tbuckley/cabot-search huggingface dataset:
Four versus six cycles of docetaxel and cyclophosphamide in early breast cancer.
Authors: Aparna Basu, Vrushali S. Dabak, Randa Loutfi, Haythem Y. Ali, Hadi Mohammed, Sharmeen Mahmood
Journal: Journal of Clinical Oncology (2019)

e12047 Background: ABC trials established the use of non-anthracycline containing regimen, docetaxel and cyclophosphamide (TC) as adjuvant therapy in early breast cancer. In clinical practice, TC is commonly used in Stage I Triple Negative (TN) and Stage I,II Hormone positive breast cancer. However, no specific recommendations exist in literature, regarding the number of cycles that can be used. i.e. TC4 vs TC6. Our aim, was to determine if TC4 is non-inferior to TC6 when used as adjuvant therapy in early breast cancer. Methods: We retrospectively reviewed 143 patients who were diagnosed with early breast cancer, between 2007 to 2017, at our institution who had received either TC4 or TC6 as adjuvant therapy. The number of cycles the patients received were based on provider preference. The two groups (TC4, TC6) were compared in regard to stage of cancer at diagnosis based on AJCC 7 th edition-stratified by TNM staging for hormone positive and T staging only for TN, grade of adverse events, recurrence and death from breast cancer. Median follow up was 5 years. Results: Out of the 143, 102(71.3%) received TC4 and 41(28.7%) received TC6. Among the hormone positive, 42 were stage I and out of which 32(76.2%) received TC4 and 10(23.8%) received TC6 and there were 24 stage II patients, out of which 17(70.8%) received TC4 and 7(29.2%) received TC6. Among the TN group, there were 64 who were T1, out of which 45(70.3%) received TC4 and 19(29.7%) received TC6, while there were 12 T2 patients, out of which 7(58.3%) received TC4 and 5(41.7%) received TC6. Recurrence of breast cancer was seen in 5(4.9%) in TC4 and 3(7.3%) in TC6, p=0.569. Death due to breast cancer was seen in 2(1.9%) in TC4 and 1(2.4%) in TC6, p=0.856. Adverse events were seen in 86(84.3%) in TC4 and 39(95.1%) in TC6,p=0.078. Adverse events of Grade 3 or higher were seen in 10(9.8%) in TC4 and 11(26.8%) in TC6, p=0.09. Conclusions: In this limited series, TC4 appears to be equally effective to TC6, with fewer adverse events of any grade and lower incidence of Grade 3 or higher side effects which was statistically significant. Although the proportion of patients who received TC 4 were higher in our series, the percentage of patients who received TC6 was higher in stage II for hormone positive and T2 for TN when compared to Stage 1 and T1 respectively. We also found a higher percentage of recurrence and death due to breast cancer in TC6 which was not statistically significant and this likely a reflection of the fact that as mentioned above patient with a higher stage at diagnosis tended to receive 6 cycles as compared to 4 cycles and therefore had a higher chance of recurrence in the future.
Association between the variation in hospital beds and inpatient chemo/radiotherapy for breast cancer: A retrospective study using the Japanese Diagnosis Procedure Combination database of over 500K records.
Authors: Rin Ogiya, Haruki Matsumoto, Shinya Matsuda
Journal: Journal of Clinical Oncology (2019)

e18008 Background: Chemo/radiotherapy for breast cancer patients does not require hospitalization in most cases. We investigated the relationship between the proportion of hospitalization for chemo/radiotherapy over total hospitalization among breast cancer cases (inpatient chemo/radiotherapy rate) and the number of hospital beds per capita using the national database in Japan. Methods: We conducted a retrospective observational study using Diagnosis Procedure Combination (DPC) database and National survey database from April 2012 to March 2016. We aggregated hospital-level data into prefecture-level data and classified the 47 prefectures into quintiles based on the number of hospital beds per capita (9-10 prefectures per quintile). Generalized estimating equations (GEE) were used for examining the relationship between the number of hospital beds and inpatient chemo/radiotherapy rate (discretionary setting) or the number of surgical operations (imperative setting). Results: Over the five-year study period, there were 561,165 records for hospitalization for breast cancer cases. The inpatient chemo/radiotherapy rate at each prefecture varied, ranging from 2.6% to 61.8% in 2016. The inpatient chemo/radiotherapy rate was significantly higher in the second highest and the highest quintile by 11.7% (95% CI 4.0-19.5%, P = 0.003) and 9.6% (95% CI 1.8-17.4%, P = 0.015), respectively, compared with the middle quintile. There was no significant difference between the lowest, second lowest and middle quintile. On the contrary, there was no significant difference in the number of surgical operations for breast cancer per capita between each quintile and middle quintile. Conclusions: We found that higher hospital beds associated with more chemo/radiotherapy in the inpatient setting. This study is a starting point for the discussion on the employment support for people with cancer and the economical utilization of the limited medical resource in the oncology field. The further studies evaluating the association between health resource and the other type of procedures are warranted.
Automated image analysis of NSCLC biopsies to predict response to anti-PD-L1 therapy
Authors: Sonja Althammer, Tze Heng Tan, Andreas Spitzmüller, Lorenz Rognoni, Tobias Wiestler, Thomas Herz, Moritz Widmaier, Marlon C. Rebelatto, Helene Kaplon, Diane Damotte, Marco Alifano, Scott A. Hammond, Marie-Caroline Dieu-Nosjean, Koustubh Ranade, Guenter Schmidt, Brandon W. Higgs, Keith E. Steele
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Immune checkpoint therapies (ICTs) targeting the programmed cell death-1 (PD1)/programmed cell death ligand-1 (PD-L1) pathway have improved outcomes for patients with non-small cell lung cancer (NSCLC), particularly those with high PD-L1 expression. However, the predictive value of manual PD-L1 scoring is imperfect and alternative measures are needed. We report an automated image analysis solution to determine the predictive and prognostic values of the product of PD-L1+ cell and CD8+ tumor infiltrating lymphocyte (TIL) densities (CD8xPD-L1 signature) in baseline tumor biopsies. <h3>Methods</h3> Archival or fresh tumor biopsies were analyzed for PD-L1 and CD8 expression by immunohistochemistry. Samples were collected from 163 patients in Study 1108/NCT01693562, a Phase 1/2 trial to evaluate durvalumab across multiple tumor types, including NSCLC, and a separate cohort of 199 non-ICT- patients. Digital images were automatically scored for PD-L1+ and CD8+ cell densities using customized algorithms applied with Developer XD™ 2.7 software. <h3>Results</h3> For patients who received durvalumab, median overall survival (OS) was 21.0 months for CD8xPD-L1 signature-positive patients and 7.8 months for signature-negative patients (<i>p</i>&nbsp;= 0.00002). The CD8xPD-L1 signature provided greater stratification of OS than high densities of CD8+ cells, high densities of PD-L1+ cells, or manually assessed tumor cell PD-L1 expression ≥25%. The CD8xPD-L1 signature did not stratify OS in non-ICT patients, although a high density of CD8+ cells was associated with higher median OS (high: 67 months; low: 39.5 months, <i>p</i>&nbsp;= 0.0009) in this group. <h3>Conclusions</h3> An automated CD8xPD-L1 signature may help to identify NSCLC patients with improved response to durvalumab therapy. Our data also support the prognostic value of CD8+ TILS in NSCLC patients who do not receive ICT. <h3>Trial registration</h3> ClinicalTrials.gov identifier: NCT01693562. Study code: CD-ON-MEDI4736-1108. Interventional study (ongoing but not currently recruiting). Actual study start date: August 29, 2012. Primary completion date: June 23, 2017 (final data collection date for primary outcome measure).
MET inhibitor resistance in patients with MET exon 14-altered lung cancers.
Authors: Robin Guo, Michael Offin, A. Rose Brannon, Andrew Chow, Lukas Delasos, Romel Somwar, Olivia Wilkins, Kerry Scott, Yuan Tian, Fabiola Cecchi, Todd A. Hembrough, Bob T. Li, Charles M. Rudin, Mark G. Kris, Maria E. Arcila, Natasha Rekhtman, Paul K. Paik, Marc Ladanyi, Ahmet Zehir, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2019)

9006 Background: MET exon 14 alterations comprise a novel class of lung cancer drivers. MET tyrosine kinase inhibitors (TKIs) are active in patients with these cancers, but objective response rates (ORRs) are modest (~30%-40%). A subset of these cancers may harbor intrinsic resistance. Moreover, patients with initial benefit invariably develop acquired resistance. We set out to identify potential resistance mechanisms. Methods: We studied patients with stage IV MET exon 14-altered lung cancers who received a MET TKI. When feasible, tumor and/or plasma samples were collected, prioritizing paired pre- and post-TKI collection. Tumor samples underwent targeted mass spectrometry analysis (Nantomics) and DNA- (including MSK-IMPACT)/RNA-based (MSK-Fusion) next-generation sequencing (NGS). Plasma cfDNA underwent targeted NGS. ORR and progression-free survival (PFS) were assessed (RECIST v1.1). Results: 74 patients received a MET TKI (1 TKI n = 55; ≥2 TKIs n = 19). 91% received crizotinib as their 1 st TKI. Pre-TKI MET levels in tumor tissue (range 0-2120 amol/µg) were associated with outcomes: ORR 63% (n = 7/11) and median PFS 6.9 mos with detectable MET vs ORR 0% (n = 0/5) and median PFS 4.6 mos with undetectable MET (HR for PFS 0.3). Pre-TKI RAS pathway activation was associated with response: ORR 0% (n = 0/6) with KRAS/NF1/RASA1 mutation vs ORR 29% (n = 25/87) in others. Similar outcomes were observed with pre-TKI KRAS expression (n = 16, all with detectable KRAS levels): ORR 0% (n = 0/2) in KRAS ≥700 amol/µg vs ORR 50% (n = 7/14) &lt; 700 amol/µg. Acquired resistance (Jackman criteria) was seen in 29 patients, 9 with paired pre-/post-treatment samples. On-target acquired resistance was found in 2/9 patients (22%): MET D1228N (n = 1), HGF amplification (n = 1). Potential off-target acquired resistance mechanisms were found in 5/9 pts (44%): KRAS G13V (n = 1), RASA1 S742* (n = 1), MDM2 amplification (n = 2), EGFR amplification (n = 1). Conclusions: Lack of MET expression or RAS pathway activation is associated with poor MET TKI outcomes in MET exon14-altered lung cancers. On-target acquired resistance is found in &lt; 25% of patients; HGF amplification is a novel mechanism. Off-target intrinsic/acquired resistance may be mediated by RAS/MDM2/EGFR pathway activation.
The microbiota and microbiome in pancreatic cancer: more influential than expected
Authors: Miao-Yan Wei, Si Shi, Chen Liang, Qing-Cai Meng, Jie Hua, Yi-Yin Zhang, Jiang Liu, Bo Zhang, Jin Xu, Xian-Jun Yu
Journal: Molecular Cancer (2019)

Microbiota is just beginning to be recognized as an important player in carcinogenesis and the interplay among microbes is greater than expected. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for which mortality closely parallels incidence. Early detection would provide the best opportunity to increase survival rates. Specific well-studied oral, gastrointestinal, and intrapancreatic microbes and some kinds of hepatotropic viruses and bactibilia may have potential etiological roles in pancreatic carcinogenesis, or modulating individual responses to oncotherapy. Concrete mechanisms mainly involve perpetuating inflammation, regulating the immune system-microbe-tumor axis, affecting metabolism, and altering the tumor microenvironment. The revolutionary technology of omics has generated insight into cancer microbiomes. A better understanding of the microbiota in PDAC might lead to the establishment of screening or early-stage diagnosis methods, implementation of cancer bacteriotherapy, adjustment of therapeutic efficacy even alleviating the adverse effects, creating new opportunities and fostering hope for desperate PDAC patients.
KEYNOTE-826: A phase 3, randomized, double-blind, placebo-controlled study of pembrolizumab plus chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer.
Authors: Ronnie Shapira-Frommer, Jerome Alexandre, Bradley Monk, Tanja N. Fehm, Nicoletta Colombo, Maria V. Caceres, Kosei Hasegawa, Coraline Dubot, Jerry Jing Li, Karen Stein, Stephen Michael Keefe, Krishnansu Sujata Tewari
Journal: Journal of Clinical Oncology (2019)

TPS5595 Background: Cervical cancer arises in the setting of persistent infection with high-risk human papillomavirus subtypes. Many patients with early-stage and locally advanced carcinoma can be salvaged with radical surgery and chemoradiation, respectively. However, women with recurrent/metastatic disease represent a poor prognostic group with high unmet clinical needs. Incorporation of anti-angiogenesis therapy has emerged as a therapeutic option, but the survival benefit of 3.7 months over chemotherapy (CT) alone is modest (Tewari et al. NEJM 2014). Because viral tumor antigen-specific T cells reside predominantly in programmed cell death 1–expressing T-cell compartments, checkpoint inhibition may unleash a diverse antitumor T-cell response. Based on the 14.3% objective response in KEYNOTE-158, the US FDA granted accelerated approval to pembrolizumab (pembro) in June 2018 for second-line therapy and beyond. Methods: KEYNOTE-826 is a phase 3, randomized, double-blind, placebo-controlled, multinational trial of CT with pembro or with placebo for first-line treatment of recurrent, persistent, or metastatic cervical cancer. Patients not previously treated with CT for recurrence who are not amenable to curative treatment will be randomized 1:1 to CT + pembro 200 mg or placebo every 3 weeks. The CT regimen (paclitaxel 175 mg/m 2 + cisplatin 50 mg/m 2 or carboplatin AUC 5, with or without bevacizumab 15 mg/kg) will be selected by the investigator before randomization. Stratification factors include metastasis status at diagnosis, bevacizumab use (yes/no), and tumor PD-L1 status (combined positive score &lt;1, 1 to &lt;10, or ≥10). Treatment will continue until disease progression, unacceptable toxicity, or voluntary patient withdrawal for up to 35 cycles (~2 years). Primary endpoints are progression-free survival (PFS) per RECIST v1.1 assessed by blinded independent central review and overall survival. Secondary endpoints are objective response, duration of response, 12-month PFS, patient-reported quality of life, and safety. Enrollment is ongoing. Clinical trial information: NCT03635567.
Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome: review of acute decompensated diabetes in adult patients
Authors: Esra Karslioglu French, Amy C Donihi, Mary T Korytkowski
Journal: BMJ (2019)

Abstract Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome (HHS) are life threatening complications that occur in patients with diabetes. In addition to timely identification of the precipitating cause, the first step in acute management of these disorders includes aggressive administration of intravenous fluids with appropriate replacement of electrolytes (primarily potassium). In patients with diabetic ketoacidosis, this is always followed by administration of insulin, usually via an intravenous insulin infusion that is continued until resolution of ketonemia, but potentially via the subcutaneous route in mild cases. Careful monitoring by experienced physicians is needed during treatment for diabetic ketoacidosis and HHS. Common pitfalls in management include premature termination of intravenous insulin therapy and insufficient timing or dosing of subcutaneous insulin before discontinuation of intravenous insulin. This review covers recommendations for acute management of diabetic ketoacidosis and HHS, the complications associated with these disorders, and methods for preventing recurrence. It also discusses why many patients who present with these disorders are at high risk for hospital readmissions, early morbidity, and mortality well beyond the acute presentation.
Cost-effectiveness of pazopanib as first-line treatment of metastatic renal cell carcinoma from National Health Service United Kingdom perspective.
Authors: Barbara Elizabeth Ratto, Ankur Khare, Kapil Gudala, Praveen Gunda
Journal: Journal of Clinical Oncology (2019)

e16088 Background: Recently, several therapies have been approved for treatment of metastatic renal cell carcinoma (mRCC) in the United Kingdom (UK); however, there is scarcity of comparative evidence to assist treatment decisions. We evaluated the cost-effectiveness of pazopanib as first-line treatment of mRCC from a UK National Health Service perspective. Methods: A partitioned-survival analysis model with 3 health states (alive with no progression, alive with progression, or dead) was used to evaluate the cost-effectiveness of pazopanib compared to sunitinib, tivozanib and cabozantinib in treatment-naive mRCC patients with treatment cycle length of 1 week and time horizon of 10 years. The model was populated with clinical effectiveness data obtained from network meta-analysis of pivotal trials and data on costs and utilities collected from UK-specific resources. The key model outcomes were quality-adjusted life years (QALY) and incremental cost-effectiveness ratio (ICER). Probabilistic and one-way sensitivity analyses were performed to test the uncertainty regarding model results. Results: Base-case analysis found that pazopanib was dominant (i.e. less costly and more effective) compared to sunitinib and tivozanib. Pazopanib had lower total costs (£69,861 vs £71,398 and £73,530) and higher QALYs (1.901 vs 1.835 and 1.669, respectively) compared to sunitinib and tivozanib. When compared with cabozantinib, pazopanib was found to be less costly (£174,735 vs £69,861) and less effective (total QALYs, 2.213 vs 1.901, respectively). Results of the probabilistic sensitivity analysis showed that at a willingness-to-pay (WTP) threshold of £30,000 per QALY, the probability of pazopanib being cost-effective was highest as compared to all comparators (84% vs sunitinib, 98% vs tivozanib and 100% vs cabozantinib). One-way sensitivity analysis revealed that effectiveness inputs, time horizon and others are model influencers. Conclusions: Based on a WTP threshold of £30,000/QALY gained, pazopanib is the most cost-effective treatment option compared to sunitinib, tivozanib and cabozantinib, for mRCC patients in UK.
The impact of a dedicated multidisciplinary tumor board on care for patients with brain metastases.
Authors: Nancy Wang, Justine Vanessa Cohen, Nathaniel C. Goss, Mia Bertalan, Maura C. Keeley, Daniel P. Cahill, Kevin S. Oh, Priscilla Kaliopi Brastianos
Journal: Journal of Clinical Oncology (2019)

e13585 Background: Brain metastases are the most common tumors to affect the central nervous system. Treatment options have recently evolved with the use of targeted therapies, immunotherapy, and increased clinical trials availability. We describe our institutional experience with a novel, weekly tumor board dedicated to brain metastases and its impact on treatment decisions and survival. Methods: We conducted a single institution cohort study at a large academic hospital with a dedicated center for CNS metastases. Attendance at tumor board included representatives from neuro-oncology, medical oncology, radiation oncology, neurosurgery, and neuroradiology. We prospectively gathered data on patient demographics, clinical history, and tumor board recommendations. Patients were followed to assess treatment course and survival. The Kaplan Meier method was used to calculate time to progression. Results: A total of 49 patients were presented over 2 months, with 4 patients presented twice. The median age at presentation was 63 yrs with a median ECOG of 1. The primary malignancy was 35% melanoma, 49% lung, 22% breast, the remainder other. Most patients had advanced, heavily pretreated disease: 69% had Stage IV disease at time of tumor board presentation with a median of 2 prior lines of systemic therapy, 73% had multiple brain metastases, 39% had prior surgical resection of brain metastases, and 57% had prior CNS radiation. The tumor board recommended a change in management in 26/53 case presentations: 5 surgery, 8 radiation, 9 medical therapy, 3 clinical trial, and 1 surveillance. Recommendations were followed in all except 4 cases due to patient preference and loss to follow-up. When active therapy was recommended, the median time to start was 7 days. Only 3 patients have died at a median follow-up of 62 days. 9 patients have progressed, with a median time to progression of 57 days. Conclusions: A multidisciplinary brain metastasis tumor board provides unique opportunities in the management of complex brain metastasis patients in an era of rapidly evolving therapeutic options. Additional follow-up is needed to assess long-term outcomes, and comparison to non-tumor board presented patients will be necessary.
Level of neo-epitope predecessor and mutation type determine T cell activation of MHC binding peptides
Authors: Hanan Besser, Sharon Yunger, Efrat Merhavi-Shoham, Cyrille J. Cohen, Yoram Louzoun
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Targeting epitopes derived from neo-antigens (or "neo-epitopes") represents a promising immunotherapy approach with limited off-target effects. However, most peptides predicted using MHC binding prediction algorithms do not induce a CD8 + T cell response, and there is a crucial need to refine the predictions to readily identify the best antigens that could mediate T-cell responses. Such a response requires a high enough number of epitopes bound to the target MHC. This number is correlated with both the peptide-MHC binding affinity and the number of peptides reaching the ER. Beyond this, the response may be affected by the properties of the neo-epitope mutated residues. <h3>Methods</h3> Herein, we analyzed several experimental datasets from cancer patients to elaborate better predictive algorithms for T-cell reactivity to neo-epitopes. <h3>Results</h3> Indeed, potent classifiers for epitopes derived from neo-antigens in melanoma and other tumors can be developed based on biochemical properties of the mutated residue, the antigen expression level and the peptide processing stage. Among MHC binding peptides, the present classifiers can remove half of the peptides falsely predicted to activate T cells while maintaining the absolute majority of reactive peptides. <h3>Conclusions</h3> The classifier properties further highlight the contribution of the quantity of peptides reaching the ER and the mutation type to CD8 + T cell responses. These classifiers were then validated on neo-antigens obtained from other datasets, confirming the validity of our prediction. Algorithm Availability: http://peptibase.cs.biu.ac.il/Tcell_predictor/ or by request from the authors as a standalone code.