tbuckley/cabot-search huggingface dataset:
Randomised phase III study of gemcitabine, cisplatin plus S-1 (GCS) compared with gemcitabine plus cisplatin (GC) for unresectable or recurrent biliary tract cancer (KHBO1401-MITSUBA).
Authors: Tatsuya Ioka, Masashi Kanai, Shogo Kobayashi, Daisuke Sakai, Amane Kitasato, Hiroki Yamaue, Hideyuki Hayashi, Naoko Chayahara, Masahiro Takahashi, Takatsugu Yamada, Etsuro Hatano, Takuma Goto, Jiro Fujimoto, Masahiro Murakami, Keiko Kamei, Kenichi Yoshimura
Journal: Journal of Clinical Oncology (2015)

TPS4141 Background: Gemcitabine plus cisplatin (GC) therapy has been the standard palliative chemotherapy for patients with advanced biliary tract cancer (BTC). Our previous KHBO1002 trial, a single-arm phase II study of GC plus S-1 combination therapy (GCS), demonstrated a favorable survival benefit in BTC patients (Kanai M, et al. Cancer Chemother. Pharmacol. (2015) 75, 293-300). This phase III study aims to confirm the superiority of GCS to GC in terms of overall survival in patients with recurrent or unresectable BTC. Methods: Eligibility criteria include chemotherapy-naïve patients with recurrent or unresectable biliary tract adenocarcinoma (gallbladder, intrahepatic biliary tract, extrahepatic biliary tract, or ampulla of Vater), an Eastern Cooperative Oncology Group performance status of 0–2, and adequate organ function. Eligible patients are randomized into either GCS arm or GC arm. In the GCS arm, gemcitabine and cisplatin were administered intravenously at doses of 1,000 or 25 mg/m (2), respectively, on day 1, and oral S-1 was administered daily at a dose of 80 mg/m (2) on days 1-7 every 2 weeks. In the GC arm, 1000 mg/m2 of gemcitabine and 25 mg/m2 of cisplatin are infused on days 1 and 8 and repeated every 3 weeks. The primary endpoint is overall survival and the secondary endpoints are progression-free survival, %response rate, %planned dose, adverse events. The sample size was calculated to be 220 (110 patients per arm), assumed median survival time of 11.2 months in GC and of 16.2 months in GCS, an accrual period of 4 years, and a follow-up period of 1 year. Forty-nine institutions are participating in this study (NCT02182778☐AUMIN 000014371). The study was activated in August 2014. Clinical trial information: NCT02182778.
NHS trusts launch legal challenge against councils over business rates
Authors: Clare Dyer
Journal: BMJ (2018)

NHS hospital trusts in England have launched a legal challenge for business rates relief that could save them millions of pounds a year if it succeeds.

The group of 20 trusts has begun legal proceedings against 49 local authorities, arguing that they should be entitled to claim an 80% reduction in their business rates, as many private hospitals do. The trusts argue that they should be entitled to charitable rate relief, which is available to bodies with charitable purposes, such as the delivery of healthcare or education, and not just to …
NHS is harming patient confidentiality by sharing data for immigration purposes, say MPs
Authors: Gareth Iacobucci
Journal: BMJ (2018)

The NHS body responsible for sharing confidential patient data with the Home Office to help track potential immigration offenders is failing in its ethical duty to protect patient confidentiality, a damning report from MPs has found.

The government recently rejected a call from the House of Commons health and social care select committee1 for NHS Digital to immediately withdraw from a memorandum of understanding with the Home Office that allows personal details to be shared, including a patient’s address and date of birth. This led to the chair and chief executive of NHS Digital being summoned to give further evidence to the committee. …
Association of soluble PD-L1 (sPD-L1) with decreased survival in metastatic melanoma.
Authors: Roxana Stefania Dronca, Susan Harrington, Mithulan Jegapragasan, Lisa A. Kottschade, Wendy Kay Nevala, Elizabeth Ann Enninga, Svetomir Markovic, Haidong Dong
Journal: Journal of Clinical Oncology (2017)

4 Background: Membrane expression of PD-L1 on tumor cells is associated with poor survival in patients with advanced malignancies including metastatic melanoma (MM). In addition, tumor-associated PD-L1 has been proposed as a predictor of response to anti-PD-1 therapy, although responses are observed in some cases of PD-L1 negative MM. We hypothesize that tumor-derived PD-L1 has additional systemic effects through the release of biologically active soluble forms of PD-L1 (sPD-L1) into the circulation, which further impedes the anti-tumor immune response and contributes to poor clinical outcomes in MM. Methods: We developed a sPD-L1 ELISA and biochemically confirmed the identity of the detected protein. We measured the levels of sPD-L1 in 276 patients with MM enrolled on 3 clinical trials who had stored pre-treatment plasma samples and 37 healthy volunteers (HV) undergoing blood donation at Mayo Clinic. We also measured sPD-L1 in baseline samples from 38 MM patients treated with anti-PD1 (pembrolizumab) 2 mg/kg every 3 weeks. ROC analysis was used to compute sPD-L1 concentration cut-off value and Wald test was used to asses the difference of overall survival (OS) in patients with low versus high sPD-L1 concentration. Results: We found that sPD-L1 levels were significantly elevated in MM patients compared with HV (p=0.0011). Mean sPD-L1 level in MM was 1.73 ng/mL (range: 0.13-18.29) compared with 0.77 ng/mL (range: 0.11–6.02) for HV. Patients with higher levels (&gt;0.293 ng/mL) had a median OS of 11.3 months compared to 14.8 months for patients with sPD-L1 level ≤ 0.293 ng/mL (p=0.040). Similarly to tumor-related PD-L1 findings, patients who had clinical benefit (OR/PR/SD) after 4 cycles of anti-PD1 had higher sPD-L1 levels at baseline (2.1 vs. 1.1 ng/mL). Conclusions: To our knowledge, our study is the first to report a correlation of sPD-L1 with MM patient outcome, although a larger study is needed to establish the utility of sPD-L1 as an independent prognostic and possibly predictive biomarker.
GRM1 to induce M-CSF and CCL2 expression to lead to an upregulation of M2 macrophages in melanoma.
Authors: Jiadong Li, Yu Wen, Byeong-Seon Jeong, Raj Shah, Allison Isola, Ann W. Silk, Suzie Chen, James Steven Goydos
Journal: Journal of Clinical Oncology (2017)

122 Background: GRM1 transgenic mice in an immune competent background (C57BL6) develope melanoma with 100% penetrance (TG-3 mice). Ectopic expression of GRM1 in immortalized mouse melanocytes (MelanA) produce cells (MASS20) that are tumorigenic in both SCID and immune competent C57BL6 mice. We have examined the downstream events of GRM1 signaling that allow transformed cells to evade immune destruction. Methods: Cytokine antibody arrays and Western blot were used to examine differences in cytokine expression between MASS20 cells and parental controls. Next, we cultured C57BL6 bone marrow cells in MASS20 conditioned medium for 24 and 48 hours and determined resultant M2 macrophage levels. Finally, we used oral weekly liposome clodronate (LC) treatment to deplete macrophages in murine models to determine the effect on tumor growth. Results: MASS20 cells produce higher levels of M-CSF and CCL2 as compared with control cells. These two cytokines recruit and induce the polarization of tumor associated macrophages (TAM) to increase the M2 fraction resulting in accelerated tumor progression. Culturing C57BL6 bone marrow cells in MASS20 conditioned medium increased expression of the M2 macrophage marker arginase1 at both time points. Weekly oral LC treatment to C57BL6 mice greatly inhibited the growth of MASS20 tumors as compared to growth in control animals. Single-cell suspensions of spleen and tumor cells from these animals were subjected to flow cytometry and showed that LC treatment depleted macrophages by 90% in the spleen, and increased the percentage of cd8+T and cd335+ NK cells in tumors from treated mice as compared to controls. Finally, we treated TG-3 transgenic mice with weekly oral LC and found that treated animals still developed tumors, but progression was greatly slowed, and survival greatly prolonged, compared to untreated animals. Within 1 week of stopping LC in the treated animals there was rapid growth of the tumors. These findings suggest a link between GRM1-signal transduction and TAM-induced suppression of tumor-immunity in melanoma. Conclusions: We conclude that GRM1-induced suppression of tumor immunity occurs through induction of M2 macrophages in the tumor microenvironment.
Immunosenescence and cancer immunotherapy.
Authors: Graham P. Pawelec
Journal: Journal of Clinical Oncology (2017)

42 Background: Geriatric oncology, important for the ever-increasing numbers of elderly cancer patients, has thus far focused primarily on tolerance to chemotherapy. With the advent of breakthrough immunomodulatory antibody treatments relying on the patient´s own immune system to control the tumor, the issue of immunosenescence becomes extremely important. There is increasingly a valid concern that anti-cancer immunity may be compromised in the elderly due to i) their low amounts of naïve T-cells (leading to holes in the repertoire for neoantigens) and ii) “exhaustion” of potentially tumor-specific memory T-cells. Encouragingly, but only anecdotally, accumulated clinical experience (thus far, limited to melanoma treated with anti-CTLA-4 antibodies) suggests that advanced aged does not result in decreased responses or increased side effects. However, the fraction of patients experiencing clinical benefit was low, and broader and more detailed studies focusing on the age question are required. Methods: In our own work, we have established prognostic phenotypic and functional “immune signatures” using peripheral blood from younger melanoma and breast cancer patients, which comprise phenotypic T-cell and myeloid-derived suppressor cell quantification and measurement of pro- and anti-inflammatory CD4+ and CD8+ T-cell responses to shared tumor antigens such as NY-ESO-1 and Her2 in vitro using intracytoplasmic flow cytometry to detect 6 cytokines simultaneously. Results: We found that these peripheral immune signatures were equally prognostic in older patients ( &gt; 80 years of age). Conclusions: We therefore conclude that immunosenescence should not be a barrier to anti-tumor immunity in elderly people treated with immunomodulatory antibodies, at least for responses targeting shared tumor antigens. It remains to be established whether responses to tumor neoantigens are compromised by immunosenescence. Given the current emphasis on neoantigen responsiveness, this remains a concern.
Estimating the health and economic effects of the proposed US Food and Drug Administration voluntary sodium reformulation: Microsimulation cost-effectiveness analysis
Authors: Jonathan Pearson-Stuttard, Chris Kypridemos, Brendan Collins, Dariush Mozaffarian, Yue Huang, Piotr Bandosz, Simon Capewell, Laurie Whitsel, Parke Wilde, Martin O’Flaherty, Renata Micha
Journal: PLoS Medicine (2018)

Background Sodium consumption is a modifiable risk factor for higher blood pressure (BP) and cardiovascular disease (CVD). The US Food and Drug Administration (FDA) has proposed voluntary sodium reduction goals targeting processed and commercially prepared foods. We aimed to quantify the potential health and economic impact of this policy. Methods and findings We used a microsimulation approach of a close-to-reality synthetic population (US IMPACT Food Policy Model) to estimate CVD deaths and cases prevented or postponed, quality-adjusted life years (QALYs), and cost-effectiveness from 2017 to 2036 of 3 scenarios: (1) optimal, 100% compliance with 10-year reformulation targets; (2) modest, 50% compliance with 10-year reformulation targets; and (3) pessimistic, 100% compliance with 2-year reformulation targets, but with no further progress. We used the National Health and Nutrition Examination Survey and high-quality meta-analyses to inform model inputs. Costs included government costs to administer and monitor the policy, industry reformulation costs, and CVD-related healthcare, productivity, and informal care costs. Between 2017 and 2036, the optimal reformulation scenario achieving the FDA sodium reduction targets could prevent approximately 450,000 CVD cases (95% uncertainty interval: 240,000 to 740,000), gain approximately 2.1 million discounted QALYs (1.7 million to 2.4 million), and produce discounted cost savings (health savings minus policy costs) of approximately $41 billion ($14 billion to $81 billion). In the modest and pessimistic scenarios, health gains would be 1.1 million and 0.7 million QALYS, with savings of $19 billion and $12 billion, respectively. All the scenarios were estimated with more than 80% probability to be cost-effective (incremental cost/QALY < $100,000) by 2021 and to become cost-saving by 2031. Limitations include evaluating only diseases mediated through BP, while decreasing sodium consumption could have beneficial effects upon other health burdens such as gastric cancer. Further, the effect estimates in the model are based on interventional and prospective observational studies. They are therefore subject to biases and confounding that may have influenced also our model estimates. Conclusions Implementing and achieving the FDA sodium reformulation targets could generate substantial health gains and net cost savings.
Impact of Next-Generation Sequencing on Treatment Choices for Patients with Acute Myeloid Leukemia
Authors: Ana Alfonso Pierola, Rita Assi, Devendra Kc, Yasmin Abaza, Abdallah Abou Zahr, Kamal Chamoun, Guillermo Montalban-Bravo, Koichi Takahashi, Elias J. Jabbour, Tapan Kadia, Farhad Ravandi, Jorge E. Cortes, Courtney D. DiNardo, Naval Daver, Gautam Borthakur, Naveen Pemmaraju, Marina Konopleva, Carlos E. Bueso-Ramos, Keyur P. Patel, Andrew Futreal, Sherry Pierce, Hagop M. Kantarjian, Guillermo Garcia-Manero
Journal: Blood (2017)
Inorganic kernel - Supported asymmetric hybrid vesicles for targeting delivery of STAT3-decoy oligonucleotides to overcome anti-HER2 therapeutic resistance of BT474R
Authors: Kai Shi, Yan Fang, Shan Gao, Dongjuan Yang, Hongshu Bi, Jianxiu Xue, Anqi Lu, Yuai Li, Liyuan Ke, Xiaojie Lin, Xuechao Jin, Min Li
Journal: Journal of Controlled Release (2018)
Zika Virus Shedding in Semen of Symptomatic Infected Men
Authors: Paul S. Mead, Nisha K. Duggal, Sarah A. Hook, Mark Delorey, Marc Fischer, Dana Olzenak McGuire, Heidi Becksted, Ryan J. Max, Michael Anishchenko, Amy M. Schwartz, Wen-Pin Tzeng, Christina A. Nelson, Erin M. McDonald, John T. Brooks, Aaron C. Brault, Alison F. Hinckley
Journal: New England Journal of Medicine (2018)

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has been linked to adverse birth outcomes. Previous reports have shown that person-to-person transmission can occur by means of sexual contact.We conducted a prospective study involving men with symptomatic ZIKV infection to determine the frequency and duration of ZIKV shedding in semen and urine and to identify risk factors for prolonged shedding in these fluids. Specimens were obtained twice per month for 6 months after illness onset and were tested by real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay for ZIKV RNA and by Vero cell culture and plaque assay for infectious ZIKV.A total of 1327 semen samples from 184 men and 1038 urine samples from 183 men were obtained 14 to 304 days after illness onset. ZIKV RNA was detected in the urine of 7 men (4%) and in the semen of 60 (33%), including in semen samples from 22 of 36 men (61%) who were tested within 30 days after illness onset. ZIKV RNA shedding in semen decreased substantially during the 3 months after illness onset but continued for 281 days in 1 man (1%). Factors that were independently associated with prolonged RNA shedding included older age, less frequent ejaculation, and the presence of certain symptoms at the time of initial illness. Infectious ZIKV was isolated from 3 of 78 semen samples with detectable ZIKV RNA, all obtained within 30 days after illness onset and all with at least 7.0 log10 ZIKV RNA copies per milliliter of semen.ZIKV RNA was commonly present in the semen of men with symptomatic ZIKV infection and persisted in some men for more than 6 months. In contrast, shedding of infectious ZIKV appeared to be much less common and was limited to the first few weeks after illness onset. (Funded by the Centers for Disease Control and Prevention.).
Cost‐effectiveness of antiviral treatment after resection in hepatitis B virus–related hepatocellular carcinoma patients with compensated cirrhosis
Authors: Li Xie, Juan Yin, Ruyi Xia, Guihua Zhuang
Journal: Hepatology (2018)

Hepatocellular carcinoma (HCC) imposes a heavy disease burden on China due to its high morbidity and mortality. China accounts for about 50% of the total new cases and deaths worldwide. Most cases are related to hepatitis B virus (HBV) infection and are associated with cirrhosis at diagnosis. Antiviral treatment with nucleos(t)ide analogues (NAs) after resection in HBV‐related HCC can reduce recurrence and improve survival. Such treatment is in fact recommended by Chinese guidelines. However, cost‐effectiveness studies regarding this treatment are rare. The objective of this study was to estimate the cost‐effectiveness of NA treatment after resection in HBV‐related HCC patients with compensated cirrhosis. A Markov model was constructed to simulate HBV‐related HCC patients with compensated cirrhosis and detectable HBV DNA, with or without NA treatment after resection, followed up over their lifetime. Costs, life expectancy, quality‐adjusted life‐years (QALYs), and incremental cost‐effectiveness ratios (ICER) were calculated for each strategy from the societal perspective. The parameters of the model were derived from published studies, government documents, and our surveys. Sensitivity analyses were used to explore the impact of parameters on the uncertainty of the results. NA treatment produced 4.22 QALYs, costing $39,898, while non‐NA treatment achieved 2.80 QALYs, costing $16,048. The ICER of NA treatment versus non‐NA treatment was $16,848/QALY, which was between 2 and 3 times gross domestic product per capita and was therefore deemed cost‐effective. Probabilistic sensitivity analysis confirmed that NA treatment was cost‐effective, with a probability of 0.852. Conclusion : NA treatment after liver resection was likely cost‐effective in HBV‐related HCC patients with compensated cirrhosis. (H epatology 2018).
PTU-048 Direct access bidirectional endoscopy for iron deficiency anaemia
Authors: M Saunders, K Cross, A Davis, A Moran
Journal: Gut (2017)

Introduction  Direct access endoscopy can provide a timely and efficient service. Since 2011 we have provided a direct access bidirectional endoscopy (BDE) service for iron deficiency anaemia (IDA) in our local catchment area. Inclusion criteria are age 50–79 years (and postmenopausal if female), ferritin ≤20 ng/ml, haemoglobin ≤13 g/dl for men and ≤11 g/dl for women. Exclusion criteria are too frail for full bowel prep or colonoscopy, IDA previously investigated, known active inflammatory bowel disease, known coeliac disease or positive tissue transglutaminase antibody result. Haemoglobin and ferritin results are checked before accepting the referral and BDE is performed within 2 weeks.  Method  To analyse the uptake and effectiveness of our local direct access BDE pathway for IDA.  All patients having same day BDE for the indication of anaemia were retrospectively identified using the endoscopy database over a 3 month period. Prior haemoglobin and ferritin were documented and clinic follow ups identified via an electronic patient record database.  Results  51 patients were identified as having BDE for anaemia over the study period. 27 had BDE via the open access pathway, age range 55–79, haemoglobin range 67–122 g/dl for men, haemoglobin range 64–110 g/dl for women and ferritin range was 3–22 ng/ml. All had distal duodenal biopsies performed. Only three of these 27 patients were subsequently seen in the local gastroenterology clinics over a one year follow up period; one had coeliac disease, one had ulcerative colitis and one had cancer. One patient had a repeat gastroscopy to check for ulcer healing.  There were 24 patients that had BDE via secondary care referral and five were >80 years and three were   Conclusion  Our mature direct access BDE service for IDA is highly utilised by primary care practitioners with over 90% of patients fulfilling the inclusion criteria (and without complicating factors) being referred via this pathway. Only 3 of the 27 patients having direct access BDE for IDA were subsequently seen in the local gastroenterology clinics over a one year follow up period. The results demonstrate a timely and efficient direct access BDE service for IDA.  Disclosure of Interest  None Declared
Precision Targeted Therapy with BLU-667 for <i>RET</i>-Driven Cancers
Authors: Vivek Subbiah, Justin F. Gainor, Rami Rahal, Jason D. Brubaker, Joseph L. Kim, Michelle Maynard, Wei Hu, Qiongfang Cao, Michael P. Sheets, Douglas Wilson, Kevin J. Wilson, Lucian DiPietro, Paul Fleming, Michael Palmer, Mimi I. Hu, Lori Wirth, Marcia S. Brose, Sai-Hong Ignatius Ou, Matthew Taylor, Elena Garralda, Stephen Miller, Beni Wolf, Christoph Lengauer, Timothy Guzi, Erica K. Evans
Journal: Cancer Discovery (2018)

The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting.Significance: Patients with RET-driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with RET mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with RET-altered tumors, clinically validating selective RET targeting. Cancer Discov; 8(7); 836-49. ©2018 AACR.See related commentary by Iams and Lovly, p. 797This article is highlighted in the In This Issue feature, p. 781.