tbuckley/cabot-search huggingface dataset:
Immune phenotype and response to neoadjuvant systemic therapy (NAST) in triple negative breast cancer (TNBC).
Authors: Clinton Yam, Gheath Alatrash, Er-Yen Yen, Haven Garber, Anne V. Philips, Lei Huo, Fei Yang, Roland L. Bassett, Xiangjie Sun, Edwin Roger Parra Cuentas, William Fraser Symmans, Sahil Seth, Jason B White, Gaiane M Rauch, Senthil Damodaran, Jennifer Keating Litton, Jennifer Ann Wargo, Gabriel N. Hortobagyi, Stacy L. Moulder, Elizabeth A. Mittendorf
Journal: Journal of Clinical Oncology (2020)

509 Background: In TNBC patients (pts) receiving NAST, increasing tumor infiltrating lymphocytes (TILs) is associated with higher pathologic complete response (pCR) rates. However, since the presence of TIL do not consistently predict pCR, the current study was undertaken to more fully characterize the immune cell response and its association with pCR. Methods: T cell receptor (TCR) sequencing, PD-L1 immunohistochemistry and multiplex immunofluorescence were performed on prospectively collected pre-NAST tumor samples from 98 pts with stage I-III TNBC enrolled in ARTEMIS (NCT: 02276443). TCR clonality was calculated using Shannon’s entropy. PD-L1+ was defined as ≥1% immune cell staining. Response to NAST was defined using the residual cancer burden (RCB) index. Associations between TCR clonality, immune phenotype, and response were examined with the Wilcoxon rank sum test, Spearman’s rank correlation and multivariable logistic regression using stepwise elimination (threshold p &gt; 0.2), as appropriate. Results: The pCR rate was 39% (38/98). pCR was associated with higher TCR clonality (median = 0.2 [in pts with pCR] vs 0.1 [in pts with residual disease], p = 0.05). Notably, the association between pCR and higher TCR clonality was observed in pts with ≥5% TIL (n = 61; p = 0.05) but not in pts with &lt; 5% TIL (n = 37; p = 0.87). Among pts with ≥5% TIL, TCR clonality emerged as the only independent predictor of response in a multivariable model of tumor immune characteristics (odds ratio/0.1 increase in TCR clonality: 3.0, p = 0.021). PD-L1+ status was associated with higher TCR clonality (median = 0.2 [in PD-L1+] vs 0.1 [in PD-L1-], p = 0.004). Higher TCR clonality was associated with higher CD3+ (rho = 0.32, p = 0.0018) and CD3+CD8+ (rho = 0.33, p = 0.0013) infiltration but lower expression of PD-1 on CD3+ (rho = -0.24, p = 0.021) and CD3+CD8+ cells (rho = -0.21, p = 0.037). Conclusions: In TNBC, a more clonal T cell population is associated with an immunologically active microenvironment (higher CD3+ and CD3/8+ T cell; lower PD-1+CD3+ and PD-1+CD3/8+ T cell; PD-L1+) and favorable response to NAST, especially in pts with ≥5% TIL, suggesting a role for deep immune phenotyping in further refining the predictive value of TILs.
Molecular features for selecting Asian metastatic melanoma patients who benefit from check-point inhibitors.
Authors: Seonggyu Byeon, Hyera Kim, Ja Hyun Yeo, Jinchul Kim, Minsuk Kwon, Jiyun Lee, Seung Tae Kim, Jeeyun Lee
Journal: Journal of Clinical Oncology (2020)

e22011 Background: There was few data for molecular characteristics of Asian metastatic melanoma patients with distinct clinical features as compared to West patients with metastatic melanoma. We conducted the molecular profiling for Asian metastatic melanoma patients with check-point inhibitors (CPIs) to find novel biomarkers to CPIs. Methods: 164 Asian patients with metastatic melanoma who received CPIs were simultaneously tested by the next generation sequencing (NGS) in tumor samples. We collected all NGS data and clinic-pathologic factors and also analyzed biomarkers for tumor response to CPIs. Results: The most common subtype was acral melanoma (39.6%) followed by cutaneous melanoma (32.3%), mucosal melanoma (26.2%) and others (1.8%). 163 pts are evaluable for efficacy; we observed 40 complete response (24.4 %), 34 confirmed partial responses (20.7%), 41 stable disease (25.0%) and 48 disease progression (29.3%). The overall confirmed response rate from the dose escalation is 45.1%. There was no significant difference of tumor response among subtypes of melanoma (p = 0.295). NRAS and TP53 mutation and NF2 deletion were significantly related to patients without the response to CPIs (p &lt; 0.05). Meanwhile, MYC and RPS6KB1 amplification were found with those with the response (p &lt; 0.05). The median progression free survival (PFS) to ICIS was 5.9 months (95% CI 3.8 - 8.05 months). Univariate analysis showed that TP53 and BRAF mutation, NF2 deletion, and BIRC2 amplification were poor prognostic values for PFS (p &lt; 0.05). Conclusions: This study reported molecular characteristics of 164 Asian patients with metastatic melanoma. The specific molecular alterations influenced on the tumor response and PFS to CPIs in those.
Establishment of evaluation index system of teaching capability of general practitioner trainers in community health service centers
Authors: Hua Yang, Juan Shou, Jie Gu, Xiaoyun Cao
Journal: BMJ (2016)

Objective
To establish an evaluation index system of teaching capability of general practitioner (GP) trainers in community health service centers.


Methods
Twenty-eight experts of general practice were invited to participate in two rounds of modified Delphi consultation during April 2014 and December 2014.A primary version of evaluation index system of teaching ability of GP trainers was developed.


Results
The evaluation index system consisted of 3 first-grade indicators and 18 second-grade indicators. The 3 first-class indicators were teaching attitude, teaching professionalism and capability, teaching skill and practice, with weight coefficients of 0.337 4, 0.327 6 and 0.335 0, respectively. In the two rounds consultation, expert activity coefficients were both 100.0%; the authority coefficients were 0.881 and 0.879, respectively; the harmonious coefficients of importance of the evaluation index were 0.228 and 0.248, respectively (all P<0.05).


Conclusion
An evaluation index system for teaching capability of GP trainers in community health service centers has been developed, which may provide the reference for regulating teaching practice and enhancing the quality of training for general practitioners in communities.


Key words: 
Delphi technique; Teaching; Community health centers; General practitioners
Extrachromosomal DNA (ecDNA) carrying amplified oncogenes as a biomarker for insensitivity to pembrolizumab treatment in gastric cancer patients.
Authors: Jason H. Christiansen, Nam-phuong Nguyen, Roel Verhaak, Hoon Kim, Vineet Bafna, Paul Mischel, Christian Hassig
Journal: Journal of Clinical Oncology (2020)

3123 Background: In the KEYNOTE-059 study, the anti-PD-1 checkpoint inhibitor pembrolizumab was shown to have a modest overall response of 11.6%. Common predictors of response including, high microsatellite instability (MSI-H), PD-L1 expression, tumor mutational burden (TMB) and tumor inflammation signature (TIS), were not individually sufficient for patient selection. Recent pancancer studies have highlighted a unique population of cancer patients whose tumors appear to be driven by oncogene amplifications on extrachromosomal DNA (ecDNA). These ecDNA-driven tumors are aggressive and characterized by high levels of genomic instability. We sought to understand if tumors that possess ecDNA may represent a subset of the patient group that is non-responsive to anti-PD-1 therapy. Methods: We determined the ecDNA status of gastric cancer patients (N = 108) using whole genome sequencing (WGS) from the TCGA Pan-cancer dataset These patients had been previously subtyped for EBV status, genomic stability (GS), microsatellite instability (MSI), and chromosomal instability (CIN). Patients that were ecDNA+ were re-classified into a set regardless of gastric subtype. Additionally, TMB, TIS, and PD-L1 expression levels were collected. Results: 32% of gastric cancer patients were positive for ecDNA signatures and mutually exclusive from the 23% of MSI-H patients. We found that ecDNA positive tumors had statistically significantly lower TIS than all other groups (p-value &lt; 0.05) except CIN tumors (p-value = 0.09). The ecDNA positive tumors also had lower PD-L1 expression than all but GS tumors. Only MSI-H showed statistically significantly higher TMB scores compared to every other group (p-value &lt; 0.001), no difference in TMB scores were observed between every other pair of groups. Conclusions: Patients whose tumors are ecDNA positive represent a unique population that display signatures for non-response to checkpoint inhibitor therapy, including MSS, low TIS, and PD-L1 expression. Thus, the determination of tumor ecDNA status may have utility as an additional patient selection strategy for checkpoint inhibitor therapy. As ecDNA are not limited to gastric cancers, this study highlights the importance of the development of a clinical diagnostic test for ecDNA status and the need for further research on ecDNA biology, its impact on immunotherapy response, and potential ecDNA-directed therapeutics
Phase II trial of a PARP inhibitor in somatic <i>BRCA</i> mutant metastatic breast cancer.
Authors: Neelima Vidula, Nora K. Horick, Erica Blouch, Amalia Rivera, Erin Basile, Ruth Fax, Leif W. Ellisen, Hope S. Rugo, Aditya Bardia
Journal: Journal of Clinical Oncology (2020)

TPS1113 Background: Poly(ADP-ribose) polymerase (PARP) inhibitors are now approved for patients with germline BRCA1/2 mutated HER2 negative metastatic breast cancer (MBC). However, germline BRCA1/2 mutations only account for 5-10% of breast cancer. We previously demonstrated that a subset of MBC may harbor somatic BRCA1/2 mutations detectable by cell-free DNA (cfDNA) (Vidula, SABCS, 2017). We hypothesize that somatic BRCA1/2 mutant MBC may also respond to PARP inhibition, similar to ovarian cancer, where PARP inhibition is efficacious in both somatic and germline tumors (Oza, 2017). Methods: This single arm, open label, phase II clinical trial is evaluating the efficacy of talazoparib, a PARP inhibitor, in 30 patients with somatic pathogenic BRCA1/2 mutant MBC identified by cfDNA. Patients may have triple-negative disease with receipt of at least 1 prior chemotherapy regimen, or hormone receptor positive, HER2 negative disease with at least 1 prior hormone therapy for MBC. Patients may have received a prior platinum, in the absence of progression on platinum chemotherapy. Patients must not have a known germline BRCA1/2 mutation. Patients will be treated with talazoparib 1 mg daily until progression, unacceptable toxicity, or withdrawal of consent, with clinical exams monthly, scans (CT chest, abdomen, and pelvis, and bone scan as appropriate) every 3 months, and serial cfDNA collected monthly. The primary endpoint is progression-free survival, as defined by RECIST 1.1. Subjects are enrolled in a 2-stage design, which provides 80% power to demonstrate that treatment is associated with “success” (PFS &gt; 12 weeks) in ³ 53% patients (4% alpha). Additional endpoints include objective response rate and toxicity (per NCI CTCAE version 5.0). Correlative endpoints include determining changes in BRCA1/2 mutant allele fraction, genomic evolution including emergence of BRCA reversion mutations, and the impact of biomarker changes on outcomes. This trial is currently enrolling patients at the Massachusetts General Hospital. Successful completion of this study may help expand the patient population that is able to benefit from PARP inhibition. Clinical trial information: NCT03990896 .
Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial
Journal: BMJ (2013)

<b>Objective</b> To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza. <b>Design</b> Double blind randomised trial. <b>Setting</b> Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam. <b>Participants</b> Patients aged ≥1 year admitted to hospital with confirmed severe influenza. <b>Interventions</b> Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent). <b>Main outcome measure</b> Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five. <b>Results</b> Of 326 patients (including 246 (75.5%) children aged &lt;15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (−5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) <i>v</i> 3.5 (2-7)), in intensive care (4.5 (3-6) <i>v</i> 5 (2-11), and on mechanical ventilation (2.5 (1-16) <i>v</i> 8 (1-16)), respectively. No important differences in tolerability were found. <b>Conclusions</b> There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital. <b>Registration</b> Clinical Trials NCT00298233
小肠重复畸形伴系膜囊肿一例
Authors: 杨家伟
Journal: BMJ (2005)

患者男,4岁零4个月,因腹痛4 d,血便3 d入院.查体:体温37.3℃,脉搏140次/min,呼吸32次/min,体重15 kg;腹膨隆,未见胃肠型;脐右侧局部压痛,可扪及5 cm×5 cm×3 cm质中包块,肝、脾未扪及;肝、肾、脾区无叩痛,移动性浊音阴性;肠鸣活跃,可闻及金属音及气过水声.血常规:白细胞10.6×109 /L,中性粒细胞0.64,淋巴细胞0.36,血红蛋白44 g/L.腹部X线片:机械性肠梗阻.B超:可疑肠套叠。
Anlotinib (AL3818) plus pemetrexed in patients with recurrent platinum-resistant advanced epithelial ovarian cancer: A single-arm, open-label, phase II study.
Authors: Yanna Zhang, Jueming Chen, Wei Wei, Lie Zheng, Han Li, Yanling Feng, Ting Wan, Jiaqi Qiu, Xingyu Jiang, Ying Xiong, Jundong Li, Libing Song, Jihong Liu, He Huang
Journal: Journal of Clinical Oncology (2020)

e18078 Background: Anlotinib (AL3818) is a novel multi-target tyrosine kinase inhibitor that has previously shown clinical antitumor activity in various cancers, including the phase I study on tumors of female reproductive system. This phase II study (ChiCTR1800018192) aims to further evaluate the safety and efficacy of anlotinib combined with pemetrexed in patients with recurrent platinum-resistant advanced epithelial ovarian cancer. Methods: Patients who underwent cytoreductive operation, with histopathologically advanced epithelial ovarian cancer ( FIGO staging III or IV), and failed to previously platinum-based chemotherapies were considered eligible for enrollment to receive combined treatment of anlotinib (12 mg per day, days 1-14; 21 days per cycle) plus pemetrexed (0.5 g/m 2 , day 1; 21 days per cycle). Total duration of combined treatment contained 6 cycles, and subsequent maintenance treatment was anlotinib monotherapy (12 mg per day, days 1-14; 21 days per cycle) till disease progression or intolerant toxicity. The primary endpoint of this study was objective response rate (ORR) and the secondary endpoints were disease control rate (DCR), progression-free survival (PFS) and safety. Results: Between 2018 July and 2019 October, 13 patients (female) with a median age of 55 years (range: 41 - 65), FIGO histopathological stage IIIA (7.7%) or IIIC (76.9%) or IV (15.4%) were enrolled. Over a mean follow-up period of 5.9 (95% CI: 3.4-8.3) months, therapeutic evaluation showed the incidence of partial response, stable disease, and progression disease was 38.5%, 53.8% and 7.7% respectively, yielding the ORR of 38.5% (5/13; 95% CI: 13.9%-68.4%) and the DCR of 92.3% (12/13; 95% CI: 64.0%-99.8%). The median PFS was not reached. Frequently occurring adverse events (AEs) were grade 1 or 2, including hand-foot syndrome (53.8%), allergic eruption (38.5%), mild hypertention (30.8%), fatigue (23.1%), diarrhea (23.1%), gum-pain (15.4%), and dry cough (15.4%). High grade AE was only observed in 1 patients with hemoglobin reduction of grade 4. Neither unexpected safety signals nor treatment related death occurred. Conclusions: Anlotinib (AL3818) plus pemetrexed showed a promising activity with an acceptable safety profile for previously platinum-treated patients with recurrent advanced epithelial ovarian cancer. Clinical trial information: ChiCTR1800018192.
Clinical values of hypothyroidism and subclinical hypothyroidism screening in pregnancy
Authors: Chunhong Song
Journal: BMJ (2015)

To explore the significance of hypothyroidism and subclinical hypothyroidism screening in pregnancy. A total of 278 pregnant women were divided into three groups of clinical hypothyroidism (n=36), subclinical hypothyroidism (n=103) and normal control (n=139). Their clinical profiles, pregnancy outcomes and fetal status were analyzed. The incidences of abortion (11.1%), premature delivery (8.3%), preeclampsia (11.1%), gestational diabetes mellitus (GDM, 13.9%), anemia (16.7%), fetal distress (8.3%) and fetal growth retardation (FGR, 5.6%) in clinical hypothyroidism group were higher than those in normal control group (2.9%, 1.4%, 1.4%, 2.2%, 4.3%, 0.0% and 3.6%). And the differences were statistically significant (P<0.05). The incidence of adverse pregnancy had a significant correlation with hypothyroidism in pregnant women. Therefore screening of thyroid functions is essential for improving pregnancy outcomes of pregnant women with hypothyroidism.

Key words: 
Hypothyroidism; Pregnancy
Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring
Authors: Asaf Zviran, Rafael C. Schulman, Minita Shah, Steven T. K. Hill, Sunil Deochand, Cole C. Khamnei, Dillon Maloney, Kristofer Patel, Will Liao, Adam J. Widman, Phillip Wong, Margaret K. Callahan, Gavin Ha, Sarah Reed, Denisse Rotem, Dennie Frederick, Tatyana Sharova, Benchun Miao, Tommy Kim, Greg Gydush, Justin Rhoades, Kevin Y. Huang, Nathaniel D. Omans, Patrick O. Bolan, Andrew H. Lipsky, Chelston Ang, Murtaza Malbari, Catherine F. Spinelli, Selena Kazancioglu, Alexi M. Runnels, Samantha Fennessey, Christian Stolte, Federico Gaiti, Giorgio G. Inghirami, Viktor Adalsteinsson, Brian Houck-Loomis, Jennifer Ishii, Jedd D. Wolchok, Genevieve Boland, Nicolas Robine, Nasser K. Altorki, Dan A. Landau
Journal: Nature Medicine (2020)
To biopsy or to not biopsy, that is the question: A single-center retrospective analysis of outcomes of liver biopsy with hepatocellular carcinoma and other liver diseases.
Authors: Sophia Seo-hyeon Lee, Wei Yang, Julie Haewon Rowe
Journal: Journal of Clinical Oncology (2020)

e16606 Background: Unlike other malignancies, hepatocellular carcinoma (HCC) is most often diagnosed radiologically, based on previous studies suggesting complication rates of 1.4%-3.4% (e.g., bleeding) and concerns regarding “tumor seeding.” Lack of tissue for analysis has led to a lag in understanding the molecular biology of HCC. Molecular characterization of biopsies may allow HCC subtyping in order to personalize medicine, thus the potential of liver biopsy’s safety and utility needs to be reassessed. Methods: We performed a retrospective review of patients who underwent biopsy for suspected HCC or other liver diseases between Jan 1, 2010 and Jan 1, 2020. Demographics and clinical data including comorbidities, renal function, ascites, hepatic encephalopathy, varices, and labs including hemoglobin, WBC, platelets, sodium, creatinine, liver function test and coagulation studies were collected. Child Pugh (CP) and MELD-Na scores were calculated. Adherent medications at the time of biopsy and type of biopsy with any complications were included. Results: A total of 427 patients underwent liver biopsy. Patient characteristics are given in the table. Most patients (97%) underwent core needle biopsy. Biopsy complication rate was 1.23% (n = 5); these included bleeding (80%, n = 4), hospitalization (60%, n = 3), infection (20%, n = 1), and death (20%, n = 1). In the 5 patients, increased creatinine was associated with bleeding complications; however, one patient was on dialysis (Cr = 11.20), and this should be interpreted with caution. Existing comorbidities, concurrent medication use (including anticoagulants), CP and MELD-NA score, and lab findings were not associated with biopsy complications. Conclusions: To our knowledge, this review is first to demonstrate a low complication rate of 1.23% in suspected HCC patients who underwent liver biopsy in the current era of improved radiological techniques. This is consistent with historical data in liver disease patients. Comorbidities, being on anticoagulants, CP and MELD scores do not predict for biopsy complications. Higher creatinine was associated with more complications, but this needs to be examined in a larger study. Biopsy should be considered a valuable tool in understanding the molecular profiles of HCC, which could lead to more novel treatment. [Table: see text]
Understanding practice variation with a clinical pathways system: Differences by physician and practice factors, and changes in practice over time.
Authors: Emily Foster, Sherri Oliver Stuver, Carole Kathleen Tremonti, Craig A. Bunnell, Joanna M. Hamilton, Joseph O. Jacobson, David Michael Jackman
Journal: Journal of Clinical Oncology (2020)

2079 Background: Clinical oncology pathways aim to support clinical decision-making and reduce unwarranted practice variation across an enterprise. The Dana-Farber Cancer Institute (DFCI) implemented web-based oncology pathways with DFCI-customized content in each disease center and at each of its satellites. Our pre-specified aim was an on-pathway rate of 70-85%. Methods: Treatment decisions were electronically captured as on- or off- pathway. Monthly metrics about usage and on-pathway rate were shared with users on a monthly basis. Physicians were categorized into quintiles based on the calculated on-pathway performance during the first 90 days of each individual’s use of the platform. On-pathway rates were then calculated for days 91-360 to study changes in behavior over time. Physician and practice factors were examined to determine any differences by initial on-pathway quintile classification. Results: 122 physicians were eligible for inclusion in this analysis (minimum 5 navigations in each study period). On-pathway rates showed significant variability in the initial 90-day period: quintile 1 median 100%, quintiles 2-4 80.2%, and quintile 5 50% (Table). In the follow-up period, median on-pathway rates shifted into the pre-specified goal range for all groups. Physicians in quintiles 1 or 5 of initial on-pathway rate were more likely to have fewer total navigations than were physicians in quintiles 2-4 (p=0.003). While no other physician or practice characteristic differed significantly by on-pathway rate group, physicians in the first or last quintile were more likely to be in an academic setting, have a PhD, or navigate fewer pathways. Conclusions: Over time, the deployment of a web-based clinical pathways program resulted in greater uniformity in physician practice, based on on-pathway rate. Familiarity with the pathways platform and its navigation, monthly feedback about usage, and evolution of content over time are some factors that might have played a role. [Table: see text]