tbuckley/cabot-search huggingface dataset:
Phase 1b study of venetoclax plus R- or G-CHOP in patients with B-cell non-Hodgkin lymphoma.
Authors: Andrew David Zelenetz, Gilles A. Salles, Kylie D. Mason, Carla Casulo, Steven Le Gouill, Laurie Helen Sehn, Herve Tilly, Guillaume Cartron, Martine E.D. Chamuleau, Andre Goy, Constantine Tam, Pieternella J. Lugtenburg, Rebecca L. Elstrom, Wanling Hsu, Mehrdad Mobasher, Franck Morschhauser
Journal: Journal of Clinical Oncology (2016)

7566 Background: Venetoclax (VEN) is a selective, potent oral Bcl-2 inhibitor with activity in patients (pts) with relapsed/refractory (R/R) NHL. In NHL xenograft models, VEN enhances efficacy of CHOP and rituximab (R) or obinutuzumab (GA101; G). Methods: Dose escalation of VEN plus R-CHOP (Arm A) or G-CHOP (Arm B) was evaluated in B-cell NHL pts with ≤1 prior therapy. Pts received VEN (200−800 mg) on Cycle (C) 1 Day (D) 4 then daily for 8 cycles in Cohort 1. VEN dosing in Cohorts 2-4 was C1 D4-10 and C2-8 D1-10. CHOP was given for six 21-day cycles, R was given D1 of C1-8 (Arm A). G was given D1, 8, 15 of C1 and D1 of C2-8 (Arm B). All pts had G-CSF, prophylaxis for TLS at start of VEN dosing (including hospitalization for pts with mass ≥10cm), and mid-cycle CBC. DLTs were assessed in C1-2. Objectives were safety, PK, determination of MTD and recommended phase 2 dose (RP2D) of VEN with R/G-CHOP. Response was assessed by Lugano criteria. Results: As of 11/30/15, 46 pts enrolled in 4 cohorts on each Arm: 19 pts (41%) had FL, 15 (33%) DLBCL, 7 (15%) transformed indolent NHL, 4 (9%) MZL and 1 WM. Only five (11%) had received one prior therapy. Sixteen pts (35%) had completed therapy, 21 (46%) were on therapy and 10 (22%) discontinued: 9 due to AEs (6 in Cohort 1) and 1 PD (C1D5). Three patients had DLT in Cohort 1 (Table), thus the VEN regimen was changed to C1 D4-10 and C2-8 D1-10 for Cohorts 2-4. Most common AEs were nausea (48%), fatigue (41%), and diarrhea (41%). Most common Gr 3/4 AEs were neutropenia (37%) and febrile neutropenia (26%). No pts died. Three pts had laboratory TLS at start of VEN dosing, without clinical sequelae. Gr 4 thrombocytopenia (TCP) was more frequent in Arm B than Arm A; in Cohorts 2-4, TCP occurred mid-cycle, with no related cycle delay or clinically significant bleeding. Conclusions: VEN + R/G-CHOP was tolerable with discontinuous VEN dosing. MTD was not reached. RP2D for VEN+R-CHOP is 800mg C1 D4-10 and C2-8 D1-10. VEN+G-CHOP dose finding is ongoing. Responses will be presented. Clinical trial information: NCT02055820.Cohort Arm (N pts) 1: 200mg continuous 2: 400mg discontinuous 3: 600mg discontinuous 4: 800mg discontinuous A (7) B (7) A (3) B (3) A (8) B (6) A (6) B (6) DLT* 1 2 - - 1 1 - - TLS - - - - 1 1 - 1 Gr 4 TCP 3 2 - - 1 3 - 4 *Cohort 1A: Gr 3 TCP; 1B: Gr 3 pneumonia, Gr 3 infection; 3A: Gr 4 TLS; 3B: Gr 4 febrile neutropenia.
Understanding factors contributing to geographic variations in end-of-life expenditures.
Authors: Nancy Lynn Keating, Haiden Huskamp, Elena Kouri, Deborah Schrag, Mark C Hornbrook, David Andrew Haggstrom, Mary Beth Landrum
Journal: Journal of Clinical Oncology (2018)

10008 Background: Health care spending at the end of life varies across geographic areas and yet is not associated with improved outcomes. The factors underlying these variations are poorly understood. We assessed the extent to which geographic variation in end-of-life spending for advanced-stage cancer patients is explained by differences in patient sociodemographic factors, clinical factors, patient beliefs, physician beliefs, and availability of services. Methods: Using data from the prospective, multi-regional CanCORS study, we studied 1132 patients with advanced-stage lung and colorectal cancer diagnosed in 2003-2005 who died before 2013. We linked patient and physician survey data, medical record data, and Medicare data, and we characterized Medicare spending in the last 30 days of life. After assessing differences in patient factors/beliefs, physician beliefs, and availability of services across areas that differed based on Dartmouth Atlas measures of intensity of end-of-life spending, we used mixed effects linear regression with random area effects to assess the area-level variance in spending in the last 30 days of life in our cohort and the proportion of that variance explained with sequentially adding groups of explanatory variables. Results: The mean (SD) expenditures in the last 30 days of life were $13,664 ($17,563). Physicians in higher-spending areas reported less knowledge and comfort caring for dying patients and less positive attitudes about hospice (all P < .05). Higher-spending areas had more physicians, a lower percentage of primary care providers, and fewer hospices/10,000 persons. Physician beliefs and availability of services each explained 45-60% of the variation in end-of-life expenditures; area-level patient beliefs did not contribute to area-level variations. Conclusions: Physicians' beliefs and area-level availability of services but not patients' beliefs were important factors explaining geographic variations in intensity of end-of-life spending for patients with advanced-stage cancer. Physician training and strategic allocation of services may have potential for decreasing unwarranted variation in care at the end of life for patients with advanced-stage cancers.
Weekly paclitaxel (WP) +/- bevacizumab (B) in angiosarcoma (AS) patients (pts): Analysis of prognostic/predictive factors from a randomized phase 2 trial.
Authors: Loic Lebellec, Francois Bertucci, Emmanuelle Tresch-Bruneel, Isabelle Laure Ray-Coquard, Axel Le Cesne, Emmanuelle Bompas, Sophie Piperno-Neumann, Antoine Italiano, Christine Chevreau, Didier Cupissol, Jacques-Olivier Bay, Olivier Collard, Esma Saada-Bouzid, Nicolas Isambert, Corinne Delcambre, Jean-Yves Blay, Anthony Goncalves, Nicolas Penel
Journal: Journal of Clinical Oncology (2017)

11024 Background: WP is an active regimen for treatment of AS pts (Ray-Coquard JCO 2015). We report here the correlative analysis conducted during a phase 2 trial assessing WP +/- B. Methods: Circulating pro/anti-angiogenic factors (FGF, PlGF, SCF, Selectin, thrombospondin, VEGF, VEGF-C) were collected at D1 and D8. Prognostic value for PFS was assessed using Cox model (biomarkers as continuous variables). We attempt to identify subgroups of pts benefiting from adding B using interaction tests (predictive factors). Results: Among the 51 pts enrolled in this trial, 45 were analyzable: 20 in Arm A (WP without B) and 25 in Arm B (with B). Median PFS was 5.5 and 6.1 months, respectively (p = 0.84). Samples were collected in 45 pts at D1 and 42 pts at D1 and 8. Baseline biomarkers were similar in both arms (excluding Selectin, significantly lower in arm A: median of 25 vs. 35 ng/mL, p = 0.03). In arm A, there was no significant difference between values at D1 and D8. In arm B, there were a significant decrease in VEGF (from a median of 0.49 to 0.08 ng/mL; p &lt; 0.01) and selectin (from a median of 35.3 to 31.7 ng/mL; p &lt; 0.01), and a significant increase in PlGF (from a median of 16.1 to 30.0 pg/mL; p &lt; 0.01). In univariate analysis, factors associated with PFS were: de novo vs. radiation-induced AS (HR = 2.39 (p &lt; 0.01), visceral vs. superficial AS (HR = 2.04; p &lt; 0.03), VEGF-C at D1 (HR = 0.77; p &lt; 0.03), FGF at D8 (HR = 1.17; p &lt; 0.01), difference in FGF D8-D1 (HR = 1.24; p &lt; 0.01), and PlGF value at D1 (HR = 1.02; p &lt; 0.05). In multivariate analysis, factors associated with PFS were: de novo AS (HR = 2.39; p = 0.03), VEGF-C at D1 (HR = 0.73; p &lt; 0.02) and FGF difference between D8 and D1 (HR = 1.16; p &lt; 0.02). None of these factors were associated with benefit of adding B. Conclusions: Baseline VEGF-C levels and change in FGF were independent prognostic factors in pts with or without B. Addition of B significantly decreased the level of circulating VEGF and selectin and increased the level of circulating PlGF in AS patients. We did not identify subgroup of pts benefiting from adding of B to WP. Clinical trial information: NCT01303497.
A randomized phase II study of the nutritional and exercise treatment for the elderly patients with advanced non-small cell lung or pancreatic cancer: The NEXTAC-TWO study.
Authors: Satoru Miura, Tateaki Naito, Shuichi Mitsunaga, Katsuhiro Omae, Keita Mori, Toshimi Inano, Teiko Yamaguchi, Naoharu Mori, Noriatsu Tatematsu, Taro Okayama, Ayumu Morikawa, Takako Mouri, Tetsuya Tsuji, Hideki Aragane, Akio Inui, Takashi Higashiguchi, Koichi Takayama
Journal: Journal of Clinical Oncology (2018)

TPS10131 Background: Most advanced cancer patients experience fatigue, anorexia, and declining physical function due to cancer cachexia and /or aging, for which effective treatment has not been established. We performed a phase I study, called NEXTAC-ONE, and demonstrated the feasibility of multi-modal interventions, namely, nutritional support and physical exercise in elderly cancer patients. We conducted the next-step multi-center, randomized phase II study to evaluate the efficacy of previously investigated multi-modal interventions in elderly cancer patients. Methods: Patients with chemo-naïve advanced non-small cell lung cancer or pancreatic cancer, age > = 70 years, PS < = 2, with adequate organ function and without disability by the modified Katz index, will be eligible. Totally, 130 participants will be recruited from 15 Japanese institutions and will be randomized into either the intervention group or a control group. Interventions and assessment will be performed 4 times every 4±2 weeks from the date of randomization. Interventions will consist of nutritional counseling, nutritional supplements (rich in branched-chain amino acids), and a home-based exercise program. The exercise program will include low-intensity daily muscle training and life-style education to promote physical activity. The primary endpoint is disability-free survival. It is defined as the period from the date of randomization to the date of developing disability or death due to any cause. This trial also plans to evaluate improvement in nutritional status, physical condition, quality of life, activities of daily living, overall survival, and safety as secondary endpoints. Enrollment began in August 2017. Eighteen of the planned 130 participants have been enrolled at the time of this submission. Study results will demonstrate efficacy of multi-modal interventions for elderly cancer patients and application for maintenance of physical and nutritional condition of patients with cancer cachexia. This work is supported by a grant-in-aid from the Japan Agency for Medical Research and Development. Clinical trial information: UMIN000028801.
IDH-wild type low grade gliomas: An AINO (Italian Association of Neuro-Oncology) retrospective study.
Authors: Roberta Ruda, Francesco Bruno, Antonio Silvani, Tamara Ius, Lorenzo Bello, Giuseppe Minniti, Andrea Pace, Giuseppe Lombardi, Riccardo Soffietti
Journal: Journal of Clinical Oncology (2018)

2050 Background: Information regarding clinical characteristics and response to treatments of IDH-wild type grade II gliomas are still lacking. This national retrospective study aimed to investigate natural history, management, factors affecting response to treatments and outcome of a cohort of WHO grade II IDH-wild type glioma patients. Methods: We collected all clinical data of patients diagnosed with WHO grade II IDH-wild type glioma from 1999 to 2017 in six major Italian Institutions. IDH mutation was assessed by either immunohistochemistry or sequencing (in cases with negative immunohistochemistry). Exclusion criteria were the presence of minimal anaplastic foci or radiological features of HGGs. Kaplan-Meier curves and Cox-regression models were used for univariate and multivariate analysis. Results: Overall, 194 patients were collected and ultimately 122 met the inclusion criteria. Median age was 45 years. Non-enhancing tumors on MRI accounted for 74% while 26% had minimal/mild contrast enhancement. Surgery consisted in gross total resection in 29%, partial/subtotal in 45%, biopsy in 24%, and unknown in 2%. According to WHO 2007 astrocytomas were 44%, oligodendrogliomas 35%, and mixed gliomas 21%. MGMT methylation was available in 68% of patients and in 40% of them was methylated. Post-surgical management consisted in watch and wait in 42%, chemoradiation in 21%, chemotherapy alone in 21%, radiotherapy alone in 5%, radiotherapy followed by chemotherapy in 5%, and 6% unknown. Median time of follow-up was 31 months. Progressive disease was observed in 64% of patients. Median PFS was 24.0 months (1.2 – 147.0), and median OS was 45.3 months (1.0 – 225.6). Factors positively associated with PFS and OS in univariate analysis were younger age, absence of contrast enhancement, and gross total resection. Age and extent of surgery retained a statistically significant importance in multivariate analysis. Conclusions: WHO grade II IDH-wild type gliomas have worse outcome compared with IDH-mutant tumors. This is the first study that details clinical and radiological presentation of this rare subgroup of tumors and suggests that gross total resection is critical in improving survival.
Genome-wide association with survival in stage II-III colon cancer clinical trials (NCCTG N0147, Alliance for Clinical Trials in Oncology; NSABP C-08, NRG Oncology).
Authors: Kathryn Penney, Barbara L. Banbury, Qian Shi, Carmen Joseph Allegra, Steven R. Alberts, Ulrike Peters, Greg Yothers, Frank A. Sinicrope, Wei Sun, Suresh Nair, Tabitha A. Harrison, Richard M. Goldberg, Peter C. Lucas, Linda H. Colangelo, James Norman Atkins, Polly A. Newcomb, Andrew T. Chan
Journal: Journal of Clinical Oncology (2018)

3582 Background: Many genetic variants have been identified as associated with colorectal cancer (CRC) risk; few have been associated with CRC survival. Identification of variants associated with survival may further explain the biology of disease progression and aid in outcome prediction. We performed a genome-wide association study (GWAS) in 2 CC clinical trials to identify genetic variants associated with overall survival (OS). Methods: We included patients from N0147, a phase III adjuvant trial in stage III CC patients, and C-08, a phase III trial comparing adjuvant therapy regimens for patients with stage II/III CC. 4974 samples were genotyped with the Illumina HumanOmniExpress + Exome array, consisting of 964,193 SNPs. Genotypes were imputed using 1000 Genomes Project data. We calculated OS as time from randomization to death from any cause and used Cox proportional hazards regression to evaluate association of each SNP with OS, adjusting for age, sex, treatment arm and principal components. Analysis was performed in N0147 and C-08 separately; results were combined in a fixed-effects meta-analysis. Results: Follow-up after diagnosis was similar for the 2 trials; median OS for N0147 and C-08 was 1678 days (IQR = 1238-2071) and 2224 days (IQR = 1901-2494), respectively. A locus on chromosome 7p15.2 was significantly associated with improved OS. The most significant variant at this locus, rs76766811 (p = 1.59e-8), is exceedingly rare in this primarily European American population but much more common in African Americans (AAs) (~19%). When the analysis is stratified by self-reported ancestry, the signal is only present in AAs (n = 359) (HR = 0.30, 95% CI: 0.21-0.43, p = 1.81e-10). Conclusions: This GWAS nested within 2 CC trials identified rs76766811 on 7p15.2 as significantly associated with OS among AA patients. This finding should be confirmed in additional study populations, particularly focusing on identifying variants associated with survival in AAs. Support: NIH R01 CA176272, U10CA-180868, -180821, -180822, UG1CA-189867, U24CA-196067, PA DoH (which disclaims certain responsibilities), Genentech, Inc., Sanofi-Synthelabo Inc.
TCT-693 Outcomes of Percutaneous Coronary Intervention in Octogenarian Patients. An Analysis of the National Inpatient Sample
Authors: Amr Idris, Yasser Al-Khadra, None Amjad Kabach, Fahed Darmoch, Homam Moussa Pacha, Mohamad Soud, Ziad SayedAhmad, Anwar Zaitoun, Amir Kaki, M Chadi Alraies
Journal: Journal of the American College of Cardiology (2018)
Whole exome sequencing identifies novel prognostic biomarker in colon cancer.
Authors: Yinchen Shen, Xiaohong Han, Zheng Wang, Dongge Liu, Yongkun Sun, Jianfei Wang, Xiaoyan Qian, Hongying Yang, Yuankai Shi
Journal: Journal of Clinical Oncology (2017)

e15098 Background: The incidence and mortality of cancer have been increasing in China, of which colorectal cancer (CRC) is ranking the fifth and among the leading cause of cancer-related deaths .Prognostic biomarker for colon cancer treated with standard adjuvant chemotherapy was rare and inconsistent, as gene mutations accumulation contribute to the carcinogenesis, available biomarkers may emerge by genome investigation. Methods: Whole exome sequencing was performed in 13 stage III colon cancers to identify gene alternations in patients with different outcomes, followed by 350 stage II-III colon cancers samples, of which clinicopathological characteristics and survival information were collected simultaneously to evaluate the clinical relevance in this cohort for evaluation of novel gene biomarkers. Results: Eight genes (CD97, ZNF568, WARS2, IL6R, APPL2, C9orf117, ANKRD32, ZNF443) were identified as differently expressed between two groups of good (DFS &gt; 60 months) and poor (DFS &lt; 25 month) separated according to treatment outcomes. ZNF443 was detected in 81.7% (286/350) samples, and ZNF443 (CA) was more common in male compared with female (56.0% vs 40.8%, P = 0.011).ZNF443 (CA) distribution differed related to different N stage, only stage N0 shared a higher frequency over 50% (P = 0.026).ANKRD32 was detected in 212 (93.8%) tumors, and ANKRD32 (CA) appeared more in left sites (included left colon and sigmoid colon, 61.1% vs 41.9%, P = 0.006). Moreover, ANKRD32 (CA) was significantly associated with superior disease-free survival (DFS) in stage III colon cancer patients (P = 0.044, HR 0.49, 95% CI0.24-0.98).Tumor nodal stage appeared as independent prognostic factor for DFS and over-all survival (OS) in stage II-III colon cancer (P &lt; 0.05), and low tumor differentiation indicated a worse OS for colon cancers. While no other significant association was obtained between genes and survival in present study. Conclusions: Whole exome sequencing was efficient in discovering novel gene biomarkers in clinical evaluation. ANKRD32 was independently prognostic for DFS in stage III colon cancer.
John E. Gerich: Father of Modern Physiology of Glucose Homeostasis, Counterregulation to Hypoglycemia, and Mechanistic Treatment of Diabetes
Authors: Geremia B. Bolli
Journal: Diabetes Care (2018)

John “Jack” E. Gerich as a young child (left panel); at graduation from medical school, age 26 (middle panel); and at present (right panel).





 
Original graph, hand drawn by John and completed by his wife, is a classic teaching example of the insulin dose-response curve. Printed with permission of the American Journal of Physiology (6).





 
Top: Jack writing papers with one of his fellows (author Geremia Bolli) at the Mayo Clinic. Bottom: Jack and the author playing a game of pool in Jack’s basement.





 
Jack, fishing on Beaver Lake (Pennsylvania).



When the letter from Diabetes Care arrived inviting me to write a Profile in Progress on John Edward Gerich (Jack, to his friends), I assumed it was because of my long-term research association and friendship with him. I felt, in a way, like a dwarf asked to report on a giant standing in front of me. After initial hesitation, I decided to accept this challenging task to acquaint younger professionals who do not know Jack Gerich with what kind of scientist—and also what kind of man—he is. To ensure that my narrative did not miss any aspect of his extraordinarily large and multifaceted research, I consulted with several of his former fellows who had been associated with him and contributed so much to the golden era of clinical research in metabolism over the last few decades.

My interest in Jack’s work started in 1979 when I came across his legendary paper in the Journal of Clinical Investigation on the relative roles of glucagon, catecholamines, and growth hormone responses in glucose counterregulation to acute, insulin-induced hypoglycemia (1). At that time, in my small laboratory in Perugia, Italy, I was able to measure plasma glucagon, catecholamines, and other counterregulatory hormones during hypoglycemia experiments in humans, but I had no idea how …
Drug profile interactions and importance of multiprofessional pharmacotherapeutic follow-up of oncology outpatients.
Authors: Nathalia Fonseca Gamboa, Fabiano Hosken Pombo, Karoline Conceição Alvellos, Carina Brasiliense, Bruna Camillo, Lucyana Carvalho, Paula Fernandes, Alessandra Campos, Marcio Borella, Larissa Ferreira, Marcos Coelho Simões Travassos Soares
Journal: Journal of Clinical Oncology (2018)

e18847 Background: Drug interaction refers to the interference of one drug or nutrient in the action of another drug. Cancer patients are often polymedicated, and therefore have an increased chance of drug-related problems. The objective of this study was to identify the profile of drug interactions in these patients and show the importance of efficient multiprofessional follow-up. Methods: The study was performed with outpatients undergoing treatment in 2017. Drug-drug and drug-food interactions wereidentified using theMicromedex™ DrugReax™ System. The potential interactions were evaluated by the pharmacist, referred to the oncologist designated by the Medical Director, and sent to the attending physicians by e-mail, who responded with the conduct to be performed according to the letters: A- Patient follow-up; B- Suspended medication; C- Substituted drug; or D- Contact your prescriber. Results: We found 254 prescriptions with interactions of a total of 2681 (9.47%). The medical response was letter A for 59 (23.23%), letter B for 3 (1.18%), letter C for 3 (1.18%) and letter D for 9 (3.54%). We did not get a medical answer for 63 (24.8%). Of these, 14 interactions involved chemotherapeutic drugs (22.22%). No contact with the physician was necessary in 117 interactions (46.06%), since they could be avoided or accompanied by the pharmacist. Conclusions: It has been observed that there are interactions that cannot be avoided by the need to use the medicines, but must be accompanied by the doctor and the pharmacist. A large percentage of them could be followed directly by the pharmacist, demonstrating the importance of a multiprofessional team. In view of the number of unanswered interactions, the importance of more efficient communication among professionals is evident, especially in ambulatory care, where part of the medication was not prescribed by the outpatient team.