tbuckley/cabot-search huggingface dataset:
Prognostic implications, predictive value, and latency analysis of Epstein-Barr virus (EBV) DNA in advanced stage cutaneous T-cell lymphoma (AS-CTCL).
Authors: Brad M. Haverkos, Jessica Hemminger, Susan Michelle Geyer, Anissa Bingman, Kelsey Van Deusen, Mark Lustberg, Henry Wong, Alejandro Gru, Richard Ambinder, Robert A. Baiocchi, Pierluigi Porcu
Journal: Journal of Clinical Oncology (2014)

e19518 Background: CTCLs are a heterogeneous group of extranodal NHL of the skin that can progress to lymph nodes, blood, and visceral organs; improved risk stratification and disease monitoring is needed. EBV is a ubiquitous lymphotropic herpervirus that has been detected in various lymphoma subsets reflecting immune suppression (IS)-induced lytic viral reactivation and/or cell-free tumor-associated viral DNA shedding. EBV has been detected in a subset of CTCL, but data on clinical significance and latency remain limited. Methods: Using an IRB-approved protocol, we retrospectively identified 46 pts with AS-CTCL (>IIB) from 2006-2013 (MF/SS=98%). We reviewed treatment history, stratified by exposure to Campath (C+/-), and outcomes from time of diagnosis (TOD) and time of progression to AS (TPAS). Serum EBV and CMV-DNA were serially measured by qRT-PCR, the latter a surrogate of impaired T-cell surveillance. In pts with detectable serum EBV-DNA (EBV+), EBER-ISH was performed on available skin tumors. Analysis of serum EBV-DNA methylation and BZLF1-IHC (lytic EBV protein) assessed latency. Results: All pts received systemic therapies, including C in a subset (15/46). Overall, 17/46 pts (37%) were EBV+ and 29 (63%) were EBV-. A smaller subset (8/46, 17%) had detectable serum CMV-DNA, including 6/17 EBV+ pts. 11/13 EBV+ pts with tumor tissue were EBER+. At time of analyses, 14 pts had died with median f/u in living pts of 71 mos. EBV+ status predicted worse OS from TOD (p=0.03) and TPAS (p=0.012). Serum EBV-DNA detection frequently occurred near diagnosis, TPAS, and death. Serum EBV-DNA methylation ranged from 2-90% in C+ and 43-98% in C-. BZLF1-IHC on two EBER+ pts were negative (both C-). Conclusions: Thirty-seven % of AS-CTCL pts in this study had detectable serum EBV-DNA. Of these, more than half had no exposure to highly immune suppressive C and no evidence of concurrent CMV reactivation. The mixture of latent and lytic virion, lack of exposure to C, or concurrent CMV reactivation suggest that detectable serum EBV-DNA in AS-CTCL is not due only to IS. Serum EBV-DNA detection predicted worse OS and may serve as a marker of disease progression warranting further investigation.
A phase II randomized study of bortezomib/dexamethasone (Bort/Dex) with or without elotuzumab (Elo) in patients (pts) with relapsed/refractory multiple myeloma (RR MM) (CA204-009).
Authors: Andrzej J. Jakubowiak, Darrell White, Philippe Moreau, Thierry Facon, Ravi Vij, Glenn Scott Kroog, Justin Kopit, Anil Singhal, Antonio Pierangelo Palumbo
Journal: Journal of Clinical Oncology (2012)

TPS8114 Background: MM is rarely curable and pts typically relapse or become refractory to current treatments. Elo is a humanized monoclonal IgG1 antibody targeting the cell surface glycoprotein CS1, which is highly expressed on &gt;95% of MM cells with little to no expression on normal tissues. The mechanism of action of Elo is primarily natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against myeloma cells. Elo + Bort significantly enhanced antimyeloma activity in a mouse xenograft model vs either agent alone. The addition of Bort enhanced the ADCC activity of Elo in preclinical studies. In a phase I study of Elo + Bort in pts with RR MM, objective response rate (ORR) was 48%, median progression-free survival (PFS) was 9.5 months, and activity was observed in 2/3 patients (67%) refractory to Bort (Jakubowiak et al. J Clin Oncol, in press). This study will assess if the addition of Elo to Bort/Dex improves PFS and, if so, whether magnitude of the improvement is linked to FcγRIIIa polymorphism. Methods: Pts (N=150) with RR MM after 1 or 2 prior therapies will be randomized in a 1:1 ratio to receive Bort 1.3 mg/m 2 IV or SQ (Cycles 1-8: days 1, 4, 8, and 11; Cycles ≥9: days 1, 8, and 15) and Dex with or without Elo. Elo dose and schedule is 10 mg/kg IV (Cycles 1-2: days 1, 8, and 15 [21-day cycles]; Cycles 3-8: days 1 and 11 [21-day cycles]; Cycles ≥9: days 1 and 15 [28-day cycles]). In the arm without Elo, Dex 20 mg PO is scheduled for Cycles 1-8: days 1, 2, 4, 5, 8, 9, 11, and 12; and Cycles ≥9: days 1, 2, 8, 9, 15, 16. In the arm with Elo, Dex 20 mg PO is scheduled for Cycles 1-2: days 2, 4, 5, 9, and 11; Cycles 3-8: days 2, 4, 5, 8, 9, 12; Cycles ≥9: days 2, 8, 9, and 16) on weeks without Elo, and on weeks with Elo, Dex 8 mg PO and 8 mg IV is scheduled on the same day as Elo. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Patients refractory or intolerant to Bort will be excluded. Efficacy will be assessed on day 1 of each cycle by IMWG criteria. The primary endpoint is PFS. Secondary endpoints include ORR and PFS/ORR in pts with ≥1 FcγRIIIa V allele. As of February 1, 2012, 1 pt was enrolled. NCT01478048.
High-dose Asian ginseng (Panax ginseng) for cancer-related fatigue (CRF): A preliminary report.
Authors: Sriram Yennurajalingam, Akhila Sunkepally Reddy, Nizar M. Tannir, Richard T. Lee, Gabriel Lopez, Carmen Escalante, Ellen F. Manzullo, Susan Frisbee-Hume, Kenneth Tarleton, Janet L. Williams, Shana L. Palla, Lorenzo Cohen, Eduardo Bruera
Journal: Journal of Clinical Oncology (2013)

9642 Background: CRF is a common and severe symptom in patients with cancer. There are limited useful treatments available. The objective of this preliminary study was to assess the safety of high-dose Panax ginseng (PG) on CRF. Methods: In this prospective open labeled study, 30 patients with cancer and fatigue ≥4/10 (0=no fatigue, 10=worst possible fatigue) received high dose PG 800mg orally daily for 29 days. Functional Assessment of Cancer Therapy-fatigue (FACIT-F), Edmonton Symptom Assessment System (ESAS) (0=best, 10=worst), and Hospital Anxiety Depression Scale (HADS) were assessed at baseline and day 29. Results: 24/30 (80%) patients were evaluable. The median age was 58yrs, 50% were females, 84% were white. The most common cancer type was genitourinary cancer (31%). Table shows the changes in fatigue, anxiety, depression scores. ESAS well-being improved from 4.67 (2.04) to 3.50 (2.34) (p=0.01374), appetite improved from 4.29 (2.79) to 2.96 (2.46) (p=0.0097). 21/24 (87%) patients had an improved FACIT-F fatigue score by day 15. Global Symptom Evaluation score of PG for fatigue was better in 15/24 patients (63%) with median improvement of 5 (1=hardly any better, 7= very great deal better). No ≥ grade 3 adverse events related to the study drug were reported. Conclusions: 1) PG is safe and rapidly improved ESAS fatigue and FACIT-F fatigue scores; 2) Overall quality of life (FACIT-General), appetite, and sleep at night also improved. Randomized controlled trials of PG are justified in CRF. Clinical trial information: NCT01375114. [Table: see text]
Lung function in African infants in the Drakenstein child health study
Authors: Diane M. Gray, Lidija Turkovic, Lauren Willennse, Ane Visagie, Aneesa Vanker, Dan J. Stein, Peter D. Sly, Graham L. Hall, Heather J. Zar
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Lower respiratory tract illness is a major cause of childhood morbidity and mortality. It is unknown whether infants are predisposed to illness because of impaired lung function or whether respiratory illness reduces lung function.  To investigate the impact of early life exposures, including lower respiratory tract illness, on lung function during infancy.  Infants enrolled in the Drakenstein child health study had lung function at 6 weeks and 1 year. Testing during quiet natural sleep included tidal breathing, exhaled nitric oxide, and multiple breath washout measures. Risk factors for impaired lung health were collected longitudinally. Lower respiratory tract illness surveillance was performed and any episode investigated.  Lung function was tested in 648 children at 1 year. One hundred and fifty (29%) infants had a lower respiratory tract illness during the first year of life. Lower respiratory tract illness was independently associated with increased respiratory rate (4%; 95% confidence interval [CI], 1.01-1.08; P = 0.02). Repeat episodes further increased respiratory rate (3%; 95% CI, 1.01-1.05; P = 0.004), decreased tidal volume (-1.7 ml; 95% CI, -3.3 to -0.2; P = 0.03), and increased the lung clearance index (0.13 turnovers; 95% CI, 0.04-0.22; P = 0.006) compared with infants without illness. Tobacco smoke exposure, lung function at 6 weeks, infant growth, and prematurity were other independent predictors of lung function at 1 year.  Early life lower respiratory tract illness impairs lung function at 1 year, independent of baseline lung function. Preventing early life lower respiratory tract illness is important to optimize lung function and promote respiratory health in childhood.
A phase 1b dose-escalation study of BYL719 plus binimetinib (MEK162) in patients with selected advanced solid tumors.
Authors: Dejan Juric, Jean-Charles Soria, Sunil Sharma, Udai Banerji, Analia Azaro, Jayesh Desai, Francois Philippe Ringeisen, Audrey Kaag, Rajkumar Radhakrishnan, Florence Hourcade-Potelleret, Heiko Maacke, Jordi Rodon Ahnert
Journal: Journal of Clinical Oncology (2014)

9051 Background: The MAPK and PI3K pathways share common upstream activators and contribute to cell proliferation, differentiation, and survival. Due to compensatory signaling, only partial tumor growth inhibition may occur when targeting either pathway alone. Preclinically-observed synergistic effects of combined PI3K and MEK inhibitors suggest that dual inhibition may be more effective. Methods: This phase 1b, open-label study (CMEK162X2109) is evaluating the PI3Kα inhibitor BYL719 combined with MEK inhibitor binimetinib (MEK162) in patients (pts) with RAS- or BRAF-mutant advanced solid malignancies (> 10 types). The objective for dose escalation was estimation of the maximum-tolerated dose (MTD) and/or recommended dose for expansion (RDE), guided by the Bayesian logistic regression model. Results: As of September 2, 2013, 58 pts were enrolled and BYL719 was orally co-administered at 80, 120, 160, 200, 220, or 270 mg once-daily (QD) with binimetinib at 30 or 45 mg twice-daily (BID) in 28-day cycles. Thirty two pts (55%) had ≥3 prior anticancer regimens. Median exposure was 7.4 wks. Common adverse events (AEs), regardless of study drug relationship, were diarrhea (86%), nausea (66%), vomiting (52%), reduced appetite (50%), rash (48%), pyrexia (41%), fatigue (38%), and hyperglycemia (36%). Grade 3/4 AEs occurred in 46 individual pts (79%), most commonly diarrhea (12%) and elevated creatine phosphokinase (10%). Dose-limiting toxicities were observed in 9 pts (19%), out of which 4 had grade 3/4 AEs including gastrointestinal and skin disorders. The MTD of the combination was determined to be BYL719 200 mg QD plus binimetinib 45 mg BID, at which 3/6 pts had grade 3/4 AEs. Of 4 ovarian cancer pts with KRAS-mutant status, 3 had confirmed partial responses (PRs). PRs were also observed in 1 pt with NRAS-mutant melanoma (confirmed) and 1 with KRAS-mutant endometrial cancer (unconfirmed). Stable disease lasting > 6 weeks was reported as best response for 18 pts (31%). Conclusions: The MTD/RDE for combined BYL719 and binimetinib was reached, and the preliminary safety and efficacy profile justifies further exploration, particularly in pts with RAS-mutant ovarian cancer. Clinical trial information: NCT01449058.
Successful implementation of a novel trial model: The Signature program.
Authors: Julio Antonio Peguero, James A. Knost, Todd Michael Bauer, Matthew Hiram Taylor, Fadi S. Braiteh, Joseph Paul Eder, Howard Safran, Bert H. O'Neil, Ajjai Shivaram Alva, Lincoln Nadauld, Prashant Joshi, Flora Miranda, Rajinder Sidhu, Joy Ero, Eric Daniel Slosberg, Claudia Lebedinsky, Barinder Kang, Sudha Parasuraman, Sarina Anne Piha-Paul
Journal: Journal of Clinical Oncology (2015)

106 Background: Here we describe 8 ongoing single agent clinical protocols under Novartis’ “Signature” program involving buparlisib (BKM120, PI3Ki), dovitinib (TKI258, multikinase inhibitor), binimetinib (MEK162, MEKi), encorafenib (LGX818, RAFi), ribociclib (LEE011, CDK4/6i), BGJ398 (FGFRi), ceritinib (LDK378, ALKi) and sonidegib (LDE225; SMOi). These are tissue-agnostic, genetic alteration-specific (mutation, amplification, translocation, etc.) protocols using patients (pts) identified via standard-of-care profiling. This brings the ‘Protocol to the Patient’ for pts with actionable genetic alterations and who would like access to drugs targeting those alterations. Methods: Pts with advanced solid and hematologic cancers and no standard therapeutic options are eligible. Pts are preidentified with a local test performed in a CLIA laboratory for an actionable genetic alteration. Indications where existing data showed no benefit, or key studies were planned, were excluded from accrual. The primary objective is to assess clinical benefit (SD or better for ≥ 16 weeks) for each compound. A novel adaptive statistical design is used to cluster pts of like indications into cohorts for independent analysis for futility (minimum 10 pts) or efficacy (minimum 15 pts). Results: Between March 2013 – January 2015, 16 academic and 151 unique community/network sites have dosed 368 pts; buparlisib (142), dovitinib (73), binimetinib (90), encorafenib (9), ribociclib (30), BGJ398 (12), ceritinib (3) and sonidegib (9) with completed cohorts for buparlisib (CRC, ovarian, sarcomas, HNSCC, cervix), dovitinib (CRC, GIST), and binimetinib (lung). The average startup timeline was 5.2 weeks.The most frequent genetic alterations were RAS mutation (68%), PIK3CA mutation (55%), and PTEN loss (41%). Preliminary activity was observed in various tumors; buparlisib (vaginal, HNSCC), dovitinib (ovarian), and binimetinib (AML, ovarian, thyroid). Conclusions: This program allows rapid enrollment of molecularly profiled pts with genetic alterations linked to cognate targeted agents. Early signs of clinical activity suggest potential for detection of new indications using a pt-sparing design that could lead to subsequent confirmatory trials.
Development of a New BCMAxCD3 Duobody® Antibody for Multiple Myeloma
Authors: Kodandaram Pillarisetti, Eric Baldwin, Alexander Babich, Nate Majewski, Linda Barone, Yingzhe Li, Xiaochun Zhang, Diana Chin, Leopoldo Luistro, Mark Mendonça, Rupesh Nanjunda, Stephen Rudnick, Kevin Bellew, Yusri Elsayed, Ricardo M. Attar, François Gaudet
Journal: Blood (2016)
Changes in lipoproteins prior to diagnosis of metastatic cancer.
Authors: Chad Pedersen, Angela Smith, Alcee Jumonville, Mohammed Al-Hamadani
Journal: Journal of Clinical Oncology (2015)

e22250 Background: The hypermetabolic nature of advanced cancer is well known. Previous research suggests that cancer patients have different cholesterol profiles compared to non-cancer controls. The magnitude of change and timeframe over which these changes occur is unknown. This retrospective study describes and quantifies the changes in lipoproteins of patients with the most common stage IV, metastatic solid-tumor malignancies. Methods: In this retrospective study, all patients (n = 173) with stage IV lung, breast, gastrointestinal, or prostate cancer, diagnosed in our institution between 2010-2013, who had a minimum of three lipid profiles within five years of diagnosis were reviewed. The mean total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides (TG) were calculated for 4 years (time 1) and 1.7 years (time 2) prior to diagnosis. The change in mean lipoprotein values over time was evaluated for significance. Subgroup analyses were performed for age, sex, body mass index (BMI), exposure to cholesterol-lowering medications, smoking status, and presence of diabetes. Results: Significant changes in lipid profile were observed from the average of time 1 vs. time 2. TC, LDL and TG reduced from 181.4 to 164.1(P < 0.001), 101.9 to 86.8 (P < 0.001) and 149 to 135.2 (P = 0.011) respectively. A significant decrease in LDL and increase in HDL were noticed in those who were prescribed lipid lowering medications vs. those who were not (P = 0.02 and 0.009 respectively). TG reduction was mostly seen in patients who are current smokers and younger than 70 years. None of the factors above influenced TC reduction. Conclusions: Significant decreases in TC, LDL, and TG were observed in this retrospective sample of patients with advanced cancer. Changes occurred irrespective of age, sex and BMI. Lipid lowering medications had an effect on LDL and HDL; however there is no way to ensure that subjects took the medications as prescribed. A greater magnitude of change in TG was noted among patients who were smokers. While the reason for this difference among smokers is unclear, it might be due to the distribution of underlying malignancies (such as a higher incidence of lung cancer among smokers) and suggests a future opportunity for research.
A phase II study of a 3-day schedule with topotecan and cisplatin every three weeks in patients with previously in treated small cell lung cancer and extensive disease: Final results
Authors: U. Lassen, M. Sørensen, P. B. Jensen, S. W. Langer, B. B. Jensen, N. Jeppesen, C. Rytter, A. Mellemgaard, O. Hansen, K. Østerlind
Journal: Journal of Clinical Oncology (2004)

7207 Background: The role of campthotecins in small cell lung cancer (SCLC) is emerging, and 5-day regimens with topetecan alone or with cisplatin have been shown to be active and tolerable. In order to provide a more feasible regimen for patients with extensive disease we developed a three-day regimen of topetecan and cisplatin. Preliminary data has previously been presented and we now present the final, updated results with a median follow-up time of 18 months. This investigators initiated study was supported by a grant from GlaxoSmithKline. Methods: This phase II study was planned to include 43 patients with histologically confirmed SCLC, extensive stage of disease, age 18–75 and WHO performance status 0–2. Patients received topetecan 2.0 mg/m2 on day 1–3 and cisplatin 50 mg/m2 on day 3, repeated every 3 weeks, for a maximum of 6 cycles. Patients with progressive disease (PD) or no-change (NC) after 3 cycles go off-study. Results: From May 2001 to September 2003, a total of 43 patients were included. An objective response has been observed in 74% (CR 16% and PR 58%). The regimen seems tolerable with no significant non-haematological toxicity. Until now there were no toxic deaths. Grade III and IV neutropenia was seen in 16% and 9%, respectively, and grade III and IV thrombocytopenia was observed in 3% and 3%, respectively. Non-hematological toxicity was mild. The median time to progression was 7.3 months (5.9–8.7), and the median survival time was 10.3 months (8.4–11.9). Conclusions: These updated results from this phase II study indicate this regimen is very active with limited toxicity. The data suggest that the efficacy and toxicity is similar to the 5-day schedule of topotecan and cisplatin. The schedule is attractive to patients with extensive stage SCLC and will now be evaluated in a phase III study. No significant financial relationships to disclose.
Hepatocellular carcinoma surveillance: Sometimes just specialists' incidental behavior?
Authors: Han Zhang, Zhen‐Li Li, Hao Xing, Meng‐Chao Wu, Tian Yang
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. To the Editor: We read with great interest the recent article by Goldberg et al.1 in hepatology (March 2017), which explored factors associated with low hepatocellular carcinoma (HCC) surveillance using US national Veterans Health Administration data. They reported that the strongest predictor of HCC surveillance was the number of specialist visits (gastroenterologist, hepatologist, or infectious diseases) in the first year after diagnosis of cirrhosis. Moreover, they also found that patients with cirrhosis caused by hepatitis (hepatitis B or C virus) had higher HCC surveillance rates than patients with cirrhosis caused by nonalcoholic hepatitis, alcohol‐induced liver disease, and cryptogenic cirrhosis. We would like to raise the following concerns. We believe that the authors' conclusion echoes with the real‐world situation. Compared to primary physicians, specialists such as hepatologists and infectious disease physicians tend to have a more comprehensive and up‐to‐date understanding of the natural history, progression, and prognosis of liver diseases. They are probably more knowledgeable in newly emerged therapeutic strategies of specific diseases such as chronic hepatitis B virus or hepatitis C virus infections. Once patients are diagnosed with hepatitis‐related cirrhosis, they are likely to be referred to specialists in clinical practice and evaluated for the need of standard antiviral treatment, which would consequently warrant repetitive checkups and follow‐ups. Important outcomes, such as response and possible resistance to antiviral medications, are evaluated during patients' regular visits. Other than standard tests like viral load, hepatic function, and hematologic tests, some specialists may probably (or “incidentally”) order ultrasound and/or alpha‐fetoprotein to rule out HCC. The tendency is higher in hepatitis‐related HCC‐prevalent countries like the United States and China. Therefore, we are very interested in whether the authors can verify our hypothesis in their present study: whether the chance of getting proper surveillance is higher in patients with hepatitis‐related cirrhosis who received standard antiviral treatment than in those who did not and whether specialists' extra test orders is a reasonable explanation for the authors' finding that the surveillance rate in patients with hepatitis‐related cirrhosis is higher than in those with cirrhosis caused by other etiologies. We believe that this further exploration can be made through mining of the authors' existing data, e.g., whether the probability of getting surveillance tests from specialists is higher in patients with cirrhosis on standard antiviral treatment than in other groups of high‐risk patients. If this was proved to be true, it would undoubtedly be interesting and thought‐provoking.