tbuckley/cabot-search huggingface dataset:
Analysis of adjuvant chemotherapy and radiotherapy for stage II endometroid type endometrial cancer.
Authors: Raanan Alter, William Adams, Alec Block, William Small, Matthew M. Harkenrider
Journal: Journal of Clinical Oncology (2017)

e17118 Background: Endometrial cancer (EC) is the most common gynecologic malignancy. Stage II EC - involving the cervix - is ideally treated with primary surgical staging; however, adjuvant treatment is not well defined. Methods: The population included 8,506 patients with 2009 FIGO Stage II endometrioid-type EC treated surgically within the National Cancer Database. Patients were categorized into six treatment groups: 1. hysterectomy (HYS) alone; 2. HYS with external beam radiation therapy (EBRT); 3. HYS with chemotherapy (CT); 4. HYS with CT and EBRT; 5. HYS with vaginal brachytherapy (VBT); and 6. HYS with CT and VBT. Univariable frailty survival analysis (UVA) that allowed for clustering of patients was used to determine the effect of sociodemographic factors and comorbidities on time to death; a generalized linear mixed effects allowing random intercepts for each treatment facility type was also used to estimate the odds of receiving any treatment beyond HYS. Results: 3,571 (42%) underwent HYS alone, while 4,312 (51%) received HYS with adjuvant radiation therapy (ART), 251 (3%) received HYS with CT, and 372 (4%) received all three modalities. Of those that received ART, 2,951 (68%) had EBRT while 1,361 (32%) had VBT. On UVA, black race, years of education, government insurance or uninsured status, higher tumor grade, greater Charlson-Deyo comorbidity count (CDCC), increased age, tumor grade, and tumor size all predicted poor survival. On MVA, patients receiving ART were only 0.747 (95% CI: 0.641 – 0.871) times as likely to die at any given time when compared with HYS alone ( p = .0002). There was no difference in survival between radiation modalities. Further, compared to patients who only received HYS, those who received HYS+CT had comparable survival estimates ( p = .20) as did patients who received HYS+ART+CT ( p = .24). When controlling for all other factors, higher tumor grade, increased CDCC, age, or tumor size, and Medicaid insurance were hazardous predictors of time to death ( p&lt; .05). Conclusions: In stage II EC patients, adjuvant EBRT and VBT improved survival. Adjuvant CT did not improve survival though this should be further studied given the infrequency it was delivered in this population.
Claudin-3 regulates bile canalicular paracellular barrier and cholesterol gallstone core formation in mice
Authors: Hiroo Tanaka, Mitsunobu Imasato, Yuji Yamazaki, Kengo Matsumoto, Koshi Kunimoto, Julien Delpierre, Kirstin Meyer, Marino Zerial, Naho Kitamura, Mitsuhiro Watanabe, Atsushi Tamura, Sachiko Tsukita
Journal: Journal of Hepatology (2018)
Projecting long term survival for avelumab in refractory Merkel cell carcinoma.
Authors: Hemant Phatak, Irina Proskorovsky, Tereza Lanitis, Apoorva Ambavane, Matthias Hunger, Sandra P. D'Angelo
Journal: Journal of Clinical Oncology (2018)

e21623 Background: In the JAVELIN Merkel 200 trial, among 88 patients with previously treated metastatic Merkel cell carcinoma (mMCC), avelumab treatment resulted in an overall response rate of 33%, 86% and 45% of which lasted at least 6 months and one year respectively. While the durable response data underpins the survival benefit of avelumab in an indication with high unmet need, further follow-up is required to observe the long-term survival benefit. The objective of this study was to project potential long-term survival of avelumab by extrapolating survival data observed in the clinical trial. Methods: Observed overall survival (OS), time to progression (TTP) and post progression survival (PPS) data from the JAVELIN Merkel 200 trial (Part A), with ≥12 months of follow-up (09/03/2016), was analyzed. Statistical techniques that assume survival times for patients follow extrapolation of the trial data were applied. OS projections were explored using three different methods 1) extrapolating the observed OS of the overall population; 2) extrapolating the observed OS of responders and non-responders separately and then combining projections; 3) estimating OS as the sum of projected TTP and PPS. Predicted OS curves using 12-month data were verified against the 18-month data (03/24/2017). Average life expectancy and proportion of patients alive at 3, 5 and 10 years was estimated. Results: OS predicted from each of the three methods replicated the 18-month observed OS (40%, 95% CI: 29%,50%) reasonably well when appropriated distribution was selected. Long-term survival projections under these methods are presented in the table. Conclusions: The projected survival benefits for avelumab in mMCC are substantial, regardless of approach used. Statistical models can provide early insights to potential long-term survival benefits associated with avelumab while the trial data are still maturing. Table. Projected survival with avelumab using different statistical techniques. Projection based on % Alive at Average life expectancy (years) 1.5 years 3 years 5 years 10 years OS extrapolated for the overall population 40% 22% 12% 5% 2.483 OS extrapolated for responders and non-responders 41% 30% 23% 11% 3.148 TTP and PPS 39% 25% 19% 11% 3.538
Feasibility of HSCT vs consolidation therapy for AML patients aged 60-75 in CR1: A randomized phase III, multicentre EBMT study.
Authors: Dietger Niederwieser, Bob Lowenberg, Wolfgang E. Berdel, Ronald Brand, Yves Chalandon, Christian Junghanss, Dirk Hasenclever, Mathias Haenel, Georg Maschmeyer, Meinhard Mende, Mohamad Mohty, Gert Ten Ossenkoppele, Jakob Passweg, Herbert Sayer, Johannes Schetelig, Harry C. Schouten, Sebastian Schwind, Matthias Stelljes, Vladan Vucinic, Jan Cornelissen
Journal: Journal of Clinical Oncology (2018)

7045 Background: AML has a particularly dismal prognosis in the elderly population. The OSHO, HOVON, SAKK and the French AML study groups performed a randomized phase III study comparing Hematopoietic Stem Cell Transplantation (HSCT) to conventional chemotherapy in these patients. Methods: Patients aged 60 – 75 years with AML CR1 (except FAB M3) were registered after induction(s) according to study group protocols. A donor search was initiated during consolidation. Patients with a related or matched unrelated donor were randomized within 150 days of diagnosis to receive either HSCT or non-HSCT in a 2:1 ratio. Patients in the HSCT arm were treated with Fludarabine/200 cGy total body irradiation followed by cyclosporine/mycophenolate mofetil. Patients in the non-HSCT arm continued therapy according to the study group protocols. Leukemia free survival was chosen as primary endpoint. Patients without a donor were included in the observation arm. Results: A total of 245 patients from 23 centers in five countries were registered and started consolidation. Sixty six patients (26.9%) exited the study before randomization because of relapse/no recovery (28), toxicities (10), consent withdrawal (10), patient choice (7), death (6) or miscellaneous reasons (5). Donors were identified for 135 (75.9%) of the 179 patients, 22.9% related and 77.0% unrelated. Ten patients with donors were allocated to the observation arm because of consent withdrawal, ineligibility, protocol violation or unknown reasons. Randomization proceeded for 125 (51,0%) patients. Of the 83 in the HSCT arm, 16 were not transplanted. Of the 42 patients in the non-HSCT arm, 6 did not receive the scheduled second consolidation and information is pending in 7. Endpoint analysis is due in 2020. Conclusions: The feasibility of HSCT for elderly patients with AML CR1 within 150 days from consolidation was demonstrated in a randomized European study. Donor identification and randomization was achieved for a large proportion of patients (75,9% and 51,0%). Despite a short treatment interval of ≤12 weeks from consolidation to HSCT/non-HSCT, relapse (n = 39) and toxicities (n = 14) were the most frequent cause of end of study. Clinical trial information: EudraCT Number 2007-003514-34.
Serum erythropoietin (sEPO) testing and treatment patterns for transfusion-dependent (TD) patients (pts) with myelodysplastic syndromes (MDS).
Authors: Aaron Thomas Gerds, Gary Binder, Albert Fliss, Michael McGuire, Stephanie Marie Hawthorne, Kristen King-Concialdi, Marco DiBonaventura
Journal: Journal of Clinical Oncology (2016)

e18215 Background: National Comprehensive Cancer Network (NCCN)guidelines for treatment of MDS describe sEPO level as a useful measure at initial evaluation and as required prior to treatment with erythropoietin-stimulating agents (ESAs). Since a high pre-treatment sEPO level is associated with a lack of response to ESAs, pts with these levels should be considered for other therapies. This study evaluated rates of sEPO testing, sEPO levels, and subsequent use of ESAs among pts who became TD at or after MDS diagnosis. Methods: A retrospective chart review of pts with MDS was conducted in the USA. 26 oncologists and hematologists provided data from sequential pt charts. Pt inclusion criteria were: age ≥ 18 years, diagnosis of International Prognostic Scoring System (IPSS) Low/Intermediate-risk MDS within the last 1–5 years, and TD onset ≥ 12 months previously. Pts with high-risk disease prior to TD onset, a concurrent malignancy, or who were in an MDS clinical trial were excluded. Demographics, disease history, treatment history, and lab values were collected and reported descriptively. Results were compared using chi-square tests. Results: Information was collected on 133 TD MDS pts. 57.9% were male; median age was 67 years (range 37–89), with a median of 25 months since diagnosis (range 12–58). 66 (49.6%) pts had a sEPO test at diagnosis; of these, 39.4% had levels ≥ 200 mU/mL, including 13.6% ≥ 500 mU/mL. For pts without sEPO testing, reasons included practice dynamics (28.4%), testing not considered worthwhile (28.4%), and no intent for ESA use (17.9%). Excluding this latter group, 21.8% of untested pts were treated with ESAs vs 36.4% of those tested (P = 0.08). Conclusions: Of the pts with TD MDS, only half had undergone sEPO testing at diagnosis. Many tested pts had sEPO ≥ 200 mU/mL, including a proportion with ≥ 500 mU/mL; alternative treatments to ESAs should be considered for these pts. Nevertheless, ESA use occurred in nearly a fifth of pts not tested at diagnosis, suggesting that expanded sEPO testing may identify additional pts not appropriate for ESAs.
Abstract 10880: Impact of Post-Extrasystolic Potentiation on Takotsubo Cardiomyopathy
Authors: Shunsuke Aoi, Blase Carabello, Maurice Rachko
Journal: Circulation (2015)

Introduction: Takotsubo cardiomyopathy (TCM) is an increasingly recognized condition that presents with transient and reversible left ventricular (LV) dysfunction despite angiographically unobstructed coronary arteries. However the detailed pathophysiology of the stunned myocardium remains to be determined. Post-extrasystolic potentiation (PESP) is an increase in contractility after an extrasystole, thought at least in part due to a net increase in myocardial calcium. When PESP occurs in akinetic LV segments, it is a marker of myocardial viability. Obviously the myocardium in TCM is viable, thus we hypothesized that the affected myocardium in TCM would demonstrate PESP. Methods: We retrospectively reviewed 61 cases of TCM diagnosed by the Mayo criteria between the periods of October 2004 to May 2015. The 24 cases wherein left ventriculography fortuitously provoked extra systoles (PVCs) were evaluated. Results: In our study, the baseline characteristics of TCM were 93.4% female patients with mean age of 67. Mean ejection fraction was 38% and mean troponin I elevation was 5.5. Apical type was the predominant (72.1%) compared to the mid-ventricular type (23.0%). None of the 24 patients in whom ventriculographic PVCs occurred demonstrated PESP in the affected region of the LV, while all did in the unaffected portion. Conclusions: Extra-systoles in TCM fail to elicit PESP in affected LV segments despite proven viability in those segments while unaffected segments behave as predicted. Since increased calcium is thought to be the basis for PESP, it is possible in TCM that either there is failure of calcium release in the affected areas or that the presumed catecholamine excess of TCM has already caused maximum calcium release so PCVs cannot enhance contractility further.
Circulating tumor DNA profiling of lung cancer patients treated with EGFR inhibitors.
Authors: Sandra Ortiz-Cuaran, Aurelie Swalduz, Emma Green, Virginie Avrillon, Michael Epstein, Karen Howarth, Solène Marteau, Clive D. Morris, Maurice Perol, Pierre Saintigny
Journal: Journal of Clinical Oncology (2017)

e23060 Background: The presence of a targetable driver mutation in nearly 50% non-small cell lung cancer (NSCLC) patients has enabled tailoring therapy regimens to improve survival. Serial repeat biopsies can offer an instrumental indication into the longitudinal evolution of cancer. However, tissue biopsies are invasive and can provide insufficient material for molecular testing. Mutation detection in plasma DNA as a “liquid biopsy” has been suggested as non-invasive approach to monitor tumor dynamics over time. Methods: We established an institutional protocol (NCT01511288) for the collection of liquid biopsies from stage IIIB/IV NSCLC patients either untreated, under therapy or progressive on therapy with a TKI. This protocol has included 134 NSCLC patients for whom clinical, pathological and genomic information is collected prospectively. Analyses were performed by Inivata using InVision (enhanced tagged-amplicon sequencing). Results: So far, samples from 50 patients have been analyzed. InVision allowed the detection of driver mutations in 20 plasma samples obtained at diagnosis. Tissue was unavailable for molecular analysis in 8/20 samples. We observed a concordance rate in mached plasma and tissue samples, of 92,3% (n = 12). In plasma samples from patients that relapsed under erlotinib or gefitinib we evidenced the EGFR T790M mutation in 57% of patients, with a concordance rate of 90,9%. Interestingly, analysis of serial samples collected from 3 patients under EGFR-targeted therapy showed the emergence of an EGFR T790M mutation 11 weeks before the radiographic confirmation of progression (P1); differential dynamics in the allelic fractions of mutated clones that reflected the pattern of dissociated tumor response to treatment (P2) and the presence of concomitant EGFR activating and T790M mutations, together with an EGFR C797G, BRAF V600E and KRAS G12D in a patient who progressed under osimertinib (P3). Conclusions: Our preliminary results provide further evidence on the use of liquid biopsies for monitoring disease response, resistance to treatment and tumor heterogeneity. Subsequently, we will evaluate the utility of liquid biopsies in the clinical setting to understand the dynamics of mutant clones over time.
Ten year mortality trends among Israeli pancreatic ductal adenocarcinoma (PDAC) patients.
Authors: Leora Ferro, Shmuel Wechsler, Sharon Pelles, Ravit Geva, Ido Wolf
Journal: Journal of Clinical Oncology (2018)

e16222 Background: PDAC is one of the most lethal cancers, with 5-year overall survival (OS) ranging from 3-8%, and median survival of 6-11 months for patients with metastatic disease. We aimed to examine survival trends of PDAC patients treated over 10 years in a large tertiary center with unique ethnic characteristics. Methods: Survival data of all PDAC patients diagnosed at our institution between 2007 and 2016 was analyzed. Data regarding efficacy of chemotherapy combinations was further examined in a subset of patients diagnosed with upfront metastatic disease during 2015-2016. Results: A total of 1213 PDAC patients were treated in our institution during 2007-2016, representing ~20% of all Israeli PDAC patients. The 5-year OS was 17%. No change in OS was observed during all these years and was also identical before and after the introduction of FOLFIRINOX and Gemcitabine-Abraxane combinations. 232 patients (23%) underwent curative surgery and their 5-year OS was 23%. Among patients with upfront metastatic disease (n = 123) diagnosed during 2015-2016, 71% received any type of chemotherapy and their survival was 10.3 months, compared to only 2.2 months in the 29% of patients not receiving any treatment (p < 0.01). The untreated patients were older (median age 76.5 vs. 66 respectively) and their albumin was lower compared to those receiving chemotherapy. Survival among those treated with FOLFIRINOX as first line (n = 49, 40%) was 14.2 months, compared to 11.2 months for those receiving Gemcitabine as first line. Conclusions: The longer survival shown in real-life data compared to statistics of other countries may reflect unique genetic factors of the Israeli population. Importantly, we identified a relatively large group of metastatic PDAC patients not receiving any treatment and demonstrated an OS of 2.2 months. This group is neglected in the literature and clinical trials, and contributes to OS data.
Evaluating PD-L1 status and its correlation with clinical features in surgically resected lung adenocarcinoma patients: Comparison of tissue microarrays and whole tissue section.
Authors: Hsu-Ching Huang, Yi-Chen Yeh, Teh-Ying Chou, Yu-Chung Wu, Chi-Lu Chiang, Chia-I Shen, Chao-Hua Chiu
Journal: Journal of Clinical Oncology (2018)

8548 Background: PD-1/PD-L1 has been a novel therapeutic target in non-small-cell lung cancer (NSCLC). PD-L1 immunohistochemical staining is the most commonly used test for therapeutic guide. Although PD-L1 expression heterogeneity is well acknowledged, data are limited in PD-L1 staining results between small biopsied sample and whole tissue section (WTS) obtained from the same specimen. Current study aimed to compare PD-L1 staining between tissue microarray (TMA) and WTS and correlate it with clinical features. Methods: Two hundred and nineteen lung adenocarcinomas from patients who underwent surgical resection in Taipei Veterans General Hospital during Sep. 2002 and Aug. 2006 were used to construct TMA. Among them, the correspondent WTS was available in 173 specimens. Tumor PD-L1 staining on TMA and WTS were evaluated by SP142 (Spring Bioscience) on Leica autostainer. Positive PD-L1 expression was defined as membranous staining in ≥ 1% of tumor cells. Correlations between TMA and WTS PD-L1 expression were performed. Patients’ demographic characteristics, survival and histology subtypes were investigated and correlated with PD-L1 expression on WTS. Results: 25 (14.5%) and 58 (33.5%) specimens were PD-L1 positive in TMA and WTS, respectively. Thirty-three (19.1%) specimens were PD-L1 negative in TMA but positive in WTS. The expression level was 1% in 8, 2-5% in 7; 6-49% in 14, and ≥ 50% in 4 specimens. Discordancy was more common in larger tumor size (p = 0.025), wild type EGFR (p = 0.044), and advanced stage (p = 0.01). Tumors with lepidic predominant histology (p < 0.001), EGFR wild-type (p = 0.002) and early disease stage (p = 0.006) were more likely to be PD-L1 negative. Kaplan-Meier survival analysis showed longer recurrence-free survival (p < 0.001) among patients with negative PD-L1 expression. Conclusions: PD-L1 IHC readout discordancy between small and large samples were not uncommon in NSCLC and it seemed related to tumor size and stage. Patients with negative PD-L1 expression tended to have longer recurrence-free survival.
Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups
Authors: Tenley C. Archer, Tobias Ehrenberger, Filip Mundt, Maxwell P. Gold, Karsten Krug, Clarence K. Mah, Elizabeth L. Mahoney, Colin J. Daniel, Alexander LeNail, Divya Ramamoorthy, Philipp Mertins, D.R. Mani, Hailei Zhang, Michael A. Gillette, Karl Clauser, Michael Noble, Lauren C. Tang, Jessica Pierre-François, Jacob Silterra, James Jensen, Pablo Tamayo, Andrey Korshunov, Stefan M. Pfister, Marcel Kool, Paul A. Northcott, Rosalie C. Sears, Jonathan O. Lipton, Steven A. Carr, Jill P. Mesirov, Scott L. Pomeroy, Ernest Fraenkel
Journal: Cancer Cell (2018)
Ireland’s cervical cancer screening system was “doomed to fail,” inquiry finds
Authors: Clare Dyer
Journal: BMJ (2018)

The system for cervical cancer screening in Ireland was “doomed to fail at some point” and had problems that were “redolent of a whole system failure,” an independent inquiry has concluded.1

The scoping review by Gabriel Scully was set up in the wake of a crisis in the country’s cervical screening programme, CervicalCheck, when it emerged that women who developed cancer had not been told of earlier smear tests which were wrongly interpreted.

Scally, president of the epidemiology and public health section of the Royal Society of Medicine, was appointed to carry out the review by the minister for health, Simon …
Reaction of hypothalamic-pituitary-adrenal axis and its skin analogue to B16/F10 melanoma growth shows gender differences.
Authors: Valeria A. Bandovkina, Oleg I. Kit, Elena M. Frantsiyants, Vyacheslav A. Sustretov, Olga V. Mkhitaryan, Irina V. Kaplieva, Lidia K. Trepitaki, Natalia D. Cheryarina
Journal: Journal of Clinical Oncology (2018)

e21634 Background: The hypothalamic-pituitary-adrenal axis (HPA) maintains homeostasis and the body's response to any stressful effects. Skin cells are capable of local synthesis of steroid, thyroid and regulatory hormones, which makes the skin an analogue of HPA. The purpose of the study was to reveal the effects of transplantable В16/F10 melanoma on central HPA axis and its skin analogue in mice taking into account the gender of animals. Methods: The study included 40 female and 40 male С57BL/6 mice with transplantable В16/F10 melanoma in weeks 1, 2, 3 and 4 of its growth. Hormonal levels were determined by ELISA and RIA in homogenates of hypothalamus, pituitary, adrenal and tumor and in the intact skin. Results: During the melanoma growth, male mice demonstrated an increase in CRF in the hypothalamus, the ACTH decrease in the pituitary and a sharp increase of cortisol in the adrenal glands. At the same time, levels of CRF, ACTH and cortisol increased from the second week in tumor which probably promoted autocrine/paracrine regulation of proliferation processes in the tumor tissue. The melanoma growth in female mice was associated with an increase in CRF in the hypothalamus, with ACTH increase starting from week 3 and a gradual increase in cortisol in the adrenal glands starting from week 2. CRF and ACTH levels increased in melanoma as well, but skin levels of cortisol decreased. Conclusions: In the dynamics of the melanoma growth, male mice demonstrated the loss of sensitivity in the pituitary component of the HPA axis to the stimulating effect of the hypothalamus; in females, regulatory connections were not impaired. In males, the skin analogue of the HPA axis was activated, which was indicated by an increase in the level of regulatory hormones in growing melanoma and surrounding tissues.