tbuckley/cabot-search huggingface dataset:
Response to Comment on Trinh et al. Successful Treatment of Immune Checkpoint Inhibitor–Induced Diabetes With Infliximab. Diabetes Care 2019;42:e153–e154
Authors: Beckey Trinh, Marc Y. Donath, Heinz Läubli
Journal: Diabetes Care (2019)

We thank Galligan et al. (1) for their interest in our observation (2) on the successful treatment of immune checkpoint inhibitor–induced diabetes with infliximab.

First, we agree with the commenters that intra-articular steroid injection could have contributed slightly to the development of insulin resistance. However, an intra-articular injection is not expected to have as much impact on insulin sensitivity as systemic corticosteroid treatment. Furthermore, our repeated mixed-meal tolerance tests indicated an impaired insulin secretion capacity—recovered by 3 months after initiation of treatment with infliximab—which points to concurrent β-cell dysfunction. Finally, after publication of our observation and after termination of …
Reply to ‘Are the 5-hydroxymethylcytosine-based wd-scores really superior over α-fetoprotein for the early diagnosis of hepatocellular carcinoma?’
Authors: Jiabin Cai, Zhou Zhang, Chuan He, Wei Zhang, Jia Fan
Journal: Gut (2019)

We thank Chen and Lin for their interest in our article.1 They raised concerns about the comparison between α-fetoprotein (AFP) and the 5-hydroxymethylcytosine (5hmC)-based weighted diagnostic (wd)-scores,2 a debate worth further clarification.

First, it should be clarified that Chen and Lin’s description did not represent the overall picture of the wd-scores.1 The performance measures mentioned by Chen and Lin were specifically for distinguishing early hepatocellular carcinoma (HCC) and non-HCC (including not just chronic hepatitis B (CHB) virus infection but also benign liver lesions, liver cirrhosis (LC) and healthy controls) in the validation set. Notably, the 5hmC-based wd-scores consistently outperformed AFP in both training and validation sets for HCC versus non-HCC, early HCC versus CHB/LC, and early HCC versus controls (healthy individuals, benign liver lesions). Compared with AFP alone, the 5hmC-based wd-scores performed especially well when detecting early …
Patient out-of-pocket payments for oral oncologic therapies: Updated results from a U.S. claims data analysis
Authors: E. Pelletier, J. Tierce, Y. Yim, C. Reyes
Journal: Journal of Clinical Oncology (2009)

6582 Background: Oral oncologic therapies are increasingly becoming part of treatment options for cancer. These agents often fall within the pharmacy benefit, with the potential for increased out-of-pocket (OOP) cost burden to patients. The objective of this study is to evaluate patient OOP payments for oral oncologic therapies in U.S. managed care plans. Methods: Patients aged 18+ years with 1 of 13 oral oncologics (bexarotene, capecitabine, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lenalidomide, sorafenib, sunitinib, temozolomide, thalidomide, vorinostat) were identified in 2007 from a nationally representative database of medical and pharmacy claims from over 90 U.S. health plans. OOP payments were calculated as the allowed amount (dollar amount a health plan allows for a therapy, including any member liability) minus the paid amount (dollar amount paid by a health plan for a therapy). Results: 10,400 patients with evidence of at least 1 of 13 oral oncologic therapies were identified in 2007. The mean age was 59.2 years, 48% were male, and 83% had a commercial payer; 26% of patients were diagnosed with lung cancer, 14% with breast cancer, and 13% with colorectal cancer at the time of the first evidence of therapy use in 2007. Mean and median OOP payments for the 13 oral oncologic therapies are provided in the table below. Medicare Advantage and Medicaid had higher mean OOP payments for most therapies compared to commercial payers and self-insured patients. Conclusions: This study evaluated OOP payments for oral oncologic therapies using current claims data. Among the 13 oral oncologics studied, the average OOP costs ranged from $117 to $1,014. As costs for therapy become a greater part of treatment decisions, an understanding of patient OOP costs will be critical in informing choices. [Table: see text] [Table: see text]
Acyclovir for Mechanically Ventilated Patients With Herpes Simplex Virus Oropharyngeal Reactivation
Authors: Charles-Edouard Luyt, Jean-Marie Forel, David Hajage, Samir Jaber, Sophie Cayot-Constantin, Thomas Rimmelé, Elisabeth Coupez, Qin Lu, Mamadou Hassimiou Diallo, Christine Penot-Ragon, Marc Clavel, Carole Schwebel, Jean-François Timsit, Jean-Pierre Bedos, Caroline Hauw-Berlemont, Jérémy Bourenne, Julien Mayaux, Jean-Yves Lefrant, Jean-Paul Mira, Alain Combes, Michel Wolff, Jean Chastre, Laurent Papazian
Journal: JAMA Internal Medicine (2019)

The role of herpes simplex virus (HSV) reactivation on morbidity and mortality in patients in the intensive care unit requiring mechanical ventilation remains unknown.To determine whether preemptive treatment with intravenous acyclovir reduces the duration of mechanical ventilation in patients with HSV oropharyngeal reactivation.A double-blind, placebo-controlled randomized clinical trial was conducted in 16 intensive care units in France. Participants included 239 adults (age, >18 years) who received mechanical ventilation for at least 96 hours and continued to receive mechanical ventilation for 48 hours or more, with HSV oropharyngeal reactivation. Patients were enrolled between February 2, 2014, and February 22, 2018.Participants were randomized to receive intravenous acyclovir, 5 mg/kg, 3 times daily for 14 days or a matching placebo.The primary end point was ventilator-free days from randomization to day 60. Prespecified secondary outcomes included mortality at 60 days. Main analyses were conducted on an intention-to-treat basis.Of 239 patients enrolled and randomized, 1 patient withdrew consent, leaving 238 patients, with 119 patients in both the acyclovir and placebo (control) groups (median [IQR] age, 61 [50-70] years; 76 [32%] women) available for primary outcome measurement. On day 60, the median (IQR) numbers of ventilator-free days were 35 (0-53) for acyclovir recipients and 36 (0-50]) for controls (P = .17 for between-group comparison). Among secondary outcomes, 26 patients (22%) and 39 patients (33%) had died at day 60 (risk difference, 0.11, 95% CI, -0.004 to 0.22, P = .06). The adverse event frequency was similar for both groups (28% in the acyclovir group and 23% in the placebo group, P = .40), particularly acute renal failure post randomization affecting 3 acyclovir recipients (3%) and 2 controls (2%). Four patients (3%) in the acyclovir group vs none in the placebo group stopped the study drug for treatment-related adverse events.In patients receiving mechanical ventilation for 96 hours or more with HSV reactivation in the throat, use of acyclovir, 5 mg/kg, 3 times daily for 14 days, did not increase the number of ventilator-free days at day 60, compared with placebo. These findings do not appear to support routine preemptive use of acyclovir in this setting.ClinicalTrials.gov identifier: NCT02152358.
Abstract B20: KrasG12D effector dependencies in the maintenance of pancreatic ductal adenocarcinoma
Authors: Adrien Grimont, Zhen Zhao, Steven D. Leach, Rohit Chandwani
Journal: Cancer Research (2019)

Abstract More than 90% of pancreatic ductal adenocarcinoma (PDAC) tumors in humans feature activating mutations in the proto-oncogene KRAS. In mice, KrasG12D mutation alone is sufficient for PanIN formation; when coupled with mutational inactivation of TP53 (Tp53R172H), PanIN formation is accelerated and these neoplastic lesions progress to invasive and metastatic disease at high frequency. Several groups have demonstrated that inactivation of mutant Kras in established PanIN and PDAC leads to redifferentiation and apoptosis of the tumor, respectively. More recently, several combinatorial genetic and pharmacologic strategies have been employed that highlight RAF kinases as key oncoeffectors for KRAS addiction, but that RAF inhibition alone demonstrates little efficiency against KRAS mutant tumors. Additionally, previous studies suggest a requirement for both C-raf and EGFR blockade or the combination of RAF-MEK or RAF-PI3K inhibitors to inhibit to tumor growth. However, a systematic evaluation of dependencies of Kras effectors in tumor maintenance has not been explicitly performed. To investigate effector dependencies in the KrasG12D setting, we have developed an organoid platform to generate isogenic lines bearing doxycycline-inducible small hairpin (sh)RNAs coupled to GFP inserted into mouse pancreatic tumor organoids derived from KPC mice. These shRNAs are directed against each of the major Kras effector molecules, including B-raf, C-raf, Pi3k, RalA, RalB, and Rac1, with Kras shRNAs and Renilla shRNA used as controls. We identified 2 effective shRNAs per target, with strong and durable inhibition of each protein observed after doxycycline treatment. To investigate the hierarchy of Kras effectors, we employed a competition assay of the shRNA organoids, and observed the drop-out of Kras, C-raf, and Rac1 shRNA-bearing tumor organoid lines. Cell number and volumetric analyses confirmed strong dependencies on Kras, C-raf, and Rac1. Chromatin accessibility and transcriptomic analyses of Kras- , C-raf- , and Rac1-depleted organoids revealed consensus features of abrogated tumor maintenance and key molecular nodes in tumor maintenance. Together, we have employed a mouse organoid platform to create a rigorous map of the requirements for the key effectors of mutant Kras, and to dissect the biologic mechanisms shared by effectors disruptive of the mutant Kras epigenetic and transcriptional landscape. In turn, we anticipate these findings can inform the subsequent development of novel therapies to address these vulnerabilities. Citation Format: Adrien Grimont, Zhen Zhao, Steven D. Leach, Rohit Chandwani. KrasG12D effector dependencies in the maintenance of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B20.
Phase I/IIa study of the novel combination of bendamustine (B) with irinotecan (I) followed by etoposide (E) and carboplatin (C) in untreated patients (Pts) with extensive-stage small cell lung cancer (ESSCLC).
Authors: Daniel Joseph Allendorf, Rodolfo Bordani, Stefan C. Grant, Mansoor N. Saleh, Mary Jerome, Debi Miley, Alan Cantor, Vishnu Reddy, Francisco Robert
Journal: Journal of Clinical Oncology (2013)

7591 Background: Standard therapy for ESSCLC consisting of E and a platin drug (Plat) yields a median time to progression (TTP) of 4 months (m) and overall survival (OS) of 9 m. DNA damage from B is repaired by excision repair, akin to Plat. The activity of I, a topoisomerase (Top)-1 inhibitor, leads to increases in Top-2, the target of E. The sequence B+I → E+C was hypothesized to increase TTP by exploiting mitotic catastrophe. Methods: This is an open label trial enrolling pts with ESSCLC and evaluable disease. The phase I primary endpoint was to determine the maximum tolerated dose (MTD) of B+I; the phase IIa primary endpoint was TTP after B+I→E+C. Secondary endpoints were objective response rate (ORR) and OS. In the phase I (N=15), cohorts received I (150 mg/m 2 , d 1) with B at 80, 100, or 120 mg/m 2 /day (d 1,2) every 3 weeks for 3 cycles. Phase IIa Pts were treated at the recommended dose of B+I for 3 cycles followed by E (100 mg/m 2 , d 1-3) + C (AUC 6, d 1) for 3 cycles. Restaging was performed after 3 cycles of each regimen. The phase IIa was powered to detect a 30% increase in TTP from 4 to 5.2 m with a of 0.1. The Kaplan-Meier method was used to calculate TTP and OS. Toxicities were evaluated using the NCI CTCAE. Results: The MTD of B was not reached. The recommended phase IIa dose of B was 100 mg/m 2 ; dose-escalation was allowed in subsequent cycles of therapy. Dose limiting toxicities were diarrhea, nausea, and vomiting. One treatment-related death from metabolic encephalopathy occurred in the phase IIa. The commonest grade 3/4 hematologic toxicity was neutropenia. Fatigue, nausea, vomiting, and diarrhea were common non-hematologic toxicities. Conclusions: B+I is an active regimen in ESSCLC and the treatment sequence B+I→E+C seems to improve the TTP and OS in ESSCLC compared to historic values for E+C. Toxicities were increased compared to historic values for E+C, but were manageable. Correlative studies with pre-treatment assessment of tumor ERCC-1, Top-1, and Top-2 as predictors of response are ongoing. Clinical trial information: NCT00856830. [Table: see text]
Cardio-Oncology and the Intersection of Cancer and Cardiotoxicity
Authors: Richard K. Cheng, James N. Kirkpatrick, Mohamed L. Sorror, Ana Barac
Journal: JACC CardioOncology (2019)

Over the last several decades, palliative care has evolved from a subspecialty focusing on end-stage disease to one that provides comprehensive care for patients with complex illness. It has been well established for many years in oncology. More recently, palliative care has been recognized as a
Safety and efficacy of VB-111, an anticancer gene therapy, in patients with recurrent glioblastoma: results of a phase I/II study
Authors: Andrew J Brenner, Katherine B Peters, James Vredenburgh, Felix Bokstein, Deborah T Blumenthal, Shlomit Yust-Katz, Idit Peretz, Bernice Oberman, Laurence S Freedman, Benjamin M Ellingson, Timothy F Cloughesy, Naamit Sher, Yael C Cohen, Noa Lowenton-Spier, Tamar Rachmilewitz Minei, Niva Yakov, Itzhak Mendel, Eyal Breitbart, Patrick Y Wen
Journal: Neuro-Oncology (2019)

VB-111 is a non-replicating adenovirus carrying a Fas-chimera transgene, leading to targeted apoptosis of tumor vascular endothelium and induction of a tumor-specific immune response. This phase I/II study evaluated the safety, tolerability, and efficacy of VB-111 with and without bevacizumab in recurrent glioblastoma (rGBM).Patients with rGBM (n = 72) received VB-111 in 4 treatment groups: subtherapeutic (VB-111 dose escalation), limited exposure (LE; VB-111 monotherapy until progression), primed combination (VB-111 monotherapy continued upon progression with combination of bevacizumab), and unprimed combination (upfront combination of VB-111 and bevacizumab). The primary endpoint was median overall survival (OS). Secondary endpoints were safety, overall response rate, and progression-free survival (PFS).VB-111 was well tolerated. The most common adverse event was transient mild-moderate fever. Median OS time was significantly longer in the primed combination group compared with both LE (414 vs 223 days; hazard ratio [HR], 0.48; P = 0.043) and unprimed combination (414 vs 141.5 days; HR, 0.24; P = 0.0056). Patients in the combination phase of the primed combination group had a median PFS time of 90 days compared with 60 in the LE group (HR, 0.36; P = 0.032), and 63 in the unprimed combination group (P = 0.72). Radiographic responders to VB-111 exhibited characteristic, expansive areas of necrosis in the areas of initial enhancing disease.Patients with rGBM who were primed with VB-111 monotherapy that continued after progression with the addition of bevacizumab showed significant survival and PFS advantage, as well as specific imaging characteristics related to VB-111 mechanism of action. These results warrant further assessment in a randomized controlled study.
MAIT Cells Promote Tumor Initiation, Growth, and Metastases via Tumor MR1
Authors: Juming Yan, Stacey Allen, Elizabeth McDonald, Indrajit Das, Jeffrey Y.W. Mak, Ligong Liu, David P. Fairlie, Bronwyn S. Meehan, Zhenjun Chen, Alexandra J. Corbett, Antiopi Varelias, Mark J. Smyth, Michele W.L. Teng
Journal: Cancer Discovery (2019)

Abstract Mucosal-associated invariant T (MAIT) cells are innate-like T cells that require MHC class I–related protein 1 (MR1) for their development. The role of MAIT cells in cancer is unclear, and to date no study has evaluated these cells in vivo in this context. Here, we demonstrated that tumor initiation, growth, and experimental lung metastasis were significantly reduced in Mr1−/− mice, compared with wild-type mice. The antitumor activity observed in Mr1−/− mice required natural killer (NK) and/or CD8+ T cells and IFNγ. Adoptive transfer of MAIT cells into Mr1−/− mice reversed metastasis reduction. Similarly, MR1-blocking antibodies decreased lung metastases and suppressed tumor growth. Following MR1 ligand exposure, some, but not all, mouse and human tumor cell lines upregulated MR1. Pretreatment of tumor cells with the stimulatory ligand 5-OP-RU or inhibitory ligand Ac-6-FP increased or decreased lung metastases, respectively. MR1-deleted tumors resulted in fewer metastases compared with parental tumor cells. MAIT cell suppression of NK-cell effector function was tumor-MR1–dependent and partially required IL17A. Our studies indicate that MAIT cells display tumor-promoting function by suppressing T and/or NK cells and that blocking MR1 may represent a new therapeutic strategy for cancer immunotherapy. Significance: Contradicting the perception that MAIT cells kill tumor cells, here MAIT cells promoted tumor initiation, growth, and metastasis. MR1-expressing tumor cells activated MAIT cells to reduce NK-cell effector function, partly in a host IL17A–dependent manner. MR1-blocking antibodies reduced tumor metastases and growth, and may represent a new class of cancer therapeutics. This article is highlighted in the In This Issue feature, p. 1
Incidence and mortality of multiple myeloma in China, 2006–2016: an analysis of the Global Burden of Disease Study 2016
Authors: Jiangmei Liu, Weiping Liu, Lan Mi, Xinying Zeng, Cai Cai, Jun Ma, Lijun Wang
Journal: Journal of Hematology & Oncology (2019)

Abstract Background The accurate information about burden of multiple myeloma (MM) at national and provincial level remains unknown in China. Methods Following the general analytical strategy used in GBD 2016, the age-, sex-, and province-specific incidence and mortality in China were analyzed. Trends in the incidence and mortality from 2006 to 2016 were evaluated. Results It was estimated that there were 16,500 new cases and 10,300 deaths of multiple myeloma in China in 2016. The age-standardized incidence rates (ASIR) and mortality rates (ASMR) per 100,000 population were 1.03 (95% UI, 0.88–1.17) and 0.67 (95% UI, 0.59–0.77) in 2016. Males had higher incidence and mortality rates than females in all age groups. An upward trend with age in incidence and mortality was observed. Higher incidence and mortality rates clustered in the developed provinces. The incidence of MM in China increased significantly from 2006 to 2016, while the mortality increased from 2006 to 2014, and remained stable from 2014 to 2016. Conclusion The burden of MM showed a heterogeneous pattern in China, which highlighted the need of tailored disease prevention and control strategies in both national and provincial levels.
NGS-based targeted RNA sequencing for expression profiling and relative quantitation of specific gene isoforms and fusions in tumor-specific panels.
Authors: Gordon Vansant, Mark Landers, Lien Vo, Kahuku Oades, Hyunsoo Kim, Jerry Lee, Rhonda Meredith, Byung-In Lee, Joseph Monforte
Journal: Journal of Clinical Oncology (2013)

11108 Background: Gene expression signatures have become a useful tool for the identification of tumor subtypes and response to specific therapies. Expression of tumor, metastatic and macrophage specific transcripts utilizing alternative promoters and transcriptional start sites can further characterize these tumors . NGS is a powerful tool for gene expression analysis, however larger sample input requirements (&gt;100ng) and excessive sequencing depth requirements (30-40M tags/sample) to detect the expression of rare isoforms or fusions in tumor samples are prohibitive for clinical assay development. We describe the development of a targeted RNA sequencing assay for the relative quantitation of specific gene expression signatures, known splice variants and gene fusions from less than 100 ng of starting material in a single tube universal amplification format. Methods: Primers for 52 genes, isoforms and gene fusion products were designed using the universal amplification strategy. 10 ng of RNA from 5 matched tumor/adjacent normal breast cancer tumor pairs were assayed. Libraries were prepared for sequencing by emPCR and sequenced on Ion Torrent PGM. Data were aligned via TMAP. Relative expression was determined vs. housekeeping genes or wild type transcripts. Results: All gene targets were detected at significant levels in at least one tumor sample. Robust expression profiling (5 log dynamic range) was obtained from FFPE macrodissected tumor and normal samples with as little as 200K reads/sample. Immune specific transcripts demonstrated differential expression (CCL3, AIF, FCGR3A and CSF1) across patients and matched pairs as well as an upregulation of CXCL12, indicative of tumor associated macrophages. Conclusions: Targeted RNAseq demonstrates detection and quantitation of relative expression levels of not only tumor subclass specific gene expression signatures, but immune cell specific transcripts from 10ng of FFPE derived total RNA derived from macrodissected tumor samples. The lower input requirements, quicker turnaround time and incredible sensitivity of targeted RNAseq make this assay a useful tool for clinical assay development.
Anti-inflammatory and immunoregulatory effects of paeoniflorin and total glucosides of paeony
Authors: Lingling Zhang, Wei Wei
Journal: Pharmacology & Therapeutics (2019)

As a Traditional Chinese Medicine, Paeonia lactiflora Pallas has been used to treat pain, inflammation and immune disorders for more than 1000 years in China. Total glycoside of paeony (TGP) is extracted from the dried root of Paeonia lactiflora Pallas. Paeoniflorin (Pae) is the major active component of TGP. Our research group has done a lot of work in the pharmacological mechanisms of Pae and found that Pae possessed extensive anti-inflammatory and immune regulatory effects. Pae could inhibit inflammation in the animal models of autoimmune diseases, such as experimental arthritis, psoriatic mice and experimental autoimmune encephalomyelitis, and so on. Pae modulates the functions and activation of immune cells, decreases inflammatory medium production, and restores abnormal signal pathway. Pae could balance the subsets of immune cells through inhibiting abnormal activated cell subsets and restoring regulatory cell subsets. Pae could regulate signaling pathways (GPCR pathway, MAPKs /NF-κB patway, PI3K /Akt /mTOR pathway, JAK2 /STAT3 pathway, TGFβ /Smads, and etc.). TGP is composed of Pae, hydroxyl-paeoniflorin, paeonin, albiflorin and benzoylpaeoniflorin etc. Pae accounts for more than 40% of TGP. Like Pae, TGP has anti-inflammatory and immune regulatory effects. TGP has been widely used to treat autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis, allergic contact dermatitis, and etc. in China. Furthermore, TGP has some superior features with immune regulation, gentle effect, many indications and few adverse drug reactions. These findings suggest that TGP may be a promising anti-inflammatory and immune drug with soft regulation and has more superiority in the treatment of AIDs. Currently, TGP is used for the treatment of RA, SLE and other AIDs in more than 1000 hospitals in China, which obtained great social and economic benefits.