tbuckley/cabot-search huggingface dataset:
A URCC NCORP nationwide randomized controlled trial investigating the effect of exercise on chemotherapy-induced peripheral neuropathy in 314 cancer patients.
Authors: Ian Kleckner, Charles Stewart Kamen, Luke Joseph Peppone, Michelle Christine Janelsins, Matthew Asare, Charles E. Heckler, Anita Roselyn Peoples, Steven Rousey, Jeffrey K. Giguere, Jeffrey L. Berenberg, Alison Katherine Conlin, Karen Michelle Mustian
Journal: Journal of Clinical Oncology (2016)

10000 Background: Over 50% of cancer patients receiving chemotherapy regimens including platinums, vinca alkaloids, and taxanes experience chemotherapy-induced peripheral neuropathy (CIPN), which presents as numbness, tingling, pain, and movement problems. CIPN is a dose-limiting toxicity that reduces quality of life and can increase mortality. There are no FDA-approved drugs to treat CIPN and behavioral interventions like exercise have received little research attention. We conducted a secondary analysis of our nationwide phase III randomized controlled trial to examine the effect of exercise on CIPN and possible moderators to identify for whom exercise best treats CIPN. Methods: Cancer patients (N = 314, 56±11 yrs, 92% female, 78% breast cancer) receiving platinum, vinca alkaloid, or taxane regimens were randomized to standard chemotherapy or chemotherapy plus Exercise for Cancer Patients (EXCAP). EXCAP is a standardized, individualized, moderate-intensity, home-based, six-week progressive walking and resistance exercise program. We assessed CIPN pre- and post-intervention using patient-reported numbness and tingling (0-10 scale; 10 = as bad as you can imagine). Moderators tested included sex, age, BMI, and cancer stage. Results: Exercise reduced CIPN compared to control (p = 0.04, effect size [ES] = 0.26, ANCOVA). Older patients benefitted more from exercise than younger patients, compared to control (p = 0.06, ES= 1.05 for ages 28-47 vs. ages 64-79). We found no evidence of moderation by other variables. Conclusions: Exercise reduces CIPN for patients receiving platinum, vinca alkaloid, and taxane chemotherapy regimens, especially for older patients. Clinicians should consider prescribing exercise for patients receiving platinums, vinca alkaloids, and taxanes and especially for their geriatric patients. Funded by NCI grants R25 CA102618, UG1 CA189961, and 2U10 CA037420-20. Clinical trial information: NCT00924651.
Abstract 15772: Chronotropic Responses to Low-Amplitude Autonomic Regulation Therapy Are Unaffected by Ace Inhibition as Well as Beta Adrenergic and Funny Channel Blockade
Authors: Jeffrey L Ardell, Heath Nier, Imad Libbus, Badri Amurthur, Eric Beaumont, Elizabeth M Southerland, Bruce H KenKnight, John A Armour
Journal: Circulation (2013)

Background: Chronic, intermittent right vagus nerve stimulation (VNS) imparts cardioprotective effects in animals and humans with heart failure. However, the cardiac effects of chronic VNS in the p...
IDO1 as a mechanism of adaptive immune resistance to anti-PD1 monotherapy in HNSCC.
Authors: Lori J Wirth, Barbara Burtness, Ranee Mehra, Jessica Ruth Bauman, Jina Lee, Nicole Marie Stauffer Smith, Armida Lefranc-Torres, William H. Westra, Justin A. Bishop, William C Faquin, Derrick T. Lin, Sara I. Pai
Journal: Journal of Clinical Oncology (2017)

6053 Background: Patients with recurrent/metastatic human papillomavirus-associated head and neck squamous cell carcinoma (HPV-HNSCC) demonstrate improved response rates to anti-PD-1 blockade, which may be attributed to the inherent inflammation associated with the local expression of foreign, highly immunogenic viral antigens. However, these response rates are at best 25%, suggesting there may be immune resistance networks that are limiting clinical responses to anti-PD-1 therapy. To address this question, we investigated other potential immune checkpoint pathways that may be upregulated in PD-L1 expressing HPV-HNSCCs. Methods: Using a custom microarray of 59 immune-related genes, we compared the gene expression profile of laser-captured micro-dissected PD-L1 (+) and (-) immune fronts in HPV-HNSCCs. Gene expression was validated using quantitative PCR (qPCR) and protein expression geographically localized using quantitative multiplex biomarker imaging in a separate cohort of HPV-HNSCCs. Furthermore, we assayed pre- and post-treatment biopsies from anti-PD-1 treated patients and correlated gene expression with clinical responses. Results: Of the immune-related genes, IDO1 was increased 65-fold in 10 PD-L1(+) as compared to 5 PD-L1(-) HPV-HNSCCs (p = 0.004). qPCR confirmed upregulated expression of IDO1 and quantitative immunofluorescence demonstrated that PD-L1 and IDO1 geographically co-localized within the tumor microenvironment in a validation cohort of 25 HPV-HNSCC patients. In anti-PD1 treated patients, IDO1 expression increased up to two-fold and correlated with disease progression in HNSCC patients. Conclusions: IDO1 is an immune checkpoint molecule that modulates T cell activity through the depletion of L-tryptophan. We propose that IDO1 is an adaptive immune resistance pathway to anti-PD-1 monotherapy. The results provide rationale for combinatorial therapies targeting the IDO1 and PD-1:PD-L1 networks in HNSCC patients.
GOG 3016/ENGOT-cx9: An open-label, multi-national, randomized, phase 3 trial of cemiplimab, an anti-PD-1, versus investigator's choice (IC) chemotherapy in ≥2 line recurrent or metastatic cervical cancer.
Authors: Krishnansu Sujata Tewari, Ignace Vergote, Ana Oaknin, Edwin Alvarez, Dana Meredith Chase, Stephanie Gaillard, Stephanie Lheureux, Danny Rischin, Alessandro Santin, Minjie Feng, Melissa Mathias, Matthew G. Fury, Israel Lowy, Bradley J. Monk
Journal: Journal of Clinical Oncology (2018)

TPS5600 Background: Patients with recurrent and metastatic cervical carcinoma experience modest survival benefit with first-line platinum-based chemotherapy with or without bevacizumab. Those with platinum-refractory disease have a median survival of only 7 months. Cemiplimab, a human monoclonal anti-PD-1, has exhibited antitumor activity and an acceptable safety profile in a phase 1 trial of solid tumors including recurrent cervical cancer. Methods: GOG 3016/ENGOT-cx9 is an open-label, randomized (1:1), phase 3 trial of cemiplimab versus IC chemotherapy in women ≥18 years with platinum-refractory recurrent and/or metastatic cervical cancer that has progressed within 6 months of the last dose of platinum-containing chemotherapy (NCT03257267). Patients will be stratified for the primary efficacy analysis by histology and geographic region. Patients will receive cemiplimab every 3 weeks (Q3W) or IC chemotherapy, ie, pemetrexed 500 mg/m2 Q3W; topotecan 1 mg/m2 daily x5 days, every 21 days; irinotecan 100 mg/m2 days 1, 8, 15, and 22, followed by 2 weeks rest, for a 42-day (6-week cycle); gemcitabine 1000 mg/m2 days 1 and 8, every 21 days; or vinorelbine 30 mg/m2 days 1 and 8, every 21 days. Treatments will be given IV for up to 96 weeks. The primary objective is overall survival (OS). Key secondary objectives include the assessment of overall response, progression-free survival, and the frequency and severity of adverse events. Stratification factors include prior bevacizumab, histology, and ECOG status. Assuming duration of study enrollment and follow-up of 20 months and 12 months, respectively, we calculated we would need to enroll approximately 436 patients, with 330 deaths expected, to provide the study with 90% power to detect a reduction in the risk of death of at least 20% with cemiplimab, with the 1-sided type 1 error rate limited to 2.5%. An independent data monitoring committee (IDMC) will monitor the data during the study conduct. Clinical trial information: NCT03257267.
Digital image analysis of automated mRNA in situ hybridization and immunohistochemistry to quantify HER3 expression in cancer tissues.
Authors: Malik Khenkhar, Philipp C. Uhlig, Kerstin A. David, Alison L. Bigley, Lorcan Sherry
Journal: Journal of Clinical Oncology (2016)

e23172 Background: Human Epidermal Growth Factor Receptor 3 (HER3) is expressed in various human cancers, and its overexpression has been associated with therapeutic resistance and poor overall survival. However, therapeutically targeting HER3 has proven challenging as currently there are no standard methods for measuring HER3 expression for patient selection and diagnostic purposes. The aim of this study was to quantitatively evaluate HER3 expression in cancer patient tissue samples utilizing both an automated in situ hybridization (ISH) and immunohistochemistry (IHC) approach in combination with digital image analysis. Methods: In our laboratories, we successfully implemented automated RNAscope HER3 ISHand validated anti-HER3 IHC on the Ventana DISCOVERY XT staining platform. Applying these assays, we analyzed a tissue microarray (TMA) of 45 formalin-fixed paraffin-embedded tumor core samples representing seven human cancer types and corresponding normal tissues. An image analysis algorithm was developed using Indica Labs HALO software to quantify in situ HER3 protein and mRNA expression levels. Results: The analysis algorithm developed for ISH and IHC allowed for a standardized quantification of HER3 expression and was valid across all seven cancer types. HER3 protein and mRNA were detected in the majority of analyzed patient samples and expression levels revealed a correlation of HER3 protein and mRNA. High co-expression was observed within some colorectal and gastric cancer tissues while a low co-expression was observed in some breast cancer and lung adenocarcinoma tissue samples. Conclusions: In this study, we demonstrated the applicability of automated ISHand IHC in combination with digital image analysis techniques to analyze clinical samples for the in situ expression of HER3 protein and mRNA. The algorithm for digital image analysis was applicable to all cancer tissue samples, ensuring a standardized quantification of HER3 expression. Using the presented technologies in combination has the potential to greatly improve diagnostic and/or therapeutic patient stratification in clinical oncology.
36 Comparsion of effectiveness of two one week treatment regimens for H.Pylori in south of ireland patient cohort
Authors: M Harrington, S Nolan, DO Connor, M Looby, MT Moriarty, W Stack, L Jackson
Journal: Gut (2017)

Background  H. pylori eradication rates for 7 day triple therapy regimens have decreased in many countries in recent years. Recent European guidelines recommend that standard triple therapy should not be used where local H. pylori resistance rates are greater than 15%.  Aim  Aim of study was to compare H. pylori eradication rates of one week, metronidazole vs Chlarithromycin based, triple therapy regimens in a south of Ireland patient cohort.  Method  From January 2015 to September 2016 undergoing upper GI endoscopy by two gastroenterologists at the Bon Secours Hospital Cork had H. pylori status determined by CLO test (BioHIT). All Clo positive patients received one of two seven day H. pylori treatment regimens; PPI, Amoxycillin, Clarithromycin (PAC) or PPI, Amoxycillin, Metronidazole (PAM). All treated patients were offered urea breath test (Diabact UBT)3- 4 months following treatment.  Results  Of 2595 patients having upper endosocpy 188 (7.2%) had positive CLO tests.45% (106/188) were females and mean age 56 (17 to 84 years).Of the 188 Clo positive patients,118 (63%) received PAC treatment and 70 (37%) received PAM treatment. Of the 118 PAC patients 83 (69%) attended for UBT and 24 (29%) were positive. Of the 70 patients treated with PAM 50 (71%) returned for UBT and 14 (28%) were positive.  Conclusions  In a patient cohort with relatively low H.pylori infection rates, one week based Clarithromycin and Metronidazole based triple therapy regimens achieved equivalent eradication of H.pylori (71% PAC,72% PAM). H. pylori eradication rates are somewhat higher than recently reported in Ireland, they are well short of current European guidelines and add further weight to the recommendation that one week triple therapy regimen should not be used in this country for first line H. pylori eradication.
Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease
Authors: Anthony J. Donato, Daniel R. Machin, Lisa A. Lesniewski
Journal: Circulation Research (2018)

Advancing age promotes cardiovascular disease (CVD), the leading cause of death in the United States and many developed nations. Two major age-related arterial phenotypes, large elastic artery stiffening and endothelial dysfunction, are independent predictors of future CVD diagnosis and likely are responsible for the development of CVD in older adults. Not limited to traditional CVD, these age-related changes in the vasculature also contribute to other age-related diseases that influence mammalian health span and potential life span. This review explores mechanisms that influence age-related large elastic artery stiffening and endothelial dysfunction at the tissue level via inflammation and oxidative stress and at the cellular level via Klotho and energy-sensing pathways (AMPK [AMP-activated protein kinase], SIRT [sirtuins], and mTOR [mammalian target of rapamycin]). We also discuss how long-term calorie restriction—a health span- and life span-extending intervention—can prevent many of these age-related vascular phenotypes through the prevention of deleterious alterations in these mechanisms. Lastly, we discuss emerging novel mechanisms of vascular aging, including senescence and genomic instability within cells of the vasculature. As the population of older adults steadily expands, elucidating the cellular and molecular mechanisms of vascular dysfunction with age is critical to better direct appropriate and measured strategies that use pharmacological and lifestyle interventions to reduce risk of CVD within this population.
Nivolumab (Nivo) as neoadjuvant therapy in patients with resectable Merkel cell carcinoma (MCC) in CheckMate 358.
Authors: Suzanne Louise Topalian, Shailender Bhatia, Ragini Reiney Kudchadkar, Asim Amin, William Howard Sharfman, Celeste Lebbe, Jean-Pierre Delord, Michi M Shinohara, Shrujal S. Baxi, Christine H. Chung, Uwe Marc Martens, Robert L. Ferris, Julie E Stein, Ibrahima Soumaoro, Ricardo F. Zwirtes, Tian Chen, Z. Alexander Cao, Janis M. Taube, Paul Nghiem
Journal: Journal of Clinical Oncology (2018)

9505 Background: MCC is a rare, aggressive skin cancer commonly associated with the oncogenic Merkel cell polyomavirus (MCPyV). The PD-1/PD-L1 immunosuppressive pathway is often upregulated in MCC, and advanced metastatic MCC is responsive to PD-1 blockade. Here we report the first trial of anti–PD-1 in the neoadjuvant setting for resectable MCC. Methods: In the phase 1/2 CheckMate 358 trial of nivo anti–PD-1 in virus-associated cancers (NCT02488759), patients (pts) with resectable MCC received nivo 240 mg IV on D1 and D15. Surgery was planned on D29. Tumor regression was assessed radiologically before surgery, and microscopically in the surgical specimen. Immunohistochemistry (IHC) was used to assess tumor MCPyV status and tumor PD-L1 expression. Data were analyzed as of August 7, 2017 with a median follow-up of 54.1 wks. Results: 25 pts with resectable MCC, AJCC stage IIA–IV, received ≥1 dose of nivo. Median age was 70 yrs (range 22–88). Among 18 patients’ tumors evaluated by IHC, 8 (44%) were MCPyV+, and 6 (30%) were PD-L1+ (1% cutoff). 22 of 25 (88%) pts had surgery at ~D29 without significant delay; 3 pts did not have surgery on trial, 1 due to rapid tumor progression and 2 due to grade 2–3 adverse events (AEs). Among 20 pts with pre/post nivo CT scans, 16 (80%) had tumor regression (range 13%–100% reduction), including 9 (45%) with > 30% reduction. Among 17 resections evaluated for pathologic response by central investigator review, 11 (65%) had a major pathologic response (MPR, defined as ≤10% residual viable tumor cells), including 8 (47%) complete responses. MPRs and radiologic responses were seen in virus+/− tumors and in PD-L1+/− tumors. Treatment-related AEs were reported in 36% (any grade) and 4% (grade 3–4) of pts, with no new safety signals. Among 21 pts followed after surgery, all were progression-free at 6 mo; 2 pts had relapsed at 12 mo. Conclusions: Nivo administered for 4 wks before surgery in MCC was safe and induced substantial radiologic and pathologic tumor regressions in 45% and 65% of patients, respectively. In some pts, this obviated the need for more extensive surgery. The majority of operated patients remain tumor-free at 12 mo. Data will be updated per a March 2018 database lock. Clinical trial information: NCT02488759.
P05.15 Surgically treated meningiomas at Dr. Cipto Mangunkusumo General Hospital: clinicopathological aspects
Authors: R A Aman, A Harlyjoy, D N Alby, S Ashari, D Tandian, S Ichwan, S W Nugroho
Journal: Neuro-Oncology (2018)

Intracranial meningiomas are a common type of primary brain tumors. We would like to examine the profile of intracranial meningiomas at our institution. We analysed the incidence and clinical, radiological, pathological features of meningiomas at Dr. Cipto Mangunkusumo General Hospital retrospectively between January 2012 and December 2017. The records of all surgically treated meningiomas were analysed from the medical record unit. We found 431 intracranial meningiomas were surgically resected at our institution. The patients had a median age of 45 years and were predominantly female (383 female and 48 male). WHO grade I meningiomas accounted for approximately 74 % of the intracranial meningiomas (316 of total 431 patients). WHO grade II and grade III meningiomas were found in 99 (22.9%) and 13 patients (3.1%) respectively. Of the histological subtypes, the most common are meningothelial in 71 patients (16.5%), mixed meningothelial and microcystic in 53 patients (12.3%) and mixed meningothelial and transitional in 41 patients (9.5%), whereas the uncommon subtypes such as atypical, angiomatous, anaplastic, clear cell, secretoric, chordoid, rhabdoid were found in 35 patients (8.1%). The most common site of meningioma is sphenoorbita region (223 patients; 51.9%.), followed by convexity (60 patients; 13.9%), and sphenoid wing (30 patients; 7.0%). Proptosis is the most common clinical presentation (176 patients; 40.8%), followed by decrease of visual acquity (75 patients; 17.4%) and headache (46 patients; 10.8%). This study showed intracranial meningiomas are a female preponderance among our patients. Proptosis is the most common clinical presentation, the sphenoorbita region as the most common site, whereas WHO grade I and meningothelial subtypes as the most common pathological finding.
Safety and efficacy and pharmacokinetic trial of glucarpidase for delayed MTX excretion: First prospective registered clinical trial.
Authors: Hiroshi Kawamoto, Toshimi Kimura, Kenichi Yoshimura, Naoko Yasui, Atsushi Ogawa, Hiroaki Hiraga, Atsushi Kikuta, Katsuyoshi Ko, Yuki Yuza, Junichi Hara
Journal: Journal of Clinical Oncology (2016)

10578 Background: High dose Methotrexate (HDMTX) has been a key element of standard therapies for lymphatic malignancy (ML), osteosarcoma (OS), etc. Despite optimal supportive care, delayed MTX excretion inevitably occur resulting in severe renal failure, mucositis, septicemia, etc. Glucarpidase (CPG2) is a recombinant enzyme hydrolyzing MTX into inactive metabolites. This is a first prospective clinical trial of CPG2 for patients (pts) with MTX nephropathy to assess clinical efficacy and clearance of MTX, Leucovorin (LV), DAMPA, 5MeTHF by LC/MS/MS method. Methods: Pts receiving HDMTX (MTX > 1g/m2) and confirmed high serum MTX concentration (cons.) after 15 hours from completing MTX administration were eligible. CPG2 50U/kg, defined by preceded phaseI, was administered with high dose LV (HDLV). If serum MTX after 46 hrs post-CPG2 was no less than 1µmol/L, additional CPG2 was planned. Primary objective is clinical important reduction (CIR: reduce and sustain serum MTX cons. under1µmol/L just after first CPG2 administration). Sample size of 16 patients provided 85% power at a one-sided alpha of 0.05 to reject the CIR rate of 42% under the expectation of 77%. Results: From 2012 to 2015, 13 pts (median age 14.5 yrs (7 pts: OS, 5 pts: ML, 1 pts: brain tumor)) were enrolled (15% had no HDMTX history). The median pre-CPG2 MTX cons. was 26.10 µmol/L (range: 1.81-486). The first dose of CPG2 was given from 1 to 4 days after starting MTX administration. Three pts was given CPG2 twice (2 of 3 was received over 24 hrs continuous MTX administration) and didn’t achieve CIR. CIR rate was 75% (95% CI, 42.8-94.5; p = 0.02). The median MTX reduction rate at 15 mins post-CPG2 was 99.1%. All adverse event except one Grade1 allergic reaction were not associated with CPG2 but with MTX. All pts with increased creatinine were normalized. Conclusions: CPG2 with HD-LV is confirmed safe and clinically effective and could rescue from irreversible renal damage for delayed MTX excretion. Although continuous MTX administration over 24 hrs may be high risk for MTX cons. rebound, additional CPG2 would possibly sustain low level serum MTX. Clinical trial information: JMA-IIA00097. Clinical trial information: #12288;.
A pilot RCT of sarcopenia-focused prehabilitation in pancreas cancer.
Authors: Elizabeth Hile, Leah Hoffman, Russell Postier, Kai Ding, Jingxuan Yang, Min Li
Journal: Journal of Clinical Oncology (2017)

TPS10127 Background: Now the 3rd leading cause of US cancer deaths, pancreatic cancer (PanC) incidence is rising. Surgery is the only chance at cure, but sarcopenia (low muscle mass, strength, function) can eliminate surgical and chemotherapy options, and independently predicts poor outcomes. Strengthening (Str) with protein combats sarcopenia of aging, and pre-op exercise (prehab) benefits other cancer survivors. But the impact of Str in a brief pre-Whipple window, and a host with PanC-mediated catabolism, is unknown. We aim to quantify the post-op QoL impact of adding Str to our standard clinical aerobic instruction before Whipple for pancreatic head and related cancers. Methods: Pilot RCT of 130 PanC survivors age 30+ randomized (stratified by neo-chemo) to 2 home-based prehab arms: Standard/NPRE = aerobic + protein, or Sarcopenia/SPRE = Standard + Str. To explore PanC-sarcopenia as moderating Str's impact, a 3rd pre-malignancy Whipple group (p-mal, n=50) also receives SPRE. All participants get protein and exercise instruction personalized to baseline status, adherence diaries, actigraphy, and phone follow-up in pre-op period only. Endpoints are QoL (primary) as Functional Assessment of Cancer Therapy (FACT), performance as 6 Minute Walk (6MW) &amp; Short Physical Performance Battery (SPPB); and self-reported symptoms &amp; activities of daily living (ADL). Assessments at baseline, 1-3 days pre-op, and post-op week 4 &amp; month 4 (primary) are blind. Sarcopenia measures are clinical (dynamometry, bioimpedance, CT body composition) and preclinical (ZIP4/ catabolic mediators in blood, muscle, tumor &amp; duodenum). Analyses: QoL change at post-op month 4 will be compared across PanC arms (SPRE &amp; NPRE) with mixed-models before Baron-Kenny and Preacher/Hayes' mediator analyses. To explore impact of PanC catabolic host environment on Str, outcomes will be compared by SPRE group (PanC &amp; p-mal). To our knowledge, this is the first PanC prehab RCT with sarcopenia focus, comprehensive mechanistic approach, and high dose (60 min daily)/short duration (2-3 week) intervention. With local feasibility established, we continue to accrue (n=30), and seek multicenter collaboration to target NCI funding. Clinical trial information: pending - in submission.