tbuckley/cabot-search huggingface dataset:
EPR19-070: Incidence Pattern of Malignant Lymphoma by Cell-Lineage/Cell-Maturity Status in Nagasaki, Japan, 1985–2012: Preliminary Results
Authors: Thi My Hanh Luong, Daisuke Niino, Hisayoshi Kondo, Shiro Miura, Masahiro Nakashima, Masako Iwanaga
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Malignant lymphoma (ML) is a heterogeneous neoplasm with a wide range of etiological factors, pathological patterns, incidence rates, and outcomes. Most epidemiological studies have reported the incidence pattern of ML by simply dividing into 2 groups, Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL). However, differences in the incidence pattern by cell-lineage or by cell-maturity have been rarely evaluated. The aim of this study was to characterize the incidence pattern of ML by cell-lineage and cell-maturity in Japanese population. Methods: This is a descriptive study based on regional cancer registry data. We obtained a dataset of anonymized 12,645 cases with ICD-O histology codes of ML diagnosed 1960–2012 from the Nagasaki Prefectural Cancer Registry. From those, we excluded 1,477 records because of codes other than ML, diagnosed before 1985, and possible relapse records of identical cases. Records based on ICD-O-1 or ICD-O-2 were substituted by the corresponding ICD-O-3 code. We also treated patients having multiple types of MLs at same diagnosis date as a single case of “composite/discordant lymphoma,” and patients having multiple types of MLs at different diagnosis date as a single case based on the first lymphoma. We finally confirmed 11,118 patients of ML that occurred in 1985–2012. The overall age-adjusted incidence rate (per 100,000 population) during 1985–2012 was already reported to be 20.5 for men and 12.9 for women. Then we divided them into the following cell-lineage/maturity groups: precursor B (B1), mature B (B2), other B (B3), precursor T (T1), mature T/NK (T2), undetermined cell-lineage NHL (U), HL (H), and other lymphomas (O). Results: The median age at diagnosis of all patients was 69.7 years (interquartile range, 59.4–78.0 years) and male sex were 5,980 (53.8%). The frequency of B-cell lineage, T/NK-cell lineage, and Hodgkin lymphoma were 5,196 (46.7%), 3,257 (29.3%), and 209 (1.9%), respectively, with a significant sex difference ( P &lt;.0001). For B-cell maturity, B2 was predominant (84.8%), followed by B3 (14.4%) with a significant sex difference ( P &lt;.0001). In T-cell, T2 was predominant (99.4%). Conclusion: This preliminary analysis suggests a significant sex difference in the cell-lineage and cell-maturity of ML. Additional analysis to elucidate whether there are any differences in the incidence pattern by cell-lineage and by cell-maturity of ML between general population and Nagasaki atomic bomb survivors are underway.
HSR19-084: Real-World Treatment Patterns and Clinical Outcomes in Non-Small Cell Lung Cancer Patients with EGFR Exon 20 Insertion Mutations
Authors: Maral DerSarkissian, Shuanglian Li, Aaron Galaznik, Rachel Bhak, Iryna Bocharova, Thomas Kulalert, Huamao M. Lin, Hui Huang, Mei Sheng Duh
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Mutations in the epidermal growth factor receptor (EGFR) gene have been identified in 10%–50% of patients with non-small cell lung cancer (NSCLC). Exon 20 insertion mutations represent about 2%–10% of this group. Reports of real world experience of NSCLC patients with EGFR exon 20 insertion mutations are limited. This study describes patient characteristics, treatment patterns, and survival outcomes of NSCLC patients with EGFR exon 20 insertions based on real world data. Methods: Flatiron Health electronic health record data, largely from community oncology practices, from January 2011–April 2018 were used for this retrospective observational study. Treatment-naïve (TN) and relapsed/refractory (RR) second-line patients diagnosed with NSCLC with EGFR exon 20 insertion mutation aged ≥18 years at treatment initiation were included. Patient characteristics were described, and Kaplan-Meier analyses were used to assess real world overall survival (rwOS) separately for TN (starting at first-line therapy) and RR (starting at second-line therapy) patients. Results: There were 128 TN and 71 RR patients identified. Median age was 66.5 and 65.0 years for TN and RR patients, respectively, and over half were female (TN: 59.4%, RR: 53.5%). Among 83 TN and 47 RR patients with known ECOG score at advanced diagnosis, most had score 0–1 (TN: 56.3%; RR: 62.0%). Central nervous system metastases were observed in 35.2% of TN and 33.8% of RR patients. While 45.3% of TN patients received any chemotherapy, approximately 20% of both TN and RR patient groups had exposure to various EGFR TKIs. Overall, median rwOS was low at 14.6 months for TN patients, and 10.1 months for RR patients. Conclusion: Real world survival of patients with EGFR exon 20 NSCLC remains poor. Treatment with any chemotherapy regimen was most commonly used followed by EGFR TKIs in TN patients, while the proportion treated with chemotherapy and EGFR TKIs was similar in RR patients. Despite limited evidence in this population, over a fifth of TN and RR patients received EGFR TKI monotherapy. This study demonstrated unmet need for improved therapeutic options in TN and RR patients with NSCLC with EGFR exon 20 insertion mutation.
Identification of Lymphocyte Subsets Associated with Outcomes in Patients with Hematological Malignancy Following Allogeneic Stem Cell Transplantation: A Single Institute Study
Authors: Taiki Ando, Yasufumi Ishiyama, Takayoshi Tachibana, Masatsugu Tanaka, Heiwa Kanamori, Hideaki Nakajima
Journal: Blood (2018)
Relationship Between PNPLA3 rs738409 Polymorphism and Decreased Kidney Function in Children With NAFLD
Authors: Giovanni Targher, Alessandro Mantovani, Anna Alisi, Antonella Mosca, Nadia Panera, Christopher D. Byrne, Valerio Nobili
Journal: Hepatology (2019)

Emerging evidence suggests that patatin‐like phospholipase domain–containing protein‐3 ( PNPLA3 ) rs738409 genotype (the major genetic variant associated with susceptibility to nonalcoholic fatty liver disease [NAFLD]) is associated with decreased kidney function in adults. Currently, it is uncertain whether this association also occurs in children/adolescents and whether any association is independent of liver disease severity. We enrolled a sample of 142 Caucasian children and adolescents with biopsy‐proven NAFLD, presenting to the Liver Unit of the “Bambino Gesù” Children's Hospital. The glomerular filtration rate (e‐GFR) was estimated using the Bedside Schwartz equation, whereas 24‐hour proteinuria was measured using a radioimmunoassay method. Genotyping for the PNPLA3 rs738409 genotype was undertaken using the single‐nucleotide polymorphism genotyping allelic discrimination method. Overall, 45 children had G/G, 56 had G/C, and 41 had C/C PNPLA3 rs738409 genotype, respectively. Children with G/G genotype had significantly lower e‐GFR (107.5 ± 20 versus 112.8 ± 18 versus 125.3 ± 23 mL/min/1.73 m 2 , P = 0.002) and higher 24‐hour proteinuria (58.5 ± 21 versus 53.9 ± 22 versus 42.9 ± 20 mg/day, P = 0.012) compared with those with either G/C or C/C genotypes. After adjustment for age, sex, systolic blood pressure, measures of adiposity, homeostasis model assessment–estimated insulin resistance and biopsy‐confirmed nonalcoholic steatohepatitis and stage of liver fibrosis, the presence of rs738409 G/G genotype was independently associated with both lower e‐GFR (β coefficient: −23.6; 95% confidence interval [CI]: −36.3 to −10.8; P &lt; 0.001) and higher 24‐hour proteinuria (β coefficient: 15.3; 95% CI: 1.12 to 30.5; P = 0.046). Conclusion : Regardless of established renal risk factors and the histological severity of NAFLD, the PNPLA3 G/G genotype was strongly associated with decreasing kidney function and increasing 24‐hour proteinuria in children/adolescents with histologically confirmed NAFLD.
Extraosseous Colonic Uptake of 99mTc-MDP Associated With Iodinated Contrast CT
Authors: Thomas S. C. Ng, Christopher G. Sakellis, Heather A. Jacene
Journal: Clinical Nuclear Medicine (2019)

Extraosseous Tc-MDP uptake on bone scans is frequently encountered and has a broad differential diagnosis. A small subset of such patients can present with intestinal Tc-MDP uptake. We present the case of a 35-year-old woman with status after right nephrectomy for renal cell carcinoma, being followed with bone scan for osseous metastases. Follow-up imaging revealed new faint Tc-MDP uptake in the right hemiabdomen. Correlation with contrast-enhanced CT localized this uptake to the ascending colon. Enteric Tc-MDP uptake and its association with iodinated contrast should be considered in the differential diagnosis of extraosseous enteric Tc-MDP uptake.
No more infant formula advertising in The BMJ
Authors: Fiona Godlee
Journal: BMJ (2019)

This week we announced our decision to stop carrying advertisements for formula milk (doi:10.1136/bmj.l1200). Regular readers of The BMJ will have seen our recent investigation by Chris van Tulleken showing the extent of ties between formula milk manufacturers and the authors of guidelines on cow’s milk protein allergy (doi:10.1136/bmj.k5056). The resultant overdiagnosis and overtreatment of this poorly defined condition are among many contributors to falling rates of breastfeeding around the world.

The decision to stop taking the advertisements has been an interesting journey for us. In …
How to make the best use of immunotherapy as first-line treatment of advanced/metastatic non-small-cell lung cancer
Authors: S. Peters, M. Reck, E.F. Smit, T. Mok, M.D. Hellmann
Journal: Annals of Oncology (2019)

Antibodies that target programmed death 1 (PD-1) or its ligand [programmed death ligand 1 (PD-L1)] have become a mainstay of first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC) without targetable genetic alterations. In this review, we summarize results from recent clinical trials that have evaluated the anti-PD-1 antibodies pembrolizumab and nivolumab and the anti-PD-L1 antibodies atezolizumab and durvalumab as first-line treatment as monotherapy and in combination with chemotherapy, other immunotherapies, and antiangiogenesis agents. We discuss factors that may influence treatment selection, including patient baseline clinical and demographic characteristics, tumor histology, and biomarkers such as PD-L1 expression and tumor mutation burden. While immunotherapy has become a central component of first-line treatment of most patients with advanced NSCLC, important questions remain about how treatment should be managed for individual patients.
An Optogenetic Controllable T Cell System for Hepatocellular Carcinoma Immunotherapy
Authors: Bixing Zhao, Yingchao Wang, Xionghong Tan, Xiaoyuan Zheng, Fei Wang, Kun Ke, Cuilin Zhang, Naishun Liao, Yuan Dang, Yingjun Shi, Youshi Zheng, Yunzhen Gao, Qin Li, Xiaolong Liu, Jingfeng Liu
Journal: Theranostics (2019)

Rationale: T-cell based immunotherapy increasingly shows broad application prospects in cancer treatment, but its performance in solid tumors is far from our expectation, partly due to the re-inhibition of infiltrated T cells by immunosuppressive tumor microenvironment. Here we presented an artificial synthetic optogenetic circuit to control the immune responses of engineered T cells on demand for promoting and enhancing the therapeutic efficiency of cancer immunotherapy. Methods: We designed and synthesized blue-light inducible artificial immune signaling circuit and transgene expression system. The blue light triggered transgene expression was investigated by luciferase activity assay, qPCR and ELISA. The in vitro cytotoxicity and proliferation assays were carried out on engineered T cells. The in vivo anti-tumor activity of engineered T cells was investigated on xenograft model of human hepatocellular carcinoma. Results: Blue light stimulation could spatiotemporally control gene expression of specific cytokines (IL2, IL15, and TNF-α) in both engineered 293T cells and human primary T cells. This optogenetic engineering strategy significantly enhanced the expansion ability and cytolytic activity of primary T cells upon light irradiation, and the light activated T cells showed high-efficiency of elimination against xenograft of hepatocellular carcinoma cells. Conclusions: The current study represented an engineered remotely control T cell system for solid tumor treatment, and provided a potential strategy to partially overcome the intrinsic shortages of current immune cell therapy.
Exosomes in the tumor microenvironment as mediators of cancer therapy resistance
Authors: Irene Li, Barzin Y. Nabet
Journal: Molecular Cancer (2019)

Exosomes are small extracellular vesicles that contain genetic material, proteins, and lipids. They function as potent signaling molecules between cancer cells and the surrounding cells that comprise the tumor microenvironment (TME). Exosomes derived from both tumor and stromal cells have been implicated in all stages of cancer progression and play an important role in therapy resistance. Moreover, due to their nature as mediators of cell-cell communication, they are integral to TME-dependent therapy resistance. In this review, we discuss current exosome isolation and profiling techniques and their role in TME interactions and therapy resistance. We also explore emerging clinical applications of both exosomes as biomarkers, direct therapeutic targets, and engineered nanocarriers. In order to fully understand the TME, careful interrogation of exosomes and their cargo is critical. This understanding is a promising avenue for the development of effective clinical applications.
A multifaceted intervention to improve syphilis screening and treatment in pregnant women in Kinshasa, Democratic Republic of the Congo and in Lusaka, Zambia: a cluster randomised controlled trial
Authors: Fernando Althabe, Elwyn Chomba, Antoinette K Tshefu, Ernest Banda, María Belizán, Eduardo Bergel, Mabel Berrueta, Jane Bertrand, Carl Bose, Maria Luisa Cafferata, Waldemar A Carlo, Alvaro Ciganda, France Donnay, Ezequiel García Elorrio, Luz Gibbons, Karen Klein, Jerker Liljestrand, Paul D Lusamba, Arlette K Mavila, Agustina Mazzoni, Dalau M Nkamba, Friday H Mwanakalanga, Abigail Mwapule Tembo, Musaku Mwenechanya, Lee Pyne-Mercier, Cintia Spira, Jean D Wetshikoy, Xu Xiong, Pierre Buekens
Journal: The Lancet Global Health (2019)

Despite international recommendations, coverage of syphilis testing in pregnant women and treatment of those found seropositive remains limited in sub-Saharan Africa. We assessed whether combining the provision of supplies with a behavioural intervention was more effective than providing supplies only, to improve syphilis screening and treatment during antenatal care.In this 18-month, cluster randomised controlled trial, we randomly assigned (1:1) 26 urban antenatal care clinics in Kinshasa, Democratic Republic of the Congo, and Lusaka, Zambia, to receive a behavioural intervention (opinion leader selection, academic detailing visits, reminders, audits and feedback, and supportive supervision) plus supplies for syphilis testing and treatment (intervention group) or to receive supplies only (control group). The primary outcomes were proportion of pregnant women who had syphilis screening out of the total who attended the clinic; and the proportion of women who had treatment with benzathine benzylpenicillin out of those who tested positive for syphilis at their first antenatal care visit. This trial is registered at ClinicalTrials.gov, number NCT02353117.The 18-month study period was Feb 1, 2016, to July 14, 2017. 18 357 women were enrolled at the 13 intervention clinics and 17 679 women were enrolled at the 13 control clinics at their first antenatal care visit. Syphilis screening was done in a median of 99·9% (IQR 99·0-100·0) of women in the intervention clinics and 93·8% (85·0-98·9) in the control clinics (absolute difference 6·1% [95% CI 1·1-14·1]; p=0·00092). Syphilis treatment at the first visit was done in a median of 100% (IQR 99·7-100·0) of seropositive women in intervention clinics and 43·2% (2·6-83·2) of seropositive women in control clinics (absolute difference 56·8% [12·8-99·0]; p=0·0028).A behavioural intervention, together with the provision of supplies, can lead to more than 95% of women being screened and treated for syphilis. The sole provision of supplies is sufficient to reach such levels of screening coverage but is not sufficient to ensure high levels of treatment.Bill & Melinda Gates Foundation.
FULL-FIELD OPTICAL COHERENCE TOMOGRAPHY OF THE NORMAL DIGESTIVE MUCOSA: A PROMISING TOOL FOR THE STUDY OF THE DIGESTIVE BARRIER
Authors: L Quénéhervé, R Olivier, JF Mosnier, C Brochard, C Bossard, M Neunlist, E Coron
Journal: Endoscopy (2019)

Full-field optical coherence tomography (FF-OCT) is a non-invasive imaging technique, based on interferometry, allowing dynamic acquisition of images of ex vivo specimens on a microscopic scale. The aim of this study was to demonstrate the feasibility of imaging normal digestive biopsies using FF-OCT.
Lentiviral gene therapy corrects platelet phenotype and function in patients with Wiskott-Aldrich syndrome
Authors: Lucia Sereni, Maria Carmina Castiello, Dario Di Silvestre, Patrizia Della Valle, Chiara Brombin, Francesca Ferrua, Maria Pia Cicalese, Loris Pozzi, Maddalena Migliavacca, Maria Ester Bernardo, Claudio Pignata, Roula Farah, Lucia Dora Notarangelo, Nufar Marcus, Lorella Cattaneo, Marco Spinelli, Stefania Giannelli, Marita Bosticardo, Koen van Rossem, Armando D'Angelo, Alessandro Aiuti, Pierluigi Mauri, Anna Villa
Journal: Journal of Allergy and Clinical Immunology (2019)

BackgroundThrombocytopenia is a serious issue for all patients with classical Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) because it causes severe and life-threatening bleeding. Lentiviral gene therapy (GT) for WAS has shown promising results in terms of immune reconstitution. However, despite the reduced severity and frequency of bleeding events, platelet counts remain low in GT-treated patients.ObjectiveWe carefully investigated platelet defects in terms of phenotype and function in untreated patients with WAS and assessed the effect of GT treatment on platelet dysfunction.MethodsWe analyzed a cohort of 20 patients with WAS/XLT, 15 of them receiving GT. Platelet phenotype and function were analyzed by using electron microscopy, flow cytometry, and an aggregation assay. Platelet protein composition was assessed before and after GT by means of proteomic profile analysis.ResultsWe show that platelets from untreated patients with WAS have reduced size, abnormal ultrastructure, and a hyperactivated phenotype at steady state, whereas activation and aggregation responses to agonists are decreased. GT restores platelet size and function early after treatment and reduces the hyperactivated phenotype proportionally to WAS protein expression and length of follow-up.ConclusionsOur study highlights the coexistence of morphologic and multiple functional defects in platelets lacking WAS protein and demonstrates that GT normalizes the platelet proteomic profile with consequent restoration of platelet ultrastructure and phenotype, which might explain the observed reduction of bleeding episodes after GT. These results are instrumental also from the perspective of a future clinical trial in patients with XLT only presenting with microthrombocytopenia.
Endothelial Sox17 promotes allergic airway inflammation
Authors: Eun Hee Ha, Jun-Pyo Choi, Hyouk-Soo Kwon, Hyeung Ju Park, Sang Joon Lah, Keun-Ai Moon, Seung-Hyo Lee, Injune Kim, You Sook Cho
Journal: Journal of Allergy and Clinical Immunology (2019)
Changes in Practice among Physicians with Malpractice Claims
Authors: David M. Studdert, Matthew J. Spittal, Yifan Zhang, Derek S. Wilkinson, Harnam Singh, Michelle M. Mello
Journal: New England Journal of Medicine (2019)

Physicians with poor malpractice liability records may pose a risk to patient safety. There are long-standing concerns that such physicians tend to relocate for a fresh start, but little is known about whether, how, and where they continue to practice.We linked an extract of the National Practitioner Data Bank to the Medicare Data on Provider Practice and Specialty data set to create a national cohort of physicians 35 to 65 years of age who practiced during the period from 2008 through 2015. We analyzed associations between the number of paid malpractice claims that physicians accrued and exits from medical practice, changes in clinical volume, geographic relocation, and change in practice-group size.The cohort consisted of 480,894 physicians who had 68,956 paid claims from 2003 through 2015. A total of 89.0% of the physicians had no claims, 8.8% had 1 claim, and the remaining 2.3% had 2 or more claims and accounted for 38.9% of all claims. The number of claims was positively associated with the odds of leaving the practice of medicine (odds ratio for 1 claim vs. no claims, 1.09; 95% confidence interval [CI], 1.06 to 1.11; odds ratio for ≥5 claims, 1.45; 95% CI, 1.20 to 1.74). The number of claims was not associated with geographic relocation but was positively associated with shifts into smaller practice settings. For example, physicians with 5 or more claims had more than twice the odds of moving into solo practice than physicians with no claims (odds ratio, 2.39; 95% CI, 1.79 to 3.20).Physicians with multiple malpractice claims were no more likely to relocate geographically than those with no claims, but they were more likely to stop practicing medicine or switch to smaller practice settings. (Funded by SUMIT Insurance and the Australian Research Council.).
No Escalation of Treatment: Moving Beyond the Withholding/Withdrawing Debate
Authors: Jason N. Batten, Jacob A. Blythe, Sarah E. Wieten, Elizabeth W. Dzeng
Journal: The American Journal of Bioethics (2019)

This article refers to:Withholding and Withdrawing Life-Sustaining Treatment: Ethically Equivalent?Withdrawal Aversion and the Equivalence Test