we evaluated data from 5323 patients with metastatic hormone receptor-positive HER2-negative (HR+/HER2-) breast cancers from a nationwide real-world clinico-genomic database, originating from approximately 280 US cancer clinics (~800 sites of care). To perform our comparisons, we defined groups based on the therapy administered in the metastatic setting and the timing of the CGP relative to treatment. We used bootstrapping to estimate the significance of the effect and stratified analyses to assess the impact of potential confounders such as the site of the collected samples or disease history. Results: ESR1 alteration prevalence increased from 5.6% (CI: 2.8-8.9) pre-treatment to 21.4% (CI: 13.3-29.6) following aromatase inhibitor. Yet, it was significantly less than the prevalence following treatments including CDK4/6 inhibitors (CDK4/6i; 37.1% [CI: 27.8-46.4]; P=0.006). Further, exposure to CDK4/6i led to an increase in FGFR1 and TP53 alterations as well as genes of the cell cycle (FDR< 0.2). Overall, we found that more pathways were likely to be altered in a given tumor following AI+CDK4/6i than after AI alone (P=0.02). In particular, alterations of the MAPK pathway were not exclusive to ESR1 alterations in the post-AI+CDK4/6i group compared to AI only, suggesting that MAPK pathway alterations alone may not overcome CDK4/6i-based treatments. Differences following exposure to CDK4/6i were retained in samples taken after the second-line treatment. Stratified analyses confirmed that these results are independent of exposure to adjuvant therapy or treatment duration and showed that ESR1 mutations occurred in both primary and metastatic samples. Conclusions: Analysis of EHR-derived clinical data linked to CGP results from routine care can replicate associations previously observed in clinical trials and uncover unknown changes in tumor genomic landscape. Bootstrapping and stratified analysis reinforced our confidence in the results and thus allowed us to identify that CDK4/6i exposure led to a different – more altered – genomic landscape in HR+/HER2- breast cancer patients. This finding can inform design of clinical trials post-CDK4/6i and may help guide treatment choice for late stage patients. Thus, our work demonstrates the feasibility of leveraging real-world clinico-genomic data for translational research in oncology and leads the way for analyses including a more diverse patient population. Citation Format: Nayan Chaudhary, Ciara Mecalfe, Marc Hafner. Real-world clinico-genomic data reveal differences in genomic landscape associated with CDK4/6 inhibitors in HR+/HER2- breast cancer [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 P5-13-03.

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Golshan, Mehra, Sibylle Loibl, Jens Bodo Huober, Joyce O'Shaughnessy, Hope S. Rugo, Norman Wolmark, Mark D. McKee et al. « Breast conservation after neoadjuvant chemotherapy for triple-negative breast cancer : Surgical results from an international randomized trial (BrighTNess). » Journal of Clinical Oncology 35, n^o 15_suppl (20 mai 2017) : 514. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.514.

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514 Background: Neoadjuvant systemic therapy (NST) increases the frequency of breast-conserving therapy (BCT) in stage II-III breast cancer, but there is little data on how often it converts patients (pts) from BCT-ineligible (BCT-I) to BCT-eligible (BCT-E) and on the impact of other factors on surgical choices. We collected surgical assessment and management data from an international randomized trial of NST in triple-negative breast cancer (TNBC). Methods: Women with operable TNBC were randomized to veliparib (V) with carboplatin (C) and paclitaxel (P), placebo with C and P or placebo with P followed by doxorubicin and cyclophosphamide. The surgeons assessed BCT candidacy by clinico-radiographic criteria before and after NST; surgical management was at surgeon and patient discretion. We assessed interactions between BCT eligibility pre- and post-NST, germline BRCA mutation ( gBRCA) status, continent of treatment and achievement of pathologic complete response(pCR) and percentage of pts who underwent BCT versus mastectomy. Results: Pre- and post-NST surgical assessments were available for 604 pts who underwent surgery. BCT rates are listed in the Table. The BCT rate was 68% among pts deemed BCT-E after NST. pCR rates were identical between BCT-E pts who chose BCT (55%) vs. mastectomy (53%). Of 141 pts deemed BCT-I at baseline, 75 (53%) converted to BCT-E but only 42 (56%) of these opted for BCT. pCR rates were 49% in BCT-E converts vs. 36% in those remained BCT-I. gBRCA pts (n = 84) were less likely to choose BCT even if they were BCT-E. Pts treated in North America (NA) were less likely to choose BCT (55% vs. 80% for Europe and Asia P<0.0001) even among non- gBRCA considered BCT-E post-NST (61% vs. 85% P<0.0001). Conclusions: This largest prospective analysis of the impact of NST in TNBC demonstrates a conversion rate from BCT-I to BCT-E of 53%. BCT rates were lower in pts with gBRCA; the much higher mastectomy rate among BCT-E pts in NA merits investigation. Clinical trial information: NCT02032277. [Table: see text]

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Mendes, Larissa, Christopher D. Brawley, Emily Grist, Adnan Ali, Sara Santos Vidal, Marina Parry, Sharanpreet Lall et al. « Proliferation index and survival in men with prostate cancer starting long-term androgen deprivation therapy in the STAMPEDE clinical trial. » Journal of Clinical Oncology 39, n^o 15_suppl (20 mai 2021) : 5076. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.5076.

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5076 Background: Treatment intensification with docetaxel or abiraterone improved survival for advanced prostate cancer starting androgen deprivation therapy (ADT) in the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE, NCT00268476) trial. However, survival and time-to-progression is highly variable on ADT, introducing the risk of unnecessary toxicity from additional treatments for some patients. Here we test the prognostic association of proliferation index using Ki67 scores in the control arm of the STAMPEDE population of high-risk localised (M0) and metastatic (M1) prostate cancer. Methods: Pre-ADT diagnostic needle biopsies were obtained from 517 men randomized in STAMPEDE arm A between 2006 and 2015. These were assessed for proliferation using an analytically optimised Ki67 immunohistochemistry assay. Ki67 was tested for associations with baseline clinico-pathological variables (Grade group, pre-ADT serum PSA and imaging metastatic burden) in univariable linear-regression models, and for associations with survival outcomes in multivariable Cox-regression models adjusted for these and additional confounding variables. Primary outcome measure was overall survival, secondary outcomes were prostate cancer-specific, failure-free, progression-free and metastatic progression-free survival. Results: Ki67 was available for 475 patients who received ADT only for at least 2 years ± radiotherapy. Of 202 M0, 74 were node positive. Of 273 M1, 116, 127 and 30 were respectively low, high and unknown radiological M1 volume. Ki67 score associated with higher Gleason (p=7.15x10-11) and presence of extra-pelvic metastases (p=1.41x10-8). Increasing Ki67 scores showed a strong linear association with poorer overall survival, with an estimated 2% increase in the hazard of death per percentage increase in the score (adjusted HR=1.02, 95% CI 1.01-1.02; p=1.04x10-5). There was also strong evidence that Ki67 associated positively with all secondary outcomes, including prostate cancer-specific survival (adjusted p=5.50x10-6) and metastatic progression-free survival (adjusted p=3.50x10-9). Conclusions: Ki67 immuno-score is strongly prognostic in clinically advanced prostate cancer independent of Gleason score and the other clinicopathological variables tested in this study. Ki67 is a clinically scalable assay that could improve selection for treatment intensification and provide a tool for screening patients most likely to benefit from further molecular investigation.

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Grist, Emily, Marina Parry, Stefanie Friedrich, Christopher D. Brawley, Larissa Mendes, Sharanpreet Lall, Leila Zakka et al. « Copy number profiles of primary tumors for risk stratification of advanced prostate cancer : A biomarker study embedded in the multicenter STAMPEDE trial. » Journal of Clinical Oncology 39, n^o 15_suppl (20 mai 2021) : 5021. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.5021.

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5021 Background: Men with advanced hormone-sensitive prostate cancer (HSPC) starting long term androgen deprivation therapy (ADT) follow a highly variable clinical course. Treatment intensification with docetaxel or AR targeted therapies improves outcomes but there is a risk of overtreatment, especially in non-metastatic (M0) or metastatic (M1) low volume disease. We established a framework for biomarker evaluation in the STAMPEDE trial. We aimed to evaluate the feasibility and clinical utility of assessing the burden of copy number (CN) aberrations in newly diagnosed advanced HSPC. We hypothesised that increased percentage genome altered (PGA) would associate with higher disease burden and worse prognosis. Methods: We implemented a scalable strategy using low coverage whole genome sequencing (lpWGS) of formalin fixed paraffin embedded (FFPE) diagnostic core biopsies from STAMPEDE participants randomised to the standard of care ADT arm, between 2005 and 2016. Tissue was retrieved from 136 trial sites. 315 cases were randomly selected, aiming for a biomarker population of 300, anticipating an assay failure rate ̃5%. We defined 40% as the minimum histopathologically determined tumor cellularity (TC) for inclusion. We performed a survival analysis investigating PGA at diagnosis as a continuous measure with fractional polynomial specification in Cox models adjusting for disease burden, Gleason grade, pre-ADT PSA (log-transformed), age at randomisation and TC. We pre-specified that all hypothesis tests required evidence at the 5% significance level to consider rejecting the null hypothesis. Results: We successfully CN profiled 300/315 cases. There were no significantly different baseline clinico-pathological features between the full trial comparison n = 3106 and final biomarker population n = 300, 290/300 cases were de novo presentations. PGA in the core with highest Gleason grade and TC was median 18% (range 0%-75%; n = 300). PGA was significantly higher in M1 (n = 169) compared to M0 (n = 131) cases (median: 21% vs 14%; p = 0.00006). 284/300 were subclassified by disease burden into M0 node negative and node positive, and M1 low and high volume. PGA was significantly associated with increased disease burden (p = 0.00002). Increased PGA was significantly and non-linearly associated with an increased hazard of failure-free survival (p = 0.004), progression-free survival (p = 0.002), metastatic progression-free survival (p = 0.003), overall survival (p = 0.045) and prostate cancer-specific survival (p = 0.011). Conclusions: Evaluation of the burden of CN aberrations in archival, poor quality FFPE diagnostic tissue from men randomised in the STAMPEDE trial is feasible using lpWGS and has potential clinical utility to identify better prognosis advanced HSPC patients, who may not require treatment intensification.

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Reddy, Sushanth, Jacob A. Swords, Mary Glenn Waldrop, Carlo M. Contreras, Martin J. Heslin, Benjamin Wei, Robert J. Cerfolio et Thomas N. Wang. « Effect of nodal status compared to tumor response after neoadjuvant radiation on outcomes for patients with esophageal cancer. » Journal of Clinical Oncology 35, n^o 4_suppl (1 février 2017) : 147. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.147.

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147 Background: The CROSS trial established the role of neoadjuvant radiation in the treatment of esophageal adenocarcinoma (EAC). While response to radiation is an important factor in predicting long-term outcomes, the vast majority of patients succumb to systemic disease. The purpose of this study is to assess predictors of survival in patients with EAC following radiation therapy. Methods: All patients who underwent resection after radiation therapy for EAC at a single institution were retrospectively identified from January 2004 to December 2014. Patients who died within 30 days of surgery were excluded. Cox-proportional hazard analyses were performed to identify clinico-pathological factors associated with survival after surgery. Results: In the time period, 334 patients underwent esophagectomy for EAC. Univariable/multivariable analyses are shown in the table. The presence of a pathologic complete response (pCR) did not correlate to survival. The most important factors in predicting outcome were pre-operative albumin and initial lymph node stage by endoscopic ultrasound (EUS). Pre-treatment N0 patients had better survival than N1 patients (median survival 37.2 vs. 16.3 months, P < 0.0001). Patients who remained N0 after radiation had much better outcomes than those that either developed N1 disease after radiation or were initially staged as N1 (stayed N0, N = 126, median survival 52.0 months; N1→N0, N = 85, median survival 22.9 months; N0→N1, N = 30, median survival 15.3 months; persistent N1, N = 44, median survival 11.4 months; P < 0.0001). Conclusions: Pathologic response to radiation does not predict outcomes for patients with EAC. Patients with node positive EAC have poor outcomes even after neoadjuvant radiation therapy. These patients are at an increased risk of distant disease and should be offered additional systemic therapies prior to surgical resection. [Table: see text]

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Rodriguez, Estelamari, Richa Dawar, Fahmin Basher, Philippos Apolinario Costa, Tisdrey Torres, Dao M. Nguyen, Nestor Villamizar et Gilberto Lopes. « Prevalence of EGFR mutation testing in early-stage lung cancer : Implications of the ADAURA trial for clinical practice. » Journal of Clinical Oncology 39, n^o 15_suppl (20 mai 2021) : e20507-e20507. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e20507.

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e20507 Background: It is reported that about 20% of patients with resected NSCLC adenocarcinoma harbor an EGFR driver mutation in the United States. Up to the recent approval of osimertinib in the adjuvant setting for resected EGFR + NSCLC based on the ADAURA trial, routine molecular profiling of early-stage lung cancer had not been standard of care. We hypothesize that there is a significant proportion of patients with resected adenocarcinoma with unknown EGFR status who could benefit from treatment that are missed with our current testing practices. Methods: We performed a retrospective analysis of Stage IB-IIIA lung adenocarcinomas resected at the University of Miami from 2014 to 2019. Eligible patients were identified from the Cancer Registry and information on EGFR mutation testing and treatment was obtained from chart review. We evaluated the prevalence of EGFR mutation testing in this population and outcomes based on EGFR mutation status. Disease free survival (DFS) and clinico-pathologic characteristics were evaluated. We estimated the number of patients that would have been eligible for EGFR testing and adjuvant osimertinib therapy in the pre-ADAURA era in our patient cohort. Results: A total of 120 patients had resected stage IB-IIIA adenocarcinoma during this five-year period (Stage IB 42.5%; Stage IIA 13.3%; Stage IIB 25%; Stage IIIA 19.2%) with a median age of 66 years. Most were females (59%), NHWs (51.5%), Hispanics (46.9%), and former smokers (66.7%). Out of patients with Stage IB-IIIA NSCLC with adenocarcinoma, 42.5% completed recommended adjuvant platinum-based chemotherapy. Only 40% of patients were referred for EGFR testing during this study period. The prevalence of EGFR mutations in this population was 10.8% (13 /120), but 59% of cases had no available EGFR testing. The most prevalent mutation was L858R (53.8%) followed by exon-19 deletions (30.8%). A total of 6 patients received an EGFR TKI therapy during the follow up period (2 in the adjuvant setting). With a median follow up of 12 mos, the rate of recurrence by stage was: Stage IB (3.9%); Stage IIB (10%); Stage IIIA (13%). Median time to disease progression or death was 13 months in this subgroup. There was no difference in disease free survival for patients with EGFR testing and those without results available in this short follow up period. Conclusions: Based on this retrospective review, up to 60% of patients with early-stage NSCLC with non-squamous histology have no available EGFR testing in the pre-ADAURA era. Of the anticipated 20% of patients with expected EGFR mutations based on historical controls, we have only identified half of patients that would have been eligible for adjuvant osimertinib. This study establishes the importance of upfront EGFR mutation testing in all NSCLC patients, not only to prognosticate, but also to identify the subset of patients who could benefit from adjuvant EGFR therapy.

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AlRawashdh, Neda, Briana Choi, Mavis Obeng-Kusi, Matthias Calamia, Ali McBride et Ivo Abraham. « Economic evaluation of six and 12 month (m) treatment with isatuximab and carfilzomib and dexamethasone (IKd) versus daratumumab and carfilzomib and dexamethasone (DKd) in patients with relapsed or refractory multiple myeloma (RRMM). » Journal of Clinical Oncology 39, n^o 15_suppl (20 mai 2021) : e20010-e20010. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e20010.

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e20010 Background: Isatuximab and daratumumab target the CD38 transmembrane glycoprotein on MM cells. IKd and DKd regimens have shown reductions of HR=0.53 (95%CI 0.32-0.89) and HR=0.63 (95%CI 0.46-0.85) resp. in progression or death risk compared to Kd in RRMM. In the absence of a direct IKd vs DKd trial, we performed an indirect treatment comparison on progression free survival (PFS) to enable cost-effectiveness analyses. Methods: A 3-state (pre-progression, progression, death) partitioned survival model was specified. NMA-adjusted transition probabilities were estimated from fitted exponential functions (time horizon of 6 and 12 m; cycle length 28 days). Inputs included the Wholesale Acquisition Cost of IKd, DKd, and premedications; cost of medication administration; and cost of adverse event management. Utility inputs for pre-progression (0.65) and progression (0.61) were per literature. Costs and utilities were discounted at 3.5%/y. A payer perspective was adopted. Life years (LY), quality adjusted LY (QALY), and incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) were estimated in base case (BCA) and probabilistic sensitivity analyses (PSA). Cost-effectiveness acceptability curves (CEAC) were generated. Results: As detailed in the Table, 6m of IKd treatment was associated with incremental gains of 0.01 (PSA 0.01) LYs but no gains in QALYs at cost savings of $24,188 ($23,762), yielding a dominant ICER of $ -2,418,800 ($-2,376,200) per LYg (ICUR not estimable). Further, 12m of IKd treatment was associated with incremental gains of 0.04 (PSA 0.04) LYs (or 0.48m) and 0.02 (0.03) QALYs at incremental cost of $1,585 ($2,239), yielding ICER of $39,625 ($55,975) per LYg and ICUR of $79,250 ($74,633) per QALYg. Per CEAC, IKd is the dominated strategy in the 6m model and had probability of 50% of being cost-effective at WTP of $100,000 in the 12m model. Conclusions: Clinically, compared to DKd, IKd is associated with slight incremental gains in LYs of 0.12m over 6m and 0.48m over 1y. The 6m clinical gain comes with cost savings of approximately $24,000 or about 15% of IKd therapy, while the 12m gain requires a minimal cost commitment of around $2,000 or 0.6% of DKd treatment. These findings imply a clinico-economic benefit of isatuximab compared to daratumumab containing regimens in RRMM. [Table: see text]

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Jain, S., V. Dhir, A. Aggarwal, R. Gupta, B. Leishangthem, G. Naidu, A. Khullar et al. « POS0566 PREDICTORS OF RESPONSE TO METHOTREXATE MONOTHERAPY IN ACTIVE RHEUMATOID ARTHRITIS : RESULTS FROM A MULTICENTRE, RANDOMIZED CONTROLLED TRIAL (MEIRA) ». Annals of the Rheumatic Diseases 81, Suppl 1 (23 mai 2022) : 548.2–549. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4257.

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BackgroundMethotrexate (MTX) is the gold standard, first-line therapy for rheumatoid arthritis (RA). However, not all patients respond to MTX, and the predictors of its response or non-response have not yet been reliably identified. Identification of these predictors will facilitate personalized therapeutic choices, and improve patient outcomes.ObjectivesTo identify the clinico-laboratory predictors of response to MTX monotherapy in active RA.MethodsThis study included patients with active RA (SJC≥2 and TJC≥4) aged 18-55 years, with disease duration <5 years, who were not receiving DMARDs (except HCQ and low-dose prednisolone) and had been enrolled in the multicentre, parallel group RCT comparing two different MTX escalation strategies in RA (MEIRA)1. All these patients received MTX monotherapy which was started at 15 mg/week, escalated to 25 mg/week by 4-8 weeks, and continued till 16 weeks. MTX response was defined as EULAR good or moderate response (based on DAS28-CRP-3v) at 16 weeks. Stepwise, multivariable logistic regression was done using key demographic (age, gender, BMI, comorbidities), clinical (disease duration, DAS28, HAQ), and laboratory parameters (RF, anti-CCP, ESR, CRP, RBC MTX-polyglutamates 1-4, IL-6, MMP-3) as independent variables to identify predictors of MTX response. A two-tailed p-value <0.05 was used for defining statistical significance. (Trial Reg: CTRI/2018/12/016549)ResultsOut of a total of 178 included patients [84% females, mean age 40 (9) years, mean DAS28-CRP=5.4 (1.1)], 113 (63.5%) were classified as MTX responders at 16 weeks. Age (OR=0.95, p=0.01), BMI (OR=1.12, p=0.006), and RF (OR=0.34, p=0.045) were found to be independent predictors of MTX response on multivariable analysis (Table 1). On sensitivity analysis with DAS28-ESR-based EULAR response, age (OR=0.94, p=0.003) and RF (OR=0.42, p=0.059) were replicated as independent predictors of MTX response, in addition to pre-treatment swollen joint count (OR=0.94, p=0.05).Table 1.Results of multivariable logistic regression analysis for prediction of response (as defined by DAS28-CRP-based EULAR good or moderate response) to methotrexate monotherapy in RAVariableOR (unadjusted)Unadjusted p-valueOR (adjusted)Adjusted p-valueAge0.97 (0.93-1.002)0.060.95 (0.91-0.99)0.01Male sex0.78 (0.35-1.76)0.55-BMI1.1 (1.02-1.19)0.011.12 (1.03-1.22)0.006Presence of comorbidities0.67 (0.31-1.44)0.31-Disease duration0.98 (0.79-1.22)0.87-Baseline DAS281.1 (0.81-1.49)0.54-Baseline HAQ1.04 (0.66-1.64)0.86-Baseline TJC1.01 (0.96-1.05)0.72-Baseline SJC0.97 (0.91-1.02)0.24-Baseline ESR1.01 (1.00-1.02)0.27-Baseline CRP1.00 (0.99-1.01)0.85-RF positive0.31 (0.11-0.85)0.020.34 (0.12-0.98)0.045Anti-CCP positive0.73 (0.27-1.99)0.54-MTX PG1 (16 weeks)0.99 (0.94-1.04)0.69-MTX PG2 (16 weeks)0.98 (0.95-1.02)0.37-MTX PG3 (16 weeks)0.99 (0.96-1.02)0.43-MTX PG4 (16 weeks)0.99 (0.95-1.03)0.62-Serum IL-6 (baseline)0.98 (0.95-1.02)0.33-Serum MMP-3 (baseline)1.00 (1.00-1.00)0.48-BMI= Body Mass Index, CCP= Cyclic Citrullinated Peptides, CRP= C-reactive protein, DAS= Disease Activity Score, ESR= Erythrocyte Sedimentation Rate, HAQ= Health Assessment Questionnaire, MTX= Methotrexate, PG= polyglutamate, OR=Odds Ratio, RF=Rheumatoid Factor, SJC= Swollen Joint Count, TJC= Tender Joint CountNote: Only variables with p-value <0.2 on univariable analysis were included in the multivariable analysis.ConclusionYounger age, RF negativity, higher BMI, and lower pre-treatment swollen joint count are potential predictors of response to MTX monotherapy in RA.References[1]Jain S, Dhir V, Aggarwal A, et al. Comparison of two dose escalation strategies of methotrexate in active rheumatoid arthritis: a multicentre, parallel group, randomised controlled trial. Ann Rheum Dis. 2021;80(11):1376-1384.Disclosure of InterestsNone declared.

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d’Amore, Francesco, Peter de Nully Brown, Lars Moeller Pedersen, Anne Bukh, Per Boye Hansen, Bjarne Bach Pedersen, Ole Gadeberg et al. « Epidemiological and Clinico-Pathological Features of Systemic Peripheral T-Cell Lymphomas (PTCL) : A Population-Based Analysis from the Danish Lymphoma Registry LYFO ». Blood 112, n^o 11 (16 novembre 2008) : 3766. http://dx.doi.org/10.1182/blood.v112.11.3766.3766.

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Abstract PTCL are a heterogeneous group of uncommon lymphoid malignancies. Geographical differences have been reported, the NK/T-cell-derived nasal type being more common in Asia and the entheropathy-type more common in western countries. Except for the alk-positive anaplastic large cell lymphoma (ALCL) subtype, PTCL have generally a poorer outcome than their B-cell counterparts when treated with conventional therapeutic strategies. In recent years, as a result of an improved biologic understanding and definition of PTCL entities, an increasing number of PTCL-specific clinical trials have been initiated. The purpose of this analysis was to describe epidemiological and clinico-pathological features of the major subtypes in PTCL, as they occur in an unselected western population, in order to provide population-based data that may be useful for the design of future PTCL-specific studies. Although the LYFO registry was initiated in 1983, the present analysis only includes patients diagnosed in the 15-year period from 1990 (when immunhistochemistry was routinely applied to all biopsy specimen) to 2004. Within this 15 yr period, 485 PTCL cases were diagnosed. They had an age range of 16–92 yrs and a male to female ratio of 1.4 (59% male and 41% female cases). The most frequent histological subtypes were PTCL unspecified (PTCLu) (44%), non-cutaneous ALCL (alk-status not available) (35%) and angioimmunoblastic (AIL) (17%). The incidence trend for PTCL, taken as one group, did not show significant changes over the 15 years observation period. Approximately two thirds of the patients (65%) had disseminated disease (stage III–IV) at diagnosis, while half of the patients (49%) presented with B-symptoms. AIL had a higher frequency of cases with disseminated disease (93%, p<0.05), mainly due to bone marrow involvement, while ALCL had a significantly higher frequency of localized cases (46%, p<0.05). Surprisingly, the majority of PTCL patients (69%) were registered at diagnosis with a good performance score (WHO) of 0–1, with figures for PTCLu and ALCL of 65% and 69%, respectively, and slightly lower (52%, p>0.05) for AIL. All three major subtypes had predominantly nodal disease at presentation (PTCLu 56%, ALCL 57%, AIL 61%). Pre-therapeutic s-LDH was elevated in 40 % of all PTCL patients (PTCLu 44%, ALCL 39%). AIL cases presented more often with elevated s-LDH (61% of the cases, p<0.05). In line with these findings, AIL also had a higher frequency of cases with IPI ≥2, which translated into an inferior 5-yr overall survival value (25%, as opposed to 33% and 39% for PTCLu and ALCL, respectively). These survival values represent the comparative background on which the potential impact of the new PTCL trial program of our nordic collaborative group will be evaluated.

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Bachelot, Thomas Denis, Isabelle Treilleux, Camille Schiffler, Ivan Bieche, Mario Campone, Anne Patsouris, Monica Arnedos et al. « mTORC1 activation assessed in metastatic sample to predict outcome in patients with metastatic breast cancer treated with everolimus-exemestan : Results from the SAFIRTOR study. » Journal of Clinical Oncology 37, n^o 15_suppl (20 mai 2019) : 1024. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.1024.

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1024 Background: Using samples from TAMRAD study (Treilleux, Ann Oncol, 2015), we previously reported that p4EBP1, a downstream protein of mTOR, was associated with higher benefit to everolimus (eve). SAFIRTOR study was designed to validate clinical utility of this biomarker. Methods: Patients (pts) with ER+, HER2 negative, AI resistant MBC were prospectively included (NCT02444390). All pts had a biopsy of a metastatic site and were then treated with standard eve + exemestane (exe) combination. The primary end point was to validate that p4EBP1 expression is associated with longer PFS in patients treated with eve. 120 evaluable pts were needed for the pre planed statistical analysis. All samples were collected and processed in a standardized procedure in order to allow phophoproteins IHC staining. In addition to p4EBP1, we explored prognostic value of pS6K, pAkt, PTEN and LKB1, together with genomic alterations assessed by NGS and CGH arrays. Results: 150 pts were included, 30 pts had no adequate sample, and further 13 had missing clinical data, 107 were evaluable for primary objective. Median age was 62, they had previously progressed on AI treatment, either in the adjuvant (22 pts) or the metastatic setting (83 pts). 20 were considered as primary hormone resistant, 87 as secondary resistant. The median Allread score for p4EBP1 was 5.5 (range: 0-6.5). Analysis of the primary endpoint showed that p4EBP1 staining above the median is associated with a longer PFS on eve+exe. (median PFS: 9.3 months, 95CI 6.3-13.1 for high p4EBP1 versus 5.8 months, 95CI 3.7-7.8 for low p4EBP1, p = 0.02). Prognostic value of high pEBP1 remained significant when assessed in a multivariate analysis along classical clinico-biological prognostic factors for MBC (HR 0.57, 95%CI 0.38-0.88, p = 0.01). In this AI resistant population, the tumor of 42 (46%), 33 (35%) and 5 (5.3%) pts carried an activating mutation for ESR1, PIK3CA and AKT1, respectively. None of these mutational statuses were correlated to outcome. Conclusions: This prospective study validates p4EBP1 expression analysis to select patients most likely to benefit from everolimus + exemestane. Clinical trial information: NCT02444390.

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Metzger Filho, Otto, Daniel G. Stover, Sarah Asad, Peter J. Ansell, Mark Watson, Sibylle Loibl, Charles E. Geyer et al. « Immunophenotype and proliferation to predict for response to neoadjuvant chemotherapy in TNBC : Results from BrighTNess phase III study. » Journal of Clinical Oncology 37, n^o 15_suppl (20 mai 2019) : 510. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.510.

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510 Background: In TNBC, the interplay between immunophenotype, tumor proliferation (prolif) and achievement of pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) remains unknown. Methods: RNA seq was performed on pre-tx research biopsies of stage II/III TNBC enrolled in BrighTNess. NAC regimens included paclitaxel alone or with carboplatin (Cb) or Cb plus veliparib, followed by AC. Computational analysis included subtyping (i.e. PAM50, Pietenpol), prolif (PAM50) and GeparSixto immune signature (GSIS). Cb-containing arms were combined due to similar pCR. Results: High quality RNA seq data was obtained from 482 of 634 pts. PAM50 classified 80.1% of tumors as basal-like. TNBC subtypes were mostly BL1 or BL2 (23.3%), IM (22.4%) or M/MSL (31.7%); 6% were LAR. pCR was higher for basal vs non-basal tumors (52.3% vs 35.4%, p = 0.003). IM had the highest pCR rate (64.2%, 95% CI 59.9%,68.5%). Basal-like was not a significant predictor for Cb benefit (p-interaction = 0.8). Prolif (OR = 0.30 p < 0.001) and GSIS (OR 0.68 p < 0.001) were significantly correlated with pCR but did not correlate with each other (Pearson’s r2 = 0.027). In multivariate analysis, prolif (HR = 0.36 95% CI, 0.21-0.61 p = 0.0002) and GSIS (HR = 0.62 95% CI, 0.49-0.79 p < 0.0001) increased the ability to predict pCR beyond standard clinico-pathologic variables (likelihood ratio = 14.9, p = 0.0001115). Among all pts, those above the median for both prolif. and GSIS had the highest pCR (67%; 84/125) while those below the median for both had the lowest pCR rate (34%; 42/125). Tumors with higher inferred CD8+ T-cell infiltration demonstrated greater benefit from Cb using either TIMER (HR = 0.83 [0.73-0.95]) or CIBERSORT (HR = 0.83 [0.76-0.91]). Tumors with higher inferred total macrophages, particularly immune suppressive M2 macrophages had a higher pCR rate on the non-Cb arm (AC-T) using CIBERSORT (HR = 1.27 [1.07,1.50]). Conclusions: Immunophenotype and proliferation are independent predictors of pCR to standard NAC regimens in TNBC. PAM50 is not a significant predictor of Cb benefit. Exploratory findings suggest that tumor infiltrating immunophenotype (i.e. CD8 T cells and macrophages) may predict response to specific NAC regimens in TNBC. Clinical trial information: NCT02032277.

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Iuliano, Francesco, Daniela Cilloni, Molica Stefano, Sterpone Paola, Di Maio Massimo, Gottardi Enrico, Messa Emanuela, Serra Anna et Peta Antonio. « Phase II Study of Liposome Encapsulated Doxorubicin Citrate Complex, NPLD (Myocet™) in Myelofibrosis with Myeloid Metaplasia (MMM). » Blood 108, n^o 11 (16 novembre 2006) : 3621. http://dx.doi.org/10.1182/blood.v108.11.3621.3621.

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Abstract MMM is a chronic myeloproliferative disorder accompanied by an intense bone marrow stromal reaction that includes collagen fibrosis, osteosclerosis, and angiogenesis. The molecular pathogenesis of MMM has not been fully characterized despite the recent discovery of an activating JAK2 mutation (JAK2V617F) in approximately half of the patients. Conventional drug therapy in MMM not improves survival and is used for palliative purposes only. Myocet™ is a proprietary liposomal formulation of doxorubicin designed to enhance delivery of the drug to tumor cells and reduce side effects while maintaining equivalent anti-tumor efficacy. Moreover liposomes are avidly removed from circulation by the macrophages of the RES or MPS and are taken up in the spleen, liver and bone marrow were show both a cytotoxic and anti-angiogenic activity We thus designed a phase II study for patients with primary MMM. The treatment program consisted of 25 mg total dose of Myocet™ given I.V. every two weeks for six months. Study eligibility criteria included a histologically confirmed diagnosis of MMM, platelet count ≥ 100 × 109/L, and neutrophil count ≥ 1 × 109/L, PS ≤ 2, LVEF > 50%, normal liver and renal function. 8 patients (median age, 66 years; range, 60–73) were enrolled to the trial. Median duration of disease prior to protocol treatment was 45 months (range, 24–144). All pts (100%) had received prior therapy for MMM, including thalidomide 3 (37%), hydroxyurea 8 (100%), interferon 2 (25%)), anagrelide 2 (25%), and erythropoietin 8 (100%). 3 patients (37%) were RBC transfusion-dependent and 1 had severe constitutional symptoms (night sweats or disease related fever). Baseline median (range) values for palpable spleen size, leukocyte count, platelet count, CD34 cell count, and serum lactate dehydrogenase (LDH) were 10 cm BCM (median, range 6 to 30), 8.5 × 109/L (3–36.2), 250 × 109/L (160–950), 151.1 × 106/L (1.9–356), and 680 U/L (316–868), respectively. 8/8 pts had JAK2 V617F mutation. In addition, pre-treatment and post-treatment quantitative assessment by real-time quantitative polymerase chain reaction (RQ-PCR) of WT1 transcripts in the peripheral blood were performed and the values were expressed as WT1 copies every 104 copies of ABL. 7/8 pts are evaluable for response and toxicity (i.e., received six months of therapy) 1 pt discontinued because of progression. Clinico-hematologic responses have been observed in 7/7 (100%) pts and were evaluated according to European Myelofibrosis Network criteria These include 1 CR, 5 Major Response,1 Minor Response 1 of 3 transfusion-dependent pts have become transfusion independent. The median time to response was 12 weeks (range, 4 to 18). Therapy has been well tolerated. Only a Grade 3 thrombocytopenia was seen. Striking WT1 gene expression levels in samples that were obtained after treatment were found to be significantly lower (median 480 range 210–520) than those before (median 1000, range 560–1230) (P < .0001, Mann-Whitney U test) The median post-treatment follow up at the time of this writing was 10 months (range 8–13) We conclude that Myocet has clinical activity in a subset of patients with myelofibrosis with an acceptable toxicity profile.

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Nanda, Riksundar, Pradip Ku. Panda, Utkalini Nayak, Sushmirekha Panda et Vinod Chandra Singh. « A Clinico-Pathological Study on Pleehodaraw.s.r. to Splenomegaly and its Comparative Management with Sarapunkha Ksharaand Sarapunkha Ghana Vati ». International Research Journal of Ayurveda & ; Yoga 05, n^o 07 (2022) : 91–101. http://dx.doi.org/10.47223/irjay.2022.5711.

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Introduction-Udara rogasare classified into 8 types according to different Acharyas.Pleehodarais one among them.The main cause behind the development of Udara rogais ‘Mandagni’. In Ayurveda Pleehodaramay be correlated with Splenomegaly. Sarapunkhaa herbal drug mentioned in Ayurvedaclassics is effective in Pleehodara.So, a comparative single blind study of Sarapunkha Ksharaand Sarapunkha Ghana Vatiare taken into consideration for clinical trial for present study. Aims:To study about the comparative clinical efficacy of Sarapunkha Ksharaand Sarapunkha Ghana Vatiin the management of Pleehodara.Material and Methods-This is a single-blind comparative clinical study with a pre-test and post-test design. The patients were Randomly categorised into two groups.30 patients of Group-A(15) and Group-B(15) patients were registered from OPD and IPD of Govt. Ayurvedic College and Hospital, Balangir presented with Subjective parameters and Objective Parameters. After diagnosis they were under trial withAyurvedicformulations of Sarapunkha Ksharagiven 500mg twice daily after food in Group A and Sarapunkha Ghana Vatigiven 2tab(1 tab-500mg) twice daily after food with luke warm water for a period of 30 days respectively. The subjective and objective parameters were assessed in 10 days interval to interpret the result by statistical evaluation.Observation and Results: It had been observed that the result of trial drug Group-A patients was significant (<0.05) to reduce both subjective and objective Parameters after 30 days of treatment as compare to Group-B patients.Conclusion:On comparison between two groups, Sarapunkha Kshara had shown more effect thanSarapunkha Ghan Vati.No adverse effects were noticed during clinical trial in both groups

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Kim, Gun Min, Kyung-min Lee, Dhivya Sudhan, Albert Lin, Arnaldo Marin, Sumanta Chatterjee, Dan Ye et al. « Abstract PD3-07 : Combined inhibition of CDK4/6 and AKT is effective in Rb-intact triple-negative breast cancer of the luminal androgen receptor (LAR) subtype ». Cancer Research 82, n^o 4_Supplement (15 février 2022) : PD3–07—PD3–07. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd3-07.

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Abstract Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease group with variable clinico-pathologic features. Based on gene expression profiles, TNBCs are grouped into 6 major subtypes. The Luminal androgen receptor (LAR) subtype is enriched for potentially targetable biomarkers, including high androgen receptor (AR) expression, high rates of PIK3CA mutations, and intact Rb. The purpose of this study was to investigate the most effective combinations of CDK4/6, AR, and PI3K-AKT inhibitors in pre-clinical models of LAR TNBC for future clinical trial design. Methods: MDA-MB-453 and MFM-223 (both Rb-intact/PTEN-intact/PIK3CA-mutant) and CAL-148 (Rb-null/PTEN-null/PIK3CA-mutant) LAR TNBC cell lines were treated with the CDK4/6 inhibitor palbociclib, the PI3Kα inhibitor alpelisib, the AKT inhibitor capivasertib, and the AR antagonist enzalutamide, each alone or in different combinations. Drug sensitivity was determined by coulter counter cell counts in 2D, colony formation, and the CellTiterGlo cell viability assay. The combination index (CI) which defines synergism (CI < 1), additive effect (CI = 1) and antagonism (CI > 1), calculated by the CompuSyn method, was used to evaluate the synergistic effects of drug combinations. Expression of cell cycle and PI3K-AKT downstream signaling molecules was measured by western blot analysis. An androgen response element (ARE) luciferase-based reporter assay was used to evaluate AR transcriptional activity. Results: Rb-intact LAR TNBC cell lines were sensitive to single-agent palbociclib, alpelisib or capivasertib (IC50, ~500 nM). Enzalutamide had minimal growth inhibitory activity (IC50, 15-25 μM). Palbociclib combined with either alpelisib or capivasertib synergistically inhibited proliferation of LAR TNBC cells (CI values, 0.07-0.86). Treatment of Rb-intact LAR TNBC cells with palbociclib monotherapy suppressed Rb phosphorylation and resulted in adaptive phosphorylation/activation of S473 AKT and AKT substrates GSKβ and PRAS40 at 24h. These responses were not observed in Rb-null CAL-148 cells. Palbociclib-induced phosphorylation of AKT substrates as well as induction P-S6 and P-4EBP1 were better suppressed by capivasertib than by alpelisib over a dose range. Addition of the PI3Kβ/δ inhibitor AZD8186 to alpelisib markedly enhanced the inhibition of P-AKT, P-PRAS40 and P-Sin, suggesting inhibition of PI3Kα is inadequate to block the adaptive response to palbociclib in these cells. Mean CI values showed that the combination of palbociclib/capivasertib was more synergistic against LAR TNBC cells compared to palbociclib/alpelisib (mean CI, 0.29 vs. 0.78). ARE reporter activity did not change upon inhibition of PI3K or AKT with alpelisib or capivasertib, respectively. Conclusions: Our results suggest that addition of an AKT inhibitor to palbociclib suppresses the rebound activation of AKT following treatment with the CDK4/6i and is effective in LAR TNBC with wild type Rb. In vivo studies are underway to investigate the antitumor activity of the combination of palbociclib and capivasertib in LAR TNBC xenografts. Citation Format: Gun Min Kim, Kyung-min Lee, Dhivya Sudhan, Albert Lin, Arnaldo Marin, Sumanta Chatterjee, Dan Ye, Vishal Kandagatla, Saurabh Mendiratta, Ariella Hanker, Carlos Arteaga. Combined inhibition of CDK4/6 and AKT is effective in Rb-intact triple-negative breast cancer of the luminal androgen receptor (LAR) subtype [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 PD3-07.

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Tobin, Joshua W. D., Colm Keane, Peter Mollee, Simone Birch, Clare Gould, Jay Gunawardana, Thanh Hoang et al. « The Tumor Microenvironment Is Independently Prognostic of Conventional and Clinicogenetic Risk Models in Follicular Lymphoma ». Blood 130, Suppl_1 (7 décembre 2017) : 728. http://dx.doi.org/10.1182/blood.v130.suppl_1.728.728.

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Abstract Follicular Lymphoma (FL) is the most common indolent Non-Hodgkin Lymphoma. Despite generally favorable survival outcomes, 20% of FL patients experience 'Progression of Disease within 24 months' (POD24) and subsequently have poor long-term overall survival (OS) (Casulo, JCO 2015). Unfortunately, POD24 has limited clinical value because it cannot guide up-front clinical decisions. Accurate pre-therapy prognosticators are vital for clinical trial design and are also increasingly being mandated by funding agencies for stratification of patients to emerging front-line treatments. The new 'state-of-the-art' prognosticators 'm7-FLIPI' and POD24-PI' (Pastore, Lancet Oncol 2015; Jurinovic, Blood 2016) supplement clinical parameters with genetic mutational status. However, their applicability to population based cohorts including early-stage and asymptomatic patients remains unknown. Furthermore, there is significant heterogeneity of outcome within these prognostic groupings. The established biological and prognostic importance of the tumor microenvironment (TME) in FL suggests that prognosis would be enhanced by incorporating information on host immunity (Scott, Nat Rev Can 2014). Forty-five pre-treatment FL biopsies were categorized into 'hot' or 'cold' immune nodes by multiplex immunofluorescent imaging and respectively characterized by concordant high or low expression of multiple immune effector and checkpoint-associated proteins. (Fig 1A). Consistent with these findings, gene expression using the Nanostring platform showed that immune effectors (CD4/CD8/TNFa/CD137/CD56) positively correlated with immune checkpoints (PD-1/PD-L1/PD-L2/TIM3/LAG3/CD163/CD68) indicative of an adaptive immune response. Additionally, high-throughput unbiased TCRb sequencing showed the intratumoral TCR repertoire was more clonal in 'hot' compared to 'cold' FL samples (p=0.024), indicative of a skewed T-cell immune response (Fig 1B). We then applied these findings to an independent population-based cohort of 175 cases of FL from the rituximab era with long-term follow-up (median ~7 years), including advanced (n=137) and localized cases (n=38). The aims were to: a) identify new targetable immune parameters of prognostic importance in the rituximab-era; and b) compare and contrast these with published prognostic tools: FLIPI, FLIPI-2, m7-FLIPI, POD24-PI and 'immune survival score' ('ISS', Dave, NEJM 2004). OS was not only inferior in those experiencing POD24 (HR 4.88, p<0.0001, Fig 1C) but these patients had a >2-fold increase in 5-year patient health costs. Hence, POD24, as well as FFS and TT2T were therefore chosen as the primary outcome measures. M7 mutation frequencies were similar to those previously published (Pastore, Lancet Oncol 2015). However, the prognostic utility of the m7-FLIPI could not be demonstrated, whereas the FLIPI, FLIPI-2, and POD24-PI retained their prognostic value. The POD24-PI was most predictive of FFS (p<0.0001, HR=3.54) and was most specific in identifying cases that experience POD24 (Sp=68%). The prognostic utility of the TME was then tested. Notably both the ISS (p=0.024, HR=1.74) and multiple immune genes not represented in the ISS including PD-L2, TIM3, LAG3, CD137, TNF and CD4 predicted FFS. PD-L2 demonstrated the strongest association with FFS (p<0.0001, HR=3.74, Fig 1D). It not only out-performed the ISS but was independent to the FLIPI and POD-24-PI. The prognostic significance of PD-L2 was validated in an independent population based cohort of uniformly R-CVP treated patients from an in-silico dataset with gene expression quantified using the Illumina DASL platform (Pastore, Lancet Oncol 2015). We have validated the TME in predicting outcome in a population based cohort of FL patients with long-term follow-up treated in the rituximab era. Furthermore, we describe the role of PD-L2 as well as several additional pertinent, clinically-actionable markers of the TME which predict survival to conventional therapies in FL. Low expression of PD-L2 appears to be a surrogate of a broadly co-ordinated downregulation of the intratumoural response. These immune scores are independent of and additive to additive to the FLIPI and POD24-PI. Development of new prognostic models require the incorporation of host immunity along with clinico-genetic features to further improve the specificity, and to accurately risk stratify FL patients. Disclosures No relevant conflicts of interest to declare.

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Chevignard*, Mathilde, Kim S. Bull*, James Holt, Bertie Harrington, Jemma Castle, Marie-Amelie Heng, Colin Kennedy et al. « QOL-28. Clinico-molecular correlates of quality of survival and neurocognitive outcomes in medulloblastoma ; a meta-analysis of the SIOP-UKCCSG-PNET3 and HIT-SIOP-PNET4 trials ». Neuro-Oncology 24, Supplement_1 (1 juin 2022) : i139—i140. http://dx.doi.org/10.1093/neuonc/noac079.511.

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Abstract Determinants of survivorship outcomes are emerging from limited studies of medulloblastoma (MB) survivors. We undertook an integrated analysis of biological (tumour group, host genetics) and clinico-demographic features in patients treated on the SIOP-UKCCSG-PNET3 and HIT-SIOP-PNET4 clinical trials with available quality of survival (QoS) data (n=218), to determine key correlates of survivorship, and their clinical potential. Treatment/demographic factors and molecular subgroup (MBWNT, MBSHH, MBGrp3, MBGrp4) were assessed against health status, behavioural functioning, and health-related quality of life (HrQoL). In DNA from HIT-SIOP-PNET4 (n=74), 39 candidate SNPs with known modifying effects on neurocognitive outcomes (e.g., involved in oxidative stress/inflammation) were genotyped and assessed against Wechsler Intelligence Scale (WISC) scores. As expected, MBSHH was associated with improved HrQoL, but subgroup did not associate further with QoS outcomes. SIOP-UKCCSG-PNET3 patients receiving chemotherapy before craniospinal irradiation (CSI) had significantly lower health status (p=0.021) and behavioural functioning (p<0.016) compared to patients treated with CSI alone, and those treated on both arms (maintenance chemotherapy and hyperfractionated (36Gy) or standard (23.4Gy) CSI) of HIT-SIOP-PNET4. SIOP-UKCCSG-PNET3 patients receiving CSI-only had better HrQoL scores than those who received pre-CSI chemotherapy and both HIT-SIOP-PNET4 arms (p=0.004). Females reported worse HrQoL/behavioural functioning across both trials (p<0.04). In HIT-SIOP-PNET4, longer intervals from diagnosis to CSI predicted worse HrQoL/health status (p<0.05). Neither molecular group nor clinico-demographic features tested were associated with neurocognition. In contrast, 6 SNPs significantly associated with ≥1 WISC domain; 4/6 showed multiple associations and were independently prognostic; further associations were apparent at the gene/pathway level. This large, integrated and multi-disciplinary analysis of two independent trials cohorts has revealed multiple factors predictive of medulloblastoma survivorship including treatment (chemotherapy, time to CSI), tumour (molecular group) and host genetic factors. Assessment in further prospective series are required to determine their potential as a basis for modifications to disease management.

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Kim, Heeje, Jae-Ho Yoon, Seung-Ah Yahng, Sung-Eun Lee, Seung-Hwan Shin, Byung-Sik Cho, Jong-Wook Lee et Woo-Sung Min. « Clinico-Immunobiologic Study By a Prospective Open-Label Clinical Trial of Deferasirox before & ; after Allogeneic HSCT in Adult Patients with AML - Preliminary Analysis Focusing on Outcomes with Immunocyte Subsets (I) - ». Blood 124, n^o 21 (6 décembre 2014) : 2543. http://dx.doi.org/10.1182/blood.v124.21.2543.2543.

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Abstract Background: The ferritin contents in immature myeloid cells could be detected in both iron overload and in AML. Ferritin itself in leukemic cells could be regarded as an important marker for leukemic activity. Serialreports have shown that the serum ferritin level in patients with acute leukemia and myelodysplastic syndrome is a critical prognostic factor after hematopoietic stem cell transplantation (HSCT). However, the exact mechanism itself is not clear. Methods: We evaluated the iron chelating efficacy and the immunomodulatory effect of deferasirox therapy as assessed by regular monitoring of serum ferritin levels and immunocyte subsets from the post-induction period to post-HSCT. In addition, we tried to reveal the effects of deferasirox on various clinical outcomes in patients with adult AML who were expected to receive allogeneic HSCT. A total of sixty-six consecutive adult patients with de novo AML who received allogeneic HSCT were prospectively enrolled during the period 2009 to 2011. Serum ferritin levels were monitored from initial diagnosis to the post-HSCT period from both the iron-chelated group (IC, n=28) and the non-treated group (NT, n=38) of patients. Among the patients of the IC group, the final 20 AML patients were followed and were collected peripheral blood samples until minimum 6 months post-HSCT. The overall median follow-up for total survivors (IC) was 58 months (range: 48~66). Deferasirox treatment was initiated at the outpatient clinic both after induction chemotherapy and post-HSCT 1 month. Various clinical outcomes in association with multiple parameters including serum ferritin levels and multiple immunocyte subsets of CD4, CD8, CD16, CD56, invariant NKT, Treg, central/effector memory T cells were simultaneously analyzed, mainly in the IC group of patients, with the usage of the multi-color flow cytometer at pre- and post-HSCT periods. Results: The median duration of total (pre- + post-HSCT) medication in IC group of patients was 241 days (109-452). The median ferritin levels at diagnosis (IC, 651 ng/mL vs. NT, 667 ng/mL) and at peak levels (IC, 3,090 ng/mL vs. NT, 3,685 ng/mL) during chemotherapy did not differ significantly between groups. However, pre-HSCT levels were different between groups, as the median level of 1,555 ng/mL (335-3,800) (IC) vs. 964 ng/mL (229-7,360) (NT). The 5-year overall survival (OS) and event-free survival (EFS) rates of total AML patients were 63.6% and 60.6%, respectively. The Kaplan-Meier estimates of OS/EFS rates were all significantly different in pre-HSCT ferritin levels (P=0.0247, 0.0212) and duration of deferasirox treatment both pre- (P=0.028, 0.0166) and post-HSCT (P=0.0102, 0.0064). The levels of CD4+CD62L-CD44+ (P=0.027) and CD8+CD62L-CD44+ cells (P=0.006) post-induction chemotherapy were significantly associated with the duration of deferasirox treatment before HSCT. To note, the levels of CD4+ cells at 1 month post-HSCT deferasirox treatment (P=0.017), CD4+ effector memory T (TEM)-cells pre-HSCT (P=0.029), and CD8+CD62L-CD44+ cells post-HSCT 1 month (P=0.003) and 6 months (P=0.021) were closely related to the relapse of AML. Most of all, regulatory T (Treg) cells both pre-HSCT (P=0.002) and post-HSCT (P <0.001) periods after deferasirox therapy showed a very close correlation with various clinical outcomes, specifically with lower rates of relapse in patients with low levels of Treg after at least 120 days in total use of deferasirox before and after HSCT. Interestingly, patients who received deferasirox therapy for a sufficient duration showed consistently lower levels of Treg cells as well as higher levels of CD16+ NK cells along the timeline of chemotherapy and HSCT compared to those who did not. Furthermore, we found a marginal significance in the increased levels of CD4+CD161+ NKT cells at post-induction chemotherapy when patients received deferasirox before HSCT (P=0.056). Conclusion: Our data suggest that despite small sample numbers, iron-chelation therapy for adult AML patients with hyperferritinemia pre- and post-HSCT is very closely related to the outcomes of allogeneic HSCT, and that it is especially associated with the modulation of immunobiologic properties during the period of immune reconstitution. Therefore, more cautious approaches to reduce iron overload by using iron chelating agents, such as deferasirox, may be warranted both before and after allogeneic HSCT. Disclosures Kim: Novartis Korea: Research Funding.

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Sethy, Ganeswar, Debasish Dash, Geetanjali Sethy, Abinash Panda et Adya Anwesha. « Clinico-Etiological Profile of New Onset Seizures in Adults in Southern Odisha - An Observational Study ». Journal of Evidence Based Medicine and Healthcare 8, n^o 22 (31 mai 2021) : 1863–67. http://dx.doi.org/10.18410/jebmh/2021/351.

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BACKGROUND Population based studies indicate that the incidence and prevalence of seizure disorders in adults increase with age, especially in elderly, after the age of 60 years. The underlying etiological spectrum is variable across geographies. Analysis of aetiology of seizure is essential for proper treatment to reduce the morbidity and mortality associated with it. The present study was planned to analyse the aetiology of new onset seizures in adult population (> 18 years of age). METHODS The cross sectional study was carried out in the Department of Medicine of MKCG Medical College & Hospital for a period of two years. 100 consecutive cases of new onset seizures admitted in the in-patient department (indoor / ward) were included in the study as per the inclusion and exclusion criteria. The data was collected by the investigators in a pre-tested Case Record Form. Data analysis was done using Microsoft Excel and GraphPad Prism trial version 7.0. Descriptive statistics were presented as proportions for discrete variables and as mean ± SD for continuous variables. P value of ≤ 0.05 was taken as statistically significant. RESULTS Acute symptomatic seizures accounted for 89 % of cases. Neuro-infection was the leading aetiology in 35 % of cases, followed by cerebrovascular accidents (30 %) and metabolic causes (10 %). Neurocysticercosis was seen in 11 % cases, followed by meningitis and cerebral malaria. Among the vascular causes, stroke accounted for 20 %. Prevalence of neuro-infection was highest in the age group of 15 - 35 years. 89 % of idiopathic seizures were generalized tonic-clonic seizure (GTCS). The prevalence of status epilepticus was 8 %. CONCLUSIONS Adult onset seizures have a varied spectrum of aetiology. With a thorough history, clinical examination and appropriate investigations, the aetiology can be identified. Accordingly, treatment can be instituted thus reducing the morbidity and mortality associated with it. KEYWORDS Aetiology, New Seizures, Stroke, Vascular, Neuro-Infection

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Frega, Stefano, Alessandro Dal Maso, Giulia Pasello, Lea Cuppari, Laura Bonanno, PierFranco Conte et Laura Evangelista. « Novel Nuclear Medicine Imaging Applications in Immuno-Oncology ». Cancers 12, n^o 5 (21 mai 2020) : 1303. http://dx.doi.org/10.3390/cancers12051303.

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The global immuno-oncology pipeline has grown progressively in recent years, leading cancer immunotherapy to become one of the main issues of the healthcare industry. Despite their success in the treatment of several malignancies, immune checkpoint inhibitors (ICIs) perform poorly in others. Again, ICIs action depends on such a multitude of clinico-pathological features, that the attempt to predict responders/long-responders with ad-hoc built immunograms revealed to be quite complex. In this landscape, the role of nuclear medicine might be crucial, with first interesting evidences coming from small case series and pre-clinical studies. Positron-emission tomography (PET) techniques provide functional information having a predictive and/or prognostic value in patients treated with ICIs or adoptive T-cell therapy. Recently, a characterization of the tumor immune microenvironment (TiME) pattern itself has been shown to be feasible through the use of different radioactive tracers or image algorithms, thus adding knowledge about tumor heterogeneity. Finally, nuclear medicine exams permit an early detection of immune-related adverse events (irAEs), with on-going clinical trials investigating their correlation with patients’ outcome. This review depicts the recent advances in molecular imaging both in terms of non-invasive diagnosis of TiME properties and benefit prediction from immunotherapeutic agents.

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Chandrakar, Bedprakash, Vinod Chandra Singh, Pradip Kumar Panda et Sushmirekha Panda. « A Clinico-Pathological Study on Vatarakta w.s.r. to Gout andits Comparative Effect of Bodhivrikshya Kashayaand Bodhivrikshya Ghana Vati. » International Research Journal of Ayurveda & ; Yoga 05, n^o 07 (2022) : 102–11. http://dx.doi.org/10.47223/irjay.2022.5712.

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Vataraktais the major example of Vatavyadhi, caused due to avaranapathology. The scenario of Vataraktafeaturing sign & symptoms which can very well be correlated with Gouty Arthritis. The literature enlists a number of formulation in the management of Vatarakta. An additional cavernous revise was indispensable to bring out the precise outcome of these products. Keeping these visions in mind, the particular comparative study was performed with Bodhivrikshya Kashayaand BodhivrikshyaGhana Vati, which are explained in the same context. This is a single-blind comparative clinical study with a pre-test and post-test design, wherein a minimum of 30 patients of either sex, suffering from Vatarakta, in an age limit of 20 to 50 years with symptoms like sandhishoola(joint pain),sotha(swelling),kandu(itching),daha(burningsensation),twakvaivarna(discolouration),sparshaasahatwa(tenderness),sphurana(twitching)and serum uric acid valuemore than 6.8mg/dl were selected and randomly categorized into two groups. The 15 patients of group A were treated with oral administration of Bodhivrikshya Kashaya25ml twice day and the group B patients with Bodhivrikshya Ghana Vati2tab(1tab-500mg) thrice daily with anupanaof Madhu. The therapeutic effect of the treatment was assessed in both the groups based on specific subjective and objective parameters. The results obtained were analyzed statistically in both the groups and the comparative effect was assessed using the unpaired “t”-test. In both the groups, a statistically significant improvement was observed in all the criteria of assessment. The outcome of the studyrevealed an identical therapeutic efficacy of Bodhivrikshya Kashayaand Bodhivrikshya Ghana Vatiin Vataraktabut Bodhivrikshya Kashayahave shown more than Bodhivrikshya Ghana Vati. No Adverse effect was noticed during clinical trial in both groups.

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Bardia, Aditya, Faye Su, Nadia Solovieff, Fabrice Andre, Carlos Arteaga, Patrick Neven, Yoon-Sim Yap et al. « Abstract PD17-08 : Pooled gene expression analysis and association with treatment response in patients with HR+/HER2− advanced breast cancer in the MONALEESA-2, -3, and -7 trials ». Cancer Research 83, n^o 5_Supplement (1 mars 2023) : PD17–08—PD17–08. http://dx.doi.org/10.1158/1538-7445.sabcs22-pd17-08.

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Abstract Background: The Phase III MONALEESA (ML)-2, -3, and -7 trials showed significant improvement in progression-free survival (PFS) and overall survival (OS) with ribociclib (RIB) + endocrine therapy (ET) over placebo (PBO) + ET in patients (pts) with HR+/HER2− advanced breast cancer (ABC); improvement in OS with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) has been observed in some, but not all clinical trials. Gene expression analyses for each separate ML study were reported previously. Given the differences in CDK4 vs CDK6 inhibition between RIB and other CDK4/6i, we evaluated the association between cell cycle (CC)–related genes and outcomes based on pooled analysis of gene expression using tumor samples from the ML-2, -3, and -7 trials. Methods: Gene expression data were generated from pre-treatment archival tumor samples (primary, 73%; metastatic, 27%) with a customized NanoString nCounter panel (781 genes) including genes involved in CC, other signaling pathways, and breast cancer biology. Samples were pooled from 1139 pre- and postmenopausal pts with HR+/HER2− ABC across the 3 ML studies, which included pts on first- and second-line therapy. Data were categorized into training (80%) and test (20%) datasets. The training dataset was used to analyze each gene (modeled continuously) individually for an association with PFS, and genes with a gene × treatment (tx) interaction P value <.10 were evaluated in the test dataset. Genes or gene signatures were classified by tertiles based on expression level (low/medium/high). For each tertile, median (m) PFS was calculated by the Kaplan-Meier method, and hazard ratios (HRs) of tx benefit (RIB vs PBO) were estimated. A Cox proportional hazards model adjusting for clinical covariates was used. A machine learning approach (elastic net survival model with stability selection), which used available gene expression data and select clinical factors and their interactions with tx arms, was applied to predict PFS. Results: This report focused on CC-related genes and signatures. Gene expression levels of CDKN2B and the expression ratio of CCND1/CDKN2A showed a predictive relationship with benefit from RIB in both training and test sets (Table). PFS benefit with RIB was consistent regardless of the CDK4/CDK6 expression ratio or level of expression of CCNE1, CDK2, RB1, combined CC-related genes, E2F gene signatures, RB gene signature, combined DNA-replication genes, or combined proliferation-related genes. A machine learning approach identified a clinico-genomic signature that was prognostic for PFS benefit with RIB. Selected variables included gene expression levels of FXBO5, PGR, RBBP8, and STC2 and several clinical features (tx arm, de novo disease, prior ET, and visceral disease). Pts with a low signature score had a longer mPFS vs pts with a high signature score, in the RIB (HR, 0.37; 95% CI, 0.22-0.62) and PBO (HR, 0.30; 95% CI, 0.15-0.59) arms. Conclusion: In the largest pooled analysis of the association of gene expression profile data with CDK4/6i tx response in pts with HR+/HER2− ABC, the PFS benefit with RIB + ET over ET alone was consistent irrespective of expression levels of most CC genes. Variation in magnitude of RIB benefit was observed, depending on CDKN2B expression levels, CCND1/CDKN2A expression ratio, and machine learning–derived signature scores. The clinico-genomic CDK4/6i signature requires validation in additional datasets. Table 1: Progression-Free Survival by Gene Expression Subgroup Citation Format: Aditya Bardia, Faye Su, Nadia Solovieff, Fabrice Andre, Carlos Arteaga, Patrick Neven, Yoon-Sim Yap, Yen-Shen Lu, Stephen K. Chia, Dennis Slamon, Seock-Ah Im, Arunava Chakravartty, Agnes Lteif, Tetiana Taran, Debu Tripathy. Pooled gene expression analysis and association with treatment response in patients with HR+/HER2− advanced breast cancer in the MONALEESA-2, -3, and -7 trials [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 PD17-08.

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Sengupta, Sanjay, Subrata Pal, Biplab Kr Biswas, Sritanu Jana, Sudhanya Biswas et Raison Shail Minz. « Clinico-pathological study of 273 cases of rhinosporidiosis over a period of ten years in a tertiary care institute catering predominantly rural population of tribal origin ». Bangladesh Journal of Medical Science 14, n^o 2 (18 avril 2015) : 159–64. http://dx.doi.org/10.3329/bjms.v14i2.16151.

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Introduction: Rhinosporidiosis is a chronic granulomatous infection caused by Rhinosporidium seeberi, an organism whose taxonomy is still debated. The present study was aimed to document the clinico-pathological presentation of rhinosporidiosis in different parts in reference to caste, age and gender. Evaluation of diagnostic role of cytology in the diagnosis of rhinosporidiosis was also explored.Materials and Methods: All histology confirmed rhinosporidial cases were included in the study. Detailed clinical history and examination findings including previous hematological and cytological reports, if available, were collected and tabulated. Periodic Acid Schiff (PAS) and Mucicarmine stains were used over cyto- and histological slides, if necessary.Observations: Male cases were more frequent in these series though this sex difference is less pronounced among tribal population. Majority of the cases belonged to 21-40 years age group. Nose and nasopharynx was the commonest site of infection and polypoid mass lesions were the commonest presentation. Both scrape and aspiration cytology could successfully detect rhinosporidiosis in 100% cases.Discussion: Most of the cases are among poor-socioeconomic status and probably out-door activities and pond bathing habit. Haematological data correlation did not revealed any significant association. Histology is the preferred method for confirmed diagnosis of rhinosporidiosis. Rare cases of misdiagnosis can be avoided by use of special stains.Conclusion: Rhinosporidiosis commonly presents as polypoidal lesions in nose and extra-nasal sites. Histopathology is the standard method for confirmation of diagnosis. Cytology can be used as an adjunct for pre-operative diagnosis of extra-nasal rhinosporidiosis. We recommended use of special stains for diagnosis of difficult cases.Bangladesh Journal of Medical Science Vol.14(2) 2015 p.159-164

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Starnoni, Daniele, Lorenzo Giammattei, Giulia Cossu, Michael J. Link, Pierre-Hugues Roche, Ari G. Chacko, Kenji Ohata et al. « Surgical management for large vestibular schwannomas : a systematic review, meta-analysis, and consensus statement on behalf of the EANS skull base section ». Acta Neurochirurgica 162, n^o 11 (29 juillet 2020) : 2595–617. http://dx.doi.org/10.1007/s00701-020-04491-7.

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Abstract Background and objective The optimal management of large vestibular schwannomas continues to be debated. We constituted a task force comprising the members of the EANS skull base committee along with international experts to derive recommendations for the management of this problem from a European perspective. Material and methods A systematic review of MEDLINE database, in compliance with the PRISMA guidelines, was performed. A subgroup analysis screening all surgical series published within the last 20 years (January 2000 to March 2020) was performed. Weighted summary rates for tumor resection, oncological control, and facial nerve preservation were determined using meta-analysis models. This data along with contemporary practice patterns were discussed within the task force to generate consensual recommendations regarding preoperative evaluations, optimal surgical strategy, and follow-up management. Results Tumor classification grades should be systematically used in the perioperative management of patients, with large vestibular schwannomas (VS) defined as > 30 mm in the largest extrameatal diameter. Grading scales for pre- and postoperative hearing (AAO-HNS or GR) and facial nerve function (HB) are to be used for reporting functional outcome. There is a lack of consensus to support the superiority of any surgical strategy with respect to extent of resection and use of adjuvant radiosurgery. Intraoperative neuromonitoring needs to be routinely used to preserve neural function. Recommendations for postoperative clinico-radiological evaluations have been elucidated based on the surgical strategy employed. Conclusion The main goal of management of large vestibular schwannomas should focus on maintaining/improving quality of life (QoL), making every attempt at facial/cochlear nerve functional preservation while ensuring optimal oncological control, thereby allowing to meet patient expectations. Despite the fact that this analysis yielded only a few Class B evidences and mostly expert opinions, it will guide practitioners to manage these patients and form the basis for future clinical trials.

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Rutkowski, P., Z. I. Nowecki, W. Michej, M. Debiec-Rychter, J. Limon, J. A. Siedlecki, M. Kakol, S. Gluszek, C. Osuch et W. Ruka. « The criteria of aggressiveness and other prognostic factors for predicting relapses of primary tumors and imatinib (IM) treatment outcomes in advanced KIT immunopositive gastrointestinal stromal tumors (GIST) : A report of the Polish Clinical GIST Registry (PCGR) ». Journal of Clinical Oncology 24, n^o 18_suppl (20 juin 2006) : 9544. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.9544.

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9544 Background: The development of adjuvant treatment trials with imatinib in GIST has raised the debate about the accuracy of NIH risk criteria consensus and about the significance of other prognostic factors. Methods: We analyzed the criteria of aggressiveness and other clinico-pathological and genetic factors influencing disease-free survival (DFS) in patients with primary CD117-positive tumors (group I: 274 patients; median follow-up 29 months; calculated from primary tumor resection) and progression-free survival (PFS) in metastatic/unresectable GIST patients treated with IM (group II: 179 patients; median follow-up 19 months; calculated from the start of imatinib therapy) enrolled into PCGR. Results: In group I statistically significant (p<0.05) factors negatively influencing DFS both in univariate (log-rank test) and multivariate (Cox’s model) analysis were: primary tumor size > 5 cm, mitotic index > 5/50HPF, male gender, primary tumor R1 resection or tumor rupture, non-gastric primary tumor localization and intermediate/high risk group (3-year DFS for high, intermediate and low/very low risk group was: 28%, 75% and 99%, respectively). In group II we identified 5 factors negatively affecting PFS statistically significant both in univariate and multivariate analyses (p<0.05): tumor genotype indicating other than exon 11 KIT mutation, mitotic index > 10/50HPF, age below 45 years at diagnosis, high baseline pre-IM granulocyte count and poor WHO performance status ≥ 2. Conclusions: We validated the value of criteria of risk groups for the assessment of the natural course of primary GIST, but we also identified additional independent prognostic factors. For the prediction of PFS during IM therapy for advanced GIST we detected 5 different, independent biological and pathological factors. No significant financial relationships to disclose.

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Castellanos, Emily, Jeremy Snider, Siraj Mahamed Ali, Daniel Backenroth, Lee A. Albacker, Karthikeyan Murugesan, Gerald Li, Garrett M. Frampton, Brian Michael Alexander et Kenneth Robert Carson. « Tumor mutational burden (TMB) and PD-L1 expression as predictors of response to immunotherapy (IO) in NSCLC. » Journal of Clinical Oncology 37, n^o 15_suppl (20 mai 2019) : 2630. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2630.

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2630 Background: PD-L1 expression and TMB, as a proxy for neoantigen burden, have been correlated with response to IO in advanced NSCLC (aNSCLC) clinical trials, but their combined utility is unclear. We assessed TMB and PD-L1 as predictors of response in aNSCLC patients (pts) after IO monotherapy in a real-world setting. Methods: Pts had a diagnosis of aNSCLC, comprehensive genomic profiling of 186-315 genes/1.1 megabase (Mb), PD-L1 testing of pre-IO specimens, and were treated in the Flatiron Health network (1/2011 - 6/2018). Clinical characteristics and real-world tumor response (rwTR) were obtained via technology-enabled abstraction of clinician notes and radiology/pathology reports, and linked to genomic data in the Flatiron Health-Foundation Medicine Clinico-Genomic Database. A general additive model examined the predictive value of TMB (as continuous measure) and PD-L1 level on rwTR. A reduced PD-L1-only model was compared to the full model using Akaike Information Criterion (AIC). rwTR predictions at representative TMB and PD-L1 levels were calculated. Results: Of 426 pts, PD-L1 expression was high (≥50%) in 140, low (1-49%) in 123, and negative (<1%) in 163. Median TMB was 9.6 mut/Mb (IQR 4.4 - 14.8) overall, 11.3 in responders and 8.7 in non-responders. TMB did not correlate with PD-L1 level (Kruskal-Wallis p=0.29). The TMB + PD-L1 model had superior prediction of rwTR than the PD-L1 model, as assessed by lower AIC score. In the combined model, higher TMB and PD-L1 levels were each associated with higher rwTR likelihood (Table). Predicted rwTR probability, % (95% CI), by TMB and PD-L1 in line 1. Conclusions: TMB and PD-L1 expression are independent markers that, when combined, have increased predictive power for response to IO. High TMB + low/neg PD-L1 behaved similarly to low TMB + high PD-L1, and high TMB + high PD-L1 predicted the highest rwTR. Investigation of these biomarkers as complementary predictors of progression and overall survival is ongoing.[Table: see text]

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Shen, John P., Miriam T. Jacobs, Ingrid L. Fuh, Joel Micah Baumgartner, Paul T. Fanta, Andrew M. Lowy et Olivier Harismendy. « Somatic mutation landscape of appendiceal cancer. » Journal of Clinical Oncology 36, n^o 4_suppl (1 février 2018) : 671. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.671.

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671 Background: Appendiceal cancers are rare, comprising just 0.5% of all intestinal neoplasia, which has prevented the systematic study of these tumors in randomized clinical trials. Given this absence of clinical data, no evidence-based guidelines exist regarding the best management of this disease. Standard treatment generally follows consensus guidelines for colorectal cancer; however, there are currently no standards to guide chemotherapy selection in the adjuvant or metastatic setting. Methods: Somatic mutation profiles covering ~300 frequently mutated genes were obtained for 385 primary appendiceal tumors (Foundation Medicine). A retrospective review was performed to gather clinico-pathologic data. The primary objective was to assess the somatic mutation profile of each subtype of appendiceal cancer and to compare these to colorectal cancer. Colorectal data was obtained from TCGA cohort via cBioPortal. Results: Appendiceal adenocarcinoma (non-mucinous) and mucinous adenocarcinoma had shared somatic mutations albeit with differing frequencies. The most common mutations were KRAS (60.1% and 80.5%, respectively), GNAS (32.4%, 58.5%), TP53 (42.8%, 19.5%), and SMAD4 (14.8%, 14.6%). Tumors with goblet cell (adenocarcinoid) histology had lower prevalence of KRAS (16.0%) and GNAS mutations (8.0%), but similar prevalence of TP53 mutation (24.0%) and a greater prevalence of ARID1A mutation (20.0%). The mutation profiles of all appendiceal histologies differed from colorectal adenocarcinoma with markedly lower prevalence of ATM (7.9% vs. 71.0%). Chemotherapy data was available for 30 metastatic patients; these patients received an average of 1.76 lines of therapy (range 1-4). All 30 were treated with either 5-FU or capecitabine, 11 (36.7%) with oxaliplatin, 23 (76.7%) with irinotecan and 19 (63.3%) with bevacizumab. Analysis of survival data and correlation with molecular and histologic features is ongoing. Conclusions: Despite clear molecular differences between appendiceal and colorectal tumors, appendiceal tumors are primarily treated with colorectal chemotherapy regimens. There remains a pressing need for both pre-clinical and clinical investigation to develop treatment regimens specific to appendix cancer.

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Ysebaert, Loic, Emilie Laprévotte, Christian Klein, Guy Laurent, Jean-Jacques Fournié et Anne Quillet-Mary. « Clinical and Biological Characteristics Associated with In Vitro Activity of Anti-CD20 Monoclonal Antibodies, Rituximab and GA101, Against Chronic Lymphocytic Leukemia Cells ». Blood 116, n^o 21 (19 novembre 2010) : 2459. http://dx.doi.org/10.1182/blood.v116.21.2459.2459.

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Abstract Abstract 2459 Introduction: The CD20 antibody rituximab (RTX) is an important therapeutic agent in the armamentarium against chronic lymphocytic leukemia (CLL) cells. Several mechanisms have been described that affect low single agent efficacy of CD20 antibodies in B-CLL and relapse after treatment. The novel CD20 antibody GA101 has been developed with the aim of further improving CLL therapy and is currently in phase II/III clinical trials. It is a type II, glyco-engineered CD20 antibody with enhanced ADCC through improved CD16A binding. Aim: To assess in vitro pre-clinical activity of RTX and GA101 against CLL cells in either freshly isolated PBMCs, or after 14 days of culture in vitro, to allow the outgrowth of Nurse-Like Cells (NLC) that may presumably alleviate mAb activity (a process called Environment Mediated-Drug Resistance, or EM-DR). Methods: In 34 CLL patients (all naive for treatment), PBMCs were isolated from blood samples by Ficoll gradient centrifugation. Antibody-mediated B cell depletions was determined by enumerating trypan blue negative, flow cytometrically CD19-positive B lymphocytes after antibody treatment. Three conditions were assessed, all with starting concentrations of 107cells/ml: (i) depletion in freshly isolated PBMCs after 7 days of culture in RPMI+10%FCS and 10μg/ml RTX or GA101 (DEP7), or, after 14 days culture of PBMCs in RPMI+10% FCS, PBMCs were collected and either (ii) washed and cultured in fresh RPMI+10%FCS and antibodies for 7 extra-days (DEP21/RPMI), or (iii) re-suspended in their own conditioned RPMI medium and cultured with NLC and antibodies for 7 extra-days (DEP21/NLC). The Mann-Whitney analysis was used to compare median depletion according to relevant clinical and biological data. Results: The median B-CLL depletion in freshly isolated PBMC were 56% for GA101 vs 5% for RTX (p=0.000031). As indicated in Table 1, no clinico-biological parameter was significantly associated with antibody response, though unmutated IgVH status seemed to impact on GA101 efficacy. We next sought to study the impact of EM-DR mechanisms afforded by CLL PBMCs+NLC co-cultures in vitro. While RTX activity was virtually abrogated under those conditions, B cell depletion induced by GA101 was significantly reduced to 27% if PBMCs were collected after 14 days of culture with NLC, and incubated with antibodies from days 14–21 either in fresh RPMI (DEP21/RPMI=27% vs 56% for DEP7 GA101, n=18, p=0.024), or to 14% in conditioned RPMI and NLC (DEP21/NLC=14% vs 56% for DEP7 GA101, n=12, p=0.008). This time, clinico-biological parameters linked with active CLL disease like bulky lymph nodes>5cm (p=0.049), presence of at least one NCIWG2008 criteria for initiation of treatment (p=0.01), and unmutated IgVH status (p=0.03) appeared significantly linked to reduced GA101 activity. Interestingly, karyotype abnormalities did not seem to negatively impact on GA101-triggered depletion. Conclusions: Our results suggest that in vitro EM-DR abrogates the small RTX activity as single agent against CLL cells, whereas GA101 still retains activity under those conditions. It remains to be studied whether this may impact the clinical activity of GA101 in subgroups of patients. Overall, GA101 appeared much more active than rituximab, and should be investigated in combination with strategies aiming at disrupting EM-DR mechanisms. Disclosures: Off Label Use: GA101 is not currently approved for CLL treatment. Klein: Roche: Employment, Equity Ownership, Patents & Royalties.

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Bastos-Oreiro, Mariana, Antonio Gutierrez, Juan Luis Reguera, Gloria Iacoboni, Lucía López Corral, María José Terol, Valentín Ortiz-Maldonado et al. « Rreal-World Results from Anti-CD19 CAR-T Cell Therapy for Relapsed or Refractory Diffuse Large B-Cell Lymphoma in Spain and Comparison with Previous Standard of Care : A Geltamo/Geth Study ». Blood 138, Supplement 1 (5 novembre 2021) : 3850. http://dx.doi.org/10.1182/blood-2021-147670.

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Abstract Introduction. The prognosis of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is poor. Chimeric antigen receptor (CAR) T-cell therapy is approved for R/R DLBCL (≥3 rd line) in Spain since April 2019, based on data from single-arm phase 2 trials that showed complete response (CR) rates between 40-50% and prolonged remissions in 30-40% of patients. Real-world (RW) data from different countries have shown similar efficacy to pivotal trials, but there are no studies focused on the global Spanish experience, including different constructs with a large number of patients and no comparative studies have been carried out in Spain between commercial CAR-T therapy and the standard treatment of the pre-CAR era. Methods This is a multicenter, retrospective, observational study that included all patients with R/R DLBCL treated with CAR-T therapy who were registered in the GELTAMO/GETH database of patients treated with CAR-T therapy in Spain (n=255). The main objective was to analyze efficacy in terms of response rates and survival and analyze prognostic factors influencing survival. In addition, this cohort was compared with a historical population of R/R DLBCL patients from the GELTAMO-IPI study (Montalbán et al, Br J Haematol 2017), treated in the pre-CAR era (n = 158). From both cohorts, refractory patients according to the Scholar-1 criteria (primary refractoriness, refractoriness to last treatment, or early relapse after autologous stem-cell transplant) were identified and included in the comparative analysis. Results Characteristics of the CAR-T group at diagnosis and at infusion are shown in Table 1. From the 255 patients registered, 13 were excluded due to absence of follow up data and 4 for mantle cell lymphoma histology. Finally, 238 patients were included in the intention-to-treat analysis and 226 received the CAR-T infusion (124 axicabtagene ciloleucel, 101 tisagenlecleucel and 1 lisocabtagenemaraleucel). Median time from official approval to infusion was 60 days (34-363), and median time from apheresis to infusion was 46 days (16-349). Regarding adverse events of special interest, 79% of patients had cytokine release syndrome (7% ≥ grade 3), and 32% of patients had neurotoxicity (13.7% ≥ grade 3). Best response rates after CAR-T infusion were: CR 42%, partial response (PR) 27%, stable disease (SD) 7% and progressive disease (PD) 24%. With a median follow up from infusion of 8 months, median progression-free survival (PFS) was 3.5 months (95% CI: 1.9-5), and median overall survival (OS) was not reached, with a 12-month OS of 53% (95% CI: 45-62); 12-month OS and PFS for patients who achieved CR was 86% (Figure 1) and 78% respectively. Factors influencing PFS and OS in the univariate analysis are shown in table 2. In the multivariate analysis, the factors with independent influence on both PFS and OS were R-IPI and Eastern Cooperative Oncology Group-Performance status (ECOG-PS) pre-CAR, and presence of refractory disease to last treatment, as shown in table 3. Regarding the comparative analysis with the historical cohort, the groups were well balanced, except for age and median follow up (Table 4). The survival for this analysis was calculated since the failure to last treatment. Patients treated with CAR T-cells vs standard of care pre-CAR had significantly better PFS (median of 7.9 vs 5.7 months, p=0.002), and OS (median of 16 vs 9.2, p<0.001). Conclusions: We conclude that efficacy results obtained from RW CAR T-cell therapy in Spain are comparable to the pivotal trials. The results of the comparative analysis suggest that the efficacy of CAR-T therapy in refractory patients is superior to that of the treatments available in the pre-CAR era. Figure 1 Figure 1. Disclosures Bastos-Oreiro: F. Hoffmann-La Roche: Honoraria, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite: Speakers Bureau; Gilead: Honoraria; BMS-Celgene: Honoraria, Speakers Bureau. Reguera: Janssen, Kite/Gilead, Novartis: Speakers Bureau; BMS-Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees. Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Corral: Gilead: Consultancy; Novartis: Consultancy; Gileqd: Honoraria. Terol: Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Roche: Consultancy; Hospital Clinico Valencia: Current Employment; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; BMS: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel. Ortiz-Maldonado: Kite, Novartis, BMS, Janssen: Honoraria. Mussetti: Gilead: Other: Unspecified, Research Funding; Novartis: Honoraria, Other: Unspecified; Takeda: Honoraria. Luzardo Henriquez: Kyte/Gilead. Takeda. Roche: Honoraria. Sancho: F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees. Salar: Roche: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Gilead: Research Funding; Janssen: Consultancy, Speakers Bureau. Herrero: Novartis: Consultancy, Honoraria. Sureda: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Support for attending meetings and/or travel; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Consultancy; GSK: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau. Barba: Novartis: Honoraria; BMS: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Gilead: Honoraria. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria. Martin Garcia-Sancho: Celgene: Honoraria, Other: travel; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Celgene/BMS: Consultancy; Janssen: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Gilead: Consultancy, Honoraria; Morphosys: Consultancy; Kyowa Kirin: Consultancy; Clinigen: Consultancy; Eusa Pharma: Consultancy; Novartis: Consultancy; Takeda: Honoraria; Incyte: Consultancy; Kern Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).

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Baltasar, Patricia, María José Terol, Juan Marquet Palomanes, Angel Ramírez Payer, Carol Moreno, Santiago Osorio, Fátima De la Cruz et al. « Efficacy and Safety of Treatment Venetoclax Monotherapy or Combined with Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) in the Real -World Setting in Spain : The Venares Study ». Blood 138, Supplement 1 (5 novembre 2021) : 1561. http://dx.doi.org/10.1182/blood-2021-147685.

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Abstract Introduction: The BCL-2 inhibitor venetoclax (Ven) has been approved on monotherapy or combined with rituximab in relapsed/refractory CLL patients (pts) and combined with obinutuzumab in previously untreated CLL pts. However, evidence from clinical trials can be difficult to generalize to real-world patient populations. The VENARES study assesses the real-world use of Ven following approval to inform of subpopulations underrepresented in clinical trials. Methods: This is Spanish non-interventional retrospective, multicenter post-marketing observational study. The main objective was to evaluate the effectiveness of Ven in adult CLL pts by the overall response rate (ORR) at 9 months (mo) after the first Ven dose administration. Secondary objective was to evaluate the effectiveness for the Ven monotherapy and the Ven combined with rituximab subpopulations. Consecutive adult pts with diagnosis of CLL who have initiated Ven at least 9 mo before the inclusion in the study were included. Data of pts are retrospectively reviewed until the date of last follow-up or death. Results: 125 pts diagnosed with CLL and who met the eligibility criteria were analyzed. The median age was 72 years (67 - 77) with 76.8% being older than 65 years. Most patients were male (68.8%), had a concurrent disease (65.6%). ECOG PS was recorded in 76 pts: 40 pts (32%) had PS 0, 30 pts (24%) PS 1 and 6 pts (4.8%) PS 2. Pts had received a median of 4 prior lines of therapy (range 1-13 lines). At baseline, among the 92 pts with known Binet stage, 31 (33.7%) had stage C and 38 (41.3%) had stage B; bulky nodes ≥ 5 cm were present in 20 of 87 pts; 49 pts (39.2%) had an absolute lymphocyte count ≥ 25 x 10 9/L and 33 of 54 pts (61%) baseline beta-2 microglobulin value above of 3500 ng/mL. In total, 29 of 90 patients (32%) assessed had Cr 17p deletion, 28 of 86 patients (32%) tested had TP53 mutations, and 46 of 56 patients (82%) who were tested had unmutated immunoglobulin heavy-chain variable (IGHV) status. Ven was administered as monotherapy in 71 pts (57.6%), combined with rituximab in 36 pts (28.8%), combined with obinutuzumab in 5 pts (4%) and combined with other drugs in 13 pts (10.4%). 83 of 125 patients included were evaluable for the primary objective of the study: the ORR at 9 mo was 84.3% (70 patients): CR/CRi in 44 (53%) pts, PR/nPR in 26 pts (31.3%), SD in 9 pts (10.8%) and PD in 4 pts (4.8%). By treatment, in the evaluable patients, ORR at 9 months were 79.2% (38 of 48 patients) in the Ven monotherapy group, with 45% of CR/CRi, and 92.3% (24 of 26 patients) in the Ven combined with rituximab, with 61% CR/Cri. The median duration of PFS was not reached at the time of the analysis (1-June-2021). Kaplan-Meier estimates of the probability of PFS at 24 mo was 75.4% (95% CI, 58.2 - 86.3). Disease progression occurred in 21 pts. Assessment of minimal residual disease (MRD) was available for 32 patients (25.6%) on the basis of peripheral-blood samples, bone marrow or both. Best undetectable MRD was reached in fourteen patients (43.8%). uMRD was more common in pts treated with Ven combined with R (83.3%, 5 of 6 pts) than in pts treated with Ven monotherapy (33.3%, 7 of 21 pts). Adverse events (AEs) were reported during Ven therapy in all 125 patients, 93 of these pts reported AEs related to Ven. Related to Ven, 67 patients (53.6%) experienced at least one AE: 52 pts (41.6%) had neutropenia being grade 3 and 4 in 22 (42.3%) and 9 (17.3%) pts, respectively. 9 pts (7.2%) had febrile neutropenia. Thrombocytopenia and anemia were less common occurring in 5.6% and 2.4%, respectively. Tumor lysis syndrome (TLS) occurred in 4 of 125 pts during ramp-up (3 laboratory and 1 clinical), 2 of them were related to Ven both lab TLS. None of the pts discontinued therapy due to TLS. Richter transformation was observed in 6 pts (4.8%). Other common AEs was diarrhea (10.4%), but most cases were mild. Conclusions: Our first real-world data show that Ven monotherapy or combined with rituximab is effective in highly pre-treated CLL patients, ORR at 9 mo was 84.3% in all population and PFS estimate at 24 mo was 75.4% with similar outcomes to those in the pivotal clinical trials. The safety profile of Ven was consistent with prior experience of Ven in monotherapy or combined with rituximab and no new safety signals were detected. Disclosures Baltasar: Janssen, Abbvie: Consultancy. Terol: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; BMS: Consultancy; Roche: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Hospital Clinico Valencia: Current Employment. Moreno: Janssen, Abbvie: Research Funding; Abbvie, Janssen, AstraZeneca: Speakers Bureau; Abbvie, Janssen, AstraZeneca, Beigene: Membership on an entity's Board of Directors or advisory committees. Osorio: Janssen, Abbvie, Roche: Consultancy. De la Cruz: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; JANSSEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirkin: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de la Serna: AbbVie, AstraZeneca, Roche: Speakers Bureau; ABBVIE, ASTRAZENECA,ROCHE: Research Funding; AbbVie, AstraZeneca, Beigene, Gilead, GSK, Janssen, Jazzpharma, Novartis, Roche: Consultancy. Arguiñano: Takeda, Sanofi, Janssen, BMS-Celgene, Abbvie: Speakers Bureau; Takeda, Sanofi, Janssen, BMS-Celgene, Abbvie: Consultancy. Loscertales: Janssen, Abbvie, Roche, Gilead: Speakers Bureau; Janssen, Abbvie, Astra-Zeneca, Beigene, Roche, Gilead: Consultancy. García: Janssen, Roche, Gilead, Celgene: Consultancy; Janssen, AbbVie: Research Funding; Janssen, Roche, Gilead, AbbVie, Celgene: Other: medical meetings funding. Pérez Persona: BMS/Celgene: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; Amgen: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Speakers Bureau; AbbVie: Other: Support for attending meetings and/or travel, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; GSK: Consultancy; Incyte: Consultancy. Pérez-Encinas: Janssen: Consultancy. Caballero: Celgene, Janssen, Novartis, Abbvie: Speakers Bureau; Celgene, Janssen, Amgen: Consultancy. Ruiz-Zorrilla: Abbvie: Current Employment. Moreno: abbvie: Current Employment. Ferrà: Janssen, Roche, Gilead, Takeda, Abbvie: Consultancy; Janssen, Roche, Gilead, AbbVie: Other: medical meetings funding.

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Kumar KV, Arun, Arun Kumar C, Pradeep E, Venkatachalam K, Arivoli Arivoli, Ganasree Ganasree, Rakesh Rakesh et Mathai NT. « METHODOLOGY TO SURGICALLY APPROACH FOR LUMBAR CANAL STENOSIS;“WHEN TO” AND “WHEN NOT TO” DO INSTRUMENTAL FUSION- A PROSPECTIVE STUDY. » INTERNATIONAL JOURNAL OF SCIENTIFIC RESEARCH, 1 mars 2021, 21–24. http://dx.doi.org/10.36106/2941493.

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Introduction:Lumbar canal stenosis is dened, as an abnormal narrowing of the ligamento-osseous canal of the lumbar vertebra or of the foramina intervertebralis, causing a direct compression or a compromise of either the dural sac or the nerve root or indirectly to their vasculature producing symptoms of radiculopathy or and claudication.Patient whose symptoms do not show improvement after non-surgical or conservative trial, become eligible for surgical relief. AIM: To Prospectively analyze, Canal decompression, interbody Lumbar fusion with or without posterior stabilization with postero-lateral bone grafting, in cases presenting with MRI proven Lumbar Canal Stenosis, not responding to conservative management. Materials and Methods:Our study was done in Chettinad Hospital and Research Institute from January 2016 to December 2020, Follow-up period was for a minimum period of 12 months. 54 patients participated in the study.JOA and VAS score was recorded at the end of 12 months postsurgery to analyze the functional outcome. Results: There were 32 males and 22 females in the study.Our mean male JOA score was pre-operatively 9.88 which improved to 14.8 at the 12th month follow-up. Our mean JOA for females was at 8.3 which improved post operatively to 13.8.The mean VAS score pre-operatively in the men th and women were 7.4 and 8.6 respectively. This, at the 12 month follow up dropped to 0.8 and 1.2 for men and women respectively.The complications encountered in the study patients are Dural tears in 6 patients, supercial infection in 8 patients, Deep infection and Neurological decit in 4 and 3 patients respectively. All of these complications subsequently got resolved without any long term sequelae. Conclusion:In patients with lumbar canal stenosis whose symptoms do not abate, with conservative management, surgical lumbar spinal canal decompression, whether it is single level or dual level, does provide for a good clinico- functional outcome.

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Duckett, Abigail, Stephen Hughes, Basharat Jameel, Mohamed Yehia, Christian Seipp, Sanjay Agarwal et Iqbal Shergill. « Clinico-pathological Outcomes of Men with Initial Likert 2 Multiparametric Magnetic Resonance Imaging of the Prostate : Findings from a Case Series in a Non-teaching Hospital in UK ». Journal of Advances in Medicine and Medical Research, 31 décembre 2020, 63–70. http://dx.doi.org/10.9734/jammr/2020/v32i2430752.

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Introduction: With the recent introduction of Multiparametric MRI (MP-MRI) for suspected prostate cancer, we investigated the clinic-pathological outcome of men who were suspected to have prostate cancer but in whom initial MP-MRI was negative (Likert 2). Methods: Demographic and clinico-pathological outcomes data were analysed in men, with minimum 2 year follow up, who had undergone investigation for suspected prostate cancer with a negative (Likert 2) initial MP-MRI. The primary outcome was subsequent identification of prostate cancer in this cohort. Secondary outcome measures included correlation of prostate volume, presence of previous prostate biopsy, age, Prostate Specific Antigen (PSA) dynamics (pre and post MP-MRI scan), Digital Rectal Examination (DRE) findings and follow-up in months with the primary outcome. Results: With respect to the primary outcome of this study, prostate cancer was identified in 8.7% of men only (n=4). Of these, two cases were low risk and two were high risk. With regards the secondary outcome measures, there was a positive correlation between PSA dynamics, age at MP-MRI and follow-up in months with subsequent diagnosis of prostate cancer, although this was not statistically significant. There was no prostate cancer specific mortality or morbidity in this cohort. Conclusions: In this study, despite initial negative MP-MRI scan, prostate cancer was subsequently diagnosed in 4 men (8.7%). Reassuringly, this compares very favourably to the negative predictive value (89%) from the PROMIS trial and as such, adds an important body of work to the contemporary literature on modern diagnosis of suspected prostate cancer.

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Scanlon, Enya, Anita Lavery, Leanne Stevenson, Chloe Kennedy, Ryan Byrne, Andrew Walker, Martin Eatock, Mark Middleton, Anne Thomas et Richard Turkington. « P-OGC08 Translational Insights from the Dual ErbB Inhibition in Oesophago-gastric Cancer (DEBIOC) Clinical Trial - A Bioinformatic Analysis ». British Journal of Surgery 108, Supplement_9 (1 décembre 2021). http://dx.doi.org/10.1093/bjs/znab430.136.

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Abstract Background Oesophageal Adenocarcinoma (OAC) incidence in the Western-world has increased markedly over 30 years. 5-year survival rates for patients remains below 20% with dismal response to neo-adjuvant or perioperative chemotherapy for operable tumours. The Dual ErbB Inhibition in Oesophago-gastric Cancer (DEBIOC) clinical trial assessed efficacy of combined oxaliplatin and capecitabine (Xelox) with dual ErbB inhibitor AZD8931 in providing additional benefit to operable patients compared to Xelox alone. We utilised a bioinformatic approach combing Almac Clara-T Transcriptional Discovery software with unsupervised machine learning methods to unveil translational clinical potential and biological insights from DEBIOC patient biopsy and resection specimens. Methods Using microarrays of DEBIOC patient specimens with documented clinical observations, we combined unsupervised machine learning techniques with state-of-the-art Almac Clara-T software to assess transcriptional changes between treatment types regarding the 10 hallmarks of cancer, characterised by representative gene-expression signatures and scores. These methods were employed to identify possible mechanisms of treatment resistance, evaluate changes in the tumour-microenvironment and determine clinically significant molecular subgroups in OAC. Differential expression and pathway analytics were used to describe signalling dissimilarities between clusters from unsupervised analysis and phenotypes respective to hallmarks of cancer, with alignment of sensitivities to single-gene drug targets for subgroups of interest. Results Unsupervised clustering analysis of biopsy specimens, resulted in the identification of two robust subgroups pre-treatment in OAC, determined to be significantly associated with the prediction of Mandard Score (Tumour Regression Grade 1-5) post-treatment (fishers exact p < 0.05). Differential expression analysis revealed distinguishing biology between subtypes and noted increased ErbB signalling in non-responding patients in addition to increased PI3K signalling, highlighting a potential mechanism of resistance to dual ErbB inhibition (nominal p-value <0.05, FDR p-value <0.2). Semi-supervised clustering revealed hallmark-specific-phenotypes associated with clinical observations including lymph node involvement, EGFR FISH classification, vascular invasion and progression events at BH adjusted p-values <0.05. Conclusions Our analysis has revealed translational insights into possible mechanisms of drug resistance as well as cancer hallmark-specific phenotypes significantly associated with clinico-pathological factors during the DEBIOC clinical trial. Continued analysis into resulting phenotypes and clusters combined with the alignment of single gene drug target sensitivities is anticipated to reveal novel molecular pathways driving phenotypic differences in an effort to further inform biological understanding and improve treatment response and survival outcomes in OAC patients.

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Zarotti, Cristina, Bärbel Papassotiropoulos, Constanze Elfgen, Konstantin Dedes, Denise Vorburger, Bernhard Pestalozzi, Andreas Trojan et Zsuzsanna Varga. « Biomarker dynamics and prognosis in breast cancer after neoadjuvant chemotherapy ». Scientific Reports 12, n^o 1 (7 janvier 2022). http://dx.doi.org/10.1038/s41598-021-04032-x.

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AbstractBreast cancer is a biologically diverse disease with treatment modalities selected based on tumor stage and tumor biology. Distinct intrinsic subtypes and surrogate biomarker profiles play a major role for therapeutic decisions. Response rates to systemic and local treatments as well as the interaction with epidemiological risk factors have been validated in clinical trials and translational studies. This retrospective study addresses the question how biomarker profiles and treatment modalities in the neoadjuvant chemotherapy setting have changed during the past 15 years and what prognostic impact these changes implicate. 342 female breast cancer stage I-IV patients receiving neoadjuvant chemotherapy between 2003 and 2017 were analyzed. Overall survival (OS) was correlated with preoperative clinical stage, postoperative pathological stage, treatment modalities and tumor biology before and after chemotherapy. Two subgroups were separated using an arbitrary cut-off year at 2009/2010, due to 2010 when platinum containing regimens were first administered. Median follow-up was 54 months. 57 (17%) patients died; recurrences occurred in 103 of 342 (30%) patients. Nodal stage and intrinsic subtypes (pre- and postoperative) significantly correlated with OS (p < 0.001). Preoperative histological grading lacked prognostic power. When comparing the patient characteristics of the subgroups, we found significant difference in the following characteristics: cT, ypT, ypN, pCR and chemotherapy regimens (p < 0.001). There was no difference in OS when comparing the two subgroups. Pathological complete response (pCR) rates had a significant impact on OS and disease-free survival (DFS) in HER2+ and triple negative subtypes (p = 0.03). In multivariate analysis, high proliferation index (> 30%), clinical metastatic stage and pathological tumor stage had prognostic impact on OS (p < 0.001, p = 0.0001, p = 0.002). Clinico-pathological factors and distinct therapy regiments especially in triple negative and HER2+ subtypes have prognostic impact on pCR, OS and DFS after neoadjuvant chemotherapy.

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