tbuckley/cabot-search huggingface dataset:
A Phase I Clinical Trial of AZD1775 in Combination with Neoadjuvant Weekly Docetaxel and Cisplatin before Definitive Therapy in Head and Neck Squamous Cell Carcinoma
Authors: Eduardo Méndez, Cristina P. Rodriguez, Michael C. Kao, Sharat Raju, Ahmed Diab, R. Alex Harbison, Eric Q. Konnick, Ganesh M. Mugundu, Rafael Santana-Davila, Renato Martins, Neal D. Futran, Laura Q.M. Chow
Journal: Clinical Cancer Research (2018)

Purpose: The WEE1 tyrosine kinase regulates G2-M transition and maintains genomic stability, particularly in p53-deficient tumors which require DNA repair after genotoxic therapy. Thus, a need arises to exploit the role of WEE1 inhibition in head and neck squamous cell carcinoma (HNSCC) mostly driven by tumor-suppressor loss. This completed phase I clinical trial represents the first published clinical experience using the WEE1 inhibitor, AZD1775, with cisplatin and docetaxel.Patients and Methods: We implemented an open-label phase I clinical trial using a 3+3 dose-escalation design for patients with stage III/IVB HNSCC with borderline-resectable or -unresectable disease, but who were candidates for definitive chemoradiation. Escalating AZD1775 was administered orally twice a day over 2.5 days on the first week, then in combination with fixed cisplatin (25 mg/m2) and docetaxel (35 mg/m2) for 3 additional weeks. The primary outcome measure was adverse events to establish MTD. Secondary measures included response rates, pharmacokinetics (PK), pharmacodynamics, and genomic data.Results: The MTD for AZD1775 was established at 150 mg orally twice per day for 2.5 days. RECISTv1.1 responses were seen in 5 of 10 patients; histologic adjustment revealed three additional responders. The only drug-limiting toxicity was grade 3 diarrhea. The PK C8hr target of 240 nmol/L was achieved on day 4 at all three doses tested. Pharmacodynamic analysis revealed a reduction in pY15-Cdk, and increases in γH2AX, CC3, and RPA32/RPA2 were noted in responders versus nonresponders.Conclusions: The triplet combination of AZD1775, cisplatin, and docetaxel is safe and tolerable. Preliminary results show promising antitumor efficacy in advanced HNSCC, meriting further investigation at the recommended phase II dose. Clin Cancer Res; 24(12); 2740-8. ©2018 AACR.
Abstract P3-14-08: The impact of a structured surveillance protocol using bioimpedance spectroscopy (BIS) on preventing breast cancer related lymphedema (BCRL) in high-Risk patients
Authors: P Whitworth, A Cooper, C Shah, F Vicini
Journal: Cancer Research (2018)

Abstract Background: We evaluated the impact of structured surveillance using bioimpedance spectroscopy (BIS) to prevent clinical BCRL in a group of high-risk (axillary lymph node dissection) patients. Methods: From April 2010 through November 2016, 93 patients who were treated with axillary lymph node dissection (ALND) were prospectively monitored with BIS using L-Dex (Impedimed). Patients received a pre-operative baseline L-Dex measurement followed by post-operative assessments at regular intervals. An elevated L-Dex score was defined as an increase of ≥10 points above baseline (considered subclinical BCRL). Intervention consisted of applying an over the counter (OTC) sleeve for 4 weeks followed by re-evaluation. The need for complete decongestive physiotherapy (CDP) represented a surrogate for the development of clinically significant, chronic BCRL. Results: Median follow-up was 24 months (range: 0.3-206.4 months). The median number of nodes removed was 19 (range: 5-41) and the median number of positive nodes was 3. Median age was 53 years old. Eighty five percent of patients underwent mastectomy and the remainder breast conserving therapy. 55% of patients received taxane based chemotherapy, 24% received some form of axillary RT (15% high tangents and 9% comprehensive regional nodal RT) and 74% had an elevated body mass index (BMI, &amp;gt; 25). Overall, 75% of these patients had at least one additional high-risk feature, 48% had at least two, and 6% had 3 (either taxane chemotherapy, axillary RT or elevated BMI). Thirty-three patients (35.4%) developed an elevated L-Dex score at some point during follow up. Overall, 10 patients (11%) required CDP at any point after treatment. Conclusions: The results of this analysis support previously published data on the efficacy of prospective BCRL surveillance and early intervention using BIS. Of the 93 high-risk patients prospectively followed and managed in this structured BCRL protocol, 11% required CDP. These results compare favorably to all contemporary studies reporting BCRL rates in high-risk patients. Citation Format: Whitworth P, Cooper A, Shah C, Vicini F. The impact of a structured surveillance protocol using bioimpedance spectroscopy (BIS) on preventing breast cancer related lymphedema (BCRL) in high-Risk patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-08.
Abstract P1-04-01: A novel oncolytic herpes simplex virus, GD116, has enhanced antitumour efficacy in human breast cancer
Authors: L Cheng, J Wang, R Liu
Journal: Cancer Research (2018)

Abstract Background: Oncolytic herpes simplex virus-1 (oHSV-1) vectors are promising new therapeutic agents for cancer. For the nuerovirulence of ICP34.5 protein, the encoding gene named γ34.5 is deleted in all oHSV-1 mutants currently in clinical trials. However, the deletion of γ34.5 also promotes the interferon-induced shutoff of virual protein synthesis, and attenuates the virus replication in cancer cells at the same time. Previous studies reported that the carboxyl-terminus of MyD116/GADD34 was homologous to that of γ34.5 gene; hence, it might substitute for γ34.5 gene to enhance the replication and cytotoxicity of the virus. Objective: To reconstruct a novel oHSV-1 mutant named GD116 by inserting γ34.5-MyD116 chimeric gene into G47Δ genome, and to investigate whether the carboxyl-terminus of murine MyD116 can enhance the antitumour efficacy of GD116 on human breast cancer cell line in vitro and in vivo. Methods: Using G47Δ genome and bacterial artificial chromesome (BAC) as the backbone, the GD116 virus expressing γ34.5-MyD116 was reconstructed via Cre/loxp and FLP/FRT recombinase systems. A GD-empty virus mutant containing only the CMV sequence was also constructed as a control at the same time. Then, the replication and cytotoxicity of these two virus mutants in MDA-MB-231 humanbreast cancer cell line was evaluated in vitro. Meanwhile, the subcutaneous tumor model was also generated by injecting MDA-MB-231 cells into the right flank of BALB/c mice. Then, the antitumor efficacy of GD116 on breast cancer in vivo was evaluated by intratumoral injection. Results: Compared with GD-empty, GD116 possessed an enhanced replication capability and oncolytic efficacy in MDA-MB-231 cell line. On the fifth day after infection with GD116 at MOIs of 0.1 and 0.3, 35.0% and 50.2% of MDA-MB-231 cells were killed respectively, which were higher than that with GD-empty (24.3% and 37.8%). Additionally, GD116 exhibited enhanced antitumor efficacy on subcutaneous tumor xenografts of human breast cancer cells in vivo compared with GD-empty. On day 21 after treatment, the average tumor volume of mice was 585.5 mm3, 289.0 mm3 and 121.9 mm3 in Control, GD-empty and GD116 group respectively. Conclusion: Our findings indicate that the carboxyl-terminus of the murine MyD116 can substitute for the corresponding domain of the γ34.5 gene in oHSV-1 to promote the replication of the virus in infected cancer cells; and the mutant GD116 armed with γ34.5-MyD116 chimaera has enhanced oncolytic effect on MDA-MB-231 breast cancer cells in vitro and in vivo. Citation Format: Cheng L, Wang J, Liu R. A novel oncolytic herpes simplex virus, GD116, has enhanced antitumour efficacy in human breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-04-01.
David Oliver: What’s wrong with acute “zero day admissions”?
Authors: David Oliver
Journal: BMJ (2018)

Emergency admissions in England now cost around £13.7bn, around 10% of the entire NHS budget, the National Audit Office (NAO) has reported.12 In 2016-17, 5.8 million people were acutely admitted to hospital: emergency admissions have risen by around 2% a year since 2013-14 despite considerable efforts to reduce them.

Some 79% of that increase was in patients who did not stay overnight, the NAO reported. These patients were admitted and discharged on the same day, without needing to be transferred to an overnight ward, and are often referred to as “zero day admissions.” They increased by 27% from 2013-14 to …
An analysis of multiple biomarkers to better predict prostate cancer metastasis and death after radical prostatectomy.
Authors: Alison Yan Zhang, Karen Chiam, Ygal Haupt, Stephen B. Fox, Simone Birch, Wayne Tilley, Lisa Butler, Karen E. Knudsen, Christopher Cornstock, Krishan Rasiah, Judith Grogan, Kate Lynette Mahon, Tina Bianco-Miotto, Maret Bohm, Susan M. Henshall, Warick Delprado, Phillip Stricker, Lisa Horvath, James Kench
Journal: Journal of Clinical Oncology (2018)

54 Background: Identification of potentially lethal disease at the time of diagnosis with localized prostate cancer (PCa) remains a significant clinical issue despite a plethora of candidate biomarkers. This study evaluates a range of biomarkers previously associated with biochemical relapse (BR) in localized PCa to determine whether a combined expression model can improve detection of clinically significant cases. Methods: The Australian PCa Research Centre NSW has completed 23 studies of molecular biomarkers associated with BR in a well-described localized PCa cohort (n=324, median followup 16 years). 12 studies were excluded due to missing data. Each biomarker was analyzed as a marker for metastatic-free survival (MFS) and prostate cancer specific survival (PCSS) and then used to develop a prognostic model for clinical outcomes incorporating clinico-pathological factors. This model is currently being validated in an independent cohort. Results: The PCa cohort experienced 39 metastatic relapses (12%) and 23 PCa deaths (7%). Of 12 biomarkers (AR, AZPG1, C0S, Cyclin D1a, Cyclin D1b, E6AP, H3K18Ac, H3K4me2, Ki67, p53, PML, SGTA) assessed, only AZGP1 and Ki67 were associated with MFS (HR 2.9, 95% CI, 1.4-5.6; P=0.002, and HR 1.2, 95% CI, 1.0-1.4; P=0.03, respectively) and PCSS (HR 4.2, 95% CI, 1.7-10.5; P=0.002; and HR 1.2, 95% CI, 1.0-1.5; P=0.04, respectively). The combined panel of AZGP1 and Ki67 was an independent predictor of MFS (HR 1.9, 95% CI, 1.1-3.2; P=0.01), and PCSS (HR 3.3, 95% CI, 1.5-7.3; P=0.002) when modeled with known clinicopathological variables. The panel was more robust in predicting MFS and PCSS compared to the individual biomarkers alone and superior to other prognostic models (See table). Data from the validation cohort will be available for the meeting. Conclusions: Our novel signature of AZPG1 and Ki67 improves existing prognostication tools in predicting PCa metastasis and death. [Table: see text]
Stem Cell Transplantation for Light Chain Amyloidosis: Decreased Early Mortality Over Time
Authors: M Hasib Sidiqi, Mohammed A. Aljama, Francis K. Buadi, Rahma M. Warsame, Martha Q. Lacy, Angela Dispenzieri, David Dingli, Wilson I. Gonsalves, Shaji Kumar, Prashant Kapoor, Taxiarchis Kourelis, William J. Hogan, Morie A. Gertz
Journal: Journal of Clinical Oncology (2018)

Purpose Autologous stem-cell transplantation (ASCT) has been used in patients with immunoglobulin light chain (AL) amyloidosis for more than two decades. Early experience raised concerns regarding safety with high early-mortality rates. Patients and Methods We report 20 years of experience with ASCT for AL amyloidosis at the Mayo Clinic Rochester. In all, 672 consecutive patients receiving ASCT for AL amyloidosis were divided into three cohorts on the basis of date of transplantation (cohort 1, 1996-2002 [n = 124]; cohort 2, 2003-2009 [n = 302]; and cohort 3, 2010-2016 [n = 246]). Results The median age for the entire cohort was 59 years, with patients in cohort 3 being slightly older than those in the other two cohorts (60 v 58 v 54 years for cohorts 3, 2, and 1, respectively; P < .001). Fewer patients in cohort 3 had more than two organs involved (9% v 18% v 19% for cohorts 3, 2, and 1, respectively; P < .001). More patients received pretransplantation therapy in cohort 3 compared with earlier time periods (49% v 38% v 42% for cohorts 3, 2, and 1, respectively; P = .02). Hematologic response was higher in cohort 3 (84% v 79% v 69% for cohorts 3, 2, and 1, respectively; P = .002). Median overall survival for the entire cohort was 122 months and improved over time (not reached v 120 months v 75 months for cohorts 3, 2, and 1, respectively; P < .001). Treatment-related mortality declined over time (2.4% v 8.6% v 14.5% for cohorts 3, 2, and 1, respectively; P < .001). On multivariable analysis, conditioning dose, Mayo stage 2012, and hematologic response were independent predictors of survival. Conclusion ASCT is a highly effective therapy for AL amyloidosis. The improved survival and markedly reduced treatment-related mortality in eligible patients indicate that this will remain an important first-line option even in the era of treatment approaches that use novel agents.
CQC will charge at least £550 for general practices to register
Authors: Caroline White
Journal: BMJ (2012)

The Care Quality Commission (CQC) is considering levying fees starting from £550 for the roughly 8300 general practices and other primary care providers expected to register with it from next April.

In its revised annual fee scale for registered providers, currently out to consultation, the regulator proposed charging providers of primary medical services that have one location between £550 and £850, depending on list size. Providers of primary medical services with more than one location could pay between £1200 and £16 000 for 2013-14.

The …
Synergistic effects of PARP inhibitors and ionizing radiation on growth and survival of rhabdomyosarcoma cells
Authors: F. Megiorni, S. Camero, S. Ceccarelli, F. De Felice, F. Marampon, B. Pizer, R. Shukla, V. Tombolini, C. Marchese, C. Dominici
Journal: Annals of Oncology (2018)
Ten year treatment outcomes of radical prostatectomy vs external beam radiation therapy vs. brachytherapy for 1,503 patients with intermediate risk prostate cancer.
Authors: Barry W. Goy, Margaret S. Soper, Raoul J. Burchette, Tangel C. Chang, Harry A. Cosmatos
Journal: Journal of Clinical Oncology (2018)

47 Background: To compare 10-year treatment outcomes of RP (radical prostatectomy) vs EBRT (external beam radiation therapy) vs BT (brachytherapy) for patients with IRPC (intermediate risk prostate cancer). Methods: A retrospective analysis using propensity score matching was performed on 1,503 IRPC patients who underwent treatment from 2004 to 2007. 819 underwent RP, 574 underwent EBRT to a median dose of 75.3 Gray, and 110 underwent BT using iodine-125. Biochemical failure was defined by the AUA (American Urological Association) definition of PSA (prostate specific antigen) failure for RP patients, and the ASTRO-Phoenix definition (American Society of Therapeutic Radiology and Oncology) for the EBRT and BT patients. Results: Median follow up was 10 years for RP, 9.6 for EBRT, and 9.8 for BT (range 1-13.4 years). With RP 76.3% had Gleason score 7 vs 72.8% for EBRT vs 57.3% for BT, p = 0.0001. Median initial PSA was 7.4 for RP, 9.4 for EBRT, and 8.3 for BT, p &lt; 0.0001. Neoadjuvant androgen deprivation therapy was given in 58.9% of EBRT patients vs 12.7% of BT vs 0.6% for RP, p &lt; 0.0001. Only 14% of BT received supplemental external radiation. The 10-year FFBF (freedom from biochemical failure) was 82.0% for BT vs 58.0% for RP vs 58.8% for EBRT, p &lt; 0.0001. Subset analysis of unfavorable IRPC patients showed a 10 year FFBF of 81.6% for BT vs 55.8% for RP vs 51.0% for EBRT, p &lt; 0.0001. The 10-year freedom from salvage therapy was 89.5% for BT vs 64.0% for RP vs 73.4% for EBRT, p &lt; 0.0001. There were no significant differences in distant metastases-free survival, prostate cancer-specific survival, or overall survival after adjusting for age. Multivariate analysis between pairwise groups with BT balanced by stabilized inverse probability of treatment weights showed that BT remained an independent predictor for improved FFBF, p = 0.049 for BT vs EBRT, and p &lt; 0.0001 for BT vs RP. Conclusions: Brachytherapy using iodine-125 is a reasonable treatment option for IRPC patients. Although BT showed improved FFBF after propensity score matching, this did not impact overall survival.
Khat chewing increases the risk for developing chronic liver disease: A hospital‐based case–control study
Authors: Stian Magnus Staurung Orlien, Irene Sandven, Nega Belay Berhe, Nejib Yusuf Ismael, Tekabe Abdosh Ahmed, Kathrine Stene‐Johansen, Svein Gunnar Gundersen, Marsha Yvonne Morgan, Asgeir Johannessen
Journal: Hepatology (2018)

The chewing of the leaves of Catha edulis (khat) has been implicated in the development of liver disease, but no controlled observations have been undertaken. The objective of the present study was to determine whether khat chewing is associated with development of chronic liver disease (CLD). A case-control study was conducted at two public hospitals in Harar, Ethiopia, between April 2015 and April 2016. A consecutive sample of 150 adult hospital attendees with CLD were included as cases, and 300 adult hospital attendees without clinical or laboratory evidence of CLD were included as controls. Khat consumption was quantified in "khat years"; 1 khat year was defined as daily use of 200 g of fresh khat for 1 year. A logistic regression model was used to control for confounders. There was a significant association between chewing khat and the risk for developing CLD (crude odds ratio, 2.64; 95% confidence interval [CI], 1.56-4.58). In men, this risk, following adjustment for age, alcohol use, and chronic hepatitis B/C infection, increased with increasing khat exposure; thus, compared to never users the adjusted odds ratios were for low khat exposure 3.58 (95% CI 1.05-12.21), moderate khat exposure 5.90 (95% CI 1.79-19.44), and high khat exposure 13.03 (95% CI 3.61-47.02). The findings were robust in a post hoc sensitivity analysis in which individuals with identifiable risk factors for CLD were excluded.A significant association was observed between chewing khat and the risk for developing CLD, and in men the association was strong and dose-dependent, suggesting a causal relationship; as the prevalence of khat chewing is increasing worldwide, these findings have major public health implications. (Hepatology 2018;68:248-257).
THE EFFECT OF A COMPREHENSIVE CARDIOVASCULAR RISK REDUCTION PROGRAM ON HEALTH-RELATED QUALITY OF LIFE AND FITNESS AMONG WOMEN WITH BREAST CANCER RECEIVING POTENTIALLY CARDIOTOXIC CHEMOTHERAPY
Authors: Michael Fradley, Marcus Kilpatrick, Bernadette Shields, Nhi Tran, Amey Sanders, Erika Bianco, Kevin Kip, Bonnie KIrby, Natasha Wick, Merna Armanious, Kyeesha Becoats, Theresa Beckie, Roohi Ismail-Khan
Journal: Journal of the American College of Cardiology (2018)
Re: Nicola Fossati, Peter-Paul M. Willemse, Thomas Van den Broeck, et al. The Benefits and Harms of Different Extents of Lymph Node Dissection During Radical Prostatectomy for Prostate Cancer: A Systematic Review. Eur Urol 2017;72:84–109
Authors: Noel W. Clarke
Journal: European Urology (2017)
Abiraterone or docetaxel in men with metastatic castration-sensitive prostate cancer: A pooled analysis of castration resistance-free survival and toxicity.
Authors: Joelle Helou, Charles N Catton, Glenn Bauman, Rouhi Fazelzad, Jacques Raphael
Journal: Journal of Clinical Oncology (2018)

354 Background: Recent meta-analyses suggested an improvement in overall survival (OS) with the addition of Abiraterone (A) vs Docetaxel (D) to androgen deprivation therapy (ADT) in the treatment of men with metastatic castration-sensitive prostate cancer. However, none have reported castration resistance-free survival (CFS) and toxicity data; two clinically relevant outcomes for physicians and patients. Methods: We conducted a systematic review and meta-analysis to assess CFS and toxicity of adding A or D to ADT in men with castration-sensitive prostate cancer. The electronic databases Ovid MEDLINE, Cochrane Central Register of Controlled Trials and EMBASE, were searched for randomized controlled trials. Pooled hazard ratios (HR) for CFS, and pooled risk ratios (RR) for grade 3 or higher toxicity were analyzed using the Mantel-Haenszel method and generic inverse variance. To account for between-studies heterogeneity, random-effect models were used to compute pooled estimates. Subgroup analyses compared patients on A and D in terms of CFS. Results: Five studies were included. The addition of A or D to ADT decreased the risk of development of castration-resistance by 53% (5 studies, 4,462 participants, HR = 0.47, 95% CI 0.33-0.67). In a subgroup analysis, the addition of A seemed to be better than D for the outcome CFS (5 studies, HR = 0.31, 95% CI 0.27-0.34 versus HR = 0.62, 95% CI 0.56-0.69, test for subgroup difference, p&lt; 0.001). Different profiles of toxicity were seen with A and D. While A increased the risk of hypokalemia (3,107 participants, HR = 6.63, 95% CI 3.5-12.5) and cardiac toxicity (3,107 participants, HR = 2.4, 95% CI 1.7-3.3), D increased the risk of neutropenia (2,151 participants, HR = 13, 95% CI 8.9-18.8) and neuropathy (2,151 participants, HR = 2.25, 95% CI 1.18-4.3). Conclusions: The addition of A and D to ADT increases CFS in men with castration-sensitive prostate cancer, with a longer CFS noted for A compared to D. Considering CFS and OS, A may be preferred to D as initial therapy. Toxicity profiles differed between A and D. Quality of life and cost differences between A and D are other important factors and were not considered in this analysis.
Infection with enteric pathogens<i>Salmonella typhimurium and Citrobacter rodentium</i>modulate TGF-beta/Smad signaling pathways in the intestine
Authors: Yong-Guo Zhang, Megha Singhal, Zhijie Lin, Christopher Manzella, Anoop Kumar, Waddah A. Alrefai, Pradeep K. Dudeja, Seema Saksena, Jun Sun, Ravinder K. Gill
Journal: Gut Microbes (2018)

Salmonella and Citrobacter are gram negative, members of Enterobacteriaceae family that are important causative agents of diarrhea and intestinal inflammation. TGF-β1 is a pleiotropic multifunctional cytokine that has been implicated in modulating the severity of microbial infections. How these pathogens alter the TGF-β1 signaling pathways in the intestine is largely unknown. Streptomycin-pretreated C57BL/6J mouse model colonized with S. typhimurium for 8 hours (acute) and 4 days (chronic) infection and FVB/N mice infected with C. rodentium for 6 days were utilized. Results demonstrated an increase in TGF-β1 receptor I expression (p<0.05) in S. typhimurium infected mouse ileum at both acute and chronic post-infection vs control. This was associated with activation of Smad pathways as evidenced by increased phosphorylated (p)-Smad2 and p-Smad3 levels in the nucleus. The inhibitory Smad7 mRNA levels showed a significant up regulation during acute phase of Salmonella infection but no change at 4d post-infection. In contrast to Salmonella, infection with Citrobacter caused drastic downregulation of TGF receptor I and II concomitant with a decrease in levels of Smad 2, 3, 4 and 7 expression in the mouse colon. We speculate that increased TGF-β1 signaling in response to Salmonella may be a host compensatory response to promote mucosal healing; while C. rodentium decreases TGF-β1 signaling pathways to promote inflammation and contribute to disease pathogenesis. These findings increase our understanding of how enteric pathogens subvert specific aspects of the host-cellular pathways to cause disease.