tbuckley/cabot-search huggingface dataset:
Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study
Authors: Yan Xie, Benjamin Bowe, Yan Yan, Hong Xian, Tingting Li, Ziyad Al-Aly
Journal: BMJ (2019)

Abstract Objective To estimate all cause mortality and cause specific mortality among patients taking proton pump inhibitors (PPIs). Design Longitudinal observational cohort study. Setting US Department of Veterans Affairs. Participants New users of PPIs (n=157 625) or H2 blockers (n=56 842). Main outcome measures All cause mortality and cause specific mortality associated with taking PPIs (values reported as number of attributable deaths per 1000 patients taking PPIs). Results There were 45.20 excess deaths (95% confidence interval 28.20 to 61.40) per 1000 patients taking PPIs. Circulatory system diseases (number of attributable deaths per 1000 patients taking PPIs 17.47, 95% confidence interval 5.47 to 28.80), neoplasms (12.94, 1.24 to 24.28), infectious and parasitic diseases (4.20, 1.57 to 7.02), and genitourinary system diseases (6.25, 3.22 to 9.24) were associated with taking PPIs. There was a graded relation between cumulative duration of PPI exposure and the risk of all cause mortality and death due to circulatory system diseases, neoplasms, and genitourinary system diseases. Analyses of subcauses of death suggested that taking PPIs was associated with an excess mortality due to cardiovascular disease (15.48, 5.02 to 25.19) and chronic kidney disease (4.19, 1.56 to 6.58). Among patients without documented indication for acid suppression drugs (n=116 377), taking PPIs was associated with an excess mortality due to cardiovascular disease (22.91, 11.89 to 33.57), chronic kidney disease (4.74, 1.53 to 8.05), and upper gastrointestinal cancer (3.12, 0.91 to 5.44). Formal interaction analyses suggested that the risk of death due to these subcauses was not modified by a history of cardiovascular disease, chronic kidney disease, or upper gastrointestinal cancer. Taking PPIs was not associated with an excess burden of transportation related mortality and death due to peptic ulcer disease (as negative outcome controls). Conclusions Taking PPIs is associated with a small excess of cause specific mortality including death due to cardiovascular disease, chronic kidney disease, and upper gastrointestinal cancer. The burden was also observed in patients without an indication for PPI use. Heightened vigilance in the use of PPI may be warranted.
What impact do the proton pump inhibitors have on the efficacy of immune check point inhibitors in metastatic malignant melanoma?
Authors: Muhammad Zubair Afzal, Keisuke Shirai
Journal: Journal of Clinical Oncology (2019)

e21040 Background: Acidic microenvironment facilitates the proliferation, progression, and metastasis of the tumors. Mouse models have shown that the proton pump inhibitors (PPI) cause neutralization of the acidic tumor microenvironment (TME) and inhibit the tumor growth. PPI also sensitize the resistant tumors to chemotherapeutic and immunotherapeutic effects. Moreover, PPI’s modify the gut microbiota, that impact the efficacy of immune checkpoint inhibitors (ICI). Clinical studies have shown variable impact of PPI on efficacy of ICI, ranging from no benefit at all to a negative impact. Since, PPI are one of the most commonly used medications, it is important to evaluate its impact on the efficacy of ICI. Methods: We conducted a retrospective analysis on 120 metastatic malignant melanoma patients treated with anti- CTLA-4 (ipilimumab), anti PD-1(pembrolizumab) alone or in combination. Cohort A included patients who were taking PPI at the time of ICI initiation. Cohort B included non-PPI users. Objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression free survival (PFS) were calculated. ORR and PFS were the primary outcomes. Cox regression univariate and multivariate analyses were performed. The proportions of grade 3 or 4 immune related adverse events (IrAE) were compared between PPI users and nonusers using the Fisher’s exact test. Results: Cohort A included 29 (24.2%) patients, of which 68.7% patients were male. Median age was 65 years. Majority of the patients were taking omeprazole (58.6%). Proportion of the patients taking ipilimumab and pembrolizumab or nivolumab were almost similar (48.3% vs. 44.8%, respectively). Significantly higher proportion of patients achieved ORR and DCR in cohort A [76%, OR = 3.8(1.39 – 10.5), P = 0.009) and 84%, OR = 4.3(1.37 – 13.7), P = 0.013, respectively). The median PFS was significantly higher in cohort A [A = 27.6 vs. B = 4.4 months, HR = 0.3, P = 0.005(0.1 – 0.7)]. Although, median OS was considerably higher in cohort A, the difference was not statistically significant [A = 39.3 vs. B = 28.0 months, HR = 1.01, P = 0.9(0.4-2.0). PPI did not significantly increase the Odds of having grade 3 or 4 IrAE. Conclusions: In this retrospective review, we have observed favorable outcomes in patients receiving PPI when starting on ICI contrary to some of the studies suggesting negative impact of PPI on ICI efficacy. As PPI is one of the commonly used chronic medications, prospective studies are needed to evaluate the real impact of PPI on ICI when taking concomitantly.
Adavosertib with chemotherapy (CT) in patients (pts) with platinum-resistant ovarian cancer (PPROC): An open label, four-arm, phase II study.
Authors: Kathleen N. Moore, Setsuko K. Chambers, Erika Paige Hamilton, Lee-may Chen, Amit M. Oza, Sharad A. Ghamande, Gottfried E. Konecny, Steven C. Plaxe, Daniel Lewis Spitz, Jill J.J. Geenen, Tiffany A. Troso-Sandoval, Janiel M. Cragun, Esteban Rodrigo Imedio, Sanjeev Kumar, Ganesh M. Mugundu, Zhongwu Lai, Juliann Chmielecki, Suzanne Fields Jones, David R. Spigel, Karen Anne Cadoo
Journal: Journal of Clinical Oncology (2019)

5513 Background: Adavosertib (AZD1775; A), a highly selective WEE1 inhibitor, demonstrated activity and tolerability in combination with carboplatin (C) in primary PROC. This study (NCT02272790) assessed the objective response rate (ORR) and safety of A in PROC. Methods: Pts with recurrent RECIST v1.1 measurable PROC received A with C, gemcitabine (G), weekly paclitaxel (P), or pegylated liposomal doxorubicin (PLD) in 3- (C) or 4-week (G, P, PLD) cycles (Table). Tumor assessments were performed every 2 cycles until disease progression. Primary objective: ORR; other objectives: disease control rate (DCR), progression-free survival (PFS) and safety. Results: In the 94 pts treated (median treatment duration 3 months; range 0–16 months), outcomes were greatest with A (weeks [W]1–3) + C (Table), with ORR of 67% and median PFS (mPFS) of 10.1 months for this cohort. Most common grade ≥3 treatment-emergent adverse events (TEAEs) are shown in the Table, with hematologic toxicity most notable with A (W1–3) + C. TEAEs led to A dose interruptions, reductions and discontinuations in 63%, 30% and 13% of the whole cohort, respectively. A possible positive relationship between CCNE1 amplification and response warrants further investigation. Conclusions: A shows preliminary efficacy when combined with CT. Pts receiving A (W1–3) + C showed greatest benefit. The increased but not unexpected hematologic toxicity is a challenge and could be further studied to optimize the dose schedule and supportive medications. Clinical trial information: NCT02272790. [Table: see text]
Tumor mutation burden analysis in a 5,660 cancer patient cohort reveals cancer type-specific mechanisms for high mutation burden.
Authors: Xiaodong Jiao, Xiaochun Zhang, Baodong Qin, Dong Liu, Liang Liu, Jianjiao Ni, Ningyu Zhou, Lingxiang Chen, Liangjun Zhu, Songbing Qin, Jianya Zhou, Shenpeng Ying, Xueqin Chen, Aijun Li, Ting Hou, Tengfei Zhang, Shannon Chuai, Yuan-Sheng Zang
Journal: Journal of Clinical Oncology (2019)

2589 Background: Tumor mutation burden (TMB), calculated by whole-exome sequencing (WES) or large NGS panels, has an important association with immunotherapy responses. Elucidating the underlying biological mechanisms of high TMB might help develop more precise and effective means for TMB and immunotherapy response prediction. Meanwhile, the landscape of TMB across different cancer types and its association with other molecular features have not been well investigated in large cohorts in China. Methods: Cancer patients whose fresh tissue (n = 1556), formalin-fixed, paraffin-embed (FFPE) specimen (n = 1794), and pleural fluid (n = 84) were profiled using 295- or 520-gene NGS panel. The association of the TMB status with a series of molecular features and biological pathways was interrogated using bootstrapping. Results: TMB, measured by 295- or 520-cancer-related gene panels, were correlated with WES TMB based on in silico simulation in the TCGA cohort. We compared the TMB landscape across 11 cancer type groups and found the highest average TMB in lung squamous cell carcinoma, whereas the lowest TMB was established in sarcoma. High microsatellite instability, DNA damage response deficiency, and homologous recombination repair deficiency indicated significantly higher TMB. The independent predictive power for TMB of twenty-six biological pathways was tested in 10 cancer groups. FoxO signaling pathway most commonly correlated with low-TMB; significant association was identified in four cancer groups. In contrast, no pathway was significantly correlated with high-TMB in more than two cancer groups. Overall, we discovered that the underlying pathways which may be the main drivers of TMB status varied greatly and sometimes had an opposite association with TMB across different cancer types. Moreover, we developed a 14- and 22-gene signature for TMB prediction for LUAD and LUSC, respectively, with only 10 genes shared by both signatures, indicating a histology-specific mechanism for driving high-TMB in lung cancer. Conclusions: The findings extended the knowledge of the underlying biological mechanisms for high TMB and might be helpful for developing more precise and accessible TMB assessment panels and algorithms in more cancer types.
First-in-human phase I trial of the combination of two adenoviral vectors expressing HSV1-TK and FLT3L for the treatment of newly diagnosed resectable malignant glioma: Initial results from the therapeutic reprogramming of the brain immune system.
Authors: Pedro R. Lowenstein, Daniel A Orringer, Oren Sagher, Jason Heth, Shawn L. Hervey-Jumper, Aaron Gerald Mammoser, Larry Junck, Denise Leung, Yoshie Umemura, Theodore Steven Lawrence, Michelle Miran Kim, Daniel Richard Wahl, Paul McKeever, Sandra Ines Camelo-Piragua, Andrew Lieberman, Sriram Venneti, Andrea Comba, David Altshuler, Karin Muraszko, Maria Castro
Journal: Journal of Clinical Oncology (2019)

2019 Background: This is the initial report on a first in human Phase I dose escalation trial of the combination of two adenoviral vectors expressing HSV1-TK or Flt3L for the treatment of newly diagnosed, resectable malignant gliomas. The absence of functional dendritic cells from the brain precludes anti-brain tumor immune responses. We combined tumor cytotoxicity (Ad-HSV1TK) with recruitment of dendritic cells to the brain (Ad-Flt3L) to induce an effective anti-tumor immune response. This strategy induced an efficacious, cytotoxic CD8 and CD4 T-dependent immune response in many animal models of glioma. This immune response also generated anti-tumor memory, and the capacity for neoantigen recognition. Methods: The trial was approved by FDA and all institutional cttees. Treatment was administered intraoperatively following complete glioma resection in newly diagnosed tumors. The trial consisted of vector dose escalation, starting at 1x10^9 i.u., and increasing to 1x10^11 i.u. of each vector. Dose escalation proceeded by increasing the vector dose through a total of 6 combinations administered to 6 cohorts of 3 patients each. Two cycles of 14 days each of valacyclovir were administered to activate HSV1-TK cytotoxicity. Cycle 1 starts on Day 1-3 post surgery for 14 days, and Cycle 2 on Week 8-12. Standard radiation, i.e., 60 Gy in 2 Gy fractions over 6 weeks, with concurrent temozolomide, was followed by cyclic temozolomide. Results: Examination of tumor samples at primary resection and first recurrence show an increase in the infiltration of inflammatory cells. The experimental treatment was well tolerated. At this time the MTD has not been reached. There were approx. 248 AEs, and 26 SAEs; these have not been linked to treatment. At this time the MTD has not been reached. A secondary outcome is overall survival. Preliminary analysis of partial data may suggest that the combined viral vector therapy may provide a clinically significant survival. Conclusions: Our results show for the first time that reprogramming of the host’s brain immune system to recognize gliomas reveals a new approach for the treatment of highly malignant brain tumors. Clinical trial information: NCT01811992.
Case 25-1976
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Gordon S. Myers, Stephen J. Galli
Journal: New England Journal of Medicine (1976)

Presentation of CaseAn 82-year-old woman was admitted to the hospital because of substernal pain.There was a history of rheumatic fever in childhood, after which a murmur was noted. At the age of 39 years dyspnea appeared, and it recurred in paroxysmal fashion, often accompanied by atrial fibrillation. At the age of 52 years atrial fibrillation became fixed, and five years later dyspnea limited her largely to her home. At the age of 61 years she underwent a mitral valvuloplasty at another hospital, followed by marked improvement, with resumption of an active life.One year after the operation an . . .
A phase II study of TAS-102 in combination with ramucirumab in advanced, refractory gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Rutika Mehta, Richard D. Kim, Neal Shah, Estrella M. Carballido, Youngchul Kim, Iman Imanirad, Dae Won Kim
Journal: Journal of Clinical Oncology (2019)

TPS4149 Background: Patients with advanced gastric cancer experience a 5 year survival rate &lt;10% even with multimodality therapy representing a clear unmet need for improved treatment. In advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma, ramucirumab (a monoclonal antibody against VEGFR2) has demonstrated clinical activity and has been approved as second line therapy in combination with paclitaxel with a response rate of 28% and absolute overall survival benefit of 8 weeks when compared to placebo. However, there are many patients that cannot tolerate paclitaxel due to prior exposure to oxaliplatin causing neuropathy. Therefore, novel combinations with ramucirumab, is highly desirable. TAS-102 is an oral cytotoxic agent with two active components; trifluridine (TFD) which inhibits tumor cell growth by being incorporated into DNA during DNA synthesis and tipiracil (TPI) which inhibits the metabolism of TFD, thereby prolonging its ability to exert effect. TPI also inhibits platelet derived endothelial cell growth factor which plays a key role with VEGF in tumor angiogenesis. The combination of a cytotoxic agent with an antiangiogenic agent has demonstrated a significant anticancer activity in multiple cancers. In a recent Phase III study, TAS-102 significantly prolonged overall survival as compared to best supportive care in patients with GEJ and gastric cancers that had received at least 2 prior lines of treatment. We hypothesize that a combination of TAS-102 and ramucirumab might increase efficacy without causing unmanageable toxicity. Methods: This is a single institutional phase II single arm two-stage design trial using the combination of TAS-102 and ramucirumab in advanced, refractory gastric or GEJ adenocarcinoma. Eligible patients include those with histologically confirmed gastric or GEJ adenocarcinoma that have received at least 1 prior line of treatment with performance status 0 or 1 and preserved organ function. Ramucirumab will be administered 8mg/kg every 2 weeks and TAS-102 at doses of 35 mg/m 2 twice daily. Each cycle length will be 28 days. The primary endpoint is 6 month OS and secondary endpoints are safety, objective response rate and PFS. Fifteen patients will be enrolled in the first stage. If ≥ 7 of the 15 are alive at 6 months, an additional 10 patients will be enrolled in the second phase. Enrollment is currently ongoing. Clinical trial information: NCT03686488.
Exploring the genetic basis of Lynch-like syndrome through paired germline and tumor exome sequencing.
Authors: Jason Willis, Maureen E Mork, Kyle Chang, Jenniffer Kinnison, Miguel A. Rodriguez-Bigas, Selvi Thirumurthi, Ester Borras, Melissa Taggart, Patrick M. Lynch, Y. Nancy You, Eduardo Vilar Sanchez
Journal: Journal of Clinical Oncology (2019)

3592 Background: Lynch-like syndrome (LLS) is characterized by a diagnosis of mismatch repair deficient (dMMR) malignancy where somatic bi-allelic mutations in canonical MMR pathway genes ( MLH1, MSH2, MSH6, PMS2) have been identified as the main cause. Yet, a substantial proportion of cases remain unexplained by MMR somatic bi-allelic events or germline mutations. We hypothesize that LLS cases with young-onset cancers carry cryptic germline alterations in other pathways. To explore this contribution, we performed analyses of the germline and tumor mutation landscapes in LLS patients diagnosed with dMMR cancers. Methods: 18 probands with young-onset (age &lt;50 years) dMMR colorectal or uterine cancers were selected from a familial cancer registry. The absence of deleterious germline MMR mutation and/or somatic MLH1inactivation was confirmed by standard clinical testing. We performed whole-exome sequencing (Illumina HiSeq) of germline (peripheral blood) DNA. Variant calls, quality-control, allele-frequency filtering (&lt;1% in reference cohorts), and in silicoannotation were performed using the GATK and polyphen/SIFT tools. Pathway analysis was performed using the DAVID suite. For 16 of 18 patients, targeted exon sequencing of 408 cancer-related genes was performed on paired tumor/normal tissue samples (Ion Torrent AmpliSeq) and analyzed with VarScan 2. Results: 237,055 rare germline variants were detected in our cohort. We enriched a subset of 758 variants with putative frameshift (45.1%), stop gain or loss (25%), or splice site alteration (29.9%). Pathway analysis of genes altered by this subset revealed excess events in DNA damage repair (e.g. ERCC5, POLM, POLN, EXO5) and mRNA splicing (e.g. SCAF1, SRSF4) pathways. Preliminary analysis of somatic mutations profiles shows frequent alteration of known drivers including APC(64%) and NOTCH1(36%). Conclusions: Our exploratory analysis provides novel evidence that LLS patients may harbor an excess of deleterious germline mutations in DNA damage repair- and mRNA splicing-related genes. Future studies will identify genes which are targeted by both germline and somatic mutation with the goal of nominating putative causal genes. Defining additional mechanisms of dMMR in LLS cancers may help to refine prevention strategies for (un)affected individuals.
Simulation modeling of the effects of adjuvant chemotherapy in early-stage breast cancer.
Authors: Jinani Jayasekera, Clyde B. Schechter, Joseph A. Sparano, Claudine Isaacs, Robert James Gray, Christopher Cadham, Jeanne S. Mandelblatt
Journal: Journal of Clinical Oncology (2019)

526 Background: The recent Trial Assigning Individualized Options for Treatment (TAILORx) was practice changing. However, several important questions remain unanswered about therapy for women with early stage, hormone receptor positive (HR+), HER2- breast cancers, including chemotherapy effects by age and different Oncotype recurrence score (RS) cut-points, and longer follow-up. We developed a simulation model to extend the trial results to begin to fill these gaps. Methods: We developed a simulation model using an empirical Bayesian approach to simulate women eligible for the TAILORx trial. The joint distributions of patient and tumor characteristics were derived from de-identified TAILORx data. The remaining inputs used data independent of the trial, including SEER, the Oxford Overview, and other trials. TAILORx was simulated to examine the effects of chemotherapy (+ hormonal Rx) vs. hormonal Rx alone on distant recurrence-free survival (DRFS) at 9- and 20-years by age (≤50 and &gt;50 years) and RS (11-25 and 16-25). We also evaluated the effects of chemotherapy in women with RS 26-30. Hazard ratios (HR) were determined using Cox regressions and DRFS by treatment were derived from Kaplan-Meier curves. We report the mean results from 1000 trial simulations, where each simulation randomly sampled values for each parameter from their observed joint distribution. Finally, the original trial was replicated for model validation. Results: The model closely replicated actual trial results. Sample sizes ranged from 7000-10000. The model estimated that chemotherapy improved DFRS in women aged ≤50 with RS 16-25 (Table). The 20-year event rates remained low in the 11-25 category. Among women with RS 26-30, HR for no chemo vs. chemo was 1.38 (95% CI:1.18-1.58). Conclusions: Simulation suggests that chemotherapy may reduce distant recurrence in younger women at different cut points between 11-25. Simulation modeling may be useful to translate trial results to broader population subgroups than those possible to test in RCTs. Nine-year distant recurrence-free survival by chemotherapy. [Table: see text]
Interim safety analysis of consolidation nivolumab and ipilimumab versus nivolumab alone following concurrent chemoradiation for unresectable stage IIIA/IIIB NSCLC: Big Ten Cancer Research Consortium LUN 16-081.
Authors: Melissa Yan, Greg Andrew Durm, Hirva Mamdani, Apar Kishor Ganti, Borys Hrinczenko, Salma K. Jabbour, Lawrence Eric Feldman, Goetz H. Kloecker, Ticiana Leal, Salah Almokadem, Jarushka Naidoo, Naomi Fujioka, Nasser H. Hanna
Journal: Journal of Clinical Oncology (2019)

8535 Background: Consolidation PD-1 inhibition after chemoradiation (chemoRT) for unresectable stage IIIA/IIIB NSCLC improves overall survival. The efficacy and safety of combining a CTLA-4 inhibitor with a PD-1 inhibitor in this setting are unknown but may further improve efficacy in this patient population. Methods: In this randomized, multi-center, phase II study, 105 pts with unresectable stage IIIA/IIIB NSCLC will receive chemoRT, then randomize 1:1 to either nivolumab 480mg IV q4 wks (nivo) or nivolumab 3mg/kg IV q2 wks + ipilimumab 1mg/kg IV q6 wks (nivo/ipi), for up to 24 wks. In this interim analysis, we assess the safety of the first 20 patients treated. Results: From 9/2017 to 11/2018, 20 patients were accrued. Characteristics of those treated on the nivo arm (n = 10) were: median age 62 years, stage IIIA/B 7/3; non-squamous/squamous 7/3; and the nivo/ipi arm (n = 10): median age 61 years; stage IIIA/B 6/4; non-squamous/squamous 7/3. Most toxicities were grade 1 or 2 and the most frequently noted grade 2 AEs included fatigue (25%), pneumonia (25%), extremity pain (20%). Adverse events reported in the Nivo only arm included 81 total events with only four grade 3 events and a single grade 4 thromboembolic event. The Nivo/Ipi arm reported 101 total AEs, with only 3 grade 3 events and a single grade 4 toxicity (amylase elevation). With respect to immune-related adverse events (irAEs), in the nivo arm there were two cases of grade 2 pneumonitis and no grade 3/ 4 events. In the nivo/ipi arm, there was one grade 2 pneumonitis, three grade 3 irAEs (pneumonitis, colitis, pancreatitis), and one asympomatic grade 4 amylase elevation. No treatment-related deaths were observed in either arm. Conclusions: There were no unexpected safety signals in the first 20 patients treated on BIG10CRC LUN 16-081. The incidence of grade 3 or higher irAEs was higher in the nivo/ipi arm, as expected, but this was manageable with the use of established guidelines. The study currently remains open to accrual (32 of 105 have been randomized as of 2/8/19). Clinical trial information: NCT03285321.