bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monocytes inhibit NK activityviaTGF-β in patients with obstructive sleep apnoea
Authors: Hernández-Jiménez Enrique , Cubillos-Zapata Carolina , Toledano Victor , Pérez de Diego Rebeca , Fernández-Navarro Isabel , Casitas Raquel , Carpio Carlos , Casas-Martín Jose , Valentín Jaime , Varela-Serrano Anibal , Avendaño-Ortiz Jose , Alvarez Enrique , Aguirre Luis A. , Pérez-Martínez Antonio , De Miguel Maria P. , Belda-Iniesta Cristobal , García-Río Francisco , López-Collazo Eduardo 
Published: July 2017

Obstructive sleep apnoea (OSA) is associated with cancer incidence and mortality. The contribution of the immune system appears to be crucial; however, the potential role of monocytes and natural killer (NK) cells remains unclear.Quantitative reverse transcriptase PCR, flow cytometry andin vitroassays were used to analyse the phenotype and immune response activity in 92 patients with OSA (60 recently diagnosed untreated patients and 32 patients after 6 months of treatment with continuous positive airway pressure (CPAP)) and 29 healthy volunteers (HV).We determined that monocytes in patients with OSA exhibit an immunosuppressive phenotype, including surface expression of glycoprotein-A repetitions predominant protein (GARP) and transforming growth factor-β (TGF-β), in contrast to those from the HV and CPAP groups. High levels of TGF-β were detected in OSA sera. TGF-β release by GARP+monocytes impaired NK cytotoxicity and maturation. This altered phenotype correlated with the hypoxic severity clinical score (CT90). Reoxygenation eventually restored the altered phenotypes and cytotoxicity.This study demonstrates that GARP+monocytes from untreated patients with OSA have an NK-suppressing role through their release of TGF-β. Our findings show that monocyte plasticity immunomodulates NK activity in this pathology, suggesting a potential role in cancer incidence.
Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study
Authors: Shigiyama Fumika , Kumashiro Naoki , Miyagi Masahiko , Ikehara Kayoko , Kanda Eiichiro , Uchino Hiroshi , Hirose Takahisa 
Published: July 2017

Abstract
Background
Recent studies reported that sodium glucose cotransporter 2 (SGLT2) inhibitors can potentially reduce the risk of cardiovascular mortality in patients with type 2 diabetes mellitus (T2DM). However, there is little or no information on the therapeutic effects of SGLT2 inhibitors on the progression of atherosclerosis. This dapagliflozin effectiveness on vascular endothelial function and glycemic control (DEFENCE) study was designed to determine the effects of dapagliflozin, a SGLT2 inhibitor, on endothelial function in patients with early-stage T2DM.

Methods
DEFENCE is a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative clinical trial. Between October 2015 and August 2016, 80 T2DM patients treated with 750 mg of metformin (hemoglobin A1c ≥6.0 and <8.0%, n = 80) were enrolled and randomized to receive either 1500 mg/day metformin (the metformin group, n = 40), or 750 mg/day metformin supplemented with 5 mg/day dapagliflozin (the dapagliflozin group, n = 40), for 16 weeks. The primary endpoint was a change in flow-mediated dilation (FMD) from baseline to the end of the 16-week treatment period. The secondary outcomes include changes in indexes of glycemic control, lipid metabolism, and oxidative stress, body composition, and safety evaluation.

Results
Although FMD tended to improve only in the dapagliflozin group, ΔFMD was comparable between the two groups. Analysis of patients with HbA1c >7.0% showed significant improvement of FMD in the dapagliflozin group than metformin group (P < 0.05). HbA1c, fasting plasma glucose, plasma glucagon, and body weight significantly decreased in both groups. Interestingly, urine 8-hydroxy-2′-deoxyguanosin, a biomarker of oxidative stress, was significantly lower in the dapagliflozin group than metformin group at 16 weeks (P < 0.001).

Conclusions
Dapagliflozin add-on therapy to metformin for 16 weeks improved endothelial function, as assessed by FMD, in patients with inadequately controlled early-stage T2DM. Improvement in oxidative stress may contribute to the improvement in FMD.
Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN000018754)
α-Glucosidase inhibitor miglitol attenuates glucose fluctuation, heart rate variability and sympathetic activity in patients with type 2 diabetes and acute coronary syndrome: a multicenter randomized controlled (MACS) study
Authors: Shimabukuro Michio , Tanaka Atsushi , Sata Masataka , Dai Kazuoki , Shibata Yoshisato , Inoue Yohei , Ikenaga Hiroki , Kishimoto Shinji , Ogasawara Kozue , Takashima Akira , Niki Toshiyuki , Arasaki Osamu , Oshiro Koichi , Mori Yutaka , Ishihara Masaharu , Node Koichi ,   on behalf of the Collaborators on the Effect of Miglitol on Glucose Metabolism in Acute Coronary Syndrome (MACS) Study
Published: July 2017

Abstract
Background
Little is known about clinical associations between glucose fluctuations including hypoglycemia, heart rate variability (HRV), and the activity of the sympathetic nervous system (SNS) in patients with acute phase of acute coronary syndrome (ACS). This pilot study aimed to evaluate the short-term effects of glucose fluctuations on HRV and SNS activity in type 2 diabetes mellitus (T2DM) patients with recent ACS. We also examined the effect of suppressing glucose fluctuations with miglitol on these variables.

Methods
This prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group comparative study included 39 T2DM patients with recent ACS, who were randomly assigned to either a miglitol group (n = 19) or a control group (n = 20). After initial 24-h Holter electrocardiogram (ECG) (Day 1), miglitol was commenced and another 24-h Holter ECG (Day 2) was recorded. In addition, continuous glucose monitoring (CGM) was performed throughout the Holter ECG.

Results
Although frequent episodes of subclinical hypoglycemia (≤4.44 mmo/L) during CGM were observed on Day 1 in the both groups (35% of patients in the control group and 31% in the miglitol group), glucose fluctuations were decreased and the minimum glucose level was increased with substantial reduction in the episodes of subclinical hypoglycemia to 7.7% in the miglitol group on Day 2. Holter ECG showed that the mean and maximum heart rate and mean LF/HF were increased on Day 2 in the control group, and these increases were attenuated by miglitol. When divided 24-h time periods into day-time (0700–1800 h), night-time (1800–0000 h), and bed-time (0000–0700 h), we found increased SNS activity during day-time, increased maximum heart rate during night-time, and glucose fluctuations during bed-time, which were attenuated by miglitol treatment.

Conclusions
In T2DM patients with recent ACS, glucose fluctuations with subclinical hypoglycemia were associated with alterations of HRV and SNS activity, which were mitigated by miglitol, suggesting that these pathological relationships may be a residual therapeutic target in such patients.
Trial registration Unique Trial Number, UMIN000005874 (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000006929)
Impact of next-generation sequencing (NGS) on diagnostic and therapeutic options in soft-tissue and bone sarcoma.
Authors: Gounder Mrinal M. , Ali Siraj Mahamed , Robinson Victoria , Bailey Mark , Ferraro Richard , Patel Nirali M , Krishnan Anita , Millis Sherri Z. , Dickson Mark Andrew , D'Angelo Sandra P. , Keohan Mary Louise , Miller Vincent A. , Schwartz Gary K. , Maki Robert G. , Tap William D. 
Published: July 2017

11001 Background: The utility of NGS in management of sarcoma pts remains undefined. Methods: We retrospectively analyzed the NGS profile of patients who were sequenced using a panel of 405 cancer-related genes in DNA and 265 genes rearranged in RNA. Diagnostic and therapeutic implications of mutations (mut) were evaluated through published literature (OncoKb.org, Pubmed). An algorithm was applied to determine germline mut. Following IRB approval, we evaluated the clinical outcomes of pts who underwent NGS at MSKCC. Results: From 2012–2016, 5635 pts worldwide with 56 histologies were tested. Median age of 52 yrs ( < 1-88), 52% females and sarcoma NOS (n = 858) was most frequent. Tumors were sequenced to a mean coverage of 634X; 1165 fusions and > 60,000 mut were found. Mut suspicious for germline defects were seen in 542 pts (9.6%) in known and novel genes ( BRCA, ARID1, FANC). Tumor mutational burden was 2.5/Mb (0–329) and glomus tumors and EHE had the highest and lowest mut, respectively. 16% and 7% of pts had treatment-linked alterations (TLA) known to respond to an FDA approved or study drug, respectively. 42% of pts had TLA eligible for NCI-MATCH, ASCO-TAPUR or other studies. Novel TLA include AKT, ESR1, BRCA, NTRK, PTCH1, SMARCB1 and others. Of the 107 MSKCC pts with clinical data, 60/107 (57%) had at least one TLA, of which 31 (30%) enrolled on a matched trial and 26 pts were ineligible or lacked access to trials. Partial/complete responses were seen with inhibitors to NTRK, IDH1, BRAF, PI3K/mTOR, MDM2, SMARCB1 and others. NGS changed the initial pathology diagnosis and treatments in 5% pts (e.g. LMS to liposarcoma, clear cell to melanoma). Resistance mutations averted futile therapies in 5% pts (e.g. Rb loss and palbociclib in liposarcoma). Conclusions: Our data suggests that NGS has a significant impact in aiding diagnosis and selecting matched therapies in sarcoma. Suspected germline aberrations, while intriguing, needs further validation.
Histopathologic review of suspected disease progression in patients with recurrent glioblastoma (GBM) receiving nivolumab ± ipilimumab: CheckMate 143.
Authors: Sahebjam Solmaz , Ramkissoon Shakti , Baehring Joachim M. , Mulholland Paul James , Grauer Oliver M. , Cloughesy Timothy Francis , Reardon David A. , Lim Michael , Zwirtes Ricardo F. , Latek Robert Raymond , Strauss Lewis C. , Ligon Keith L. 
Published: July 2017

2001 Background: Patients treated with immunotherapies can have a transient increase in lesion size due to immune cell infiltration that is suggestive of disease progression, but undergo subsequent regression with continued treatment. For patients with GBM, distinguishing progression from immune-related treatment effects using neuroimaging is challenging. Histopathologic examination of tumors could show the activity of immunotherapies in GBM and potentially minimize premature discontinuation of therapy and increase clinical benefit. Neuropathologic data from patients with recurrent GBM treated in CheckMate 143 who underwent biopsy/resection after suspected progression are presented. Methods: Patients received nivolumab 3 mg/kg (nivo 3) Q2W or nivo 3 + ipilimumab 1 mg/kg (ipi 1) Q3W × 4 doses then nivo 3 Q2W. Tissue collected from patients with suspected radiologic progression was submitted for blinded central review by 2 neuropathologists. Potentially significant treatment effect was defined as ≥30% necrosis/reactive changes and ≤50% viable solid tumor by area in posttreatment samples, or significant morphological changes from a prior biopsy if available. Results were compared with those from automated morphometry, pretreatment biopsy, and control pairs from unrelated patients with GBM treated with standard of care. Results: Of patients treated with nivo 3 (n = 20) or nivo 3 + ipi 1 (n = 1), 13 had potential treatment-related effects and 8 had no evidence of treatment effects (consistent with disease progression). Results were sent in real time to the treating physician to help inform treatment decisions; 4/13 patients with potential treatment effects continued therapy. Treatment effects were unrelated to age, MGMT methylation status, or PD-L1 expression (clone 28-8; archival tissue). Results were similar for automated morphometry analyses and showed differences between patients receiving nivo ± ipi and unrelated controls. Conclusions: These results suggest that histopathologic analyses may help better inform decisions on continuing nivo ± ipi in challenging cases, and show that immunotherapies may have intracerebral biological activity. Clinical trial information: NCT02017717.
Personalized, molecularly matched combination therapies for treatment-na.
Authors: Sicklick Jason K. , Leyland-Jones Brian , Kato Shumei , Hahn Michael , Williams Casey , De Pradip , Miller Vincent A. , Ross Jeffrey S. , Benson Adam , Webster Jennifer , Stephens Phil , Scur Michael , Porter Robert , Tran Lisa , Jepperson Shelby Hintze , Fanta Paul T. , Kurzrock Razelle 
Published: July 2017

2512 Background: Precision medicine has been studied in patients (pts) with advanced, heavily-treated cancers by administering molecularly matched monotherapies. With increasing availability of large gene assays and cognate agents, we hypothesized that offering customized combination therapies to treatment-naïve tumors would be feasible and improve response rates. Methods: Investigation of Profile-Related Evidence Determining Individualized Cancer Therapy (I-PREDICT, NCT02534675) targeted metastatic and/or unresectable, untreated lethal cancers ( > 50% 2-yr mortality). Comprehensive genomic profiling (CGP, Foundation Medicine; 315 genes), and, if possible, PD-(L)1 IHC, tumor mutational burden (TMB) and circulating tumor DNA were performed. A molecular tumor board discussed results immediately upon receipt, and emphasized customized combinations. Final decisions were the treating physician’s choice. Results: CGP was evaluable in 40/47 treatment-naïve pts (85.1%); 22 (46.8%) were treated [17 matched (36.2%); 5 unmatched (10.6%); 11 different diagnoses). The other 25 pts (53.2%) are awaiting therapy (8, 17%) or could not be treated (17, 36.2%), mainly due to patient deterioration or payor limitations. Each tumor had a unique genomic portfolio. The median (range) of genomic alterations/patient was 5 (1-12). TMB was available in 17 pts (12 low; 4 intermediate; 1 high). The median (range) Matching Score [(matches (#)/characterized genomic alterations (#)] was 33% (14-100%; 100% designated immunotherapy match or all alterations matched to targeted agents) [Reference PMID 2719717]. Nine/17 matched pts (53%) achieved SD > 6 months (N = 2) or CR (1)/PR (6). The median progression-free survival (PFS) for matched vs. unmatched pts was 4.7 vs. 1.0 months ( P= 0.0019). There were no drug-related deaths. Conclusions: With the use of broad-based DNA sequencing assays, inclusion of pts earlier in their disease course, timely mandated molecular tumor board discussions, and increasing availability of cognate drugs for customized combinations, we report: 1) high molecular matching rates (~36%); 2) high rates of SD > 6 months/CR/PR (~53%); and 3) improved PFS. Study expansion is ongoing. Clinical trial information: NCT0253467.
Mutational burden of tumors with primary site unknown.
Authors: Gay Laurie M. , Fabrizio David , Frampton Garrett Michael , Connelly Caitlin F. , Sun James , Daniel Sugganth , Elvin Julia Andrea , Ramkissoon Shakti , Severson Eric Allan , Suh James , Vergilio Jo-Anne , Stephens Philip J. , Ross Jeffrey S. 
Published: July 2017

3039 Background: Higher levels of tumor mutational burden (TMB) can predict sensitivity to immunotherapies (IO), which are FDA approved to treat NSCLC, melanoma, and urothelial carcinoma (Ca). TMB may be a biomarker for sensitivity to IO, irrespective of tumor type. TMB has not been explored widely for tumors of unknown primary site, but may reveal additional treatment options. Methods: Comprehensive genomic profiling of DNA from FFPE tissue samples was performed using hybrid-capture, next-generation sequencing. TMB was calculated by counting all coding short variant alterations (base substitutions and indels), including synonymous alterations, and subtracting from this functionally oncogenic or germline alterations (per ExAC, dbSNPT, or internal algorithmic analysis). To calculate the TMB per Mb, the total number of relevant mutations is divided by the coding region of the bait set (0.8 Mb, 1.1 Mb, or 1.2 Mb). High, intermediate, and low TMB were defined as ≥20 mut/Mb, ≥6 and <20 mut/Mb, or <6 mut/Mb, respectively. Tumor types with >100 samples were analyzed. Results: From a database of 102,878 samples sequenced during routine clinical care, 6116 samples for which the primary tumor site was unclear at sequencing were identified. Table shows TMB metrics (mut/Mb) and median patient age for these cohorts. Conclusions: Significant numbers of patients with each tumor type have high TMB that may indicate benefit from IO, excepting GIST. As expected, urothelial tumors have higher than average TMB and more patients have high TMB. SCC tumors are commonly TMB high (23%), as are tumors difficult to define histologically (15%). For ACUP or CUP, the most common tumors, 8-11% have high TMB. Analysis of responses to treatment with IO are ongoing. [Table: see text]
Tumor mutational burden (TMB) and co-existing actionable mutations in biliary tract cancers (BTC).
Authors: Jain Apurva , Shroff Rachna T. , Zuo Mingxin , Weatherly Jacqueline , Meric-Bernstam Funda , Isaacs Randi , Ali Siraj Mahamed , Bekaii-Saab Tanios S. , Javle Milind M. 
Published: July 2017

4086 Background: Mutations in DNA repair pathway were identified in 13% of Biliary Tract Cancers (BTC) [ Cancer2016;122:3838–3847]. High TMB tumors including melanoma, lung cancer and those with microsatellite instability (MSI-H) are associated with susceptibility to immune blockade using checkpoint inhibitors. TMB data in BTC is limited and its association with actionable somatic mutation (mut) profiles in BTC is unknown. Methods: Comprehensive genomic profiling (CGP) of 309 FFPE tissue blocks of BTC pts with a hybrid capture of all coding exons of 236 cancer-related genes and 47 introns of 19 genes rearranged in cancer was done using FoundationOne. Base substitutions, indels, gene fusion/rearrangements, TMB, and MSI status were assessed. TMB was calculated by counting mutations across a 1.25Mb region and classified into high (TMBH; ≥20 mut/Mb), intermediate (TMBI; 6 - 19mut/Mb) and low (TMBL; < 6mut/Mb). MSI high (MSIH) and Stable (MSS) status was assigned by a computational algorithm examining 114 intronic homopolymer loci. Patients with TMB ≥6 mut/Mb (N = 60) were included in the clinical correlative portion of this study. Results: Sixty patients with TMB ≥6 mut were identified out of 309 pts of which 9 (15%) were TMBH and 51 (85%) were TMBI. These included 3 (5%) MSIH and 18 (30 %) MSS. The median age was 59 years (range: 29-86), 35 (58%) were females, majority were intrahepatic cholangiocarcinoma (n = 31; 52%) and 28 (47%) presented with advanced disease at diagnosis. Twenty three (38%) pts had received radiation therapy, 28 (47%) surgery and 3 (5%) received immunotherapy. Most frequent co-existing mut seen was TP53 (N = 35; 58%). APC mut was seen in 7 (12%) pts. DNA repair pathway muts ( MSH6, BRCA1, BRCA2, ATM, MLH1, or MSH2 genes) were identified in 78% of TMBH versus 16% in TMBI cases (p < 0.0001). Frequency of PIK3CA mut differed significantly between TMBH and TMBI (44% vs 10%, p < 0.0001). Pts with TMBI had a significantly better median OS (110 weeks) as compared to TMBH (43 weeks) (p = 0.003). Conclusions: DNA repair pathway and PIK3CA mut maybe associated with TMBH in BTC. A better understanding of TMB and associated actionable mutations in BTC may be of value for the management of BTC patients with targeted agents and immunotherapy.
BRCA1/2 reversion mutations in prostate cancer identified from clinical tissue and liquid biopsy samples.
Authors: Daniel Sugganth , Gornstein Erica , Frampton Garrett Michael , Sun James , Morley Samantha , Heilmann Andreas , Reddy Prasanth , Chung Jon , Suh James , Ramkissoon Shakti , Severson Eric Allan , Vergilio Jo-Anne , Stephens Philip J. , Miller Vincent A. , Elvin Julia Andrea , Ross Jeffrey S. , Gay Laurie M. 
Published: July 2017

5024 Background: Prostate tumors with genomic alterations (GA) in BRCA1 or BRCA2 ( BRCA) may be sensitive to treatment with PARP inhibitors (PARPi). However, secondary reversion mutations (revGA) can arise that may restore BRCA function and underlie reduced sensitivity to PARPi or platinum (Pt)-based therapy. Comprehensive genomic profiling (CGP), using either tissue or liquid biopsies, can detect the variety of clinically relevant revGA that can arise. Methods: DNA extracted from FFPE tumor tissue or blood samples obtained during routine clinical care for 1911 patients with predominantly relapsed, refractory or metastatic prostate carcinoma was analyzed by hybrid-capture, next-generation sequencing for all classes of GA: base substitutions, indels, rearrangements, and copy number changes. RevGA were any GA that could restore the reading frame if in cis with a nonsense or frameshift (fs) GA. Results: 216/1911 (11.3% ± 1.4%) tumors had ≥1 deleterious BRCA GA. Of these, 7 samples harbored potential revGA in BRCA1 (1) or BRCA2 (6): prostate acinar adenocarcinoma (5), neuroendocrine carcinoma (1), or undifferentiated carcinoma (1). Of these, 2 samples were liquid biopsies (blood), 4 were FFPE tissue samples (liver), and 1 sample was a bone marrow core biopsy. All samples with revGA were metastases. Potential revGA were of 3 types: overlapping indel (4), compensatory fs (2), and missense (1). One case harbored 2 revGA, an overlapping indel and a compensatory fs. Alteration frequencies for TMPRSS2 (fusions), PTEN, and AR were similar with or without BRCA mutations; revGA-positive samples had a modest increase in PTEN alterations (42.9% vs 33.8%, NS). The frequency of CDK12 alterations was significantly reduced in BRCA-mutated tumors (0.9% vs 6.9%, p = 0.00002). Clinical histories for patients with reversion mutations will be presented. Conclusions: CGP of 1911 prostate carcinomas reveals ≥1 deleterious BRCA1/2 in 11.3% of samples. From these, a series of 7 cases, all metastases, with co-occurring potential revGA were identified. Although rare, revGA can be acquired during treatment and may underlie resistance to PARPi or Pt-based therapy. BRCA revGA can be detected from both tissue and liquid biopsies.