tbuckley/cabot-search huggingface dataset:
RBM20 Mutations Induce an Arrhythmogenic Dilated Cardiomyopathy Related to Disturbed Calcium Handling
Authors: Maarten M.G. van den Hoogenhof, Abdelaziz Beqqali, Ahmad S. Amin, Ingeborg van der Made, Simona Aufiero, Mohsin A.F. Khan, Cees A. Schumacher, Joeri A. Jansweijer, Karin Y. van Spaendonck-Zwarts, Carol Ann Remme, Johannes Backs, Arie O. Verkerk, Antonius Baartscheer, Yigal M. Pinto, Esther E. Creemers
Journal: Circulation (2018)

Background: Mutations in RBM20 (RNA-binding motif protein 20) cause a clinically aggressive form of dilated cardiomyopathy, with an increased risk of malignant ventricular arrhythmias. RBM20 is a splicing factor that targets multiple pivotal cardiac genes, such as Titin (TTN) and CAMK2D (calcium/calmodulin-dependent kinase II delta). Aberrant TTN splicing is thought to be the main determinant of RBM20-induced dilated cardiomyopathy, but is not likely to explain the increased risk of arrhythmias. Here, we investigated the extent to which RBM20 mutation carriers have an increased risk of arrhythmias and explore the underlying molecular mechanism. Methods: We compared clinical characteristics of RBM20 and TTN mutation carriers and used our previously generated Rbm20 knockout (KO) mice to investigate downstream effects of Rbm20-dependent splicing. Cellular electrophysiology and Ca 2+ measurements were performed on isolated cardiomyocytes from Rbm20 KO mice to determine the intracellular consequences of reduced Rbm20 levels. Results: Sustained ventricular arrhythmias were more frequent in human RBM20 mutation carriers than in TTN mutation carriers (44% versus 5%, respectively, P =0.006). Splicing events that affected Ca 2+ - and ion-handling genes were enriched in Rbm20 KO mice, most notably in the genes CamkIIδ and RyR2. Aberrant splicing of CamkIIδ in Rbm20 KO mice resulted in a remarkable shift of CamkIIδ toward the δ-A isoform that is known to activate the L-type Ca 2+ current ( I Ca,L ). In line with this, we found an increased I Ca,L , intracellular Ca 2+ overload and increased sarcoplasmic reticulum Ca 2+ content in Rbm20 KO myocytes. In addition, not only complete loss of Rbm20, but also heterozygous loss of Rbm20 increased spontaneous sarcoplasmic reticulum Ca 2+ releases, which could be attenuated by treatment with the I Ca,L antagonist verapamil. Conclusions: We show that loss of Rbm20 disturbs Ca 2+ handling and leads to more proarrhythmic Ca 2+ releases from the sarcoplasmic reticulum. Patients that carry a pathogenic RBM20 mutation have more ventricular arrhythmias despite a similar left ventricular function, in comparison with patients with a TTN mutation. Our experimental data suggest that RBM20 mutation carriers may benefit from treatment with an I Ca,L blocker to reduce their arrhythmia burden.
Trials in progress: A phase II study of in situ therapeutic vaccination against refractory solid cancers with intratumoral poly-ICLC.
Authors: Chrisann Kyi, Rachel Lubong Sabado, Yvonne M. Saenger, William Loging, Michael J. Donovan, Deborah Lehrer, John P Mandeli, Andres M. Salazar, Philip Adam Friedlander, Nina Bhardwaj
Journal: Journal of Clinical Oncology (2017)

166 Background: Poly-ICLC, a RNA complex, can activate dendritic cells and trigger NK cells to kill tumor cells. It can be given intramuscularly (IM) to induce systemic inflammation and intratumorally (IT) to induce immune infiltration of tumors. Methods: In this phase II study, eligible subjects are head and neck, and skin cancer patients with refractory or metastatic disease. In each treatment cycle, one accessible tumor site was targeted for IT injection of 1 mg of Poly-ICLC 3 times a week for 2 weeks followed by IM boosters biweekly for 6 weeks and then a 2 week rest period. Tumor biopsies were performed at baseline, week 3, and week 26. Pre- and post-vaccination tumors were evaluated by quantitative immunohistochemistry (IHC) and RNA sequencing. Blood samples were collected at baseline and prior to each cycle for immune response evaluations. Results: A phase I pilot portion of this study showed 1 patient who achieved clinical benefit with stable disease (progression-free survival of 6 months). Poly-ICLC was well tolerated with principal side effects of fatigue and inflammation at injection site (&lt; grade 2). One case of grade 3 tumor necrosis was observed. In the patient with clinical benefit, IHC analysis of tumor showed increased CD4(60x), CD8(10x), PD-1(20x), and PD-L1(3x) compared to patients with progressive disease whose tumor biopsies showed unchanged/decreased CD4, CD8, PD-1, and PD-L1 levels over treatment period. Furthermore, RNASeq analysis of the same patient’s tumor and peripheral blood mononuclear cells (PBMC) showed dramatic changes such as upregulation of interferon-stimulated genes, chemokines, and genes associated with T cell activation and antigen presentation indicative of local and systemic immune activation in response to Poly-ICLC treatment. Conclusions: Preliminary findings show that Poly-ICLC is well tolerated in advanced solid cancer patients, and generates local immune response in tumor microenvironment and systemic immune response as evident in the patient achieving clinical benefit. These results warrant further investigation, and are currently being explored in this ongoing larger multicenter adaptive phase II clinical trial. Clinical trial information: NCT01984892.
Single-Arm Longitudinal Study to Evaluate a Decision Aid for Women Offered Neoadjuvant Systemic Therapy for Operable Breast Cancer
Authors: Nicholas Zdenkowski, Phyllis Butow, Andrew Spillane, Charles Douglas, Kylie Snook, Mark Jones, Christopher Oldmeadow, Sheryl Fewster, Corinna Beckmore, Frances M. Boyle
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: Neoadjuvant systemic therapy (NAST) is an increasingly used treatment option for women with large operable or highly proliferative breast cancer. With equivalent survival outcomes between NAST and up-front surgery, the situation-specific preference-sensitive nature of the decision makes it suitable for a decision aid (DA). This study aimed to develop and evaluate a DA for this population. Methods: A DA booklet was developed according to international standards, including information about adjuvant and neoadjuvant treatment, outcome probabilities, and a values clarification exercise. Eligible women, considered by investigators as candidates for NAST, were enrolled in a multi-institutional, single-arm, longitudinal study. Patient-reported outcome measure questionnaires were completed pre- and post-DA, between chemotherapy and surgery, and at 12 months. Outcomes were feasibility (percentage of eligible patients accessing the DA); acceptability to patients (percentage who would recommend it to others) and clinicians (percentage who would use the DA in routine practice); and decision-related outcomes. Results: From 77 eligible women, 59 were enrolled, of whom 47 (79.7%; 95% CI, 69.4–89.9) reported having read the DA; 51 completed the first post-DA questionnaire. Of these 51, 41 participants (80.4%; 95% CI, 69.5–91.3) found the DA useful for their decision about NAST. Of 18 responding investigators, 16 (88.9%; 95% CI, 74.4–103.4) indicated they would continue to use the DA in routine practice. Post-DA, decisional conflict decreased significantly (P<.01); anxiety and distress decreased significantly; and 86.3% (95% CI, 73.7–94.3) achieved at least as much decisional control as they desired. Conclusions: This DA was feasible and acceptable to patients and clinicians, and improvement in decision-related outcomes was demonstrated when used in combination with clinical consultations. This DA could safely be implemented into routine practice for women considering NAST for operable breast cancer.
Abstract 17396: Effect of Donor Troponin on Heart Transplant Outcomes: A UNOS Registry Analysis
Authors: Shivank A Madan, Omar Saeed, Daniel Sims, Jooyoung J Shin, Ileana Pina, David D'Alessandro, Daniel Goldstein, Ulrich Jorde, Snehal R Patel
Journal: Circulation (2015)

Introduction: Heart transplantation is the treatment of choice for end stage heart failure, but is limited to approximately 4000 globally every year due to donor shortage. Despite this, only one-third of the potential donor hearts are recovered for transplantation. Although elevated donor troponin levels have generally been considered a contraindication, the data supporting this practice is limited. Hypothesis: Elevated donor troponins in the presence of normal left ventricular ejection fraction (LVEF) do not impact outcomes after transplantation. Methods: All adult heart transplant recipients in the UNOS database between 2007 and 2014, with LVEF≥50%, and reported donor troponin I levels were included. The overall cohort was divided into groups based on clinically meaningful troponin I levels: below 1, 1-10, 10.1-20 and above 20 and compared for recipient survival and coronary allograft vasculopathy (CAV). Results: 11,640 transplants met the study criteria. On comparison of baseline characteristics, higher troponin groups had younger donors and greater donor CPR. Importantly, the ischemic time and proportion of recipients in the ICU and on temporary circulatory support were similar. As shown, there was no difference in survival (figure 1) or CAV (figure 2) up to 5 years of follow up using Kaplan-Meir analysis and cox-hazards ratio. After adjusting for differences in baseline covariates and clinically relevant factors, the findings remained unchanged. Conclusions: In this largest analysis to date, elevated donor troponin levels in the setting of preserved LVEF did not impact recipient survival or CAV up to 5 years of follow up. This finding can help expand the donor pool.
Total tumor burden as predictive tool of response and survival of patients with metastatic melanoma treated with nivolumab.
Authors: Milton Jose Barros e Silva, Bianca Salgado Boneti, Rafael de Moares
Journal: Journal of Clinical Oncology (2017)

48 Background: Nivolumab (NIVO) has shown increased results either in objective response rate (ORR), progression free survival (PFS) and overall survival (OS), which have completely changed the treatment of patients with metastatic melanoma (MM). Tools to guide selection of patients are absent. Methods: This is a retrospective, observational, single-center study. The TBT was calculated considering the sum of the largest diameter of all measurable lesions and the smallest diameter of lymph nodes affected. Results: 54 patients with histologiacally confirmed MM were included in the protocol (OCT/14-may/16). Patients had a median age of 61 years (22-86 years), 58% were male, and 73% of tumor were located in the skin. 42% had ECOG 1, 72% had M1c, and 36% had LDH over the upper limit of normality (ULN). 34% had the mutation of the BRAF (half of them treated with IBRAF). About 75% had no prior benefit with anti-CTLA4 and 21% of the population had brain metastases. The median follow-up was 11.1 months and the median NIVO doses was 10 cycles. The ORR was 30.2% and the clinical benefit rate was 54.7%. The median PFS was 6.89 months (95% CI 1.12 to 12.6 months) and OS was not reached. TBT being &lt; or &gt; the median impact on OS with HR 4.5 (95% CI 1.22 to 16.9; p = 0.024). Once again, there was a statistically significant difference in terms of PFS and OS when related to pooled TBT ≤ or &gt; 200 mm. The PFSm was 9.4 months (95% CI NR) for TBT ≤ 200 and 2.6 months ( 95% CI 1.9 to 3.2 months) to TBT &gt; 200, with a HR: 2.64 (95% CI 1.03 to 6.74; p = 0.042). OSm regarding TBT ≤ 200 was not reached and was 2.6 months (95% CI 2.0 to 3.2 months) to TBT &gt; 200, with RH:8.9 (95% CI 2.56 to 30.9; p = 0.001). According to the Fisher's exact test analysis, there is a significant association between LDH &gt; ULN and pooled TBT &gt; 200, with p = 0.023. Also, a relation between grouped TBT ( ≤ 200 or &gt; 200) and the type of response seemed to be significant, with p = 0.021. Conclusions: The results of our study are very consistent with current medical literature. In our study, high TBT was associated with less response rates and both less OS and PFS rates.
Radiotherapy to enhance T-cell infiltration and efficacy of PD-L1 blockade in murine orthotopic models of head and neck cancer.
Authors: Ayman Oweida, Shelby Lennon, Dylan Calame, Shilpa Bhatia, David Raben, Lynn Heasley, Raphael Nemenoff, Sana Karam
Journal: Journal of Clinical Oncology (2017)

101 Background: Cancers of the head and neck (HNC) represent some of the most debilitating and aggressive tumors. Radiotherapy (RT) is the primary treatment modality for locally advanced HNC, but less than 50% of patients treated with RT survive to 5 years. Clinical trials with the immune checkpoint inhibitor PD-L1 have shown considerable promise, but on its own has only yielded a 20% response rate. RT has the potential to transform the tumor microenvironment promoting infiltration of T-cells in poorly immunogenic tumors and activating T-cells in tumors with pre-existing T-cell populations. We hypothesized that the combination of PD-L1 inhibition with radiation can enhance therapeutic efficacy through re-invigoration of exhausted T-cells. Methods: Tumor cells were injected into the right buccal mucosa. Treatment was initiated when established tumors were observed. Forty mice per tumor model were randomized to IgG2b control, anti PD-L1, RT alone or RT+anti PD-L1. Anti PD-L1 was started 3 days before RT (single dose of 10Gy) and maintained for 3 weeks. For mechanistic studies, mice received the same treatment but were euthanized 72 hours after RT. Flow cytometric analysis of T-cell expression of PD-1, CTLA-4, FOXP3, CD44 and IFNG was performed on freshly harvested tumors and regional lymph nodes. Results: Tumor-bearing mice formed aggressive tumors with regional lymph node metastasis. Mice treated with RT or anti PD-L1 had slightly improved survival whereas mice treated with RT+anti-PD-L1 had significantly improved survival (p = 0.0007). Tumor control was significantly improved in the RT+anti-PD-L1 group compared to other groups. Anti PD-L1 alone did not improve tumor control. Average tumor volume on day 23 was 175±60.1 mm 3 in the RT+anti-PD-L1 group compared to 623±91.0 mm 3 in the PD-L1 group. Flow cytometric analysis revealed that this is mediated by enhancement in T-cell infiltration. Analysis of T-cell activation showed increased expression of CD44 and IFNG. Conclusions: Our results show a critical role for RT in mediating sensitivity to PD-L1 inhibition in HNC. In combination with anti PD-L1, RT significantly increased survival and tumor control compared to either modality alone.
Review: What Is the Current Evidence for Disease Subsets in Giant Cell Arteritis?
Authors: Kornelis S. M. van der Geest, Maria Sandovici, Yannick van Sleen, Jan‐Stephan Sanders, Nicolaas A. Bos, Wayel H. Abdulahad, Coen A. Stegeman, Peter Heeringa, Abraham Rutgers, Cees G. M. Kallenberg, Annemieke M. H. Boots, Elisabeth Brouwer
Journal: Arthritis & Rheumatology (2018)

Giant cell arteritis (GCA) is an autoimmune vasculitis affecting large and medium-sized arteries. Ample evidence indicates that GCA is a heterogeneous disease in terms of symptoms, immune pathology, and response to treatment. In the current review, we discuss the evidence for disease subsets in GCA. We describe clinical and immunologic characteristics that may impact the risk of cranial ischemic symptoms, relapse rates, and long-term glucocorticoid requirements in patients with GCA. In addition, we discuss both proven and putative immunologic targets for therapy in patients with GCA who have an unfavorable prognosis. Finally, we provide recommendations for further research on disease subsets in GCA.
Treatment outcomes of peritoneal carcinomatosis arising from gastric cancer with no measurable disease using systemic chemotherapy.
Authors: Guk Jin Lee, Sook Hee Hong, Sang Young Roh, Young Seon Hong, Kyo Young Song, Cho Hyung Park, Myung Ah Lee, Jin Hyoung Kang, Hee Yeon Lee, Ji Hyung Hong, Yun Hwa Jung, Si Young You
Journal: Journal of Clinical Oncology (2012)

e14558 Background: Although many clinical trials of newly developed chemotherapeutic drugs have been conducted, limited studies have focused on gastric cancer patients specifically diagnosed with peritoneal carcinomatosis (PC) without measurable regions. In the current study, we characterized the outcomes of systemic chemotherapy and prognostic factors for patients with gastric cancer PC, particularly in cases without measurable disease. Methods: Clinical data from 211 gastric cancer PC patients (137 without and 74 with measurable disease) subjected to systemic chemotherapy between January 2000 and December 2010 at a single center were reviewed. Results: Median OS rates of gastric cancer PC patients with no measurable disease were significantly longer than those of patients with measurable disease (18.2 vs 12.0 months, p=0.011). In multivariate analysis, poor PS (Hazard ratio (HR) = 2.33, 95% CI, 1.42-3.8, P=0.001), presence of metastatic lymphadenopathy (LAP) (HR=2.23, 95% CI, 1.42-3.5, p=0.002) and high-grade PC (HR=1.82, 95% CI, 1.09-3.04, p=0.025) were associated with significantly decreased OS. Combined with clinical PC grade and measurability of disease, median OS of patients with low-grade PC without measurable disease was 19.6 months (95% CI, 15.5-23.7 months). Median OS rates of 12.6, 13.7 and 6.8 months were estimated in high-grade PC without measurable disease, low-grade PC with measurable disease, and high-grade PC with measurable disease, respectively. Median OS of low-grade PC patients with no measurable disease was significantly higher than that of patients in all other groups (p=0.001, p=0.029 and p&lt;0.001, respectively). Conclusions: Gastric cancer PC is a heterogeneous disease entity. In our study, clinically low-grade PC without measurable disease was associated with better outcomes than other groups following systemic chemotherapy. According to the carcinomatosis grade, specific groups of patients may benefit from systemic chemotherapy. Despite the difficulties of response assessment, further clinical trials for newer treatment strategies and molecular studies focusing on the heterogeneity of gastric cancer PC should be introduced.
Study backs alcohol UK limit of six glasses of wine a week
Authors: Jacqui Wise
Journal: BMJ (2018)

A massive study supports the UK’s latest guidance on alcohol, which recommends a limit of 100 g alcohol a week—around five to six standard glasses of wine or pints of beer.1 This limit is much lower than that recommended in many other countries.

The study, published in the Lancet , includes data from 599 912 current drinkers taken from 83 prospective studies in 19 high income countries. It found an increase in all causes of death above 100 g alcohol a week.

The research was restricted to current drinkers who had no history of cardiovascular disease. Non-drinkers were excluded to minimise the possibility of reverse causality—for example, if former drinkers had abstained because of …
Can a Framework Be Established for the Safe Use of Ketamine?
Authors: Robert Freedman, Alan S. Brown, Tyrone D. Cannon, Benjamin G. Druss, Felton J. Earls, Javier Escobar, Yasmin L. Hurd, David A. Lewis, Carlos López-Jaramillo, Joan Luby, Helen S. Mayberg, Terrie E. Moffitt, Maria Oquendo, Roy H. Perlis, Daniel S. Pine, A. John Rush, Carol A. Tamminga, Mauricio Tohen, Eduard Vieta, Katherine L. Wisner, Yu Xin
Journal: American Journal of Psychiatry (2018)
Polymeric nano-shielded islets with heparin-polyethylene glycol in a non-human primate model
Authors: Hyojun Park, Muhammad R. Haque, Jae Berm Park, Kyo Won Lee, Sanghoon Lee, Yeongbeen Kwon, Han Sin Lee, Geun-Soo Kim, Du Yeon Shin, Sang-Man Jin, Jae Hyeon Kim, Hee Jung Kang, Youngro Byun, Sung Joo Kim
Journal: Biomaterials (2018)
The hard road to data interpretation: the road is hard too for the patient
Authors: J. Gore-Booth
Journal: Annals of Oncology (2018)

As patients and patient advocates, we read with great interest the article by Sobrero et al. [1.Sobrero A. Grothey A. Iveson T. et al.The hard road to data interpretation: three or six months of adjuvant chemotherapy for patients with stage III colon cancer?.Ann Oncol. 2018; 29: 1099-1107Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] investigating whether patients with stage III colon cancer should have 3 or 6 months of adjuvant chemotherapy. EuropaColon and its members are supportive of all clinical research conducted to improve outcomes for patients, whether in terms of improved survival, side-effects or quality of life. We appreciate that oxaliplatin is associated with peripheral neurotoxicity, which can have a significant impact on quality of life. We have spoken to many of our members on this topic. Peripheral neurotoxicity is present among the vast majority of this specific patient population, and for many it does affect their everyday activities. However, the majority of patients are also of the opinion that the primary goal of treatment of stage III colorectal cancer is to provide the best possible chance of survival, without recurrence of the disease. Although there is some difference of opinion among patients on whether 3 or 6 months treatment is preferable, all would like the opportunity to make their own informed decision. We passionately believe that the best treatment option for each colorectal cancer patient can only be determined through an individualized approach. Each oncologist should explain to their patients in plain, non-technical language, the potential benefits, side-effects and outcomes of treatment. Only when armed with all the relevant information can each patient, in partnership with their oncologist, make an informed decision about their own treatment. None declared.