tbuckley/cabot-search huggingface dataset:
Defective mismatch repair associated mutational signatures, a prognostic and predictive biomarker in endometrial cancer.
Authors: Yifan Emily Chang, Naomi N Adjei, Wafa Khadraoui, Gary Altwerger
Journal: Journal of Clinical Oncology (2021)

5528 Background: Mismatch repair (MMR) deficiency is the distinguishing molecular feature of a significant portion of endometrial cancers (UCEC), and tumors with MMR deficiency have been identified as candidates for immune checkpoint blockade therapy. We studied MMR deficiency in UCEC using defective mismatch repair associated mutational signatures (MMRd-ams). Methods: WES-derived somatic mutation data of 531 UCEC samples from TCGA Pan-Cancer Atlas were analyzed. COSMIC mutational signatures for each sample were calculated using the R package deconstructSigs. MMRd-ams were correlated with clinical and molecular features for 507 TCGA samples (cBioPortal). Samples were divided into High MMRd-ams ( n = 192) and Low MMRd-ams ( n = 315) groups by the average of the representative MMRd-ams (0.2396). Fractions of tumor immune infiltrates were derived from CIBERSORT. Results: A significantly higher percentage of patients (47/192, 24.5%) in the High MMRd group had somatic putative driver mutations in at least 1 of the MMR genes ( MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2 and EPCAM), compared with patients in the Low MMRd group (37/315, 11.8%, p = 0.0003). 15% (54/359) of tumors in the non-MSI subtypes expressed significant MMRd-ams and were categorized in the High MMRd-ams group. Patients in the High MMRd-ams group had longer progression-free survival (PFS) ( p = 0.0457, log-rank). Analysis of the inferred composition of tumor immune infiltrates revealed that the High MMRd-ams group had significantly higher fraction of CD8+ T cells ( p &lt; 0.0001), higher fraction of T follicular helper cells ( p &lt; 0.0001) and lower fraction of M2 macrophages ( p &lt; 0.001). Tumors in the High MMRd-ams group also displayed higher mRNA expression levels of immune checkpoint genes: PDCD1 ( p = 0.0013), and CTLA4 ( p = 0.0016). Conclusions: MMRd-ams may be a prognostic and predictive biomarker with significant clinical impact. High MMRd-ams patients prognostically demonstrated longer PFS. Predictively, high MMRd-ams was associated with increased tumor immune infiltrates and elevated expression levels of CTLA4 and PDCD1 , known immune checkpoint genes exploitable by immune checkpoint therapies. MMRd-ams importantly characterized a subset of patients that were non-MSI but fit the MMR deficient phenotype by mutational signature. Together these findings open an avenue for recognizing and treating a previously unidentifiable group of patients.
SARS-COV-2 in endoscopy: still a long way to go
Authors: Maria Valeria Matteo, Ivo Boškoski, Guido Costamagna
Journal: Gut (2021)

We thank Chaussade et al that raised important questions regarding the potential ways of airborne transmission of microorganisms through endoscopes light source processors1 2 and their discussion on our previously published work on endoscopes used in positive and critically ill patients with SARS-CoV-2.2 Today we know that high viral loads on nasal and throat specimens characterise the early stage of COVID-19 disease, with viral load peaks during the first 7–10 days after symptoms onset and subsequent progressive decline over time.3–5 The dynamic of SARS-CoV2 infection is not yet completely understood but can be strongly influenced by clinical factors such as age, comorbidities, serological response and many other factors.5 For instance, elderly patients might have higher viral loads.5 Our analysis included 12 …
Profile and management of toxicity of selinexor and belantamab mafodotin for the treatment of relapsed/refractory multiple myeloma: A systematic review.
Authors: Karun Neupane, Hamid Ehsan, Ahsan Wahab, Adeel Masood, Tehniat Faraz Ahmed, Saman Bahram, Abdul Hannan, Mobeen Zaka Haider, Moazzam Shahzad, Muhammad Umair Mushtaq, Faiz Anwer
Journal: Journal of Clinical Oncology (2021)

e20014 Background: Selinexor (Sel) and belantamab mafodotin (belamaf) were recently approved by the US FDA for treatment of relapsed/refractory multiple myeloma on July 2019 and August 2020 respectively. The toxicity profile of these drugs is a concern since these are approved for use in patients who have already undergone multiple lines of treatment. Methods: Six studies for Sel and two for belamaf were included after a systematic search of PubMed, Embase, Cochrane, and Clinicaltrials.gov. Results: The most common hematological toxicity associated with these two drugs is thrombocytopenia. The common G-3/4 hematological AEs of Sel were thrombocytopenia (39%-71%), anemia (16%-33%), leukopenia (8%-33%) and neutropenia (9%-33%) whereas common G-3/4 non-hematological AEs were hyponatremia (5%-26%), fatigue (13%-15%), diarrhea (5%-10%), eye disorders (9%-10%), musculoskeletal disorders (4%-10%), elevated liver enzymes (10%), peripheral neuropathy (5%) and vomiting (2-4%). Keratopathy and anemia were the major toxicities of belamaf. Most of these toxicities are manageable. Treatment modifications and dose interruption are usually needed when AEs are more than grade II. REMS program guidelines is recommended for close monitoring and evaluation of Sel and belamaf toxicities and early ophthalmological intervention. Conclusions: As these are newer drugs with limited data, continuous surveillance and monitoring is warranted during the treatment course with early mitigation strategies. The physician should be aware of thrombocytopenia and its management as well as belamaf ocular toxicity which is manageable but if missed could have serious complications.[Table: see text]
Immune checkpoint inhibitor myocarditis: elucidating the spectrum of disease through endomyocardial biopsy
Authors: Nicolas L. Palaskas, Ana Segura, Laura Lelenwa, Bilal A. Siddiqui, Sumit K. Subudhi, Juan Lopez‐Mattei, Jean B. Durand, Anita Deswal, Bihong Zhao, L. Maximilian Buja, Cezar Iliescu
Journal: European Journal of Heart Failure (2021)
Fatal Dengue Acquired in Florida
Authors: Tyler M Sharp, Stephen Morris, Andrea Morrison, Daniela de Lima Corvino, Gilberto A Santiago, Wun-Ju Shieh, Edhelene Rico, Edgar Kopp, Jorge L Muñoz-Jordán, Antonio Marttos, Gabriela Paz-Bailey, Lilian M Abbo, Danielle Stanek
Journal: New England Journal of Medicine (2021)

Fatal Dengue Acquired in Florida A woman presented with acute cholecystitis to a hospital in Miami. She subsequently died from complications of locally acquired dengue virus infection.
The association of skeletal muscle mass and cisplatin pharmacokinetics in head and neck cancer patients: The prospective PLATISMA study.
Authors: Laura Molenaar-Kuijsten, Najiba Chargi, Lot Devriese, Remco de Bree, Alwin Huitema
Journal: Journal of Clinical Oncology (2021)

6021 Background: Locally advanced head and neck squamous cell carcinoma (HNSCC) is commonly treated with cisplatin-based chemoradiotherapy (CRT). Cisplatin is associated with severe toxicity, which negatively affects survival. In recent years, a relationship between low skeletal muscle mass (SMM) and toxicity has been described. This increased toxicity may be related to an altered cisplatin distribution and binding in the fat-free body mass, of which SMM is the largest contributor. This study aims to investigate the association between cisplatin pharmacokinetics and SMM in HNSCC patients. Methods: We performed a prospective observational study in HNSCC patients treated with CRT with cisplatin. Patients received standard-of-care chemotherapy with three cycles of cisplatin, at a dose level of 100 mg/m 2 per cycle. Quantitative data on body size descriptors including SMM, measured on computed tomography scans, and cisplatin pharmacokinetics (total and ultrafilterable plasma concentration) were collected, as well as data on toxicity. Results: 45 evaluable patients were included in the study. A large proportion of the study population had a low SMM (46.7%). The majority of patients (57.8%) experienced cisplatin dose limiting toxicities. Pharmacokinetic analysis showed a significant relationship between cisplatin pharmacokinetics and the body size descriptors SMM, weight, fat-free mass, and body surface area ( p&lt; 0.005). In a simulation, patients with a low SMM were predicted to reach higher bound cisplatin concentrations. The higher concentration of bound cisplatin could be seen as a reflection of the smaller volume of distribution, and could thereby explain the increased toxicity in patients with a low SMM. Conclusions: We found an association between cisplatin pharmacokinetics and SMM. Patients with a low SMM were predicted to reach higher bound cisplatin concentrations, which could be an explanation for the increased toxicity in this patient group. Clinical trial information: Trial NL7469 (NTR7711).
Anti α4β7 Integrin Monoclonal Antibody (Vedolizumab) for the Treatment of Steroid-Resistant Severe Intestinal Acute Graft Versus Host Disease
Authors: Ivetta Danylesko, Roni Shouval, Noga Shem-Tov, Ronit Yerushalmi, Arie Apel, Avichai Shimoni, Arnon Nagler
Journal: Blood (2017)
CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma.
Authors: Jedd D. Wolchok, Vanna Chiarion-Sileni, Rene Gonzalez, Jean-Jacques Grob, Piotr Rutkowski, Christopher D. Lao, Charles Lance Cowey, Dirk Schadendorf, John Wagstaff, Reinhard Dummer, Pier Francesco Ferrucci, Michael Smylie, Marcus O. Butler, Andrew Graham Hill, Ivan Marquez-Rodas, John B. A. G. Haanen, Tuba Bas, Wim van Dijck, James Larkin, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2021)

9506 Background: In the phase 3 CheckMate 067 trial, a durable and sustained clinical benefit was achieved with nivolumab (NIVO) + ipilimumab (IPI) and NIVO alone vs IPI at 5-y of follow-up (overall survival [OS] and progression-free survival [PFS] rates: 52%, 44%, 26% and 36%, 29%, 8%, respectively). Here we report 6.5-y efficacy and safety outcomes. Methods: Eligible pts with previously untreated unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio and stratified by PD-L1 status, BRAF mutation status, and metastasis stage. Pts received NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W followed by NIVO 3 mg/kg Q2W (n = 314), NIVO 3 mg/kg Q2W + placebo (n = 316), or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Co-primary endpoints were PFS and OS with NIVO + IPI or NIVO vs IPI. Secondary endpoints included objective response rate (ORR), descriptive efficacy assessments of NIVO + IPI vs NIVO alone, and safety. Results: With a minimum follow-up of 6.5 y, median OS was 72.1 mo with NIVO + IPI, 36.9 mo with NIVO, and 19.9 mo with IPI (table). Median time from randomization to subsequent systemic therapy was not reached (NR; 95% CI, 59.6–NR) with NIVO + IPI, 25.2 mo (95% CI, 16.0–43.2) with NIVO, and 8.0 mo (95% CI, 6.5–8.7) with IPI; 36%, 49%, and 66% of pts, respectively, received any subsequent systemic therapy. Median treatment-free interval (which excluded pts who discontinued follow-up prior to initiation of subsequent systemic therapy) was 27.6 mo (range, 0–83.0), 2.3 mo (range, 0.2–81.6), and 1.9 mo (range, 0.1–81.9) with NIVO + IPI, NIVO, and IPI, respectively. Of the pts alive and in follow-up, 112/138 (81%; NIVO + IPI), 84/114 (74%; NIVO), and 27/63 (43%; IPI) were off treatment and never received subsequent systemic therapy; 7, 8, and 0 pts, respectively, were still on treatment. Grade 3/4 treatment-related adverse events were reported in 59% of NIVO + IPI-treated pts, 24% of NIVO-treated pts, and 28% of IPI-treated pts. Since the 5-y analysis, no new safety signals were observed and no additional treatment-related deaths occurred. Conclusions: This 6.5-y analysis represents the longest follow-up from a phase 3 melanoma trial in the modern checkpoint inhibitor combination therapy and targeted therapy era. The results show durable improved outcomes with NIVO + IPI and NIVO vs IPI in pts with advanced melanoma. We observed improvement in OS, PFS, and ORR with NIVO + IPI over NIVO alone. Clinical trial information: NCT01844505. [Table: see text]
Improving outcomes and shared decisions in pancreatic cancer using animated pancreas patient (APP) visual formats of learning: A National Pancreas Foundation (NPF) patient education initiative.
Authors: Satish Munigala, Eileen Mary O'Reilly, Matthew Alsante, Jane Holt, Andrew H. Ko, Andres Gelrud
Journal: Journal of Clinical Oncology (2021)

e16242 Background: Pancreatic cancer (PC) outcomes continue to be dismal in the United States (US) and worldwide. Efforts are focused on early diagnosis, treatment, and prevention. However, knowledge translation in PC and effective resources that address patient-provider collaborative decisions are limited and barriers to health literacy continue to impede patient understanding. Evidence increasingly supports the need for informative education for patients to facilitate shared decisions in critical cancer interventions. We evaluated the National Pancreas Foundation’s APP, a visual approach to learning, to determine how shared-decision making and patient barriers to health literacy can be improved, leading to better patient-provider decisions and outcomes. Methods: Using visual formats of learning (animations, videos, and slide shows), we monitored APP website and YouTube metrics from September 2013 to February 2021. We evaluated learner activity, number of views with highest retention in US and globally. Results: APP gathered 4,551,079 views (489,091 views on the APP website and 4,061,988 views on YouTube) from over 100 countries. The majority of viewers (60%) were from the US with 54% being patients, 17% family/caregivers, 16% healthcare providers and 13% other. The animations "Understanding Clinical Trials", "Pancreatic Cancer: Treatment and Outcomes", “Pancreatic Cancer: Signs, Symptoms and Risk Factors", and "Pancreatic Cancer: Pathophysiology, Diagnosis and Staging" had 1,372; 4,643; 8,819 and 4,359 views respectively on the website and 180,845; 77,942; 56,151 and 23,112 views respectively on YouTube. Top expert videos viewed most were "What are the different stages of pancreatic cancer?", "What are the symptoms of pancreatic cancer?", “What is a “Placebo” in a clinical trial and is it always used?”, and “What should I expect following surgery to remove a malignant pancreatic cancer tumor?" with 488; 1,558; 76 and 239 views respectively on the website and 14,869; 10,917; 5,206 and 3,624 views respectively on YouTube. Conclusions: Our study suggests visual formats of education are effective in communicating complex health information to persons with poor health literacy. Pancreatic cancer education based on visual formats have vast potential to provide effective learning for patients. Continued efforts should be made to provide resources for patient-provider shared decisions and address patient health literacy barriers for best health outcomes.
Nonhematologic neoplasia in biallelic BRCA2 mutated Fanconi anemia.
Authors: Vasant Chinnabhandar, Todd E DeFor, Rebecca Tryon, John E Wagner, Margaret L MacMillan
Journal: Journal of Clinical Oncology (2021)

10041 Background: Fanconi anemia (FA) is a cancer predisposition disorder. Affected individuals do not tolerate conventional doses of chemotherapy or radiation well. Biallelic BRCA2 mutations cause a rare (̃3%) form of FA. Most patients with this subtype have a family history of breast cancer and die in early childhood. Optimal management remains uncertain. Herein, we report the world’s largest single center cohort of biallelic BRCA2 patients, with a focus on non-hematologic malignancies. Methods: The University of Minnesota’s prospectively maintained FA database was analyzed for data on biallelic BRCA2 mutated FA patients. IRB-approved consent was obtained for all subjects. Results: Twenty patients with biallelic BRCA2 were identified. Median age of FA diagnosis was 1.5 years (range: 0-16.2 years). All patients had a significant history of cancer in the family with breast cancer being particularly frequent (65%). Eight (40%) patients developed non-hematologic neoplasia before 18 years of age. These included 10 malignant tumors and 4 benign neoplastic lesions; 3 patients had more than one solid tumor (see Table). Surgical resection was attempted in all malignant tumors, dose reduced adjuvant chemotherapy was utilized in 5 cases and radiation in one case. Thirteen (65%) patients developed hematologic malignancies (AML=6, ALL=3, MDS=4), all without preceding marrow failure. Fourteen patients underwent allogeneic HCT. Eleven patients have died, 3 from solid tumors and 5 from leukemias. Nine patients are currently alive, of whom 3 are post-HCT. Only 4 (age range: 6.5-16.3 years) patients in the cohort remain free of any oncologic diagnoses. Conclusions: Patients with FA due to biallelic BRCA2 mutations have a unique phenotype with an extraordinarily high risk of early-onset de-novo acute leukemia and solid tumors, often both diagnosed in the same patient. They require extensive, lifelong cancer surveillance from an early age to optimize outcomes. Therapy for malignant diagnoses should aim to minimise exposure to genotoxic / crosslinking agents and radiation. BRCA2 mutation testing in family members and appropriate genetic counselling is essential. Additionally, a family history of BRCA2 mutated cancers should prompt FA testing in offspring with any relevant FA-related clinical findings. Nonhematologic neoplasia and therapy.[Table: see text]
Generation of Megakaryocytes and Platelets from Valproic Acid Expanded Human Cord Blood CD34+ Cells in Culture
Authors: Nadim Mahmud, Rajeev Ranjan, Jia J. Wu, Benjamin Petro, Meryem K. Terzioglu, Hasan Issa, Darryl A. Abbott, Dolores Mahmud, William M. Miller
Journal: Blood (2017)
Trastuzumab biosimilar (Kanjinti) in breast cancer patients: One-center retrospective observational study.
Authors: Agnieszka I. Jagiello-Gruszfeld, Izabela Lemanska, Elzbieta Brewczynska, Katarzyna Pogoda, Roman Dubianski, Renata Sienkiewicz, Ewa Szombara, Beata Jagielska, Zbigniew Nowecki
Journal: Journal of Clinical Oncology (2021)

e13015 Background: The switch of anti-HER2 therapy from the reference drug Herceptin to a biosimilar has presented challenges to the clinics. Real world data on trastuzumab biosimilars are very limited or not available. In our clinic we perform observational retrospective study to confirm safety and efficacy Kanjinti. Methods: 195 patients (pts) with HER2-positive breast cancer were treated with Kanjinti from Jul.18. 2018 to Jan.29.2020. Cardiac events (↓LVEF) and other unexpected or serious adverse events were monitored in all pts. 34 pts received carboplatin, docetaxel pertuzumab and trastuzumab biosimilar in neoadjuvant setting, 99 received trastuzumab biosymilar in monotherapy or with other cytostatic drugs in neoadjuvant or adjuvant setting, and 62 received docetaxel, pertuzumab and Kanjinti in metastatic setting. Results: Pertuzumab was used in combination with Kanjinti in 49% of pts (32% in the 1st. line of palliative tretment and 17% in the neoadjuvant settings, respectively).Switching from Herceptin to Kanjinti was observed in 65% of MBC patients and 37% of EBC patients. Switching was done at a median of 4th cycle. 6 patients had a decline in LVEF. No other trastuzumab related adverse events was observed. Conclusions: The management of HER2 positive breast cancer in our clinic follows the international recommendations. This is the first real world safety data of Kanjinti from Poland. The 12-month follow-up treatment with Kanjinti an acceptable cardiac safety profile. In cases where there was a switch from Herceptin to Kanjinti or Kanjinti combined with pertuzumab, the safety profile was similar to that previously reported in other studies.
Mobile and comprehensive assessment of patient-reported outcomes (PRO) in routine inpatient cancer care: A three-arm randomized controlled feasibility study.
Authors: Hanna Salm, Leopold Hentschel, Michael Kramer, Daniel Pink, Markus K Schuler
Journal: Journal of Clinical Oncology (2021)

e18664 Background: Most of the work on PRO has been done in outpatient setting. However, cancer patients might even suffer from more severe problems when admitted to hospital for anticancer therapy. The question whether and how patients’ well-being changes during the course of the hospital stay and if electronically assessed PRO (ePRO) will bring benefit to patients and physicians remains unanswered. Implementing such a tool into routine clinical care can be considered as an additional challenge.The objectives of this study were to implement a multidimensional ePRO system to improve patient-physician interaction in inpatient cancer care and test its feasibility. A comprehensive set of PRO measures that would broadly assess the patient’s situation was developed by a multidisciplinary expert team. Before study initiation, semi-structured interviews with patients were carried out to optimize visualization and user experience. The tool included a rapid response ePRO system with a patient-tailored graphical feedback for physicians. The effect of the mobile tool on quality of life (QoL), symptom burden and patients’ satisfaction with care were explored. Methods: The study is an interventional, three-arm and multicenter inpatient trial. A self-administered questionnaire based on validated PRO-measures was applied and completed at admission, one week after and at discharge. Group A (intervention arm) and B received tablet versions while group C (control) completed the questionnaire on paper. Additional to the mere assessment of electronic patient reported outcome, results from group A were presented graphically to the treating physicians. Standardized instruments included measures of QoL (EORTC QLQ-C30), patients’ satisfaction with care (IN-PATSAT32) and adverse events (PRO-CTCAE). A feasibility questionnaire was administered to arm A and B. Results: N = 185 patients (mean age 63.5, 44.3% female) were recruited in oncology wards. 62% of patients were treated for oncological disease (33% with stage IV disease) and 37% for hematological disease. Feasibility questions revealed that the majority of patients preferred the electronic tool and believed that the tool was of high value for individualized patient care. Among others, symptom burden and global QoL did not significantly change during hospital stay. Satisfaction with care was significantly lower ( p = 0.047) in the intervention group (mean 3.55) versus the control group (mean 3.77) with scores ranging from 0-5. Conclusions: Results indicate that the intervention is feasible. Some of the results are counterintuitive and could possibly be influenced by a lack of physician compliance due to a busy daily routine. Moreover, the optimal interval and composition of questionnaires has yet to be determined in inpatient setting.