tbuckley/cabot-search huggingface dataset:
Phase II trial of bevacizumab (B) and ixabepilone (Ix) for advanced non-squamous NSCLC progressive after first-line therapy.
Authors: Rachel E. Sanborn, Philip C Mack, Laurel Beckett
Journal: Journal of Clinical Oncology (2012)

e13550 Background: Ix is a semisynthetic epiothilone analog which inhibits mitosis through microtubule stabilization, with activity in multiple tumor types. Weekly dosing may have less toxicity. B improves survival in combination with carboplatin and paclitaxel for previously untreated non-squamous NSCLC. The use of B in the salvage setting has not been extensively studied. Methods: Non-randomized, open-label, single arm phase II trial of B, 10 mg/kg iv every 2 weeks and Ix, 20 mg/m2 iv weekly for 3 out of 4 weeks. An initial lead-in phase of 6 patients (pts) treated with B and Ix (16 mg/m2 iv weekly for 3 out of 4 weeks) was planned. Pts with advanced non-squamous NSCLC progressive after 1 or 2 lines of therapy are eligible, prior erlotinib is allowed, ECOG 0-1. Prior B is allowed. Pts are treated for a maximum of 6 28-day cycles, with staging every 2 cycles. Pts with response or stable disease may continue on maintenance B for up to 1 year. Primary endpoint is progression free survival, with secondary endpoints ORR, OS, toxicity, and correlative studies to assess potential predictors of response. Correlative studies include evaluations of tumor and plasma levels of VEGF, PDGF, sICAM, bFGF, and IL-8, with hypothesis that lower levels of tumor or plasma levels will correlate with improved outcomes. VEGF and IL-8 polymorphisms will be measured, as will tumor expression of Aurora B, survivin, Ki-67, hyperphosphorylation of BCL2, and overexpression of Tau. Total accrual goal is 46 pts. Results: To date, the first 6 pts for the run-in phase have been accrued. 2 pts required dose reduction in the first 2 cycles (Gr 2 thrombocytopenia, Gr 3 ALT elevation; 1 each). Max treatment cycles: 9 (Range, 2-9). 2 pts had disease progression after 2 cycles and were discontinued from study. Toxicity in the first 2 cycles is primarily hematologic, with related Gr 2 toxicity of thrombocytopenia, anemia, lymphopenia (1 each). Gr 3 lymphopenia occurred in 2 pts. Gr 3 hyperglycemia occurred in 2 pts, attributed to steroid premeds. Conclusions: With 2 pts requiring dose reduction with the run-in dose, Ix will not be increased as previously planned and the ongoing dose for the phase II study will be 16 mg/m2. Accrual to the phase II portion will continue.
Phase I/II study of concurrent chemoradiotherapy for localized nasal NK/T-cell lymphoma: Final results of JCOG0211
Authors: M. Yamaguchi, K. Tobinai, M. Oguchi, Y. Isobe, K. Ishizawa, N. Maseki, I. Wasada, N. Ishizuka, T. Hotta, K. Oshimi
Journal: Journal of Clinical Oncology (2009)

8549 Background: Nasal NK/T-cell lymphoma is rare and its standard therapy has not been established. Tumor cells express P-glycoprotein concerning multi-drug resistance (MDR). Anthracycline-containing chemotherapy is not effective and %2-yr overall survival (OS) of radiotherapy (RT) alone is only 45%. Methods: To explore a more effective treatment for localized nasal NK/T-cell lymphoma, we conducted a phase I/II study of concurrent chemoradiotherapy consisted of 50 Gy of RT and 3 courses of DeVIC [carboplatin (CBDCA), etoposide (ETP), ifosfamide (IFM), dexamethasone (DMS)]. Patients (Pts) with newly-diagnosed, localized (IE &amp; contiguous IIE with cervical node involvement) diseases, 20–69 years of age and PS 0–2 were eligible. The 3-D conformal RT planning was required to cover adequately target volumes (2 cm margin to gross tumor, entire nasal cavities and nasopharynx) and to minimize doses to organs at risk. Primary endpoint of the phase II portion was 2-yr OS and the enrollment of 24 pts to the phase II portion was planned. Based on the results of the phase I portion (ASH 2005, #2685), 2/3-dose of DeVIC (CBDCA 200mg/m 2 d1 IV, ETP 67mg/m 2 d1–3 IV, IFM 1.0g/m 2 d1–3 IV, DMS 40mg/body d1–3 IV; every 3 wks) was applied for the phase II portion. RT quality assurance review confirmed no protocol violation (ASTRO 2008, #2682). Results: From Sep 2003 to Dec 2006, 33 pts were enrolled in the phase I/II study. 27 pts evaluated in the phase II portion showed the following features: age 21–68 yrs (median 56), M:F=17:10, stage IE 18, stage IIE 9, B symptom (+) 10, elevated serum LDH 5, PS2 2. With a median follow-up of 32 months (range, 24–62), %2-yr OS was 78% (95% CI, 57–89). Of 26 pts evaluable for response, 20 achieved CR, 1 PR, 2SD, and 3PD. %CR and %ORR were 77% (95% CI, 56–91) and 81%, respectively. The most common grade 3 non-hematologic toxicities were mucositis due to RT (30%) and infection (30%). Grade 4 hyponatremia and dermatitis due to RT were observed in each 1 pt. No treatment-related death was observed. Conclusions: Concurrent chemoradiotherapy using MDR-non-related agents and ETP is a safe and effective treatment for localized nasal NK/T-cell lymphoma, providing the basis for subsequent studies. No significant financial relationships to disclose.
Reticular dysgenesis: international survey on clinical presentation, transplantation, and outcome
Authors: Manfred Hoenig, Chantal Lagresle-Peyrou, Ulrich Pannicke, Luigi D. Notarangelo, Fulvio Porta, Andrew R. Gennery, Mary Slatter, Morton J. Cowan, Polina Stepensky, Hamoud Al-Mousa, Daifulah Al-Zahrani, Sung-Yun Pai, Waleed Al Herz, Hubert B. Gaspar, Paul Veys, Koichi Oshima, Kohsuke Imai, Hiromasa Yabe, Lenora M. Noroski, Nico M. Wulffraat, Karl-Walter Sykora, Pere Soler-Palacin, Hideki Muramatsu, Mariam Al Hilali, Despina Moshous, Klaus-Michael Debatin, Catharina Schuetz, Eva-Maria Jacobsen, Ansgar S. Schulz, Klaus Schwarz, Alain Fischer, Wilhelm Friedrich, Marina Cavazzana
Journal: Blood (2017)
Safety and tolerability profile of raltitrexed in Chinese patients with locally advanced or recurrent and metastatic colorectal cancer: A phase IV trial.
Authors: Shukui Qin, Jin Li, Yunpeng Liu, Yin Chen, Nong Xu, Jianming Xu, Yuxian Bai, Jianjin Huang, Jun Liang, Leizhen Zheng
Journal: Journal of Clinical Oncology (2017)

571 Background: The clinical benefit and safety profile associated with raltitrexed in patients with advanced colorectal cancer (CRC) were established. However, safety information of raltitrexed in Chinese patients is rare. We aimed to assess the safety of raltitrexed monotherapy in Chinese patients with advanced CRC. Methods: This single-arm, open-label, multi-center, phase IV trial was conducted in 13 hospitals across China between March 2011 and July 2014. Patients with locally advanced or recurrent and metastatic colorectal cancer (mCRC) received raltitrexed (3mg/m 2 ) as a 15-min infusion on day 1, every 21 days. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was safety and the secondary objectives were disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results: A total of 215 patients were enrolled, and the safety was assessed in 205 patients. 92 patients had 394 Adverse events (AEs) during the study. A majority (94.4%) of AEs was grade 1/2 and only 5.3% was grade 3/4. Most AEs were either resolved spontaneously or treated successfully with standard medical interventions. Severe AEs were reported by 5.8% (12/205) of patients. The most commonly reported AEs were increase of transaminases, leukopenia, nausea and vomiting. Serum transaminase elevation, an important safety concern associated with raltitrexed therapy, were transient, self-limiting and manageable. No deaths were reported during the study. The DCR in second-line and third-line therapy by raltitrexed reached 49.5% and 37.4%, respectively. The median PFS in second-line and third-line therapy was 1.43 months and 1.47 months, respectively. The median OS was 13.6 months and 8.9 months, respectively. Conclusions: Raltitrexed monotherapy is a safe, well-tolerated and convenient therapy option for Chinese patients. The treatment-associated toxicity is manageable and does not lead to discontinuation of treatment in oncology practice.
Phase II trial of prolonged infusion gemcitabine as second line treatment in non-small cell lung cancer
Authors: M. B. Kleinman, I. Stewart, S. Ratmanskiy, M. Gayle, P. Bonomi
Journal: Journal of Clinical Oncology (2004)

7316 Background: Gemcitabine (2'2'- diflurordeoxycytidine, dFd) is conventionally administered over 30 minutes (800–1250mg/m2). Prolonged gemcitabine infusion achieves higher intracellular dFd-triphosphate concentrations and might produce greater cytotoxicity in treatment for nonsmall cell lung cancer. The objective of this trial was to evaluate the treatment with prolonged infusion gemcitabine in non small cell lung cancer patients who had progressive disease after one platinum containing regimen. Methods: Patients received gemcitabine 800mg/m2 intravenously at 10mg/m2/min on day 1 and 8 every 21 days. Objective response, time to progression, overall survival and toxicity were assessed. Results: 28 patients were enrolled (March 1998 until September 1999). Median age was 62 (37–82). Most patients had an ECOG performance status (PS) of 0–1; 9 patients had an ECOG PS =2. Histology was primarily adenocarcinoma followed by squamous, bronchioalveolar and adenocystic. In 27 evaluable patients, 1 achieved PR (3.7%), 8 (29.6%) stability of disease and 18 remained progressive despite therapy. Median time to progression was 2 months (0–14 mo) and median overall survival was 6 months (1–38). 6 patients (22%) were alive at 1 year. Median number of cycles administered was 2. Grade 3–4 neutropenia and thrombocytopenia was observed in 6 (22.0%) and 1 (3.7%) case respectfully. Grade 3–4 non-hematologic toxicities included 2 patients (7.4%) with diffuse pulmonary infiltrates. There were no treatment related deaths. Median time from original diagnosis to first dose of gemcitabine was 7 months (1–57) and from most recent chemotherapy exposure to the first gemcitabine was 2 months (<1mo-10). Conclusions: Although the response rate was relatively low, survival was similar to other second line regimens and toxicity was mild. Prolonged gemcitabine infusion at a dose of 1000mg/m2 is being considered. No significant financial relationships to disclose.
Comorbidities limiting recruitment of colorectal cancer (CRC) patients in early-phase trials.
Authors: Narjust Duma, Yucai Wang, Miguel Gonzalez Velez, Sejal Kothadia, Veronica Mariotti, Ricardo Daniel Parrondo, Joleen Marie Hubbard, Alex A. Adjei, Thorvardur Ragnar Halfdanarson
Journal: Journal of Clinical Oncology (2017)

791 Background: With the surge of drug development in the past decade, early phase clinical trials (EPCT) have gained value evaluating the potential benefits of new therapies. The inclusion/exclusion criteria in EPCT are usually rigorous and may exclude many patients (pts) commonly seen in clinical practice. Our objective was to identify the most common comorbidities excluded in EPCT for CRC. Methods: ClinicalTrials.gov was queried on December 1 st of 2015. We reviewed the characteristics and eligibility criteria of 369 phase I/II interventional drug trials including: experimental arm therapy, location, and exclusion/inclusion criteria. Logistic regressions were completed and exclusion was studied as a binary variable. Results: Of the 369 trials, 68% were phase II and 32% phase I. 46% were conducted in the United States, 30% in Europe, 15% in Asia and 9% in other locations. 74 (20%) trials excluded pts &gt; 70 years of age. 142 (39%) trials required creatinine levels &lt; 1.5 mg/dl, liver enzymes (AST/ALT) &lt; 2.5 and bilirubin &lt; 1.5 of the upper limit of normal. Cytopenia was a significant exclusion factor: 147 (47%) trials required Hgb &gt; 9 g/dl and 218 (59%) excluded pts with platelets &lt; 100,000/dl. In terms of comorbidities, 98 (27%) trials excluded pts with heart failure (NYHA class 3/4), 74 (20%) with atrial fibrillation, 112 (31%) with any anticoagulation therapy and 155 (42%) with positive HIV. Trials located in the US were more likely to exclude pts with Hgb &lt; 9g/dl (OR: 1.5, 95%CI: 1.1-2.3, p &lt; 0.05), immunotherapy trials were more likely to exclude pts on any anticoagulation (OR:1.8, 95%CI: 1.2-2.8, p &lt; 0.007) and targeted therapy trials were more likely to exclude pts with history of DVT/PE or cardiovascular diseases (OR: 3.4, 95%CI: 1.9-5.8, p &lt; 0.0001; OR: 2.3, 95%CI: 1.3-3.8, p &lt; 0.002, respectively). Conclusions: 20% of EPCTs on CRC excluded pts with advanced age, organ dysfunction and common comorbidities. Many of the EPCT reviewed were not inclusive of our aging oncology population who are more likely to have multiple comorbidities. Investigators should review whether sufficient justification exists for every exclusion criterion before their incorporation in future trial protocols.
Risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families.
Authors: Hildur Helgadottir, Veronica Hoiom, Goran Jonsson, Rainer Tuominen, Christian Ingvar, Ake Borg, Hakan Lars Olsson, Johan Hansson
Journal: Journal of Clinical Oncology (2014)

1513 Background: Germline mutations in the tumor suppressor gene CDKN2A occur in 5-20% of familial melanoma cases. A single founder mutation, p.Arg112dup, accounts for the majority of CDKN2A mutations in Swedish carriers. This mutation alters the peptide sequences of tumor suppressors p16-INK4A and p14-ARF. The aim of this study was to assess cancer risks in CDKN2A p.Arg112dup carriers and their first (FDRs) and second degree relatives (SDRS). Methods: In this prospective cohort study, cancer diagnoses in CDKN2A p.Arg112dup mutation carriers (n=120), non-carriers (n=111), carriers’ FDRs (n=275) and SDRs (n=321) and controls (n=3976) were obtained from the Swedish Cancer Registry. Relative risks (RR) for cancers were calculated (number of cancers/person years). Due to the finding of high risks in mutation carriers of cancers that are normally associated with tobacco smoking, data was retrospectively collected on smoking history in carriers. Odds ratios were calculated to compare smoking (ever-smoker/never-smoker) in carriers with or without a diagnosis of non-melanoma cancer. Two-sided 95% confidence intervals (95% CI) were calculated for all RRs. Results: In carriers prospective RR for non-melanoma cancers was 5.0 (95% CI=3.7-7.3), for pancreatic cancer 43.8 (95% CI=13.8-139.0), for cancers in upper digestive tissues 17.1 (95% CI=6.3-46.5), and in respiratory tissues 15.6 (5.4-46.0). In FDRs and SDRs, RRs were significantly elevated for cancers in pancreas, respiratory and upper digestive tissues. In ever-smoking carriers compared with never-smoking carriers, the odds ratio of cancers in pancreas, respiratory or upper digestive tissues was 9.3 (95% CI= 1.9-44.7). Conclusions: CDKN2A p.Arg112dup mutation carriers from melanoma-prone families and their FDRs and SDRs have elevated risk for pancreatic, lung, head and neck and gastro-esophageal carcinomas. These cancers were mainly seen in ever-smoking carriers. This is the first study that shows association between smoking history and cancer diagnoses in CDKN2A mutation carriers. Germline CDKN2A mutations may confer an increased sensitivity to carcinogens in tobacco smoke. CDKN2A mutation carriers should be counseled to abstain from smoking.
New approaches to measurement and management for high integrity health systems
Authors: Albert Mulley, Angela Coulter, Miranda Wolpert, Tessa Richards, Kamran Abbasi
Journal: BMJ (2017)

We need better tools to achieve the next generation reforms essential for delivering care that matters most to patients, say Albert Mulley and colleagues 

Healthcare economies across the globe are in crisis. High income countries—whether their healthcare economies are market driven like the US or tax funded like the UK—are struggling with relentless demand for more services that are increasingly costly to deliver. Low and middle income countries are struggling to provide better and more equitable access to potentially lifesaving interventions while wisely allocating scarce resources across all sectors that affect human and social development. In rich and poor countries alike, policy makers, citizens, and health professionals are drawn to technology but are not learning how to use it most effectively or from mistakes made when its limits go unrecognised or unheeded.1

Variation in regional rates of therapeutic and diagnostic interventions and hospital based care exists globally with no measurable benefit in populations receiving more services.2345 At the same time effective primary healthcare and social services that can have a greater effect on health and wellbeing are being underused.467 The failure to deliver the right care at the right time in the right place contributes to the waste of as much as 40% of healthcare expenditures.48

Recognition of this waste, which is often associated with harm to patients, has spurred health policy reforms across the globe. One common objective is people centred care, which focuses on the needs and wants of individuals and engages them in management of their own care, including behaviours that promote and sustain health and wellbeing. A policy forum held earlier this year, which included health ministers and other representatives from members of the Organisation for Economic Cooperation and Development and seven other countries, advocated a …
Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1: Potential role in latent reservoir dynamics
Authors: Nina N. Hosmane, Kyungyoon J. Kwon, Katherine M. Bruner, Adam A. Capoferri, Subul Beg, Daniel I.S. Rosenbloom, Brandon F. Keele, Ya-Chi Ho, Janet D. Siliciano, Robert F. Siliciano
Journal: The Journal of Experimental Medicine (2017)

A latent reservoir for HIV-1 in resting CD4
Long Noncoding RNA MANTIS Facilitates Endothelial Angiogenic Function
Authors: Matthias S. Leisegang, Christian Fork, Ivana Josipovic, Florian Martin Richter, Jens Preussner, Jiong Hu, Matthew J. Miller, Jeremy Epah, Patrick Hofmann, Stefan Günther, Franziska Moll, Chanil Valasarajan, Juliana Heidler, Yuliya Ponomareva, Thomas M. Freiman, Lars Maegdefessel, Karl H. Plate, Michel Mittelbronn, Shizuka Uchida, Carsten Künne, Konstantinos Stellos, Ralph T. Schermuly, Norbert Weissmann, Kavi Devraj, Ilka Wittig, Reinier A. Boon, Stefanie Dimmeler, Soni Savai Pullamsetti, Mario Looso, Francis J. Miller, Ralf P. Brandes
Journal: Circulation (2017)

The angiogenic function of endothelial cells is regulated by numerous mechanisms, but the impact of long noncoding RNAs (lncRNAs) has hardly been studied. We set out to identify novel and functionally important endothelial lncRNAs.Epigenetically controlled lncRNAs in human umbilical vein endothelial cells were searched by exon-array analysis after knockdown of the histone demethylase JARID1B. Molecular mechanisms were investigated by RNA pulldown and immunoprecipitation, mass spectrometry, microarray, several knockdown approaches, CRISPR-Cas9, assay for transposase-accessible chromatin sequencing, and chromatin immunoprecipitation in human umbilical vein endothelial cells. Patient samples from lung and tumors were studied for MANTIS expression.A search for epigenetically controlled endothelial lncRNAs yielded lncRNA n342419, here termed MANTIS, as the most strongly regulated lncRNA. Controlled by the histone demethylase JARID1B, MANTIS was downregulated in patients with idiopathic pulmonary arterial hypertension and in rats treated with monocrotaline, whereas it was upregulated in carotid arteries of Macaca fascicularis subjected to atherosclerosis regression diet, and in endothelial cells isolated from human glioblastoma patients. CRISPR/Cas9-mediated deletion or silencing of MANTIS with small interfering RNAs or GapmeRs inhibited angiogenic sprouting and alignment of endothelial cells in response to shear stress. Mechanistically, the nuclear-localized MANTIS lncRNA interacted with BRG1, the catalytic subunit of the switch/sucrose nonfermentable chromatin-remodeling complex. This interaction was required for nucleosome remodeling by keeping the ATPase function of BRG1 active. Thereby, the transcription of key endothelial genes such as SOX18, SMAD6, and COUP-TFII was regulated by ensuring efficient RNA polymerase II machinery binding.MANTIS is a differentially regulated novel lncRNA facilitating endothelial angiogenic function.
Comparison of three different induction regimen in nasopharyngeal cancer: CF versus DC versus DCF.
Authors: Neyran Kertmen, Sercan Aksoy, Mustafa Cengiz, Gozde Yazici, Özge Keskin, Taner Babacan, Saim Furkan Sarici, Serkan Akin, Kadri Altundag, Ibrahim Halil Gullu
Journal: Journal of Clinical Oncology (2014)

6075 Background: The standard treatment of local advanced nasopharyngeal cancer is chemoradiotherapy. There is no enough data about the induction therapy. In this study we retrospectively examined patients treated with induction therapy and chemoradiotherapy. Methods: Locally advanced nasopharyngeal cancers patients were included into the study who were treated between 1996-2013 in our clinic. Three different induction regimen were administered to our patients in different time periods; CF, DC and DCF. The dosage of the regimens as follows: CF regimen; cisplatin 50 mg/ m2 1-2 days , fluorouracil 500 mg/ m2 1-5 days, DC; docetaxel 75 mg/ m2 1.day, cisplatin 75 mg /m2 1.day and DCF; docetaxel 75 mg/ m2 1.day, cisplatin 75 mg / m2 1.day, 5-fu 750 mg/ m2 1-5 days. Results: One hundred fifty-four patients were included, 76% (n= 117) of the patients was male and 24% (n= 37) of them female. Median age at diagnosis was 47 (20-73). Most of the patients were at stage III (36.4%) and stage IV (51.7%). In terms of induction therapy, cisplatin-fluorouracil (CF) was administered to 24.7% (n= 38) of patients, docetaxel-cisplatin (DC) to 35.1% (n= 54) and docetaxel-fluorouracil (DCF) to 40.3% (n= 62). Median follow-up time was 50 months (2-201 months). Response rate to induction therapy in the CF group were 5.7% (n= 2) complete response, 82.9% (n= 29) partial response.In the DC group they were 11.4% (n= 5) complete response, 59.1% (n= 26) partial response and 10.6% (n= 5) complete response, 74.5% (n= 35) partial response in the DCF group. (p=0.20). 3- Year progression-free survival (PFS) levels was 79.3% and 5-year PFS of 72.4 % in all patients. 3-year overall survival (OS) rate were 87.4% and 5-year OS rate 76% in all patients. In terms of induction therapies, 3-year OS was 96.5% in the DCF group, 86.6% in the DC group and 76.3% in the CF group (p= 0.036). There was no statistically significant PFS difference according to the chemotherapy regimens. Conclusions: There was no significantly difference in response rate and PFS between three regimens. OS of the DCF group was significantly higher than the others. However, this study was retrospective and limited toxicity data were available, the findings need to be interpreted with care.