tbuckley/cabot-search huggingface dataset:
Genomic and metabolic characterization of succinate dehydrogenase B deficient renal cell carcinoma.
Authors: Chung-Han Lee, Elizabeth Wei, William Lee, Yingbei Chen, Roy Mano, A. Ari Hakimi, Yiyu Dong, Almedina Redzematovic, Justin R. Cross, Satish Tickoo, Ramaprasad Srinivasan, Dayna Oschwald, Victor E. Reuter, Mark Dunphy, Emily Cheng, Robert J. Motzer, W. Marston Linehan, James Hsieh
Journal: Journal of Clinical Oncology (2016)

e16102 Background: Succinate dehydrogenase B (SDHB)-deficient renal cell carcinoma (RCC) is a rare histologic subtype characterized by loss of SDHB expression, a key subunit of succinate dehydrogenase (SDH) in the tricarboxylic acid (TCA) cycle. Loss of SDH is also seen in gastrointestinal stromal tumors and hereditary paraganglioma-pheochromocytoma syndrome. SDHB-deficient RCC is typically indolent; however, it can develop into highly aggressive disease, and the pathogenesis and pathophysiology remain poorly understood. Methods: From 2014 – 2015, 3 patients with highly aggressive hereditary SDHB-deficient RCC were identified. The genomics were examined by whole genome and targeted exome sequencing. SDHB-/- and SDHB+/-cell lines were generated from the tumor and tumor-associated stroma of 1 patient. Results: Patients had high 13F-deoxyglucose (FDG) uptake on PET scan (Max SUV up to 48) and hyperlactatemia (up to 13 mM/L) that increased with tumor burden. Increased glutamine uptake was also seen by 13F-glutamine PET. Histologies were diverse, but all showed loss of SDHB expression by IHC and loss of heterozygosity of SDHB with a germline mutation in the remaining allele. In one patient, no other genomic alterations were identified by whole genome sequencing, suggesting that loss of SDHB may be sufficient for tumorigenesis. SDHB-/- cells had disturbed mitochondrial architecture with less cristae and an enlarged matrix by electron microscopy. Metabolic assessment of SDHB-/- cells showed increased glucose consumption and lactate production, and defective oxidative respiration. Measurement of intracellular metabolites by mass spectroscopy showed a > 60 fold increase in succinate, which could be reduced by glutamine deprivation. The SDHB-/- cell line was also more sensitive to glucose and glutamine deprivation compared to SDHB+/+cell lines. Conclusions: Loss of SDHB alone appears to be sufficient for tumorigenesis and induces dramatic metabolic shifts, as an extreme example of the Warburg Effect. Agents directed towards altering metabolism, such as mTOR targeted and glutaminase inhibitors, should be further explored.
Quality improvement project for prevention of infusion related reactions of daratumumab therapy in multiple myeloma patients.
Authors: Vishal Jindal, David Scott Shepro, Leigh Pranckevicius, Ahmad Daniyal Siddiqui
Journal: Journal of Clinical Oncology (2018)

e18877 Background: Daratumumab (DARA) is an IgG1K human monoclonal antibody that binds to CD38 and inhibits the growth of myeloma cells. The most common adverse reaction of DARA is infusion related reactions (IRRs). To prevent IRRs, pre-infusion and post-infusion pre-medications are recommended. However, 45% of patients still develop infusion reactions as per previous studies. Most of the IRRs occur in first four hours with median of 1.4 hours and especially after increasing the infusion rate from 50ml/hr to 100 ml/hr at 1hr. Three patients who received DARA with standard protocol all had infusion reactions before 2 hours. This lead to introduction of quality improvement project to give pre-medications at 1hr along with usual pre-infusion and post-infusion medications. Methods: This is a quality improvement project with a goal to prevent IRRs with standard therapy plus pre-medications at one hour of the first two infusions. Standard therapy includes Pre-infusion medications (Diphenhydramine 50mg IV, methylprednisolone 100mg IV, Famotidine 20mg IV, Cetirizine 10mg and Tylenol 975 mg) and post-infusion medications (20mg oral Prednisone on day 2 and 3). In this project a total 8 patients were treated with pre-medications (Methylprednisolone 40mg IV, Famotidine 20mg IV, and Diphenhydramine 25mg IV) at one hour, after the initiation of DARA infusion along with standard therapy. IRRs were graded as per CTCAE 4.03. Results were compared with the previous studies which used standard timing of therapy. Results: Out of 8 patients treated during their initial infusions of DARA, one patient (12.5%) developed grade 2 IRRs. The other 7 patients did not have any IRRs. The incidence of infusion modification due to IRR was 12.5 % in our study as compared to 42% with standard pre-medications schedule. There have been no short term or long term adverse effects seen with this change in our pre-medications schedule. Conclusions: With the addition of pre-medications at 1 hour after initiation of DARA infusion, the rate of IRRs reduced dramatically. This led to a decrease in the total infusion time and increased the tolerability. Additional clinical trials may be needed to confirm this outcome.
Phase III randomized trial of comparing chemoradiotherapy vs. radiotherapy alone in lymph node negative patients with early-stage cervical cancer following radical hysterectomy.
Authors: Congying Xie, Xiance Jin, Lili Li, Xuebang Zhang, Shengliu Xue
Journal: Journal of Clinical Oncology (2016)

e17002 Background: Chemotherapy concurrent with radiotherapy has become the standard treatment for cervical cancer patients with high risk factors. However, the treatment modality in patients with low-risk is still disputable. The purpose of this study is to determine whether concurrent paclitaxel/cisplatin chemoradiotherapy are more effective than radiotherapy (RT) alone in treating early-stage cervical cancer patients with negative lymph nodes after radical hysterectomy. Methods: Between January 2011 and November 2014, 165 eligible cervical cancer patients with stage IA2 to IIB and negative lymph nodes were enrolled, randomized to chemoradiotherapy (CRT) (80 patients) and radiotherapy (RT) (85 patients), respectively. A RT dose of 46-50 Gy was administered in 23-25 fractions with two or four-field box technique. Chemotherapy consisted of paclitaxel 135 mg/m2 d1 and cisplatin 25mg/m2 d1-3 intravenously every 4 weeks with radiation. Results: The hazard ratios (HR) for disease -free survival (DFS) and overall survival (OS) in the CRT arm and the RT only arm were 0.84 (95% CI = 0.36–1.93, p = 0.67) and 0.61 (95% CI = 0.20–1.86, p = 0.38), respectively. The 5-year DFS and OS for CRT and RT alone groups were 85.9% vs. 83.5%, and 92.6% vs. 88.4%, respectively. For subgroup analysis, CRT significantly increased the 5-year DFS and OS for patients tumor sizes ≥ 3 cc (HR 0.23; 95% CI 0.05–1.0 and HR 0.21; 95% CI 0.04–0.99, for DFS and OS, respectively). For patients with negative lymphovascular invasion, CRT increased 5-year DFS (HR 0.21; 95% CI 0.04–0.99). Multivariate analysis indicated that tumor size was a significant prognostic factor for both DFS and OS, and age was significantly associated with OS. Grade 2 to 4 gastrointestinal disorders, radiation enteritis, radiation cystitis and myelosuppression were more frequent side effects observed in the CRT arm. Conclusions: CRT with cisplatin and paclitaxel achieved better DFS and OS in early-stage cervical cancer patients with negative lymph nodes compared with RT alone, along with a higher rates of acute grade 2–4 complications. Grade 3 and 4 toxicities were infrequent and tolerable overall. Clinical trial information: NCT01756170.
Evaluation of liquid biopsies for molecular profiling and monitoring in non-small cell lung cancer (NSCLC) patients.
Authors: Jordi Remon, Jean-Charles Soria, Ludovic Lacroix, Karen Howarth, Andrew Lawson, Sarah Smalley, Davina Gale, Vincent Plagnol, Emma Green, Nitzan Rosenfeld, Cecile Jovelet, Chloe Pannet, Benjamin Besse
Journal: Journal of Clinical Oncology (2016)

11533 Background: Effective and non-invasive methods for actionable molecular alterations in NSCLC patients (pts) are urgently needed. Molecular profiling is often limited by access to sufficient tumour tissue for comprehensive analysis and due to tumour heterogeneity, the complete range of tumor DNA abnormalities may not be represented. Circulating tumour DNA (ctDNA) can be used as a minimally-invasive liquid biopsy for the detection and quantification of molecular abnormalities Methods: We enrolled a prospective cohort of 70 Stage IIIB/IV NSCLC pts to collect blood (10ml K2-EDTA) prior to treatment (D1) and after treatment (D2, D21, D42 and every imaging assessment until relapse in a subset of 25 patients). Blood samples were processed (double-spin method) and analysed using an enhanced TAm-Seq method, which enables detection of molecular abnormalities across 35 genes. Statistical analyses are in progress to quantify the concordance of ctDNA with tissue biopsy, and to assess the value of ctDNA as a dynamic tool following treatment. Results: As of January 2015, 26 pts were analysed (69% were male, 19% never-smoker, 84% had an adenocarcinoma subtype, and 88% stage IV). Only 46% (n = 12) of tumor biopsies provided sufficient sample tissue for molecular analysis, obtaining a molecular profile for 9 out of 12 pts. ctDNA profiling was possible for all pts, which detected cancer mutations in 20 out of 26 pts. Median number of plasma somatic mutations was 2, predominantly located in KRAS, TP53 and EGFRmutation. Of that, 46% of mutations detected in ctDNA were observed at a frequency below 1%. ctDNA profiling reported the same molecular abnormality than in the tissue in 7 out of 9 patients, with a 78% concordance rate. Indeed, 51% of mutations detected at D1 were also detected at D21. For mutations present at both time points, the reduction in allele fraction was small (median 18%). Conclusions: ctDNA can be used as a ‘liquid biopsy’ for molecular profiling of NSCLC pts to detect actionable molecular alterations when tissue biopsy is unavailable providing real-time information. The full analysis of 70 pts, including dynamic analysis profiles following treatment will be presented during the meeting.
Actionable genomic biomarkers in a low socioeconomic status (SES) population with gastrointestinal (GI) cancers.
Authors: Vi Kien Chiu, Diaa Osman, Jessica Belmonte, Joshua K Routh, Heloisa P Soares, David R. Martin, Joshua A Hanson, Rama R Gallupalli, Anita Kinney, Mohammad Vasef, Anne-France Le Rolle
Journal: Journal of Clinical Oncology (2018)

e24310 Background: Immunotherapy and Precision Medicine therapy have increased survival in a minority of cancer patients. Genomic biomarkers that select for high tumor responders are not widely implemented in clinical practice, especially in GI cancer patients with low SES. Methods: Actionable genomic biomarkers, which included MSI status, HER2 amplification, and mutations in KRAS, NRAS and BRAF, were determined in New Mexico GI cancer patients from 2011 - 2018. Results: Testing for genomic biomarkers increased significantly in New Mexico GI cancer patients from 2011 to 2018. MSI-High status was observed in > 10% of GI cancer patients. The presence of actionable genomic biomarker in GI cancer patients correlated with increased tumor response rate. Conclusions: Testing for actionable genomic biomarkers in a low SES GI cancer population identified patients most likely to benefit from immunotherapy and Precision Medicine therapy.
Frailty and health-related quality of life (HRQOL) in older women with breast cancer (BC).
Authors: Grant Richard Williams, Allison Mary Deal, Hanna Kelly Sanoff, Mackenzi Pergolotti, Kirsten A Nyrop, Shlomit Strulov Shachar, Bryce B. Reeve, Emily Jean Guerard, Jeannette T Bensen, Seul Ki Choi, Hyman B. Muss
Journal: Journal of Clinical Oncology (2016)

e21536 Background: BC treatments impact the physical, mental, and social health of women, and older women who are frail may experience significant HRQOL declines. This study evaluated the association between frailty and long-term HRQOL in older adults with BC undergoing cancer treatment. Methods: This prospective single institution study utilized the Carolina Senior Registry (CSR) (NCT01137825). BC patients within CSR were recontacted to complete a follow-up HRQOL questionnaire (median 4 years). Baseline Geriatric Assessment (GA) variables were used to calculate a 32-item frailty index based on the principles of deficit accumulation [ASCO 2015, abstr 9535] and categorized as robust (0-0.2), pre-frail (0.2-0.35), and frail (>0.35). Outcomes included HRQOL domains of physical function (PF), social roles, fatigue, depression, anxiety, pain, and sleep disturbance measured using Patient-Reported Outcomes Measurement Informational System (PROMIS) instruments scored as T scores (mean 50, standard deviation 10) with higher PF and social scores and lower symptom (e.g., fatigue) scores indicating better HRQOL. Regression modeling compared outcomes between frailty groups. Results: Of 190 eligible patients: 47 deceased, 71 completed HRQOL survey (64 with sufficient data to calculate frailty index), 14 declined, and 58 were lost to follow-up. Mean age was 71 years (range 65-86), 90% were white, and 61% had at least some college education. Using the frailty index, 49 (77%) patients were robust, 12 (19%) pre-frail, and 3 (5%) frail. Patients identified as pre-frail/frail reported worse physical function and social roles, and more fatigue, depression, anxiety, and pain (see Table 1). Conclusions: A baseline GA-based frailty index was associated with all domains of long-term HRQOL in older adults with BC. Further research is necessary to develop interventions for frail patients who are potentially at high-risk for poor HRQOL outcomes. Association of baseline frailty index and HRQOL at follow up. PROMIS HRQOL domains Robust N=49 Pre-frail/Frail N=15 p Physical Function 48 36 <0.001 Social Roles 60 50 <0.001 Fatigue 44 53 <0.001 Depression 44 51 <0.001 Anxiety 44 50 0.019 Pain Interference 49 54 0.049 Sleep Disturbance 45 50 0.034
Gender differences in faculty rank amongst radiation oncologists in United States: A cross-sectional study.
Authors: Irbaz Bin Riaz, Umar Zahid, Nageena Khalid, Farman Ali, Rehan Mansoor Farooqi, Siddhartha Yadav, Ammad Raina, Sandipan Bhattacharjee, Faisal Khosa
Journal: Journal of Clinical Oncology (2018)

11016 Background: Female faculty in academic medicine is underrepresented in leadership positions and reportedly has fewer publications, lower h-indices and grant funding. However, there is a lack of evidence examining whether this gender disparity persists after adjusting for scholarly productivity and clinical experience among academic radiation oncologist. Methods: We used the Fellowship and Residency Electronic Interactive Database (FREIDA) to identify faculty members of radiation oncology residency training programs in the US . Faculty rank (assistant, associate and full professor) was obtained by review of program website. Data on physician gender, clinical experience in years, number of publications, h-index, clinical trial investigator, advance degree and ranking of medical school was collected using program websites, Doximity and Scopus databases. Primary outcome of the study was a binary outcome odd of professorship versus assistant plus associate professorship. We used a multivariable logistic regression model to estimate the gender difference in full professorship after adjusting for these factors. Results: A total of 906 radiation oncologists were included in the final analysis. 70.2% (n = 636) were men and 29.8% (n = 270) women. Women had less clinical experience (median of 10 years vs 14 years, p < 0.0004), fewer publications (median of 17 vs 32 publications, p < 0.0001), less h-index (median of 7 vs 12, p < 0.0001), less likely to be clinical trials investigator (41% vs 48%, p = 0.05), less likely holding advance degree (22% vs 28%, p = 0.067) but were more likely to be graduate of top 20 medical schools in research (27% vs 25%, p = 0.66). Women were under represented at higher faculty rank with 43 out of 270 (15.9%) were full professors compared to 194 out of 636 (30.5%) men with the absolute difference of 14.6% (p < 0.001). Moreover, women were found less likely to be full professors compared to men (odds ratio, 0.55; 95% confidence interval, 0.32-0.94; p = 0.029) in adjusted logistic regression analysis. Conclusions: Among radiation oncology faculty gender disparity exists at higher faculty ranks even after accounting for academically relevant factors influencing the academic progress.
Extended 5-y follow-up (FU) of phase 3 ELOQUENT-2 study of elotuzumab + lenalidomide/dexamethasone (ELd) vs Ld in relapsed/refractory multiple myeloma (RRMM).
Authors: Sagar Lonial, Meletios A. Dimopoulos, Katja Weisel, Darrell White, Philippe Moreau, Maria-Victoria Mateos, Jesus San-Miguel, Kenneth Carl Anderson, Ofer Shpilberg, Sebastian Grosicki, Ivan Spicka, Adam Walter-Croneck, Hila Magen, Andrew Belch, Donna Ellen Reece, Meral Beksac, Suresh Shelat, Oumar Sy, Anil K. Singhal, Paul G. Richardson
Journal: Journal of Clinical Oncology (2018)

8040 Background: The immunostimulatory monoclonal antibody elotuzumab exhibits a dual mechanism of action, directly activating natural killer cells and mediating myeloma cell death via antibody-dependent cell-mediated cytotoxicity. In ELOQUENT-2 (NCT01239797), ELd showed sustained reduction in risk of disease progression or death at 2- (30%), 3- (27%), and 4-y (29%) FU vs Ld, and a favorable trend in overall survival (final analysis at 427 deaths). Here we present progression-free survival (PFS) data at 5 y, a milestone timepoint in cancer survival analyses. Methods: RRMM patients (pts) randomized 1:1 to ELd or Ld in 28-d cycles until disease progression/unacceptable toxicity. Coprimary endpoints: PFS and overall response rate (ORR) per independent review committee. Results: In all, 646 pts were randomized to ELd (n = 321) and Ld (n = 325). At database lock (Nov 29, 2017), 13% (ELd) vs 7% (Ld) of pts remained on treatment; discontinuation was mostly due to disease progression (55 vs 56%). At 5-y FU (minimum 60 mo), ELd showed 27% reduction in risk of progression or death vs Ld (HR 0.73, 95% CI 0.60–0.87) and relative improvement of 50% in PFS rate at 5 y (18 vs 12%). Pts with ≥very good partial response (ELd 36% vs Ld 30%) had the greatest reduction in risk of progression/death (HR 0.63, 95% CI 0.44–0.89). ORR was 79% (ELd) vs 66% (Ld). G3–4 AEs included blood and lymphatic system disorders (ELd vs Ld: 46 vs 46%), infections (35 vs 27%), vascular diseases (11 vs 8%), second primary malignancies (SPMs; 10 vs 6%), and cardiac disorders (5 vs 8%). Higher rate of any-grade infection (84 vs 75%) and SPMs (17 vs 11%) may reflect longer median duration of treatment with each agent of the ELd vs Ld regimens (E/L/d vs L/d: 17/17/17 vs 12/12 mo). Fewer deaths occurred with ELd than Ld (193 vs 208), mostly due to disease progression. Conclusions: Elotuzumab (+ Ld) has the longest median FU of an immuno-oncology agent in MM. At the milestone timepoint of 5 y, ELd showed sustained, durable clinically relevant improvement in PFS, a 27% reduction in the risk of progression or death, and a safety profile with minimal incremental AEs with ELd vs Ld. Study funding: BMS. Writing support: L Yee, Caudex, funded by BMS. Clinical trial information: NCT01239797.
Abstract 14896: Premature Atrial Contractions Are Not associated With Left Ventricular Dysfunction
Authors: Daniel Akyeampong, Alex Tan, Karoly Kaszala, Kenneth A Ellenbogen, Jose F Huizar
Journal: Circulation (2016)

Introduction: Frequent ventricular ectopy (PVCs) is known to be associated and cause non-ischemic cardiomyopathy (PVC-cardiomyopathy). Similar to PVCs, few studies and a single animal model have su...
A novel scoring system to predict survival in patients with advanced pancreatic adenocarcinoma: The Memorial Sloan Kettering Cancer Center (MSKCC) Prognostic Score (MPS).
Authors: Andrew Chung Yang, Alison Wiesenthal, Andrew S. Epstein, Jessica Goldberg, Jason Meadows, Eileen Mary O'Reilly, Paul A. Glare
Journal: Journal of Clinical Oncology (2017)

4105 Background: A major limitation of several common prognostic tools, e.g. the Eastern Cooperative Oncology Group (ECOG), Karnofsky, and Palliative Performance Scales, is a reliance on subjective clinical assessment. An objective tool, the Glasgow Prognostic Score (GPS) derived from C-reactive Protein (CRP) and albumin levels, has been validated in patients with operable and inoperable malignancies but has the disadvantage that CRP is not routinely measured in the United States. We examined if the Neutrophil-Lymphocyte Ratios (NLR) (Ahn, H.K., et al., Neutrophil-Lymphocyte Ratio Predicts Survival in Terminal Cancer Patients. J Palliat Med, 2016) could be substituted for CRP in the GPS to predict survival in patients with advanced pancreatic adenocarcinoma. Methods: A retrospective review chart identified patients at MSKCC with pathology-confirmed stage IV pancreatic adenocarcinoma diagnosed between 2011 to 2014. Pre-treatment absolute neutrophil count, absolute lymphocyte count, and albumin were extracted. The NLR for each patient was calculated and assigned NLR ≤ 4 a value of 0; NLRs &gt; 4 a value of 1, serum albumin &gt; 4 g/dl assigned a value of 0; and serum albumin &lt; 4 g/dl assigned a value of 1. Combining NLR and albumin scores results in a composite MPS score of 0-2, similar to GPS. We evaluated the association of the MPS with overall survival. Results: N = 833 patients were identified with median survivals in the table below. A log-rank test showed statistically significant differences in survival between MPS groups (p &lt; 0.00005). The MPS on univariate analysis had a HR of 1.36 (95% CI 1.23 – 1.50, p &lt; 0.0005) associated with overall survival. Conclusions: The MPS, a composite of NLR and albumin, is an objective prognostic tool that divided this sample of patients into three clinically and statistically significant subgroups. Further interrogation will control for performance status, disease characteristics and therapy. [Table: see text]
Overall survival in patients with metastatic melanoma treated with concurrent ipilimumab and radiotherapy.
Authors: Kristian Michael Koller, Heath B. Mackley, Henry Wagner, Giampaolo Talamo, Todd Schell, Colette Pameijer, Rogerio Izar Neves, Bryan Anderson, Kathleen M Kokolus, Carol Mallon, Joseph J. Drabick
Journal: Journal of Clinical Oncology (2016)

3023 Background: There is a growing body of evidence supporting the complementary roles of radiation therapy and immunotherapy in the treatment of malignancy. The mechanism of this phenomenon is unclear, but is thought to be mediated by synergistic mechanisms of immune activation. Ipilimumab (Ipi) is a monoclonal antibody used in the treatment of malignant melanoma that inhibits cytotoxic T-Lymphocyte antigen 4 (CTLA-4), an immunologic checkpoint on T cells. There are a few small studies suggesting an interaction between ipilimumab and radiation therapy, but larger systematic studies supporting these observations are limited. Methods: We conducted a retrospective analysis to evaluate all patients treated with ipilimumab for metastatic melanoma at a single institution from May 2011 to June 2015. Patients were grouped into those that had received concurrent radiation therapy while on ipilimumab (Ipi-RT) treatment, and those who did not. We then evaluated the treatment response following completion of ipilimumab. Primary outcome measured was rate of complete response (CR) in both radiated and distant disease sites, measured by RECIST criteria. Secondary outcome measures included ORR and OS. Results: A total of 101 patients received ipilimumab in the prespecified time frame. Seventy received Ipi-RT and 31 received ipilimumab without concurrent RT. Among the 70 who received Ipi-RT, 18 (25.7%) achieved a CR, compared to 2 out of 29 (6.45%) in the Ipi alone group [Odds ratio 5.02 (95%CI 1.09-23.2), p = 0.04]. Median OS was significantly increased in the concurrent Ipi-RT arm at 21 months vs 10 months for Ipi alone (p = 0.025). Conclusions: Patients treated with concurrent ipilimumab plus radiation therapy had a statistically significant increase in rates of complete response and median OS than those treated with ipilimumab alone. Prospective studies are needed to validate these findings.