tbuckley/cabot-search huggingface dataset:
Toxicity profile of approved anti-PD1 monoclonal antibodies in solid tumors: A systematic review and meta-analysis of randomized clinical trials.
Authors: Ricardo Lima Barros Costa, Benedito A. Carneiro, Alfred Rademaker, Mark Agulnik, Victoria Meucci Villaflor, Maria Matsangou, Sachin Gopalkrishn Pai, Aparna Kalyan, Young Kwang Chae, Sunandana Chandra, Jason B. Kaplan, Massimo Cristofanilli, Francis J. Giles
Journal: Journal of Clinical Oncology (2016)

3064 Background: Clinical trials supported the FDA approval of anti-PD1 antibodies nivolumab and pembrolizumab for treatment of advanced melanoma, renal cell carcinoma, and non-small cell lung cancer. This meta-analysis aimed to investigate the relative risk (RR) of adverse events (AEs) when compared to standard of care. Methods: PubMed search was conducted using the keywords or medical subject headings: “nivolumab” and “pembrolizumab”. Solid tumor randomized trials meeting the following inclusion criteria were included: at least one of the study arms consisting of nivolumab or pembrolizumab monotherapy; at least one of the control arms containing no anti-PD1 therapy. Treatment related (AEs) data were extracted according NCI CTCAE version 4.0 classification. The Q heterogeneity statistic was tested using a chi-square test. The percentage of between study variance was estimated using the I-squared statistic. Results: Our search yielded 442 published articles, after screening of the study titles 418 studies were excluded. After abstract and text review, eight phase III trials and one phase II randomized trial were included in our meta-analysis. A total of 5,666 patients were evaluable for toxicity. There was evidence of significant heterogeneity between studies. The random effect pooled RR for treatment-related all grade AEs and all grade 3 and 4 AEs was 0.878 (95% CI 0.807-0.955; p= 0.002) and 0.292 (95% CI 0.192-0455; p < 0.001) favoring anti-PD1 therapy versus standard of care approach. The pooled RR for all serious and grade 3&4 serious AEs was 0.566(95% CI 0.307-1.041; p= 0.067) and 0.45 (95% CI 0.194-1.044; p = 0.063). The RR of treatment-related death was 0.448 (95% CI 0.185-1.085; p= 0.075). In this large cohort, all grade hypothyroidism, rash, pneumonitis and colitis were documented in 6.5%, 12.5%, 2.6%, and 1% of patients, respectively. Conclusions:PD1 inhibitors (nivolumab and pembrolizumab) are associated with lower risk of AEs when compared to standard of care therapy. Despite their clinical relevance, the risk of selected immune-related adverse events was lower in this large cohort when compared to previously published phase I and II trials.
A phase I dose-escalation of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) carboplatin for the frontline treatment of advanced ovarian cancer.
Authors: Leslie M. Randall, Dan Gillen, Lauren S. Krill, Fong Wu Liu, Krista Pfaendler, Ramez Nassef Eskander, Krishnansu Sujata Tewari, Robert Bristow, Wen-Pin Chen
Journal: Journal of Clinical Oncology (2018)

5554 Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of frontline ovarian cancer surgery has shown preliminary overall survival benefit, but selection of chemotherapy agent and dose is mostly arbitrary. Methods: For this prospective study, women with peritoneal carcinomatosis of suspected ovarian, tubal, or peritoneal origin with optimal (R1 or R0) primary or interval debulking were eligible. Those with non-gynecologic primary, suboptimal surgery, or intraoperative complications were excluded. Dose for a pre-planned sample size (n = 30) was escalated according to a Bayesian continual reassessment schedule. The simulated maximum tolerated dose (MTD) estimate was 970 mg/m2. Closed-technique HIPEC was administered at 41oC for 60 minutes. Serum and perfusate samples were collected at time 0 and every 15 minutes for PK. Adverse events (AEs) were assessed every other day until discharge and weekly for 30 days according to NCI CTCAE v4.03. Results: We enrolled 52 subjects to reach n = 30 (attrition rate 42% for non-gynecologic primary or suboptimal surgery). Median age was 63 (range 33-78) with 15 Caucasian, 6 Hispanic, 7 Asian, and 2 other. Any AE was observed in 26 (87%) of subjects with 15 (50%) experiencing grade 3 or greater AEs. The most common grade 1-2 AEs were anemia (40%) and nausea (13.3%). Grade 3 AEs included anemia (10%), pancreatic leak (3.3%), wound dehiscence (3.3%), and sub diaphragmatic abscess (3.3%). One patient had grade 4 neutropenia and thrombocytopenia and grade 5 C. difficile colitis and sepsis; this was the only patient death. The post-trial MTD was 1115 mg/m2. PK analysis is ongoing. Conclusions: HIPEC with carboplatin was well tolerated at the protocol-specified doses in this cohort. The majority of AEs were attributable to surgery. Intraoperative protocol assignment is associated with a significant attrition rate that should be accounted for in sample size calculations and reported in clinical trials of HIPEC therapy. Clinical trial information: NCT02199171.
Inherited pulmonary cylindromas
Authors: S.M. Brown, M. Arefi, R. Stones, P.S. Loo, S. Barnard, C. Bloxham, N. Stefanos, J.A.A. Langtry, S. Worthy, E. Calonje, A. Husain, N. Rajan
Journal: British Journal of Dermatology (2018)

CYLD cutaneous syndrome (CCS) is a rare inherited skin disease. This disease affects about 1 in every 100,000 people in the U.K. and is more severe in females. It causes the development of multiple, sometimes hundreds, of skin tumours in each patient; these skin tumours, called cylindromas, can be painful and may grow rapidly. Depending on where they grow they can also cause problems; for example, blockage of the ear canal affecting hearing, and pubic tumours causing sexual dysfunction. We showed for the first time, evidence of cylindromas in the lung in a mother and daughter with CCS. Samples of both patients’ lung and skin tumours were taken, and studied with pathologists, and investigated with cutting‐edge genetic tests. These genetic tests allowed us to demonstrate that the gene signature of the lung cylindromas were similar to the gene signature of skin cylindromas. This suggests that sometimes, cylindroma cells may travel from the skin to the lung. It is important that doctors looking after CCS patients are aware of this possibility and understand the need to investigate if patients with this condition present with new symptoms of lung disease. It also guides doctors regarding follow‐up with repeat scans for these patients and treatments such as laser to trim back these lung tumours if they are going to block the large airways in the lung.
<sup>18</sup>FDG-PET/CT for the detection of residual/recurrent in patients with head and neck cancer: A systematic review and meta-analysis.
Authors: Jinbiao Shang, Jialei Gu, Wendong Wang, Kejing Wang, Yaping Xu
Journal: Journal of Clinical Oncology (2017)

e17502 Background: To evaluate the diagnostic accuracy of positron emission tomography (PET) and PET/computed tomography (CT) for detecting residual and/or recurrent local and regional disease in patients with head and neck cancer (HNC) following radiotherapy with or without chemotherapy. Methods: Studies about 18 FDG-PET/CT for detecting residual or recurrent disease after treatment in patients with HNC were systematically searched in the MEDLINE and EMBASE databases. The Stata software was used to obtain pooled estimates of sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio for 18 FDG-PET/CT. Results: 31 articles bulled all inclusion criteria. The pooled sensitivity and specificity of PET and PET/CT for detecting residual or recurrent disease at the primary site was 88.7% and 89.6%, respectively. For residual or recurrent neck disease, the sensitivity and specificity were 75.9% and 92.0%, while for residual or recurrent localregional disease, the values were 89.6% and 87.8%. Conclusions: 18 FDG-PET/CT has good diagnostic performance for the detection of residual and/or recurrent in HNC patients.
Effective fecal microbiota transplantation for recurrent <i>Clostridioides difficile</i> infection in humans is associated with increased signalling in the bile acid-farnesoid X receptor-fibroblast growth factor pathway
Authors: Tanya Monaghan, Benjamin H Mullish, Jordan Patterson, Gane KS Wong, Julian R Marchesi, Huiping Xu, Tahseen Jilani, Dina Kao
Journal: Gut Microbes (2018)

The mechanisms of efficacy for fecal microbiota transplantation (FMT) in treating recurrent Clostridioides difficile infection (rCDI) remain poorly defined, with restored gut microbiota-bile acid interactions representing one possible explanation. Furthermore, the potential implications for host physiology of these FMT-related changes in gut bile acid metabolism are also not well explored. In this study, we investigated the impact of FMT for rCDI upon signalling through the farnesoid X receptor (FXR)-fibroblast growth factor (FGF) pathway. Herein, we identify that in addition to restoration of gut microbiota and bile acid profiles, FMT for rCDI is accompanied by a significant, sustained increase in circulating levels of FGF19 and reduction in FGF21. These FGF changes were associated with weight gain post-FMT, to a level not exceeding the pre-rCDI baseline. Collectively, these data support the hypothesis that the restoration of gut microbial communities by FMT for rCDI is associated with an upregulated FXR-FGF pathway, and highlight the potential systemic effect of FMT.
P04.65 Towards new therapies for glioblastoma treatment: role of Dkk-3 and Claudin-5
Authors: M Caffo, E Esposito, G Casili, V Barresi, G Caruso, M Lanza, N Gorgoglione, A Germanò, S Cuzzocrea, S M Cardali
Journal: Neuro-Oncology (2018)

Glioblastomas (GBM) are highly aggressive brain tumors commonly treated with a combination of surgery, radiation therapy, and systemic chemotherapy. However, despite recent improvement in the multimodality approach, patient median survival times range between 3 and 30 months. New data by genomic approaches have allowed the subdivision of GBM into molecular subtypes, allowing us, in this way, to identify new targets. An important role in carcinogenesis is played by Dickkopf protein-related 3, which is involved in embryonic development through its interaction and modulation of the Wnt pathway. The expression of the REIC/Dkk-3 gene is down-regulated in many tumor cell lines and could contribute to the immunomodulatory properties of the tissue microenvironment. The mutations of Wnt pathway are of clinical importance, because they lead to the onset of several cancers, including brain tumors, being also involved in tumor angiogenesis. The Wnt signaling contributes also to activity of the claudins, that are critical components of tight junctions (TJ), implicated in blood-brain barrier (BBB) formation, whose expression was altered in cerebral microvessels of human GBM. In the present study we investigated the Wnt-signaling-mediated role of Dkk-3 and claudin-5 in vitro on GBM cell lines, and in the histopathological study on tissues of 30 WHO grade IV GBM patients. We evidenced that the expression of Dkk-3 was higher in normal human astrocytes cell line (NHA) used as control compared to human GBM tissues. Similarly, intracellular claudin-5 expression was significantly lower in U-138MG, A-172, LN-18 and LN-229 cell lines, while NHA cells significantly expressed claudin-5. Dkk-3 is able to regulate the WNT pathway, while the claudin-5 appears to interfere in maintaining the integrity of BBB permeability. By molecular analysis, our findings suggest a key role of Dkk-3 protein in GBM, as a potential tumor suppressor, evidenced by its reduced expression in tumor tissues. In addition, the down-regulation of claudin-5 observed confirms the protective role of BBB to maintain its integrity. Our research clearly demonstrated that Dkk-3 in GBM had pro-apoptotic effects up-regulating both intrinsic and extrinsic apoptotic pathways. The restoration of the levels of these proteins could induce a slowdown in tumor progression. We hypothesize that a more complete evaluation of the role of these proteins might suggest interesting new molecular targets for future therapeutic protocols.
Predictors of chemotherapy modification at first cycle in elderly patient.
Authors: Jaime Feliu Batlle, Laura Basterretxea, Irene Paredero Pérez, Elisenda Llabres, Beatriz Losada Vila, Maite Antonio Rebollo, ANA Belen Custodio, Regina Girones, Mar Munoz Sanchez, Beatriz Jimenez-Munarriz, Alvaro Pinto, Hellis Telleria, Juana Saldana, MJ Molina-Garrido
Journal: Journal of Clinical Oncology (2018)

e22019 Background: Modification of initial chemotherapy (CT) doses and monotherapy treatment are common practices in elderly patient. However, age is not considered in clinical practice guidelines as a criterion for primary treatment modification (PTM). The aim of our study is to determine the frequency with which PTM is performed in elderly patients and to identify which factors are involved in making this decision. Methods: This is a multicentric, prospective study including patients 70 years or older who are initiating a CT treatment. Treatment schedule and dose were decided by the responsible physician. The prevalence of PTM was assessed as well as its association with treatment intent (curative vs. palliative), sociodemographic characteristics, laboratory data, geriatric assessment, tumor type and CT aggressiveness (MAX-2 score). Results: A total of 448 patients (mean age 77, range 70-92 years) were included. CT was administered with palliative intent in 294 patients and with curative intent in 154 patients. PTM was more common in the first group (59% vs. 42%; p < 0.001). Increasing age, MAX-2 score and the decision to prescribe G-CSF as primary prophylaxis were related to PTM in both groups. The Pfeiffer test was the variable independently associated with PTM in the group treated with palliative intent, whereas in the group treated with curative intent were plasma albumin levels and the IADL scale. Neither ECOG PS nor comorbidity were associated with PTM. There were no statistically significant differences either in grade 3-4 toxicity or in dose reductions in the PTM group. Conclusions: PTM is significantly more common in elderly patients treated with palliative intent. Factors associated with PTM include age, type of CT, Peiffer test, IADL scale and albumin.
Phase II open-label randomized multi-centre study of neoadjuvant olaparib in patients (pts) with platinum sensitive (PS) relapsed high grade serous ovarian cancer (OC): The NEO trial.
Authors: Yada Kanjanapan, Stephanie Lheureux, Taymaa May, Michelle K. Wilson, Marcus Bernardini, Patricia Ann Shaw, Ignace Vergote, James D. Brenton, Diane M. Provencher, Iain A. McNeish, Prafull Ghatage, Jonathan A. Ledermann, Nicoletta Colombo, Charlie Gourley, Johanne Weberpals, Janelle Ramsahai, Nicole Ricker, Sarah Accardi, Lisa Wang, Amit M. Oza
Journal: Journal of Clinical Oncology (2017)

TPS5608 Background: Olaparib is a PARP inhibitor with clinical benefit in relapsed OC, especially in pts with germline BRCA1/2 mutation ( gBRCA). Study 19 (NCT00753545) found a progression free survival (PFS) gain from maintenance olaparib, post chemotherapy for PS relapse. Olaparib treatment in gBRCA OC pts relapsing post ≥ 3 prior chemotherapy regimens gave a response rate (RR) of 46% in the PS subgroup (Study 42; NCT01078662). Efficacy of olaparib may extend to OC with homologous recombination DNA repair pathway deficiency (HRD); susceptible to synthetic lethality from PARP inhibition. NEO [NCT02489006] is a window of opportunity study to assess tumor heterogeneity and the pharmacodynamic effects of olaparib given prior to surgery in PS OC, analyse the tumor genomic landscape pre and post olaparib, and assess for predictive biomarkers beyond BRCA mutation. Methods: This phase 2 study enrols pts with high grade serous OC, primary peritoneal or fallopian tube cancer with a progression free interval of ≥6 months and sensitive to their last line of platinum therapy. Pts must be suitable for secondary debulking surgery and agree to pre-operative tumour biopsy. All pts receive olaparib tablets 300mg po bid for 6 ± 2 weeks pre-surgery. Post-operatively, pts are randomised 1:1 to olaparib or 6 cycles of platinum-based chemotherapy followed by maintenance olaparib. The primary endpoint is the degree of PAR and PARP-1 inhibition in the blood and tumor following pre-operative olaparib in PS relapsed OC. Clinical efficacy is assessed by RR (RECIST 1.1), CA125, PFS and PFS2. Translational studies include next generation sequencing HRD panel to assess for somatic and germline mutations including RAD51B/C/D, PPM1D, FANCM, BRIP1, PALB2 and BARD1; evaluation of gene expression change in tumor tissue pre and post olaparib; assessment for resistance mechanisms and impact of heterogeneity. Circulating tumor DNA measured weekly pre-surgery is assessed for its prognostic value, alone and compared with CA125. The study will enrol 50-70 pts with estimated accrual of 3 pts/month across multiple sites, and opened at Princess Margaret Cancer Centre in 7/2016. Clinical trial information: NCT02489006.
The association between healthy days and patient-reported cancer symptoms in a metastatic cancer population.
Authors: Dana Drzayich Antol, Adrianne Waldman Casebeer, Sari Hopson, Raya Khoury, Aparna Parikh, Alisha Stein, Todd Michael, Stephen Stemkowski, Mikele Bunce
Journal: Journal of Clinical Oncology (2016)

e18179 Background: There is an established link between patient-reported symptoms and health related quality of life (HRQoL) for patients with cancer. This study aims to quantify the impact of patient reported symptoms on HRQoL using the Healthy Days measure. Methods: In 2015, we surveyed 7,432 Humana members with metastatic breast, lung or colorectal cancer, diagnosed with > 1 comorbid condition and actively receiving cancer treatment. The Center for Disease Control and Prevention’s Healthy Days measure assessed self-reported number of unhealthy days (unHD) in the past 30 days. The survey captured the degree to which the cancer-related symptoms [pain, fatigue, diarrhea/constipation (DC), nausea/vomiting (NV) and shortness of breath (SB)] interfered with daily activities in the past 30 days on a Likert scale ranging from never to always. The symptom was considered present for individuals reporting the symptom sometimes, often and always. The symptom was considered absent for patients reporting the symptom never or rarely. The number of unHD were compared using t-tests and are presented as mean (SD). Results: Of the 1,847 respondents (25%), 67% were female; 88% were Medicare beneficiaries; the mean age was 69.2±9.2. Pain was reported by 47.3% of the patients, 64.9% reported fatigue, 18.1% reported NV, 37.4% reported DC and 38.1% reported SB. Patients reporting pain or fatigue had the greatest increase in unHD in relation to those without pain or fatigue; [pain: 20.9(10.4) vs 8.8(10.1), p< 0.0001] and [fatigue: 18.8 (11.1) vs 6.6 (8.9), p< 0.0001], respectively. Patients experiencing SB had 9.3 more unHD than those without SB [20.3 (10.9) vs 11.0 (11.0), p< 0.0001]. Patients with NV had 8.2 more unHD than patients without NV [21.2 (10.7) vs 12.0 (11.6), p< 0.0001]. Patients experiencing DC had 7.2 more unHD than those without DC [19.0 (11.4) vs. 11.8 (11.3), p< 0.0001]. Conclusions: Patient reported cancer-related symptoms, especially pain and fatigue, accounted for a substantial increase in unhealthy days among patients with cancer actively undergoing treatment. Further investigations should examine how the management of cancer related symptoms may effectively increase patient reported healthy days.
Development and safety of a novel, irreversibly-binding PSMA-targeted prostate cancer radiodiagnostic.
Authors: Elizabeth Whalley, Clifford Berkman, Henry Vanbrocklin, Beatrice Langton-Webster
Journal: Journal of Clinical Oncology (2016)

11568 Background: CTT1057 is an 18F radiolabeled small molecule inhibitor of Prostate Specific Membrane Antigen (PSMA) that possesses nanomolar affinity and binds irreversibly to its target. PSMA is overexpressed on greater than 90% of prostate cancers, with expression correlated to disease progression. CTT1057 is being developed as a novel PET imaging diagnostic for prostate cancer. A first-in-human clinical trial of CTT1057 is currently under way. Methods: X ray structures of CTT1057 bound to PSMA were determined using difference Fourier methods. Uptake and internalization of CTT1057 were analyzed in two PSMA+ human prostate cancer cell lines, LNCaP and CWR22Rv1. In vivo PET imaging at 1hr and 4hr post-injection of CTT1057 was performed on mouse xenografts implanted with human PSMA+ CWR22Rv1 prostate cancer tumors to determine diagnostic efficacy and selectivity. Lastly, a 14-day single dose GLP safety study was performed in 60 male rats at doses greater than 100x the expected human equivalent dose. Results: X ray crystallography of CTT1057 bound to the PSMA target indicates that the drug binds in the active site of the enzyme irreversibly as well as at a second site (arene binding site) that confers unique stability of the biomarker-ligand complex. LNCaP cells showed 93% internalization of CTT1057 at 1 hr, while CWR22Rv1 cells showed 81%, which is in keeping with the higher PSMA expression in the LNCaP cells. PET imaging of mouse xenografts indicates that greater than 70% of CTT1057 is internalized by PSMA+ tumor within 30 minutes. Tumor:blood ratios of CTT1057 are 20:1 at one hour and 265:1 at four hours, with minimal uptake in non-tumor tissues. A GLP toxicity study demonstrated that CTT1057 is safe and well tolerated in rats. Conclusions: CTT1057 is the only known irreversible binder of PSMA and is shown to be a safe, potent and highly selective diagnostic PET imaging agent in animal models of human prostate cancer.