tbuckley/cabot-search huggingface dataset:
Metronomic chemotherapy (mCHT) in HER2-ve advanced breast cancer (ABC) patients (pts): Final results of the VICTOR-6 study.
Authors: Marina Elena Cazzaniga, Giovanni Scognamiglio, Daniele Giulio Generali, Antonella Ferzi, Anna Maria Vandone, Pietro Spadaro, Carmela Mocerino, Emilia Montagna, Elisabetta Cretella, Anna Gambaro, Cristiana Taverniti, Anna Turletti, Giuseppina Sarobba, Laura Iezzi, Michela Roberto, Mariangela Ciccarese, Paolo Tralongo, Luca Clivio, Stefania Pedroli, Valter Torri
Journal: Journal of Clinical Oncology (2018)

e13076 Background: mCHT is the minimum biologically effective dose of a CHT agent, given at regular dosing regimen with no prolonged drug free interval. Aim of this observational retrospective study is to describe the use of mCHT in ABC pts across 5 years and efficacy of old (CM-like) vs new (VRL/CAPE-based) metronomic regimens in terms of response and disease control. Methods: We retrospectively identified from clinical records those HER2-ve ABC pts who have received any kind of mCHT in the years 2011-2015, alone, or in combination with a non-metronomic drug. Standard statistical approaches were used for describing the sample characteristics. This analysis focuses on Response Rate (RR) and Disease Control Rate (DCR). Results: From June 2011 to December 2015, 601 pts have been enrolled. Main tumour characteristics were ductal histology (84.2%), pT2 stage (41.6%), pN1 stage (35.2%), ER+/PgR+ (81%), Grade 2 (47.1%). ECOG PS was 0-1 in most patients (92.0%). mCHT use increased over the time from 15.0% (2011) to 30% (2015). VRL-based were the most used regimens (51.9%), mainly in combination with CAPE±CTX (40.8%), followed by CTX-based ones (23.7%), mostly in combination with MTX (15.8%). Single-agent mCHT, independently of the drug, has been used in 214 patients (37.1%). VRL-based regimens have been mainly administered as combination schedules (40.8%), whereas CAPE was predominantly used alone (18.9%). At the moment of data cut-off date 149 patients (24.8%) were still on treatment without progression and 215 were alive (35.8%). Median duration of mCHT treatment was 6.28 months (5.65 – 7.01). Main reason for drug interruption was progression of the metastatic disease (77.3%), discontinuation due to adverse events was observed in 51 patients (8.8%). Overall Response Rate was 25.5% and Disease Control Rate was 74.0%. Main Grade 3-4 toxicities were hematologic (11.6%), skin reaction (4.5%) and nausea/vomiting (3.9%). Conclusions: The use of mCHT in the treatment of HER2-ve ABC pts has deeply changed across the last 5 years, new generation regimens being used in earlier lines of treatment, producing interesting results in terms of objective response and disease control with less toxicity.
53BP1 as a predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer.
Authors: Rachel M Hurley, Andrea Elisabeth Wahner Hendrickson, Daniel W. Visscher, Peter J Ansell, Maria I Harrell, Jill M Wagner, Vivian Negron, Krista M. Goergen, Matthew John Maurer, Ann L. Oberg, Maja J. De Jonge, Carla M.L.- Van Herpen, Jourik A. Gietema, Rutger H.T. Koornstra, Agnes Jager, Martha W. den Hollander, Matthew W. Dudley, Stacie Peacock Shepherd, Elizabeth M. Swisher, Scott H. Kaufmann
Journal: Journal of Clinical Oncology (2018)

5538 Background: Poly(ADP-ribose)polymerase (PARP) inhibitors have shown substantial activity in homologous recombination (HR) deficient ovarian cancer and are undergoing testing in other HR-deficient tumors. For reasons that are poorly understood, not all patients with HRD cancers respond to these agents. Preclinical studies have demonstrated that changes in alternative DNA repair pathways affect PARP inhibitor (PARPi) sensitivity. As this has not previously been assessed in the clinical setting, we examined the relationship between HRD score, BRCA1 and BRCA2 mutation status, expression of NHEJ pathway repair proteins, and response of ovarian cancers treated with single agent PARPi. Methods: Archival biopsies from ovarian cancer patients undergoing treatment on a single-agent PARPi trial were stained for PARP1, RAD51, and multiple components of the nonhomologous end-joining (NHEJ) pathway, including 53BP1, KU70, KU80 and DNA-PKCS. Assays were validated by showing that the IHC signal was markedly attenuated with gene knockout or highly effective siRNA. Histochemistry- (H-) scores were determined for each repair protein in each sample. HRD score was determined from tumor DNA. Results: Responses to the PARPi ABT-767 were observed exclusively in ovarian cancers with an HR-deficiency. In this HR-deficient subset, 7 of 18 patients (39%) had objective responses, however actual HRD score did not further correlate with change from baseline tumor volume (r = 0.0499; p = 0.87). Conversely, in the HR-deficient subset, 53BP1 H-score showed a strong correlation with change from baseline tumor volume (r = -0.69, p = 0.004), followed by KU80 (r = -0.46; p = 0.08). Conclusions: Differences in complementary repair pathways, particularly in the NHEJ pathway, correlate with PARPi response of HR-deficient ovarian carcinomas. Among HR-deficient ovarian carcinomas, 53BP1 H-score demonstrated a strong correlation with the percent change of tumor volume.
An immunoregulatory and tissue-residency program modulated by c-MAF in human TH17 cells
Authors: Dominik Aschenbrenner, Mathilde Foglierini, David Jarrossay, Dan Hu, Howard L. Weiner, Vijay K. Kuchroo, Antonio Lanzavecchia, Samuele Notarbartolo, Federica Sallusto
Journal: Nature Immunology (2018)
Non-invasive diagnosis and tracking of tumor evolution by targeted sequencing of circulating tumor DNA in metastatic pancreatic cancer patients.
Authors: Thomas Seufferlein, Andreas W. Berger, Daniel Schwerdel, Thomas Jens Ettrich, Stefan A. Schmidt, Alexander Kleger, Ralf Marienfeld
Journal: Journal of Clinical Oncology (2017)

e15769 Background: Treatment of stage IV pancreatic ductal adenocarcinoma (PDAC) has made substantial progress over the last years, therapy monitoring still is at an early stage. This could be substantially supported by tools that allow to establish and monitor the molecular setup of the tumor even during treatment. In particular, non-invasive approaches are desirable. Characterization of circulating tumor DNA (ctDNA) may help to achieve this goal. Methods: We analyzed a cohort of 20 patients with histologically confirmed metastatic PDAC (mPDAC) prior to and during palliative treatment including disease progression. ctDNA and corresponding tumor tissue were analyzed by targeted NGS and droplet digital PCR for the 7 most frequently mutated genes in PDAC ( TP53, SMAD4, CDKN2A, KRAS, APC, ATM, FBXW7). Findings were correlated with clinical and imaging data to establish its prognostic and predictive value. Results: ctDNA was analyzed at baseline prior to initiation of the respective line of treatment. Mutations in either of the genes examined were detectable in 15/20 patients (75%). Tissue-blood concordance was 80% in therapy naïve patients. 96% of mutations in ctDNA of therapy naïve patients were in KRAS and/or TP53. The combined mutated allele frequencies (CMAF) of theese 2 genes significantly decreased (p = 0.0173) during therapy and increased at progression (p = 0.0145) across all treatment lines. By sequential ctDNA analyses we detected a change in the mutational landscape compared to the respective baseline ctDNA status in 7/11 patients during 1 st line, in 3/7 patients during 2 nd line and 2/2 patients during 3 rd line treatment. In therapy naïve patients, the decline of the CMAF during therapy significantly correlated with progression-free survival (p = 0.0013). Conclusions: Molecular genotyping of ctDNA in mPDAC patients proved to be feasible and there was a high concordance between tumor tissue and ctDNA. The molecular genotype changed significantly during treatment and changes correlated with outcome. Monitoring of ctDNA may enable to adapt therapeutic strategies to the specific molecular changes present at a certain time during treatment of mPDAC.
Bevacizumab (B) + bi-weekly capecitabine (C) and oxaliplatin (O) (XELOX2) or FOLFOX4 in first-line treatment of metastatic colorectal cancer (mCRC): Final results of a multicenter randomized phase II trial of the Gruppo Oncologico dell’Italia Meridionale (GOIM protocol 2802).
Authors: Evaristo Maiello, Gabriele Di Maggio, Stefano Sergio Cordio, Saverio Cinieri, Francesco Giuliani, Salvatore Pisconti, Antonio Rinaldi, Antonio Febbraro, Tiziana Pia Latiano, Michele Aieta, Daniele Rizzi, Massimo Di Maio, Giuseppe Colucci, Roberto Bordonaro
Journal: Journal of Clinical Oncology (2018)

3542 Background: B plus bi-weekly FOLFOX4 or three-weekly XELOX represents a standard 1-line therapy for mCRC pts. In our previous phase II study (Fedele P et al, ASCO 2009) we demonstrated a similar efficacy of a bi-weekly schedule of C combined with O (XELOX2). In this randomized phase II trial, pts with mCRC, previously untreated, ECOG PS 0-1, age 18-75, were randomized to receive, in a 2:1 ratio, XELOX2 + B (experimental arm) vs. FOLFOX4 + B (calibration arm). Primary endpoint was ORR; secondary endpoints were PFS, OS and toxicity. Methods: B (5 mg/kg on d1 of a 2-week cycle) was administered before O, with FOLFOX4 (Arm A) or XELOX-2 (Arm B; O 100 mg/m2 on d1 followed by oral C 1,000 mg/m2 twice daily on d1 through 7 of a 14-day cycle). After a maximum of 12 cycles (induction phase), pts in CR,PR and SD were randomized to maintenance with B alone or B+Fluoropyrimidine (C or FU). Sample size of experimental arm was calculated according to Simon's two-stage design, with a type I error rate 0.05 and 0.90 power. With null hypothesis ORR 32% and alternative hypothesis ORR 48%, 46 pts had to be accrued in the first stage, for a final number of 80 pts. Study design was formally non comparative, but exploratory comparison between arms was performed. Results: One-hundred thirty-two pts were randomized (45 arm A; 87 arm B). The main characteristics of the entered pts were well balanced. ORR (Arm A vs B) was 55.6% vs 48.3% (p = 0.43). With a median follow-up of 47.2 months, PFS was 10.0 vs 9.9 months (HR 0.96, 95%CI 0.65-1.41; p = 0.84) and OS was 29.8 vs 25.0 months (HR 1.21, 95%CI 0.77-1.92; p = 0.41). Main G3-4 toxicity rate (A vs B) were as follows: thrombocytopenia 2/2, anemia 4/3, neutropenia 15/3, nausea 9/5. vomiting 2/3, diarrhea 7/7, neurotoxicity 2/2 and hypertension 2/1. Conclusions: GOIM study 2802 showed that the XELOX2+B regimen is active as FOLFOX4+B in pts with mCRC. Given the extreme tolerability and convenience of administration of therapy, XELOX2 + B appears to be indicated even in frail or elderly patients. Clinical trial information: 2010-022091-31.
Replication stress response deficiency (RSRD) and response to immune therapy in clear cell renal cell carcinoma (ccRCC).
Authors: Patrick Glen Pilie, Daniel James McGrail, Shiaw-Yih Lin, Eric Jonasch
Journal: Journal of Clinical Oncology (2018)

4566 Background: Despite treatment advances with immune therapy (IO), advanced stage ccRCC still has poor prognosis, due in part to a lack of predictive biomarkers. Replication stress (RS) is a hallmark of ccRCC initiation, contributing to genomic instability. However, cancer evades death from instability via deficient DNA damage repair (DDR) and RS response (RSR). The ATM/ATR and CHK2/CHK1 axes are critical to DDR and RSR; and deficiencies in these axes may activate innate immune signaling and lead to improved IO response. In this study, we assessed protein signaling changes in early ccRCC patient tumors, performed in silico analysis of ccRCC cohorts for the presence of a novel RSR deficient (RSRD) score, and evaluated the prognostic and predictive value of this RSRD score in ccRCC. Methods: We performed reverse phase protein microarray (RPPA) on 12 stage I ccRCC tumors vs 12 normal kidney tissues. We analyzed the Cancer Genome Atlas (TCGA) for a novel gene expression score of RSRD, and its impact on OS. We assessed immune cell infiltrate in TCGA tumors using CIBERSORT. We assessed RNA data from previously published cohort of 28 ccRCC patients treated with IO (Miao et al, Science 2018) and clinical outcomes based on RSRD score. Results: Early ccRCC tumors already showed loss of p-ATM/p-CHK2 and p-ATR/p-CHK1 protein signaling with increased IRF1 and ADAR1 expression (p < 0.05). From TCGA, RSRD-high tumors were more likely to be advanced stage and had significantly worse OS in multivariate analysis. In silico analysis revealed RSRD-high tumors had significantly higher T cell infiltrate compared to RSRD-low tumors. In the Miao et al IO-treated ccRCC cohort, 11/33 tumors were RSRD-high, with 73% of RSRD-high showing clinical benefit compared to only 18% of the RSRD-low and 36% of the bulk study population even when controlling for PBRM1 mutation. Conclusions: RSR and DDR signaling are dysregulated in ccRCC and may activate innate immune pathways. A novel RSRD score has potential as both prognostic and predictive biomarker for IO response. Further studies are warranted to validate the predictive power of this biomarker and understand how DDR and RSR deficiencies in ccRCC may impact immune activation.
Outcomes and prognostic factors of localized, resected malignant salivary gland tumors: Examining a single institution’s 12-year experience to discover indications for adjuvant chemotherapy.
Authors: Tyler Gutschenritter, Michael Machiorlatti, Sara Vesely, Bilal Ahmad, Wajeeha Razaq, Mohammad Razaq
Journal: Journal of Clinical Oncology (2017)

e17587 Background: Survival outcomes remain poor in salivary gland malignancies (SGMs) with multiple poor prognostic factors despite adjuvant radiotherapy. We examined prognostic factors that portended poor survival in resected SGMs to determine possible indications for adjuvant chemoradiotherapy. Methods:Patients who underwent curative resection with or without adjuvant radiotherapy between 2002 and 2014 were identified and retrospective chart review was performed. Bivariate analysis was performed on continuous variables using Analysis of Variance. Chi-Square analysis and Fishers Exact Tests were performed on categorical variables. To evaluate the overall survival (OS) and disease-free survival (DFS), Kaplan-Meier curves and log-rank tests of homogeneity were used. Results: Overall, 99 patients met inclusion criteria. Median follow-up time was 46.8 months. Univariate analysis revealed male sex, smoking history ≥ 10 pack-years, high grade, stage III-IVB, squamous cell histology, and perineural invasion significantly impacted OS and DFS. High-risk histopathology significantly impacted DFS and trended towards poor OS. Positive resection margins trended towards significantly impacting DFS. Multivariate analysis revealed only male sex and perineural invasion significantly impacted OS and DFS. Conclusions: Survival outcomes remain poor for patients with high-grade, late-stage tumors with perineural invasion. Specifically, perineural invasion is a poor prognostic factor regardless of age, histology, stage, and grade. Males and patients with a smoking history ≥ 10 pack-years have worse survival outcomes with male sex being a more influential prognostic factor. Notably, this is the first study to quantify patient’s smoking history in malignant salivary gland tumors and assess the impact of pack-year smoking history on survival outcomes. Given our observed trend, positive resection margins would likely become significant influencer of DFS with larger sample size and longer follow up. Adjuvant chemoradiotherapy should be evaluated in patients with the above-mentioned characteristics.
The incidence, prognosis and survival of primary breast lymphoma: A SEER experience.
Authors: Vivek Kumar, Prabhsimranjot Singh, Makardhwaj Shrivastava, Abhinav Binod Chandra, Yiqing Xu, William B. Solomon
Journal: Journal of Clinical Oncology (2016)

e19026 Background: Primary breast lymphoma (PBL) are rare neoplasms involving breasts and draining lymph nodes without evidence of disease elsewhere. By definition PBL are stage IE and IIE non-Hodgkin’s lymphoma (NHL). The staging of bilateral tumors is controversial. We evaluated the trends of incidence and prognosis in PBL. Methods: We analyzed all cases of PBL registered in the Surveillance, Epidemiology, and End Results (SEER) database from 1983 to 2012. Age-adjusted incidence and survival rates were calculated. K-M curves were plotted and log-rank statistics computed to detect differences between survival curves for sex, race, stage, radiation, age, and year of diagnosis. Results:: 1545 cases of PBL were identified. The cumulative age standardized incidence rate per 100, 000 was 0.147. The rate increased with advancing age from .032 per 100,000 (95% CI; .026-.038) in below 50 years old to .767 (95% CI; .66-.89) per 100,000 above 80 years. The incidence rate per 100,000 almost doubled from .094 (95% CI; .08-.11) during 1983-92 to.172 (95%CI; .16-.19) in 2003-12. (p = .02) The median overall survival (OS) (115 months; 95% CI 103-127) was better than all NHL (median OS 97 months; 95% CI 95.6-98.4) (p = .03). 30 patients had bilateral tumors staged as I and II NHL in the SEER database. The outcome in bilateral tumors (median OS 115 months: 95% CI 102.8 – 127.2) was similar to unilateral tumors. Stage I (HR .46-.67) and age below 50 years (HR .05 -.108) were the strongest predictors of favorable outcome on multivariate analysis. (P = 0.00) Histological type didn’t affect the prognosis in PBL unlike in NHL. (P = 0.15). Median OS increased from 51 months (95% CI; 55-95) during 1983-92 to 124 months (95% CI; 103-127) in 2003-12 (p = .03). No differences were seen in the distribution of stage or age at diagnosis among these time periods. Conclusions: The incidence of PBL is increasing in United States. The prognosis of bilateral tumors is similar to the stage I and II unilateral tumors and thus current view of staging bilateral tumors as stage IV may not be valid. The survival of PBL patients is better than NHL and continues to improve. Prognosis is not affected by histological type unlike in NHL. Age and stage are the strongest predictors of outcome in PBL.
The Prevention of Tuberculosis
Journal: BMJ (1901)

First published in 1908, this book presents a study of tuberculosis. It looks first at its causes, before examining how the problem of mortality from illness had already been reduced. The third part of the book then focuses on measures for reducing and annihilating tuberculosis altogether. Being written in the earlier years of the twentieth century, the book will not only be of interest to medical students and practitioners, but also to historians.
Anti–IL-5 in Mild Asthma Alters Rhinovirus-induced Macrophage, B-Cell, and Neutrophil Responses (MATERIAL). A Placebo-controlled, Double-Blind Study
Authors: Yanaika S. Sabogal Piñeros, Suzanne M. Bal, Marianne A. van de Pol, Barbara S. Dierdorp, Tamara Dekker, Annemiek Dijkhuis, Paul Brinkman, Koen F. van der Sluijs, Aeilko H. Zwinderman, Christof J. Majoor, Peter I. Bonta, Lara Ravanetti, Peter J. Sterk, René Lutter
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Eosinophils drive pathophysiology in stable and exacerbating eosinophilic asthma, and therefore treatment is focused on the reduction of eosinophil numbers. Mepolizumab, a humanized monoclonal antibody that neutralizes IL-5 and efficiently attenuates eosinophils, proved clinically effective in severe eosinophilic asthma but not in mild asthma.To study the effect of mepolizumab on virus-induced immune responses in mild asthma.Patients with mild asthma, steroid-naive and randomized for eosinophil numbers, received 750 mg mepolizumab intravenously in a placebo-controlled double-blind trial, 2 weeks after which patients were challenged with rhinovirus (RV) 16. FEV1, FVC, fractional exhaled nitric oxide, symptom scores (asthma control score), viral load (PCR), eosinophil numbers, humoral (luminex, ELISA), and cellular (flow cytometry) immune parameters in blood, BAL fluid, and sputum, before and after mepolizumab and RV16, were assessed.Mepolizumab attenuated baseline blood eosinophils and their activation, attenuated trendwise sputum eosinophils, and enhanced circulating natural killer cells. Mepolizumab did not affect FEV1, FVC, and fractional exhaled nitric oxide, neither at baseline nor after RV16. On RV16 challenge mepolizumab did not prevent eosinophil activation but did enhance local B lymphocytes and macrophages and reduce neutrophils and their activation. Mepolizumab also enhanced secretory IgA and reduced tryptase in BAL fluid. Finally, mepolizumab affected particularly RV16-induced macrophage inflammatory protein-3a, vascular endothelial growth factor-A, and IL-1RA production in BAL fluid.Mepolizumab failed to prevent activation of remaining eosinophils and changed RV16-induced immune responses in mild asthma. Although these latter effects likely are caused by attenuated eosinophil numbers, we cannot exclude a role for basophils. Clinical trial registered with www.clinicaltrials.gov (NCT 01520051).
Undifferentiated endometrial sarcomas (UES): Results of a French sarcoma group (FSG) retrospective series of 52 patients (pts).
Authors: Marie Meurer, Anne Floquet, Antoine Italiano, Morgane Auriche, Julien Mancini, Nicolas Penel, Isabelle Laure Ray-Coquard, Martine Delannes, Sophie Piperno-Neumann, Francois Bertucci, Sébastien Salas, Jean-Yves Blay, Patricia Pautier, Florence Duffaud
Journal: Journal of Clinical Oncology (2017)

e17109 Background: UES are rare tumors of very poor prognosis. Although large surgical resection is the cornerstone of curative intent treatment, the optimal post-operative strategy remains unclear. Methods: We conducted a retrospective analysis of UES pts over the last 8 years in 10 FSG centers, from Netsarc and RRePs databases. Results: Fifty-two pts with primary UES treated from 2008 to 2016 were included. The median age was 59 years (range, 42-82), and median ECOG was 0 (range, 0-3): 33 were localized (FIGO I-III) and 19 metastatic at diagnosis. Metrorrhagia, abdominal pain, and pelvic mass bleeding were the most common symptoms. Surgical procedures were radical hysterectomy and bilateral adnexectomy for 23/33 (70%) of localized and 11/19 (58%) of metastatic UES. Metastases were identified post operatively for 9/19 pts. In the localized group, 19 pts (58%) received radiotherapy, 10 (30%) complementary brachytherapy and 9 (27%) adjuvant chemotherapy. In the metastatic group, 16/19 (84%) received chemotherapy (polyCT, n=11). With a median follow-up of 28 months (0.3-112),24/52 pts are alive, 18/33 (58%) localized pts relapsed with 6 local relapses and 11 metastases. The 3- and 5-year Overall Survival (OS) rates were 40.7% and 29.1% respectively, for the whole group. In the localized group; median OS and Relapse-Free Survival (RFS) were 32.7 (23.3-42.1) and 22.9 months (2.3-43.7). In univariate analysis; early FIGO stage (p &lt;0.0001), complete resection (R0-R1 vs R2; p=0.015) and adjuvant radiotherapy (p=0.001) were associated with a better OS; complete resection (p=0.021) and adjuvant radiotherapy (p=0.026) were associated with a better RFS. In the metastatic group, median OS was 16.4 months (12.0-20.7). In univariate analysis, no significant prognostic factor was retrieved neither on OS nor on RFS. Conclusions: Treatment of primary UES is radical hysterectomy and bilateral adnexectomy. Adjuvant radiotherapy appears beneficial for RFS. Due to the rarity and complexity of UES, referring patients to expert sarcoma centers is highly recommended.