tbuckley/cabot-search huggingface dataset:
Diagnostic evaluation of immune checkpoint inhibitor (CPI) colitis: The role of CT scan.
Authors: Sienna Durbin, Meghan Mooradian, Leyre Zubiri, Ian Matthew Allen, Florian Fintelmann, Avinash Kambadakone, Nisanard Pisuchpen, Kerry Lynn Reynolds, Michael Lawrence Dougan
Journal: Journal of Clinical Oncology (2020)

821 Background: CPI therapy has expanded rapidly in recent years and represents a major advancement in the treatment of many cancers, including hepatocellular carcinoma, gastric cancer, and colon cancer. However, these therapies are associated with significant toxicities. CPI colitis is one of the most common toxicities and can be fatal, especially when not diagnosed and treated promptly. The current gold standard for diagnosis is endoscopy with biopsy, an invasive procedure that is resource- and time-intensive. CT has emerged as a possible alternative. The primary objective of this study is to identify the diagnostic performance of CT in the evaluation of CPI colitis. Methods: With IRB approval, we conducted a retrospective cohort study of patients who received CPI therapy between 2009-2019 across a single healthcare system. Patients were included if they underwent both abdominal CT and upper/lower endoscopy with biopsy within 72 hours of each other. We reviewed the electronic medical record to identify possible cases of colitis based on either CT or pathology. All cases were labeled as either true positive or false positive based on pathology. We examined clinical characteristics, including CTCAE grade and treatment received. We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CT for diagnosing CPI colitis when compared to the gold standard of tissue diagnosis. Results: Of the 4,474 patients screened, 141 met inclusion criteria. Average age was 63 years (23 – 91); 43% were male. Most common tumor types were melanoma (36%) and NSCLC (20%). Seventy-four percent of patients were treated with anti-PD-1/PD-L1 monotherapy. Forty percent had signs of colitis on CT scan and 59% had biopsy-proven CPI colitis. Sensitivity and specificity of CT were 51% and 74%, respectively. PPV of CT was 74% and NPV was 51%. Of those with confirmed CPI colitis, 78% had symptoms that were classified as grade 3 or above. Seventy-three percent received IV steroids and 38% received infliximab. Conclusions: CT demonstrates moderate specificity and PPV and remains an important diagnostic test but does not replace endoscopy/biopsy in the evaluation of CPI colitis.
The effect of lysosomal-associated membrane protein-1-targeting of Epstein–Barr virus nuclear antigen 1 (EBNA1) on immune response and tumor growth in preclinical studies.
Authors: Pratima Sinha, Claire Buchta Rosean, Teri Heiland
Journal: Journal of Clinical Oncology (2020)

74 Background: Epstein-Barr virus (EBV) is an oncogenic γ-herpes virus that infects &gt; 90% of the global population. EBV is the primary cause of infectious mononucleosis and is associated with several epithelial and lymphoid malignancies, including nasopharyngeal carcinoma, gastric carcinoma, non-Hodgkin’s and Hodgkin’s lymphoma. Of these, nasopharyngeal carcinoma is particularly prevalent in East and Southeast Asia and is highly metastatic. Current treatment strategies for nasopharyngeal carcinoma are limited to radiation and chemotherapy, demonstrating a need for new, targeted therapies. Most nasopharyngeal carcinomas express EBNA1, a DNA-binding protein involved in maintenance of the episomal virus genome that is required for EBV latency and associated transformation. Targeting EBNA1 allows for an immunotherapeutic approach, by exploiting the potential of the immune system to recognize tumor cells through their expression of this viral antigen. Methods: We designed a DNA vaccine encoding EBNA1 using the UNITE (UNiversal Intracellular Targeted Expression) platform. The UNITE platform is based in part on lysosomal targeting technology which results in enhanced antigen presentation and a balanced T cell response. Results: We report that the EBNA1-UNITE vaccine induced IFNγ-producing effector memory (EM) CD4 + T and CD8 + T cells with complete rejection of EBNA1-expressing tumors observed in 50% of mice. Mice rejecting tumors were protected from rechallenge with CT26-EBNA1, demonstrating that antigen-specific memory was induced in these animals. Tumor microenvironment (TME) analysis showed vaccine-induced mobilization of effector cells, including tumor infiltration of IL-12-producing type 1 dendritic cells, iNOS-producing M1 macrophages, activated EM CD4 + T, and CD8 + TNFα + T cells. Furthermore, increased PD-1 + CD8 + T cells in the TME suggests that a combination strategy with PD-1/PD-L1 blockade may be beneficial in a therapeutic setting. Conclusions: This pre-clinical data suggests that the EBNA1-UNITE vaccine has the potential to be used as an immunotherapeutic agent against EBV-associated cancers.
Rapid development of bullous lung disease: a complication of electronic cigarette use
Authors: Saminder Singh Kalra, Faye Pais, Eloise Harman, Daniel Urbine
Journal: Thorax (2020)

Electronic cigarettes (EC) use can result in acute lung injury with varying severity of the hypoxic respiratory failure. Spontaneous resolution can result with the cessation of EC use, although some patients with severe disease have required mechanical ventilation. We describe a previously healthy patient who presented with severe hypoxemic respiratory failure and developed a rapidly progressive bullous disease and bilateral pneumothoraces. The exponential increase in lung injury from EC use combined with limited mechanistic insights into the disease process highlights the importance of promptly recognising both the disease and its complications.

A 34-year-old man was admitted with a 1-week history of pleuritic chest pain, dyspnoea and subjective fevers. He had a 15-pack year history of smoking but …
Human Rabies — Utah, 2018
Authors: Dallin Peterson, Bree Barbeau, Keegan McCaffrey, Randon Gruninger, Jeffrey Eason, Cindy Burnett, Angela Dunn, Melissa Dimond, Jesse Harbour, Alessandro Rossi, Bert Lopansri, Kristin Dascomb, Tara Scribellito, TaLeah Moosman, Louise Saw, Curtis Jones, Michael Belenky, Lily Marsden, Michael Niezgoda, Crystal M. Gigante, Rene Edgar Condori, James A. Ellison, Lillian A. Orciari, Pamela Yager, Jesse Bonwitt, Erin R. Whitehouse, Ryan M Wallace
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

On November 3, 2018, the Utah Department of Health (UDOH) was notified of a suspected human rabies case in a man aged 55 years. The patient's symptoms had begun 18 days earlier, and he was hospitalized for 15 days before rabies was suspected. As his symptoms worsened, he received supportive care, but he died on November 4. On November 7, a diagnosis of rabies was confirmed by CDC. This was the first documented rabies death in a Utah resident since 1944. This report summarizes the patient's clinical course and the subsequent public health investigation, which determined that the patient had handled several bats in the weeks preceding symptom onset. Public health agencies, in partnership with affected health care facilities, identified and assessed the risk to potentially exposed persons, facilitated receipt of postexposure prophylaxis (PEP), and provided education to health care providers and the community about the risk for rabies associated with bats. Human rabies is rare and almost always fatal. The findings from this investigation highlight the importance of early recognition of rabies, improved public awareness of rabies in bats, and the use of innovative tools after mass rabies exposure events to ensure rapid and recommended risk assessment and provision of PEP.
A phase I/II study combining a TMZ-CD40L/4-1BBL-armed oncolytic adenovirus and nab-paclitaxel/gemcitabine chemotherapy in advanced pancreatic cancer: An interim report.
Authors: Benjamin Leon Musher, Brandon George Smaglo, Wasif Abidi, Mohamed Othman, Kalpesh Patel, James Jing, Nir Stanietzky, Jinyu (Jim) Lu, Amanda Brisco, Jessica Wenthe, Benjamin Brenner, Emma Eriksson, Ann M. Leen, Susan G. Hilsenbeck, Gustav J. Ullenhag, Eric Keith Rowinsky, Bambj Grilley, Angelica Sara Ingrid Loskog
Journal: Journal of Clinical Oncology (2020)

716 Background: Pancreatic ductal adenocarcinoma (PDAC) has been highly resistant to immunotherapeutics to date. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, has been shown to lyse tumor cells selectively, induce anti-tumor cytotoxic T-cell responses, reduce myeloid-derived suppressor cell (MDSC) infiltration, and induce tumor regression in preclinical studies. Methods: In this phase I/II trial, patients with unresectable or metastatic PDAC are treated with LOAd703 intratumoral injections and standard nab-paclitaxel/gemcitabine (nab-P/G) chemotherapy. Starting on cycle 1 day 15 of nab-P/G, LOAd703 is injected with image guidance into the primary pancreatic tumor or a metastasis every 2 weeks for 6 injections. In the event of sustained tumor control, subjects are eligible to receive 6 more injections. Three dose levels of LOAd703 are being investigated using a BOIN dose escalation design. Primary endpoints are safety and feasibility. Secondary endpoints include response rate and overall survival. Results: To date, 13 subjects are evaluable for safety and feasibility. Three patients were treated at dose 1 (5x10e10 VP), 4 subjects at dose 2 (1x10e11 VP), and 6 subjects at dose 3 (5x10e11 VP). The most common adverse events (AEs) attributed to LOAd703 have been fever, chills, nausea, and increased transaminases. AEs have been transient and grade 1-2, with the exception of a grade 3 transaminase elevation in 1 subject receiving dose 3 (the only dose-limiting toxicity observed thus far). During protocol treatment, circulating MDSCs decreased in 8/13 subjects while effector memory T-cells increased in 10/13. ELISPOT analyses showed a rise in tumor antigen-specific T-cells in 10/13 subjects. At the lowest dose level, best response was stable disease, and 6/10 patients who received higher LOAd703 doses have had partial responses. Only 1 patient has had progressive disease as best response. Conclusions: Adding LOAd703 to nab-P/G has been safe and feasible. Treatment-emergent immune responses have been demonstrated in most subjects, with a notable proportion having objective anti-tumor responses. Clinical trial information: NCT02705196.
Radiomics to predict response to pembrolizumab in patients with advanced rare cancers.
Authors: Rivka R. Colen, Sara Ahmed, Nabil Elshafeey, Daniel D. Karp, Shubham Pant, Vivek Subbiah, Sarina Anne Piha-Paul, David S. Hong, Timothy A Yap, Siqing Fu, Apostolia Maria Tsimberidou, Bettzy Stephen, Jing Gong, Jordi Rodon Ahnert, Aung Naing
Journal: Journal of Clinical Oncology (2020)

66 Background: To predict responders versus non-responders to Pembrolizumab, an anti PD-1 monoclonal antibody, in patients with advanced rare cancers. Methods: The study included 58 patients with advanced rare cancers (eg. squamous cell carcinoma of the skin, adrenocortical carcinoma, carcinoma of unknown primary, and paraganglioma) who were enrolled in a phase 2 trial of Pembrolizumab. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients were categorized into: 21 responders (stable disease, partial response, and complete response) and 37 non-Responders (progressive disease). Target lesion(s) obtain from standard-of-care, pre-treatment contrast enhanced CT scans were segmented using 3D slicer v4.8.1. A total of 610 features (10 histogram-based and 600 second-order texture features) were calculated from each extracted volume of interest (VOI). Radiomic features were obtained using a feature selection approach based on Least Absolute Shrinkage and Selection Operator (LASSO). Selected features were used to build a classification model, using XGboost, for prediction of tumor response to Pembrolizumab. To evaluate the robustness of the estimates, Leave-One-Out Cross-Validation (LOOCV) was performed. Results: A total of 10 radiomic features were selected; the XGboost-based classification robustly differentiated between responders vs non-responders (area under the curve, sensitivity and specificity were 99%, 100%, and 95%, respectively [p&lt;0.0001]). Conclusions: Our radiomic derived features were able to identify imaging differences that can evaluate patients’ response to Pembrolizumab treatment.
Tracheostomy practice and timing in traumatic brain-injured patients: a CENTER-TBI study
Authors: Chiara Robba, Stefania Galimberti, Francesca Graziano, Eveline J. A. Wiegers, Hester F. Lingsma, Carolina Iaquaniello, Nino Stocchetti, David Menon, Giuseppe Citerio
Journal: Intensive Care Medicine (2020)
Reduced–dose intensity therapy for pediatric lymphoblastic leukemia: long-term results of the Recife RELLA05 pilot study
Authors: Francisco Pedrosa, Elaine Coustan-Smith, Yinmei Zhou, Cheng Cheng, Arli Pedrosa, Mecneide Mendes Lins, Marcia Pedrosa, Norma Lucena-Silva, Alessandra Maria de Luna Ramos, Ester Vinhas, Gaston K. Rivera, Dario Campana, Raul C. Ribeiro
Journal: Blood (2020)
Efficacy and safety of endoscopic ultrasound-guided therapy versus direct endoscopic glue injection therapy for gastric varices: systematic review and meta-analysis
Authors: Babu P. Mohan, Saurabh Chandan, Shahab R. Khan, Lena L. Kassab, Sushruth Trakroo, Suresh Ponnada, Ravishankar Asokkumar, Douglas G. Adler
Journal: Endoscopy (2020)

Abstract Background Gastric variceal bleeding carries significant mortality in the setting of portal hypertension. Among the endoscopic treatment options, endoscopic ultrasound (EUS)-guided glue and/or coil injection is a novel approach, but its role in the treatment of gastric varices is not established due to a lack of robust data. Methods We conducted a comprehensive search of several databases (inception to June 2019) to identify studies evaluating EUS in the treatment of gastric varices. Our primary goals were to estimate the pooled rates of treatment efficacy, obliteration and recurrence of gastric varices, early and late rebleeding, and adverse events with EUS-guided therapy in gastric varices. We also searched for studies that evaluated direct endoscopic glue (END-glue) injection for treatment of gastric varices, and used the pooled rates as comparators. Results 23 studies (851 patients) evaluating EUS-guided therapy were included. The pooled treatment efficacy was 93.7 % (95 % confidence interval [CI] 89.5 – 96.3, I 2 = 53.7), gastric varices obliteration was 84.4 % (95 %CI 74.8 – 90.9, I 2 = 77), gastric varices recurrence was 9.1 % (95 %CI 5.2 – 15.7, I 2 = 32), early rebleeding was 7.0 % (95 %CI 4.6 – 10.7, I 2 = 0), and late rebleeding was 11.6 % (95 %CI 8.8 – 15.1, I 2 = 22). The rates were comparable to END-glue therapy (28 studies, 3467 patients) except for obliteration, which was significantly better with EUS-guided therapy. On subgroup analysis, EUS-coil/glue combination showed superior outcomes. Conclusions EUS-guided therapy demonstrated clinical efficacy for treatment of gastric varices in terms of obliteration, recurrence, and long-term rebleeding, and may be superior to END-glue.
Tyme-88-Panc Part 2: A randomized phase II/III of SM-88 with MPS as third-line in metastatic PDAC.
Authors: Shubham Pant, Sant P. Chawla, Vincent Chung, Giuseppe Del Priore, Dae Won Kim, Marcus Smith Noel, Paul Eliezer Oberstein, Allyson J. Ocean, Philip Agop Philip, Vincent J. Picozzi, Diane M Simeone, Andrea Wang-Gillam
Journal: Journal of Clinical Oncology (2020)

TPS789 Background: Patients with metastatic pancreatic cancer who have progressed on two prior lines of therapy have a poor prognosis with an overall survival in the range of 2-2.5 months. (Manax, et al. J Clin Oncol 37, 2019 suppl 4; abstr 226). There is currently no standard of care for these patients that has demonstrated improved outcomes. SM-88 (D,L-alpha-metyrosine; racemetyrosine [USAN]) is a proprietary dysfunctional tyrosine derivative and is the backbone of SM-88 used with MPS (Methoxsalen 10mg, Phenytoin 50mg and Sirolimus 0.5mg; all administered daily). SM-88 monotherapy was relatively well tolerated, with improvement in survival in select patients with heavily pretreated PDAC who achieved stable disease on therapy (HR 0.08, p = 0.02). Circulating tumor cells (CTC’s) were prognostic and decreased on therapy with SM-88 potentially identifying a subgroup of PDAC that may be most likely to benefit from therapy (Noel et al. Annal Oncol V30, Suppl 4, 2019). Preliminary radiomic analysis of the largest metastases at baseline suggested the same benefits including a correlation with baseline CTCs, changes in CTCs on therapy and OS (Ocean et al, Annal Oncol, V30, Suppl 5, 2019). Here, we describe a randomized, open-label, phase 2/3 trial evaluating the efficacy of SM-88 + MPS vs physician’s choice treatment as third line therapy for patients with metastatic PDAC. Methods: This is a multi-center Phase 3 study of patients ≥18 years with metastatic PDAC that progressed after 2 lines of chemotherapy (gemcitabine [gem] and 5-fluorouracil [5-FU] based) with an ECOG &lt;2. Randomization will be 1:1 with 250 patients being stratified by site, ECOG, and choice of chemotherapy. SM-88 will be administered at a dose of 460mg twice daily (920 mg/day). Primary end point is Overall Survival (OS). Secondary end points include progression free survival, response rate, duration of response, pharmacokinetics, safety and CTCs. Clinical trial information: NCT03512756.
Exploring telotristat ethyl’s antiproliferative effects in patients with carcinoid syndrome (TELEACE): A real-world observational study.
Authors: Michael Morse, Eric Liu, Vijay N. Joish, Lynn Huynh, Mu Cheng, Todor Totev, Mei S. Duh, Pablo Lapuerta, David C. Metz
Journal: Journal of Clinical Oncology (2020)

618 Background: Serotonin may have proliferative effects on neuroendocrine tumors (NETs). Inhibition of tryptophan hydroxylase (TPH), with resulting reduction of serotonin, may impact tumor size and growth (TG) in patients with NETs. We investigated the effects of TPH inhibitor telotristat ethyl (TE) on TG among patients receiving TE in clinical practice. Methods: A chart review study of 200 patients who had initiated TE was conducted. All patients had ≥2 radiological scans in the past 12 months prior to TE initiation and ≥1 scan post-TE initiation. Data were collected via a secure online portal. Descriptive statistics summarized physician and patient characteristics, and documented background NET treatment (i.e., somatostatin analog [SSA] and/or non-SSA). Longitudinal analyses of TG were assessed using a generalized linear regression model after controlling for documented background NET treatment and time since first scan. Results: Most physicians (71/114) were community-based oncologists. On average, patients were 61 ± 10 years old when initiating TE, 57% male, and 74% white; 61% had well-differentiated tumor with 61% of gastrointestinal origin. Patients received TE for an average of 12.0 ± 7.3 months and 82% (n = 163) were still receiving TE treatment at the time of data collection. The mean time from first scan to TE initiation was 5.6 ± 4.7 months and from TE initiation to last scan was 7.2 ± 6.3 months. Significant mean reductions in tumor size, after TE initiation, of 0.6 cm (p = 0.006) and TG of 8.5% (p = 0.045) were observed. Documented background NET treatment prior to initiating TE and time since first scan were not significant predictors of TG reduction. Results were consistent in a subset (n = 65) of patients who had no change in documented background NET treatment before and after initiating TE (mean reductions in tumor size 0.6 cm, p = 0.044 and TG 8.1%, p = 0.203). Conclusions: Treatment with TE may impact TG in patients with NETs. Prospective clinical studies are warranted to further examine the antiproliferative effects of TE.
Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial
Authors: Jesús Villar, Carlos Ferrando, Domingo Martínez, Alfonso Ambrós, Tomás Muñoz, Juan A Soler, Gerardo Aguilar, Francisco Alba, Elena González-Higueras, Luís A Conesa, Carmen Martín-Rodríguez, Francisco J Díaz-Domínguez, Pablo Serna-Grande, Rosana Rivas, José Ferreres, Javier Belda, Lucía Capilla, Alec Tallet, José M Añón, Rosa L Fernández, Jesús M González-Martín, Gerardo Aguilar, Francisco Alba, Julián Álvarez, Alfonso Ambrós, José M. Añón, María J. Asensio, Javier Belda, Jesús Blanco, Marisa Blasco, Lucia Cachafeiro, Rafael del Campo, Lucía Capilla, José A. Carbonell, Nieves Carbonell, Agustín Cariñena, Demetrio Carriedo, Mario Chico, Luís A. Conesa, Ruth Corpas, Javier Cuervo, Francisco J. Díaz-Domínguez, Cristina Domínguez-Antelo, Lorena Fernández, Rosa L. Fernández, Carlos Ferrando, José Ferreres, Eneritz Gamboa, Elena González-Higueras, Raúl I. González-Luengo, Jesús M. González-Martín, Domingo Martínez, Carmen Martín-Rodríguez, Tomás Muñoz, Ramón Ortiz Díaz-Miguel, Raquel Pérez-González, Ana M. Prieto, Isidro Prieto, Rosana Rivas, Leticia Rojas-Viguera, Miguel A. Romera, Jesús Sánchez-Ballesteros, José M. Segura, Pablo Serna-Grande, Ainhoa Serrano, Rosario Solano, Juan A. Soler, Marina Soro, Alec Tallet, Jesús Villar
Journal: The Lancet Respiratory Medicine (2020)
A study using two methods to examine a skin layer called the upper basket‐weave pattern layer
Authors: H. Goto, A. Tada, A. Ibe, Y. Kitajima
Journal: British Journal of Dermatology (2020)

The skin is made up of several layers, the very outermost of which is the stratum corneum. The normal stratum corneum (SC) itself has two layers, an upper basket‐weave (B‐W) pattern layer and, below this, a lower compact layer. Corneodesmosomes are cells found in the stratum corneum, and in healthy skin, their number decreases (the cells degrade) from the lower compact layer up to the upper basket‐weave pattern layer, and their distribution (layout) changes. This can be seen by a process that looks at levels of desmoglein 1 (Dsg1) in skin cell samples taken on sticky tape (tape stripping), as levels of Dsg1 represent the numbers of corneodesmosomes. In some skin diseases such as ichthyosis vulgaris and X‐linked ichthyosis, there is no basket‐weave pattern layer, or it is incomplete. In this study, the function of the upper basket‐weave pattern layer was explored, using reconstructed human epidermis (RHE, a type of model of skin developed from skin cells) as well as skin cells taken from female volunteers by tape stripping. The scientists used an oil‐in‐water emulsion, prepared cream‐A, and successfully generated the upper basket‐weave pattern layer in reconstructed human epidermis in which the degradation of corneodesmosomes was promoted. This could be a useful tool for investigating the physiological significance of the basket weave layer in vitro (meaning in the lab rather than on humans). Using the cells from the female volunteers, the researchers found that degradation of Dsg1 in the outermost stratum corneum, which represents the basket‐weave pattern layer forming, was correlated with water‐barrier functions (a sign of a healthy skin barrier) and the SC softness of healthy skin, which varied widely. Being able to measure Dsg1 content in the stratum corneum obtained by tape‐stripping from human skin, can make it possible to study the effects of external stimulants, such as creams/ointments, on the completeness of the basket weave layer without the need for a biopsy. This summary relates to the study: Basket‐weave structure in the stratum corneum is an important factor for maintaining the physiological properties of human skin as studied using reconstructed human epidermis and tape stripping of human cheek skin