tbuckley/cabot-search huggingface dataset:
Minimising the environmental impact of inhaled therapies
Authors: Lauri Lehtimäki, Unnur Björnsdóttir, Christer Janson, Tari Haahtela
Journal: European Respiratory Journal (2020)

We read with interest the recent editorial by Keeley et al. [1] on the timely topic of changing pressurised metered dose inhalers (pMDIs) to dry powder inhalers (DPIs) due to the much higher carbon footprint of pMDIs [2]. We agree with the authors that global warming cannot be tackled only by focusing on inhaler devices, but as long as we can provide safe and effective treatment to our patients, we cannot overlook environmental facts either. We feel that Keeley et al. [1] gave an unjustified negative impression on the performance of DPIs. They imply that DPIs are more expensive than pMDIs, that switching from pMDI to DPI leads to poorer asthma control, and that patients using DPIs should have a pMDI+spacer rescue pack since DPIs cannot be relied on as rescue medication. However, we feel that these misleading claims are based on wrong interpretations of the publications they cite, or on opinions without any supporting data. Since in many countries, like in Finland and Sweden, good control of asthma and COPD is achieved at a national level [3, 4] while the majority of patients using inhaled therapies are treated with DPIs, (56% in Finland and 71% in Sweden, according to IQVIA standard units volume data for 2019), we think it is worth correcting these wrong impressions. Environmental burden of inhaled therapies needs to be considered, as long as treatment efficacy and safety are secured <https://bit.ly/3bRSl07>
高糖胰岛素混合液在外科感染中的应用
Authors: 程亭秀, 俞建臣
Journal: BMJ (2004)

2000年7月～2002年9月我们使用高糖胰岛素混合液为外科感染患者66例换药,效果良好. 1.对象与方法:治疗组患者66例,对照组65例,两组患者在性别、年龄、创面面积与类型、糖尿病患病率方面差异均无显著性。
Phase Ia dose escalation of IBI318, a first-in-class bispecific anti-PD-1/PD-L1, in patients with advanced tumors.
Authors: Rui-hua Xu, Hongyun Zhao, Xiao-Li Wei, Yang Zhang, Feng Wang, Zhiqiang Wang, Fenghua Wang, Yu-Hong Li, Ben-Yan Zou, Xiaomin Zhu, Wencheng Yu, Hui Zhou
Journal: Journal of Clinical Oncology (2020)

3062 Background: With the proven success of PD-1 and PD-L1 monoclonal antibodies, exploiting antibody based immune checkpoint strategies has potential to reduce disease burden and improve patient survival outcome. IBI318, as a first-in-class anti-PD-1/PD-L1 bispecific antibody, could provide more potent anti-tumor activity and more durable response. Here we report preliminary results from an ongoing phase 1a/1b study of IBI318 in advanced tumors. Methods: In the dose escalation of Phase 1a, patients with advanced and/or refractory solid tumors or hematological malignancies were enrolled to receive IBI318. Dose escalation was from 0.3 mg to 600 mg (8 cohorts) via an accelerated titration followed by a modified toxicity probability interval-2 design with a 28-day dose-limiting toxicity (DLT) observation period. Patients without DLT will receive IBI318 every two week (Q2W). Tumor assessments were performed every 6 weeks. Results: As of Jan 10, 2020, 15 pts who had failed at least one line of treatment had been enrolled (1 pt each in 0.3 mg, 1 mg, 3 mg and 10 mg; 3 pts in 30 mg; 3 pts in 100 mg, 3 pts in 300 mg and 2 pts in 600 mg) for dose escalation and received at least 1 dose of treatment. Median duration of treatment was 6.1 (range: 2.1-24.7) weeks. IBI318 had been well tolerated with no DLT from 0.3mg to 300mg group. 11 of 15 pts had treatment related AEs (TRAEs) and the most common (≥10%) TRAEs were pyrexia (20.0%, G1/2) and infusion-related reaction (20.0%, G1/2). 1 patient in 300 mg had an immune-related AE (G2 arthritis). No ≥G3 TRAE had been observed. 12 pts had at least one on-study tumor assessment. 3 of 9 pts receiving dose level ≥10mg had achieved partial response (1 confirmed, 1 pending confirmation and the other PD after the first PR scan). A total of 10 pts discontinued treatment due to disease progression (8) and AE (2, G4 lung infection and G4 upper gastrointestinal hemorrhage, both were not related to treatment). Conclusions: IBI318 has shown an acceptable safety profile. Preliminary efficacy results are promising in advanced cancer patients. The study is currently ongoing at dose level of 600 mg Q2W. Clinical trial information: NCT03875157 .
Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-agnostic ovarian cancer.
Authors: Lucy Gilbert, Ana Oaknin, Ursula A. Matulonis, Gina Mantia-Smaldone, Peter C Lim, Cesar Martin Castro, Diane M. Provencher, Sanaz Memarzadeh, Jiuzhou Wang, Brooke Esteves, Patrick A Zweidler-McKay, Kathleen N. Moore, David M. O'Malley
Journal: Journal of Clinical Oncology (2020)

6004 Background: Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. As part of the Phase 1b FORWARD II trial (NCT02606305), the combination of MIRV with bevacizumab (BEV) was evaluated in pts with FRα-positive (medium/high expression; ≥ 50%/ ≥75% of cells with PS2+ staining intensity), platinum agnostic ovarian cancer, defined as pts with either platinum resistant (PR) (recurrence within 6 months after last platinum dose) or platinum sensitive (PS) responded to the last platinum therapy received before study entry and did not progress within 6 months) disease for whom a non-platinum based doublet would be appropriate. Methods: Pts received MIRV (6 mg/kg; adjusted ideal body weight) and BEV (15 mg/kg) on Day 1 of a 21-day cycle. Responses were assessed by investigator according to RECIST 1.1 and adverse events (AEs) evaluated by CTCAE v4.03. Results: In total, 60 pts received the combination, with a median age of 60 years, and a median of 2 prior lines of systemic therapy (range 1-4). Platinum status was determined for 56 pts, with 30 (50%) considered PR and 26 (43%) considered PS; platinum status data were incomplete for 4 pts. The most common treatment related AEs (percent all grade/grade 3+) were diarrhea (65/2), blurred vision (62/3), nausea (55/0), and fatigue (55/5). The most common treatment related grade 3+ AEs were hypertension and neutropenia, (10% each); all other grade 3+ events occurred in ≤ 5% of pts. Serious AEs regardless of relationship to study drug were infrequent, with the most common events being small intestinal obstruction in 3 pts, 5% (grade 3) and pneumonitis in 3 pts, 5% (2 grade 1; 1 grade 2). Objective responses were seen in 26 pts for a confirmed overall response rate (ORR) of 43% (95% CI, 31, 57). In a subset analysis of pts with high FRα expressing tumors (n = 33), the confirmed ORR was 61% (95% CI, 42, 77), with an ORR of at least 50% in each of the PR and PS subsets. With a median follow-up of 5.5 months, the duration of response and progression free survival data are immature. Conclusions: The combination of MIRV with BEV demonstrates an encouraging ORR with a favorable tolerability profile in pts with recurrent ovarian cancer regardless of platinum sensitivity, particularly in those with tumors that express high levels of FRα. Clinical trial information: NCT02606305.
The impact of programmed death-ligand 1 expression on the prognosis of early-stage resected non-small cell lung cancer: A meta-analysis of literatures.
Authors: Shuai Zhu, Xiongfei Li, Shikang Zhao, Yanye Wang, Xi Lei, Dingzhi Huang, Jun Chen, Ziming Li, Song Xu
Journal: Journal of Clinical Oncology (2020)

e21004 Background: Previous studies have demonstrated that programmed cell death-ligand 1 (PD-L1) serves as a poor prognostic biomarker for the survival in advanced-stage non-small-cell lung cancer (NSCLC) patients. However, the value of PD-L1 expression for the prognosis of early-stage NSCLC patients after complete resection remains controversial. Here, we conduct a meta-analysis to investigate the relationship between PD-L1 expression and prognosis in resected NSCLC. Methods: Electronic databases, including PubMed, EMBASE, and the Cochrane Library, were searched up until June 30 2019, for studies evaluating the expression of PD-L1 and prognosis of the resected NSCLC. Hazard ratios (HRs) with 95% confidence interval (CI) of overall survival (OS) and disease-free survival (DFS) were pooled and analyzed. Heterogeneity and publication bias analyses were also performed. Results: A total of 15 studies involving 3501 patients were enrolled. The pooled hazard ratio (HR) showed that PD-L1 expression was related to a much shorter DFS (HR = 1.63, 95% CI: 1.26-2.12, P = 0.022), as well a significantly worse OS (HR = 1.68, 95% CI: 1.32-2.14, P = 0.000). Furthermore, our analysis indicated that PD-L1 expression was significantly associated with gender (male vs. female: HR = 1.25, 95% CI:1.02-1.52, p = 0.028), tumor stage (III/IV vs. I/ II: HR = 2.39, 95% CI:1.85-3.08, p = 0.000), lymph node metastasis (N+ vs N-: HR = 3.54, 95%CI:2.56-4.88, p = 0.000) and smoking status (Yes vs No: HR = 1.37,95% CI:1.20-1.560, p = 0.000). Conclusions: The results of this meta-analysis suggest that PD-L1 expression predict an unfavorable prognosis in early-stage resected NSCLC. The role of individualized anti-PD-L1/PD-1immunotherapy in the adjuvant settings of resected NSCLC is worthy of being further investigated.
Algorithm for blood-based panel of methylated DNA and protein markers to detect early-stage hepatocellular carcinoma with high specificity.
Authors: Naga P. Chalasani, Abhik Bhattacharya, Adam Book, Brenda Neis, Kong Xiong, T Ramasubramanian, Scott Johnson, Graham P. Lidgard, Lewis R. Roberts, John B. Kisiel, K Rajender Reddy, Amit G Singal, Marilyn Olson, Janelle J Bruinsma
Journal: Journal of Clinical Oncology (2020)

4577 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Though biannual ultrasound surveillance with or without alpha-fetoprotein (AFP) testing is recommended for at-risk patients, its sensitivity for early-stage HCC detection is suboptimal. We therefore evaluated performance of a biomarker panel incorporating methylated DNA markers (MDMs) and proteins for early HCC detection in at-risk patients with chronic liver disease. Methods: In an international, multicenter, case-control study, blood specimens were collected from patients with HCC per AASLD criteria and controls matched for age and liver disease etiology. All patients had underlying cirrhosis or chronic HBV infection. Whole blood was collected in cell-free DNA stabilizing and serum-separation tubes and shipped to a central laboratory for processing. The levels of 5 MDMs, AFP, and AFP-L3 were assessed along with age and sex. We used 537 samples in a 5-fold validation for developing a LASSO regression algorithm to classify samples as HCC positive or negative. Model robustness was tested by perturbing the data in silico and analyzing results with the predictive algorithm. Algorithm performance was compared to AFP alone and the GALAD score (Gender, Age, AFP-L3, AFP, and DCP). Results: The study included 136 HCC cases (81 early-stage—BCLC stage 0/A) and 401 controls. With specificity set at 89%, we developed a model using sex, AFP, and 3 MDMs (HOXA1, TSPYL5, B3GALT6) with higher sensitivity (70%) for early-stage HCC compared to GALAD (54%) or AFP (31% at 20 ng/mL or 52% at ≥7.7 ng/mL) (Table). The AUC for the HCC marker panel was 0.91 (95% CI 0.89 – 0.94) compared to GALAD (0.88; 95% CI 0.85 – 0.91) or AFP (0.84; 95% CI 0.81 – 0.87). The panel performed similarly in viral (AUC = 0.94) and non-viral (AUC = 0.89) etiologies. Conclusions: The robust algorithm based on novel blood-based biomarkers presented here provides higher sensitivity for early-stage HCC compared to other available blood-based biomarkers and, therefore, could significantly impact HCC clinical management and patient outcomes. Further clinical studies to validate the algorithm are ongoing. Clinical trial information: NCT03628651 . [Table: see text]
Effects of iodine status on maternal and infant health during pregnancy
Authors: Kexin Zhang
Journal: BMJ (2020)

Iodine is one of the essential elements in human body, involving in the synthesis of thyroxine. Monitoring of iodine nutrition in the population is of great concern worldwide. During the special period of pregnancy, improper iodine intake may cause thyroid dysfunction of the mothers and their infants, even lead to adverse pregnancy outcomes and permanent neurological damage of infants. The accurate test methods, standardized diagnostic criteria, closely monitoring iodine nutrition and reasonable intervention are vital to prevent improper iodine intake in pregnat women. This article reviews the effects of iodine status on the maternal and infant health and the measures to prevent improper iodine intake during pregrancy.


Key words: 
Iodine; Pregnancy outcome; Fetal development; Therapy
Efficacy of immune check point inhibitors (ICIs) in metastatic gastric or gastroesophageal junction (GEJ) cancer by patient subgroups: A systemic review and meta-analysis.
Authors: Hadar Goldvaser, Michal Sternschuss, Assaf Moore, Gali Perl, Baruch Brenner, Yulia Kundel
Journal: Journal of Clinical Oncology (2020)

e16587 Background: Patients with metastatic gastric or GEJ cancer have short duration of response to chemotherapy and poor outcome. Treatment with ICIs has been investigated for this population with inconsistent results. It is uncertain whether the effect of ICIs is comparable in different subgroups. Methods: Randomized controlled trials (RCTs) that compared standard treatment to treatment with ICIs, either as a monotherapy or in combination with chemotherapy, for metastatic gastric or GEJ cancer were identified. Hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival (OS) were extracted and pooled in a meta-analysis using generic inverse variance and random effects modelling. Pre-specified subgroups included: patients’ age at time of randomization (age &lt; /≤ 65 years versus ≥/ &gt; 65 years), gender (female versus male), ethnicity (Asians versus the rest of the world), Eastern Cooperative Oncology Group performance status (0 versus 1), primary tumor location (gastric versus GEJ) and histological subtype (diffuse versus other subtypes). Data on progression free survival (PFS) and on OS in patients with programmed death ligand (PDL1) positive were also collected. Results: Four RCTs comprising 1,765 patients were analyzed. Treatment with ICIs compared to standard therapy did not significantly improve OS (HR = 0.84, 95% CI 0.66-1.07, p = 0.17), PFS (HR = 1.22, 95% CI 0.75-1.96, p = 0.52), or OS in patients with PDL1 positive disease (HR = 0.86, 95% CI 0.73-1.02, p = 0.08). The effect of ICIs on OS was similar in all subgroups. Non-significantly greater effect sizes were seen in younger patients (HR = 0.82 versus 0.86, p for subgroup difference 0.80), male (HR = 0.81 versus 0.97, p = 0.32), performance status 0 (HR = 0.84 versus 0.88, p = 0.81), GEJ tumors (HR = 0.76 versus 0.89, p = 0.44) and non-diffuse subtype (HR = 0.71 versus 0.79, p = 0.62). Conclusions: Compared to standard treatment, ICIs in metastatic gastric or GEJ cancer did not improve OS significantly. As none of the evaluated subgroups has shown increased magnitude of effect to ICIs, other biomarkers for ICIs response are desired in order to optimize the risk versus benefit balance of these patients.
Decompressing Stoma vs Stent in Left-Sided Obstructive Colon Cancer
Authors: Joyce Valerie Veld, Jeanin Elise van Hooft, Pieter Job Tanis
Journal: JAMA Surgery (2020)

In Reply With interest, we read the letters from Hallqvist-Everhov et al, Sterpetti, and Zhou et al regarding our article “Comparison of Decompressing Stoma vs Stent as a Bridge to Surgery for Left-Sided Obstructive Colon Cancer.”1
Mathematical Oncology Comes to the Clinic: A Data-Driven Treatment for Financial Toxicity?
Authors: Timothy J. Triche
Journal: Cancer Research (2020)

Abstract Over the past two decades, progress in tumor immunology and targeted therapy has reshaped oncology, and in many cases, reshaped the course of once-intractable diseases. Yet the cost of its clinical manifestation has created a disease of its own: “financial toxicity,” the burden of drugs such as imatinib, where a year's supply can easily cost as much as a house. Equally rapid progress in mathematical oncology over this time period has often come in the form of fundamental, rather than applied, advances. However, in new work by Hähnel and colleagues, we can see the outlines of a viable treatment for financial toxicity: precise, dynamic, clinically validated, and immune-aware models, able to accurately identify patients who remain disease-free in the months and years after discontinuing effective, but pricey, targeted therapies. See related article by Hähnel et al., p. 2394
Clonal hematopoiesis in the bone marrow and blood of healthy volunteers.
Authors: Pierre Hirsch, Noémie Ravalet, Helene Guermouche, Nathalie Gallay, Emmanuel Gyan, François Delhommeau, Olivier Herault
Journal: Journal of Clinical Oncology (2020)

7517 Background: Clonal hematopoiesis of indeterminate potential (CHIP) has been described in blood samples from large series of patients. Its prevalence and consequences remain questioned because sequencing methods vary and because most studies were performed in cohorts of individuals suffering from non-hematological diseases (solid cancers, diabetes, cardiovascular or psychiatric diseases). CHIP has been described as a risk factor for blood cancer. However, the diagnosis of most blood cancers relies on morphologic and genetic examination of the bone marrow, and clonal hematopoiesis has never been evaluated in bone marrow samples from healthy individuals. Hence, it is not clear whether the current definition of CHIP is clinically relevant. To address this issue, we studied clonal hematopoiesis in paired peripheral blood and bone marrow samples from an unprecedented cohort of rigorously selected healthy volunteers. Methods: Here, we investigated the frequency of clonal hematopoiesis in 82 paired bone marrow and blood samples from carefully selected healthy adult volunteers (HEALTHOX clinical trial, ClinicalTrials.gov Identifier: NCT02789839). This study was approved by the ethics committees (CPP Tours and AFSSAPS identifier ID-RCB: 2011-A00262-39; CPP Ile-de-France III: 2753). Forty-one genes known to be mutated in myeloid malignancies were sequenced with a 1% threshold of detection. All variants were checked using IGV software v2.3. Statistical analyses were performed using Mann-Whitney, chi-squared, Fisher’s exact, Wilcoxon matched-pairs tests or Spearman correlation using GraphPad Prism 6. Results: In bone marrow samples, clones were found in almost 40 % of healthy volunteers over 50 years-old (yo). The most frequent mutations were found in DNMT3A (48%) and TET2 (28%) and the other mutations were found in ASXL1 (8%), JAK2 (8%), RAD21 (4%) and SRSF2 (4%) with one individual carrying three variants. Blood parameters and bone marrow smears were normal with the exception of two individuals with mild macrocytosis or thrombocytosis. Clonal hematopoiesis cases differed from others by age (62.8 vs. 38.6 years, P &lt; .0001) and platelet count (294 vs. 241 G/L, P &lt; .0208). Conclusions: These results confirm that clonal hematopoiesis is a very common condition in healthy adults over 50 years old. Consequently, the detection of driver myeloid mutations should be interpreted with caution in the absence of cytologic abnormalities in the blood and/or in the bone marrow.
A case of diffuse pneumocephalus induced by sneezing after brain trauma
Authors: Yunxu Zhang, Yanyun Xing, Kun Fu, Qi Liu, Hongtao Zhang
Journal: BMJ (2017)

外伤性颅内积气是开放性颅脑损伤常见的并发症之一，其原因是损伤所致的颅底骨折线经过鼻窦并撕裂脑膜，使颅腔直接或间接与外界相通，空气进入颅内形成颅内积气。颅内积气常合并脑脊液耳和/或鼻漏，临床处理不当易发生逆行性颅内感染。
An analysis of growth in the genetic counseling profession 2009 to 2019.
Authors: Gillian Hooker, Dawn C. Allain, Adam H Buchanan, Melanie Care, Laura Conway, Alessandra Cumming, Shannan Dixon, Kristin Paulyson-Nuñez, Sara Riordan, Janet Williams
Journal: Journal of Clinical Oncology (2020)

e13526 Background: Genetic counselors (GCs) are health care professionals who provide support to patients and physicians navigating the rapidly changing landscape of genetic testing and the genetic underpinnings of disease. Increased demand for genetic counseling services prompted an analysis of changes in the workforce over the last decade. Methods: To quantify the growth in the GC profession in the U.S and Canada in the last decade, we acquired data from the American Board of Genetic Counseling, National Society of Genetic Counselors, Canadian Association of Genetic Counselors, Accreditation Council for Genetic Counseling and Association of Genetic Counseling Program Directors. Results: Between 2009 and 2019, the workforce more than doubled, growing from 2,205 ABGC-certified GCs to 5,172. In Canada, the number of CAGC-certified GCs has grown from 211 in 2009 to 327 in 2019. Growth is striking in cancer genetic counseling; the proportion of GCs providing direct patient care in North America who report cancer as a primary specialty has increased from 25% in 2008 to 50% in 2019. Similar growth has been seen in training opportunities for GCs. The number of accredited graduate programs has increased from 33 in 2009 to 51 in 2019, with several more in development. Combined, these programs had 464 training slots in 2019, up from 223 in 2009. In 2019, 1569 applicants registered for the applicant match for training. Training opportunities and clinical genetic counselors are concentrated in large metropolitan areas, with over half of GCs working in 28 metro regions. GC services in rural areas are increasingly provided remotely via telemedicine, with 59% of GCs in direct patient care in 2018 reporting providing services by phone and 19% using web or video services to deliver care. In cancer genetics, about 50% of GCs nationwide reported in 2018 their 3rd next available appointment for new patients was within 14 days. Conclusions: The past decade has seen significant growth in the numbers of GCs and more patients have access to GCs than a decade ago. Reimbursement for services remains a significant barrier to access. Further research is warranted to understand additional political, administrative and logistical facilitators and barriers to providing care to all who need genetics services.