tbuckley/cabot-search huggingface dataset:
Safety and Efficacy of Immune Checkpoint Inhibitor Therapy in Patients With HIV Infection and Advanced-Stage Cancer
Authors: Michael R. Cook, Chul Kim
Journal: JAMA Oncology (2019)

<h3>Importance</h3> Patients with HIV infection are at increased risk for cancer. Cancer is the leading cause of death among non–AIDS-defining illnesses in these patients. Immune checkpoint inhibitor (ICI) therapy has transformed the treatment of cancer. However, clinical trials of ICIs have historically excluded patients with HIV infection. The safety and efficacy profile of ICIs is unknown in this underrepresented population. <h3>Objective</h3> To summarize results on the safety and efficacy of ICI therapy in HIV-infected patients with advanced-stage cancer. <h3>Evidence Review</h3> This systematic review was conducted in accordance with PRISMA guidelines. A literature search of PubMed was performed on April 16, 2018, using the keyword<i>HIV</i>and the names of ICIs approved by the US Food and Drug Administration (<i>ipilimumab</i>,<i>nivolumab</i>,<i>pembrolizumab</i>,<i>avelumab</i>,<i>atezolizumab</i>, and<i>durvalumab</i>). Patients with HIV infection who were being treated with ICIs for advanced-stage cancer were included. In addition, abstracts and posters from major oncology and AIDS society annual meetings from 2016 through 2018 were reviewed. <h3>Findings</h3> Seventy-three patients (66 [90.4%] male; mean age, 56.1 years [range, 30.0-77.0 years]) were identified from 13 articles (11 case reports and 2 case series) and 4 meeting abstracts. Sixty-two patients were treated with anti–programmed cell death 1 (anti–PD-1) therapy, 6 with anti–cytotoxic T-lymphocyte antigen 4 (anti–CTLA-4) therapy, 4 with anti–PD-1/CTLA-4 therapy, and 1 with sequential ipilimumab and nivolumab therapy. Immune checkpoint inhibitor therapy was generally well tolerated, with grade 3 or higher immune-related adverse events noted in 6 of 70 patients (8.6%). Among 34 patients with known paired pretreatment and posttreatment HIV loads, HIV remained suppressed in 26 of the 28 (93%) with undetectable HIV load. Among the 25 with paired pretreatment and posttreatment CD4 cell counts, the counts increased (mean [SD] change, 12.3 [28.5] /μL). Objective response rates were 30% for non–small cell lung cancer, 27% for melanoma, and 63% for Kaposi sarcoma. <h3>Conclusions and Relevance</h3> Immune checkpoint inhibitor therapy for the treatment of advanced-stage cancer in patients with HIV infection was associated with no new safety signals. Immune checkpoint inhibitors may be a safe and efficacious treatment option in this patient population. Several ongoing prospective clinical trials will shed further light on the safety and efficacy of ICI therapy in HIV-infected patients with cancer.
Preclinical Studies and a Phase I Trial of the TGF-β Receptor Inhibitor, Vactosertib (TEW-7197), in Combination with Pomalidomide in Patients with Multiple Myeloma Refractory to Bortezomib or Lenalidomide
Authors: Ehsan Malek, Byung-Gyu Kim, Jason Valent, James Driscoll, Paolo Caimi, Seong-Jin Kim, Marcos de Lima, John Letterio
Journal: Blood (2018)
Caspase-3 cleavage of <i>Salmonella</i> type III secreted effector protein SifA is required for localization of functional domains and bacterial dissemination
Authors: Samir Patel, Daniel M. Wall, Antonio Castillo, Beth A. McCormick
Journal: Gut Microbes (2019)

SifA is a bi-functional Type III Secretion System (T3SS) effector protein that plays an important role in Salmonella virulence. The N-terminal domain of SifA binds SifA-Kinesin-Interacting-Protein (SKIP), and via an interaction with kinesin, forms tubular membrane extensions called Sif filaments (Sifs) that emanate from the Salmonella Containing Vacuole (SCV). The C-terminal domain of SifA harbors a WxxxE motif that functions to mimic active host cell GTPases. Taken together, SifA functions in inducing endosomal tubulation in order to maintain the integrity of the SCV and promote bacterial dissemination. Since SifA performs multiple, unrelated functions, the objective of this study was to determine how each functional domain of SifA becomes processed. Our work demonstrates that a linker region containing a caspase-3 cleavage motif separates the two functional domains of SifA. To test the hypothesis that processing of SifA by caspase-3 at this particular site is required for function and proper localization of the effector protein domains, we developed two tracking methods to analyze the intracellular localization of SifA. We first adapted a fluorescent tag called phiLOV that allowed for type-III secretion system (T3SS) mediated delivery of SifA and observation of its intracellular colocalization with caspase-3. Additionally, we created a dual-tagging strategy that permitted tracking of each of the SifA functional domains following caspase-3 cleavage to different subcellular locations. The results of this study reveal that caspase-3 cleavage of SifA is required for the proper localization of functional domains and bacterial dissemination. Considering the importance of these events in Salmonella pathogenesis, we conclude that caspase-3 cleavage of effector proteins is a more broadly applicable effector processing mechanism utilized by Salmonella to invade and persist during infection.
Patterns of care and outcomes of low-lying adenocarcinoma and squamous cell carcinoma of the rectum.
Authors: Paul Adedoyin, Anna Lee, Nikita Malakhov, Ami Kavi, Niki Sheth, Elizabeth Garay, David Schreiber
Journal: Journal of Clinical Oncology (2019)

715 Background: To analyze the patterns of care and survival for stage I-III squamous cell (SCC) and adenocarcinoma (AC) of the rectum from 2004-2015 based on receipt of surgery alone (S), neoadjuvant chemoradiation followed by surgery (CRT+S), surgery followed by adjuvant chemoradiation (S+CRT) and definitive chemoradiation (CRT). Methods: The NCDB was explored to identify patients diagnosed with low-lying stage I-III AC and SCC of the rectum from 2004-2015 who received S, CRT+S, S+CRT or CRT. Frequency distributions between the categorical variables were compared using the Chi-square test. Overall survival data and Kaplan-Meier curves were compared via the log-rank test stratifying the groups (AC vs. SCC) by stage and treatment. Cox proportional hazards regression models were performed to assess for covariates that had an impact on survival. Results: There were 22,227 patients included in this study, from which 21,587 (97.1%) were AC and 640 (2.9%) were SCC. Median follow-up for the entire cohort was 54 months. The median RT dose for AC was 5040 cGy and for SCC 5400 cGy. 5-year OS of AC vs. SCC in the entire cohort was 61.6% vs. 56.1%, respectively (p&lt;0.001). The OS for AC was 51.5% for S alone, 71.1% for CRT+S, 65.6% for S+CRT, and 36.2% for CRT (p&lt;0.001). The OS for SCC was 49.2% for surgery alone, 54.2% for CRT+S, 67.1% for S+CRT, and 65.7% for CRT (p=0.227). On multivariable Cox regression for AC, patients who received CRT+S (HR 0.61, p&lt;0.001) or S+CRT (HR 0.67, p&lt;0.001) had improved survival compared to S alone while those who had definitive CRT (HR 1.55, p&lt;0.001) had worse survival. Conclusions: This is the largest case series of rectal SCC in the literature to date. Analysis suggests that SCCs of the rectum are more often treated with definitive CRT but are associated with slightly worse survival than adenocarcinoma, suggesting that perhaps surgery may need an increased utilization in this disease. [Table: see text]
A phase I/II study of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition in refractory colorectal cancer.
Authors: M. Cecilia Monge B., Changqing Xie, Seth M. Steinberg, Suzanne Fioraventi, Melissa Walker, Donna Mabry-Hrones, Bradford J. Wood, David E Kleiner, Tim F. Greten
Journal: Journal of Clinical Oncology (2020)

117 Background: The benefit of immune checkpoint inhibition is limited to the small percentage of advanced colorectal cancer (CRC) patients whose tumors present mismatch repair (MMR) gene abnormalities; immunotherapy has not shown benefit in patients with MMR proficient CRC. Oncolytic immunotherapy represents a unique therapeutic platform. This phase I trial tests the safety of the combination of pexastimogene devacirepvec (Pexa-Vec) plus durvalumab (durva) in patients with locally advanced or metastatic CRC. Methods: Eligible patients with advanced proficient mixed match repair (pMMR) CRC received intravenous infusion of Pexa-Vec at dose level 3 x 10 8 plaque forming units (pfu) (DL1) or at 10 9 pfu (DL2) every 2 weeks for 4 doses and durva 1500 mg every 28 days. Response was assessed with CT every 8 weeks. Adverse events were recorded and managed. The primary endpoint included safety, tolerability and feasibility of this combination therapy. Samples of tumor and peripheral blood were collected for assessment of immune parameters. Results: Sixteen patients (6 males and 10 females) enrolled with a median age of 52.1 years (range 39-69) from Dec, 2017 to Oct, 2018. Four patients were treated with Pexa-Vec at DL1 and durva;twelve patients were treated with Pexa-Vec at DL2 and durva.The most common treatment related adverse events (TRAE) included fever 15/16 (94 %), hypotension 12/16 (75 %), chills 12/16 (75%), fatigue 8/16 (50%), sinus tachycardia 7/16 (44%) and rash 6/16 (38%). Grade 3/4 TRAEs were reported in 8/16 (50%)patients; the most common were fever 7/16 (44 %), lymphopenia 2/16 (13%), neutropenia 1/16 (6%) and anemia 1/16 (6%). 14 patients were evaluable for response analysis; one patient 1/14 (7 %) achieved a confirmed partial response (lasting 7.1 months) and continues to receive treatment, while 13 patients had progressive disease. The median progression free survival (PFS) was 2.2 months (95% CI: 2.2-2.3 months) and the median overall survival (OS) was 7.5 months (CI: 4.9-10.1 months). Conclusions: Combination therapy of Pexa-Vec with durva ICI issafe, well tolerated and demonstrates possible activity in patients with advanced pMMR CRC. Clinical trial information: NCT03206073.
The Esophageal Online Patient Reported Outcomes (EsO-PRO) Questionnaire: Formal implementation and assessment of a combined clinical and research data collection tool.
Authors: Shirley Xue Jiang, Shubhangi Shah, Elliot Charles Smith, Justine Baek, Mindy Liang, M. Catherine Brown, Allyson Mayo, Geoffrey Liu, Jonathan Yeung, Rebecca Wong, Elena Elimova, Gail Elizabeth Darling
Journal: Journal of Clinical Oncology (2019)

37 Background: Systematic symptom monitoring improves quality of life, and possibly overall survival in cancer outpatients receiving chemotherapy. To reduce patient, staff, and resource burden, combining research surveys with electronic PRO assessments in a multidisciplinary academic esophageal cancer clinic may allow dual clinical-research goals to be met. Methods: EsO-PRO is a data collection tool directed at esophageal cancer outpatients created through expert feedback. Using the Canadian Institutes of Health research (CIHR) Knowledge-to-Action (KTA) framework, clinic flow and stakeholder maps were constructed. Facilitators and barriers were then identified, and responses were generated to address implementation barriers. Multiple iterations of the questionnaire were implemented; patient and clinic staff feedback was collected through key informant interviews, and major themes were described. Results: Creation of EsO-PRO included multiple validated tools: the FACT-E, modified Cancer Research UK esophageal cancer risk questionnaire, EQ5D-5L, PRO-CTCAE for common esophageal symptoms, and baseline clinico-demographic data. Four iterations of the KTA cycle for pilot implementation identified specific key facilitators (clinician champions, staff engagement, resource-integration, and clinician-researcher synergy) and barriers (familiarity with technology, survey length, and communication barriers). Qualitative assessment also identified perceived importance of questions as key to patient completion, and role delegation, staff burden, clinic flow interruption as critical issues to address. Splitting EsO-PRO into two separate visits for completion, allowing completion at home, and changing fill-in-the-blanks to check-off boxes were identified as potential solutions. Conclusions: The CIHR-KTA framework identified concrete methods for improved integration of a combined clinical-research survey tool for routine use in a multidisciplinary esophageal cancer outpatient clinic. Our process serves as an effective model for integration of innovations in multidisciplinary esophageal cancer clinics.
The Metabolic Enzyme Hexokinase 2 Localizes to the Nucleus in AML and Normal Hematopoietic Stem/Progenitor Cells to Maintain Stemness
Authors: Geethu Thomas, Laura Garcia Prat, Marcela Gronda, Rose Hurren, Neil MacLean, Xiaoming Wang, Botham Aaron, John E. Dick, Aaron D Schimmer
Journal: Blood (2018)
A man having a convulsion
Authors: Shing Fung Lee, Frank Chi Sing Wong
Journal: BMJ (2019)

A 40 year old right handed man was admitted to the emergency department after experiencing a convulsion at home. During the episode, he lost consciousness and experienced twitching of the left limbs. He regained consciousness after a few minutes, with no post-ictal drowsiness. He had no further seizures and reported no recent head injury, medication use, or recreational drug use. He had no fever, weight loss, or malaise. Physical examination, including neurological examination, was normal.

Urgent non-contrast computed tomography of the brain showed cortical thickening in the right parietal lobe with adjacent ill defined white matter hypodense changes; there was no hyperdensity.

Blood tests, including full blood counts, a liver function test, electrolytes, urea, and c-reactive protein levels, were normal.

Further investigation with magnetic resonance imaging (MRI) of the brain was arranged (fig 1, 2).



Fig 1 
Magnetic resonance imaging (MRI) of the brain with fluid attenuation inversion recovery (FLAIR)





Fig 2 
Axial diffusion weighted MRI brain



1.  What are the differential diagnoses of seizures with changes on …
Targeting intermittent hypoxia downstream pathways for biomarker discovery and new treatment perspectives in cutaneous melanoma
Authors: Mélanie Minovès, Jean-Louis Pépin, Diane Godin-Ribuot
Journal: European Respiratory Journal (2019)

<b>Targeting the pathways induced by obstructive sleep apnoea-associated intermittent hypoxia could significantly improve biomarker discovery and new treatment perspectives in patients with cutaneous melanoma</b>http://ow.ly/wF3J30nlzL4
Emergence of divergent enterovirus (EV) D68 sub-clade D1 strains, northern Italy, September to October 2018
Authors: Laura Pellegrinelli, Federica Giardina, Giovanna Lunghi, Sara Colonia Uceda Renteria, Letizia Greco, Alice Fratini, Cristina Galli, Antonio Piralla, Sandro Binda, Elena Pariani, Fausto Baldanti
Journal: Eurosurveillance (2019)

Between September and October 2018, an enterovirus D68 (EV-D68) outbreak occurred in patients hospitalised with severe acute respiratory infection in northern Italy; 21 laboratory-confirmed cases were reported. Phylogenetic analysis revealed that 16/20 of the EV-D68 sequences belonged to a divergent group within the sub-clade D1. Since its upsurge, EV-D68 has undergone rapid evolution with the emergence of new viral variants, emphasising the need for molecular surveillance that include outpatients with respiratory illness.
Abstract 18182: Inferior Vena Caval Filter Use for Prevention of Pulmonary Embolism: A Systematic Review
Authors: Behnood Bikdeli, Saurav Chatterjee, Nihar Desai, Mayur Desai, Mannuel Monreal, Samuel Goldhaber, Harlan Krumholz
Journal: Circulation (2016)

Background: Insertion of inferior vena caval filters (IVCFs) has had an 80% increase in 12 years in the US. We sought to meta-analyze high-quality studies of IVCF use for preventing pulmonary embol...
<scp>DNA</scp> methylation and allergic sensitizations: A genome‐scale longitudinal study during adolescence
Authors: Hongmei Zhang, Akhilesh Kaushal, Simon Kebede Merid, Erik Melén, Göran Pershagen, Faisal I. Rezwan, Luhang Han, Susan Ewart, S. Hasan Arshad, Wilfried Karmaus, John W. Holloway
Journal: Allergy (2019)

The presence of allergic sensitization has a major influence on the development and course of common childhood conditions such as asthma and rhinitis. The etiology of allergic sensitization is poorly understood, and its underlying biological mechanisms are not well established. Several studies showed that DNA methylation (DNAm) at some CpGs is associated with allergic sensitization. However, no studies have focused on the critical adolescence period.We assessed the association of pre- and postadolescence genome-wide DNAm with allergic sensitization against indoor, outdoor and food allergens, using linear mixed models. We hypothesized that DNAm is associated with sensitization in general, and with poly-sensitization status, and these associations are age- and gender-specific. We tested these hypotheses in the IoW cohort (n = 376) and examined the findings in the BAMSE cohort (n = 267).Via linear mixed models, we identified 35 CpGs in IoW associated with allergic sensitization (at false discovery rate of 0.05), of which 33 were available in BAMSE and replicated with respect to the direction of associations with allergic sensitization. At the 35 CpGs except for cg19210306 on C13orf27, a reduction in methylation among atopic subjects was observed, most notably for cg21220721 and cg11699125 (ACOT7). DNAm at cg10159529 was strongly correlated with expression of IL5RA in peripheral blood (P-value = 6.76 × 10-20 ). Three CpGs (cg14121142, cg23842695, and cg26496795) were identified in IoW with age-specific association between DNAm and allergic sensitization.In adolescence, the status of allergic sensitization was associated with DNAm differentiation and at some CpGs the association is likely to be age-specific.
Predictors of Quality of Life of Partners of High-Grade Glioma Patients
Authors: W. Hoeben, K. Hilverda, J.J. Heimans, M.J.B. Taphoorn, T.J. Postma, J. Buter, J. Lenting, E.H. Collette, J.C. Reijneveld, M. Klein
Journal: Neuro-Oncology (2010)
Association of the Great East Japan Earthquake and the Daiichi Nuclear Disaster in Fukushima City, Japan, With Birth Rates
Authors: Noriaki Kurita
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The association of the Great East Japan Earthquake and the subsequent Fukushima Daiichi Nuclear Power Plant disaster of March 11 and 12, 2011, in Fukushima, Japan, with birth rates has not been examined appropriately in the existing literature. <h3>Objective</h3> To assess the midterm and long-term associations of the Great East Japan Earthquake and the Fukushima Daiichi Nuclear Power Plant disaster with birth rates. <h3>Design, Setting, and Participants</h3> Cohort study in which interrupted time series analyses were used to assess monthly changes in birth rates among residents of Fukushima City, Japan, from March 1, 2011, to December 31, 2017, relative to projected birth rates without the disaster based on predisaster trends. Birth rates from January 1, 2007, to December 31, 2017, in Fukushima City were determined using information from the Fukushima City government office. <h3>Exposure</h3> The Great East Japan Earthquake and the Fukushima Daiichi Nuclear Power Plant disaster, expressed via 5 potential models of the association with birth rate: level change, level and slope changes, temporal level change, and temporal level change with 1 or 2 slope change(s). <h3>Main Outcomes and Measures</h3> Birth rate, calculated from monthly data on the number of births and total population. <h3>Results</h3> The mean birth rate before the Great East Japan Earthquake and the Fukushima Daiichi Nuclear Power Plant disaster was 69.8 per 100 000 people per month; after the disaster, the mean birth rate was 61.9 per 100 000 people per month. Compared with birth rates before the Great East Japan Earthquake and the Fukushima Daiichi Nuclear Power Plant disaster, there was an estimated 10% reduction in monthly birth rates in Fukushima City (rate ratio, 0.90; 95% CI, 0.86-0.93) in the first 2 years after the disaster. After that, the birth rate trend was similar to the predisaster trend. The predisaster trend suggested a continuous decrease in birth rate (rate ratio for 1 year, 0.98; 95% CI, 0.98-0.99). This gap model was optimal and parsimonious compared with others. A similar association was found when trimonthly averaged data were analyzed. <h3>Conclusions and Relevance</h3> The Great East Japan Earthquake and the Fukushima Daiichi Nuclear Power Plant disaster were followed by significant reductions in birth rates for 2 years. There was insufficient evidence to indicate that the trend in the 3 to 7 years after the disaster differed from the predisaster trends. The recovery from the reductions in the birth rate may be indicative of the rebuilding efforts. The continuing long-term decrease in birth rates observed before the Great East Japan Earthquake and the Fukushima Daiichi Nuclear Power Plant disaster suggests that continuing measures to support birth planning should be considered at the administrative level.
Allogeneic CAR-T Cell Therapy for Treatment of Relapse after Allo-HSCT in Patients with Refractory CML Lymphoid Blast Crisis: Significance of HLA Matched Donor/Patient Pair in the Safety/Efficacy of CAR-T Cell Therapy
Authors: Kai Sun, Xuejun Zhang, Zhen Wang, Yuqing Chen, Lei Zhang, Wei Cheng, Mingyue Shi, Lei Huo, Yanliang Bai, Xiaona Niu, Honggang Guo, Jing Yang, Chunrong Tong, AlexH Chang
Journal: Blood (2018)
Tumor-Lysis Syndrome in Relapsed or Refractory Multiple Myeloma Patients Treated with Proteasome Inhibitors
Authors: Kazuhito Suzuki, Kaichi Nishiwaki, Tadahiro Gunji, Mitsuji Katori, Rika Hosoba, Kei Hirano, Hidekazu Masuoka, Shingo Yano
Journal: Blood (2018)