tbuckley/cabot-search huggingface dataset:
A randomized, double-blind, phase II clinical trial of GI-6301 (yeast-brachyury vaccine) versus placebo in combination with standard of care definitive radiotherapy in locally advanced, unresectable, chordoma.
Authors: Peter Joseph DeMaria, Marijo Bilusic, Deric Park, Christopher Ryan Heery, Ravi Amrit Madan, Julius Strauss, Renee Nicole Donahue, Jenn Marte, Mark R. Gilbert, Seth M. Steinberg, Jeffrey Schlom, James L. Gulley
Journal: Journal of Clinical Oncology (2020)

11527 Background: Chordoma is a rare neoplasm of the notochord that overexpresses brachyury, a transcription factor associated with epithelial-to-mesenchymal transition, metastasis, poor prognosis, and chemotherapy resistance. GI-6301 is a recombinant yeast-brachyury vaccine shown to demonstrate brachyury-specific immunogenicity, excellent safety profile, and some evidence of clinical activity in patients with chordoma in a previous phase I trial. Radiation therapy (RT) can modulate the tumor to become an immunostimulatory milieu. Preclinical studies have shown a synergistic effect combining RT with vaccine, thus prompting this clinical trial evaluating the combination of GI-6301 with RT in chordoma (NCT02383498). Methods: Adults with locally advanced, unresectable chordoma were treated on a randomized, double-blind, placebo controlled, phase 2 clinical trial. Patients received 3 doses of GI-6301 (80 x 107 yeast cells) vs placebo followed by photon or proton RT, followed by GI-6301 vs placebo until disease progression. Primary outcome was overall response rate (ORR) defined as a complete response or partial response in the irradiated tumor site at 24 months. Immune assays were conducted to evaluate immunogenicity. Due to slow accrual, an unplanned interim analysis was undertaken. Results: 24 pts were randomized and treated between May 2015 and September 2019. Vaccine was well tolerated with no dose reductions or treatment discontinuation. Treatment-related serious adverse events included: nausea/emesis (2); fatigue (2); dehydration (2); diarrhea (1); radiation necrosis (1); stroke (1); sepsis (1). There was no difference in ORR between the two arms. Pre-existing brachyury-specific T-cells were detected in the majority of patients but did not correlate with response to therapy. Most patients developed T-cell responses during therapy, regardless of treatment arm. Conclusions: There was no difference in ORR between the two arms. GI-6301 was well tolerated with toxicities related to RT, not vaccine. The trial was stopped early due to low conditional power for finding a statistical difference at the planned end of accrual, based on findings to date. Future studies will define utility of vaccines targeting brachyury in chordoma. Clinical trial information: NCT02383498 . [Table: see text]
Assisted reproductive technology outcomes in childhood cancer survivors: A report from the Childhood Cancer Survivor Study.
Authors: Kimberly W. Keefe, Andrea Lanes, Kayla Stratton, Daniel M. Green, Eric Jessen Chow, Kevin C. Oeffinger, Sara Barton, Lisa Diller, Yutaka Yasui, Wendy M. Leisenring, Gregory T. Armstrong, Elizabeth S. Ginsburg
Journal: Journal of Clinical Oncology (2020)

10528 Background: Some treatment exposures for childhood cancer reduce ovarian reserve. Registry-based evaluation has not been conducted for assisted reproductive technology (ART) outcomes of female survivors. Methods: The Childhood Cancer Survivor Study, a retrospective cohort of five-year survivors and siblings, was linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS), which captures nationwide, CDC-required reporting of ART outcomes. We assessed live birth rate and relative risk (RR, 95% CI) as a function of treatment exposure, using generalized estimating equation to account for multiple ovarian stimulations per subject. Results: Among 9885 female survivors, 137 (1.4%; median age at diagnosis 10 years, range 0-20; 11 years of follow-up, 2-11) underwent 243 ART cycles (mean 1.8 cycles) and among 2419 siblings, 33 (1.4%) underwent 60 ART cycles (mean 1.8). Median age at autologous egg retrieval was 30 years (19-44) for survivors and 34 (24-43) for siblings. In the subset using autologous eggs (Table), 99 survivors underwent 155 ovarian stimulation cycles that resulted in 113 embryo transfers and 49 live births for a live birth rate of 32% per ovarian stimulation and 43% per transfer. Sibling live birth rate was 38% (p = 0.39 compared to survivors) per autologous ovarian stimulation and 53% (p = 0.33) per transfer. 38 survivors and 1 sibling underwent egg donor ovarian stimulation cycles. Two survivors used autologous eggs with gestational carriers and one cycle resulted in live birth. Cranial radiation therapy (RT) [RR 0.48 (0.27-0.87) p = 0.02] and pelvic RT [0.30 (0.14-0.66) p = 0.002], compared with no RT, resulted in lower RR of live birth in survivors. The likelihood of live birth after ART in survivors was not impacted by alkylator exposure [CED &lt; 8000 mg/m2 vs. none: 1.14 (0.65-2.02); CED &gt;8000 mg/m2 vs none: 1.07 (0.06-1.91)]. Conclusions: While live birth rates among survivors were lower compared with siblings, differences were not statistically significant. Pelvic and cranial RT were associated with a decreased likelihood of live birth, with no association with alkylator exposure identified. [Table: see text]
Comparison of X-ray, CT, MRI and ultrasonography in diagnosis of knee joint lipohemarthrosis
Authors: Guang-hui Zhang, Ying-ping Chu, Xu-lin Liu
Journal: BMJ (2010)

Forty eight patients with knee joint lipohemarthrosis underwent X-ray, CT, MRI and ultrasonography examinations, the diagnosis was confirmed by knee operation or puncture.The findings of 4 imaging methods were compared.Plain radiographs displayed fracture lines in 39 cases and fat-liquid layer of suprapatellar bursa in 40 cases, it displayed suprapatellar fat-liquid layer in 5 out of 9 occult fracture cases.CT displayed fracture lines in 48 cases and joint lipohemarthrosis in 48 cases; 3D imaging showed fracture lines better.MRI displayed fracture lines in 45 cases and joints lipohemarthrosis in 48 cases, and also showed the intracapsular structure injury.Ultrasonography revealed fracture lines in 15 cases and joint lipohemarthrosis in 48 cases, lipohemarthrosis was displayed in 7 out of 9 occult fracture cases.All 4 diagnostic imaging methods have advantages and disadvantages for diagnosis of lipohemarthrosis, and should be chosen on the basis of clinical needs.

Key words: 
Lipohemarthrosis;  Knee joint
FDA’s Oncology Center for Excellence Pilots Project Orbis: A framework for concurrent submission and review of oncology products among international partners.
Authors: Dianne Spillman, Shaily Arora, Rajesh Venugopal, Bradley Scott, Sarah Golding, Nicholas Richardson, Yvette L. Kasamon, Jean-Francois Ethier, Kate Gurd, Harpreet Singh, R. Angelo DeClaro, Julia A. Beaver, Tamy Kim, Kirsten B. Goldberg, Paul Gustav Kluetz, Marc Robert Theoret, Richard Pazdur
Journal: Journal of Clinical Oncology (2020)

e14125 Background: Cancer therapeutics often receive FDA approval months to years before regulatory submission to other countries. [i] Registrational trials in oncology are increasingly international, with many patients enrolled outside of the United States. Harmonizing access to new global standards of treatment may facilitate optimal design and conduct of global clinical trials. Methods: In May 2019, the Oncology Center for Excellence launched Project Orbis in collaboration with the Australian Therapeutic Good Administration (TGA) and Health Canada. The aim of this initiative is to provide a framework for concurrent submission and review of oncology products among international partners to facilitate global access. Results: The first Project Orbis was a collaborative review of a supplemental application for lenvatinib and pembrolizumab for patients with advanced endometrial cancer. This review also deployed other OCE regulatory review tools including the Real-Time Oncology Review (RTOR) pilot program, which can streamline the submission of data prior to the completion and submission of the entire application, and its accompanying Assessment Aid, to facilitate discussions among regulatory agencies. Lenvatinib and pembrolizumab was approved on September 17, 2019, in conjunction with the TGA and Health Canada, three months prior to the FDA goal date. FDA, TGA, and Health Canada issued a second action under Project Orbis on November 21, 2019, with the approval of acalabrutinib for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. Several other products are under international review as part of this pilot program and a summary of timelines and outcomes will be described. Conclusions: Project Orbis is an innovative OCE initiative that leverages the Center’s longstanding communication and collaboration with international regulators. This pilot program facilitates concurrent submission and review of oncology products among global regulatory health agencies. Continued efforts under Project Orbis will build on the initial success to incorporate additional global partners including Swissmedic and Singapore’s Health Science Authority. [i] The Centre for Innovation in Regulatory Science (CIRS). R&amp;D Briefing 70 New drug approvals in six major authorities 2009-2018: Focus on Facilitated Regulatory Pathways and Orphan Status
麻痹性痴呆二例临床分析
Authors: 江珊, 胡萍, 雷铁池, 徐世正
Journal: BMJ (2007)

回顾分析2例麻痹性痴呆患者的临床资料.2例患者早期均表现为不同程度的性格改变和记忆力下降.随着病情的发展,1例出现行走欠稳,四肢震颤等神经病变症状,1例出现严重的癫痫发作.2例患者脑脊液中与梅毒螺旋体直接相关的实验室检查均阳性.治疗首选青霉素,疗效确切.麻痹性痴呆是一种可治性痴呆,故早期诊断、积极治疗对预后有重要意义。
类风湿关节炎和抑郁
Authors: 魏镜
Journal: BMJ (2005)

类风湿关节炎(RA)是一类以慢性、对称性、多关节炎症为主要表现的常见系统性自身免疫性疾病,在人群中的发病率约为0.5%～1.0%,女性发病率高于男性[1].由于该病致残率高,因而给患者的心理、生理、社会活动和日常生活带来了极大的负面影响,本文主要针对RA合并抑郁和抑郁症进行讨论。
ERDAFITINIB in locally advanced or metastatic urothelial carcinoma (mUC): Long-term outcomes in BLC2001.
Authors: Arlene O. Siefker-Radtke, Andrea Necchi, Se Hoon Park, Jesús García-Donas, Robert A Huddart, Earle Frederick Burgess, Mark T. Fleming, Arash Rezazadeh, Begona Mellado, Sergei Varlamov, Monika Joshi, Ignacio Duran, Scott T. Tagawa, Yousef Zakharia, Min Fu, Ademi E. Santiago-Walker, Manish Monga, Anne OHagan, Silvia Mosher, Yohann Loriot
Journal: Journal of Clinical Oncology (2020)

5015 Background: Erdafitinib (JNJ-42756493; ERDA) is the only pan-FGFR kinase inhibitor with US FDA approval for treatment of adults with mUC with susceptible FGFR3/2 alterations (alt) and who progressed on ≥ 1 line of prior platinum-based chemotherapy (chemo). Approval was based on data from the primary analysis of the pivotal BLC2001 trial 1 . Here we report long-term efficacy and safety data from the 8 mg/d continuous dose regimen in BLC2001. Methods: BLC2001 (NCT02365597) is a global, open-label, phase 2 trial of pts with measurable mUC with prespecified FGFR alt, ECOG 0-2, and progression during/following ≥ 1 line of prior chemo or ≤ 12 mos of (neo)adjuvant chemo, or were cisplatin ineligible, chemo naïve. The optimal schedule of ERDA determined in the initial part of the study was 8 mg/d continuous ERDA in 28-d cycles with uptitration to 9 mg/d (ERD 8 mg UpT) if a protocol-defined target serum phosphate level was not reached and if no significant treatment-related adverse events (TRAEs) occurred. Primary end point was the confirmed objective response rate (ORR=% complete response + % partial response). Key secondary end points were progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Results: Median follow-up for 101 patients treated with ERDA 8 mg UpT was ~24 months. Confirmed ORR was 40%. Median DOR was 5.98 mos; 31% of responders had DOR ≥ 1 yr. Median PFS was 5.52 mos, median OS was 11.3 mos. 12-mos and 24-mos survival rates were 49% and 31%, respectively. Median treatment duration was 5.4 mos. The ERDA safety profile was consistent with the primary analysis. No new TRAEs were seen with longer follow-up. Central serous retinopathy (CSR) events occurred in 27% (27/101) of patients; 85% (23/27) were Grade 1 or 2; dosage was reduced in 13 pts, interrupted for 8, and discontinued for 3. On the data cut-off date, 63% (17/27) had resolved; 60% (6/10) of ongoing CSR events were Grade 1. There were no treatment-related deaths. Conclusions: With a median follow-up of 2 yrs, ERDA in mUC + FGFR alt showed a manageable safety profile and consistent efficacy, with median OS of 11.3 mos. 31% had a DOR ≥12 mos and 31% were alive at 24 mos. ERDA monotherapy vs. immune checkpoint inhibitor (PD-1) or chemo is being further analyzed in a randomized control study (THOR; NCT03390504).Reference: Loriot Y, et al. N Engl J Med. 2019;381:338-48. Clinical trial information: NCT02365597 .
Molecular subtypes and clinical outcomes to initial systemic treatment in patients with small cell lung cancer.
Authors: Wei-Chu Victoria Lai, Jacklynn V. Egger, Hira Rizvi, Allison L. Richards, Amanda Beras, Marina K. Baine, Min-Shu Hsieh, Jason C. Chang, Natasha Rekhtman, Andrew J. Plodkowski, Michelle S. Ginsberg, Mark G. Kris, Matthew David Hellmann, Triparna Sen, John T. Poirier, Charles M. Rudin
Journal: Journal of Clinical Oncology (2020)

9018 Background: Investigators have proposed that differential expression of the transcription regulators ASCL1 and NeuroD1 can be used to define molecular subtypes of small cell lung cancers (SCLCs). Here we evaluate SCLC subtypes based on ASCL1 and NeuroD1 expression in patients (pts) treated with first-line (1L) chemotherapy profiled with targeted next-generation sequencing (NGS). Methods: We used NGS (MSK-IMPACT) to profile tumors from pts with SCLCs. We performed IHC to assess ASCL1 (A) or NeuroD1 (N). Objective response rate (ORR) to therapy was determined using RECIST. PFS and OS were analyzed using Kaplan-Meier. Results: 281 pts with SCLCs were profiled with NGS (102 LS-SCLC; 179 ES-SCLC). Most frequently mutated genes were TP53 (90%), RB1 (68%), KMT2D (22%), NOTCH1 (15%), FAT1 (14%), PTPRD (12%). Mutations in BIRC3, FOXL2, TENT5C, TET1, NRAS, KIT, TSHR, ESR1 were enriched in ASCL1-/NeuroD1+ (A-/N+), and mutations in KMT2D and EP300 were enriched in A-/N- (p&lt;0.05). Copy number alterations in WWTR1, ATR, IKZF1, PALB2, PIK3CB were enriched in A-/N+ (p&lt;0.05). IHC for ASCL1 and NeuroD1 was performed on 78 samples: 11 A-/N-, 32 A+/N-, 4 A-/N+, 31 A+/N+. Overall survival at 1 year based on subtype was 25% in A-/N- (2/9), 60% in A-/N+ or A+/N- (13/32), and 55% in A+/N+ (10/25). For the 10 pts who survived 2 years, 5 were A+/N- and 5 were A+/N+. 146 pts treated with 1L platinum had RECIST-evaluable disease. ORR was 75% (110/146; 95% CI 68-82%). Median PFS was 7 months with CR/PR and 3.5 months with SD/PD (HR 0.32; 95% CI 0.18-0.56). Median OS was 17 months with CR/PR and 11 months with SD/PD (HR 0.55; 95% CI 0.34-0.9). Mutations in RUNX1, EPHA7, CDKN2A, FLT1 and copy number alterations in FGFR1, CCND1 were enriched in patients with SD/PD (p&lt;0.05). PFS rate at 6 months was 25% in A-N- (1/4), 60% in A-/N+ or A+/N- (9/15), and 55% in A+/N+ (6/11). For the 7 pts who survived 2 years, 3 were A+/N- and 4 were A+/N+. Conclusions: Molecular subtypes defined by ASCL1 and NeuroD1 encompass molecular characteristics that may predict patient outcomes. Further investigation is needed to delineate the underlying biological differences among the various subtypes to help define therapeutic vulnerabilities of each subtype of SCLC. Completion of IHC for ASCL1, NeuroD1 and additional key transcription factors POU2F3 and YAP1 are in progress for the entire cohort. WES and RNA sequencing are occurring in parallel and will be correlated with IHC results and clinical outcomes.
Assessing the risk of serious adverse events (SAEs) and death in non-small cell lung cancer (NSCLC) trials.
Authors: Nirali Marvania, Abigail Sy Chan, Joseph Abraham, Kenneth David Miller
Journal: Journal of Clinical Oncology (2020)

e21576 Background: Lung cancer is a leading cause of morbidity and mortality despite advances in targeted therapy and immunotherapy. Clinical trials play a critical role in improving treatment options however, pose significant known and unknown risks. The purpose of this study was to analyze the risk of SAEs (Grade 3 and 4 toxicity) and deaths in advanced NSCLC patients participating in phase I/II and III clinical trials. Methods: A literature search using Clinicaltrials.gov was conducted to identify published phase I/II and III clinical trials in advanced NSCLC patients. The data extracted included study name, total number of participants, SAEs, and deaths attributable to a study drug. A fixed-effects model was implemented to estimate summary proportions of SAEs among participants. The Freeman-Tukey double arcsine transformation was applied to stabilize the variances of SAEs and mortality proportions. Results: We evaluated 112 studies, of which 87% were phase I/II, and 13% were phase III clinical trials. Study sample sizes ranged from 7 to 659 patients for phase I/II studies and from 186 to 1391 for phase III studies. 107 studies had SAEs while 5 phase I/II studies had no SAEs reported. The overall estimated percentage of SAEs was 39.5% (95% Confidence Interval, CI: 38.8%, 40.2%). The estimated percentages of patients with SAE in phase I/II and phase III trials were 40.9% (95%CI: 39.8%, 42.0%) and 38.7% (95%CI: 37.8%, 39.6%), respectively (p = 0.001). The estimated percentages of deaths among patients were 1.1% (95%CI: 0.90%, 1.3%) overall, 1.1% (95%CI: 0.7%, 1.5%) in phase I/II trials and 1.7% (95%CI: 1.5%, 2.0%) in phase III trials. The difference in mortality between phase I/II and phase III trials was not statistically significant (p = 0.408). Conclusions: Patients with advanced stages (III/IV) of NSCLC have a high risk of morbidity and mortality from their primary disease and also from their treatment. Our study demonstrated SAEs and toxic deaths attributable to the treatment of approximately 40% and 1%, respectively. Phase I/II trials patients are at a slightly higher risk of SAEs compared to patients participating in phase III trials, although the differences might not be clinically significant.
Pathogenesis and diagnosis of male climacteric syndrome
Authors: Zhengguo Ji
Journal: BMJ (2017)

男性更年期综合征是男性老龄化过程中出现的健康问题，迟发性性腺功能减退症(LOH)是男性更年期综合征的主要表现形式，低睾酮水平和/或睾酮受体异常是LOH的基本病因学机制。睾酮作用低下不仅导致男性更年期综合征，也能使男性更年期更容易合并其他代谢性疾病。除老龄化因素外，肥胖、不良生活方式、某些慢性疾病也是导致男性更年期综合征的危险因素。在临床诊疗过程中需要结合患者的血清睾酮水平与临床症状评估综合考虑。
Diagnostic value of virtual touch tissue quantification in the evaluation of liver fibrosis in patients with chronic hepatitis B
Authors: Sen-hao Lin, Wen Shen, Hong Ding, Li-juan Mao, Jian-fang Xu, Bei-jian Huang
Journal: BMJ (2013)

Objective
To explore the diagnostic value of virtual touch tissue quantification (VTQ) for the assessment of liver fibrosis in patients with chronic hepatitis B.


Methods
VTQ was prospectively performed in 181 patients with chronic hepatitis B and a shear wave velocity (Vs) indirectly reflecting liver stiffness was obtained for each patient. With the gold standards of fibrotic stages and inflammation grades, the relationship between Vs, fibrotic stages and inflammation grades was evaluated.


Results
A relatively high correlation existed between Vs and liver fibrotic stages (r=0.812, P<0.001). Significant differences existed among groups with different fibrotic stages except for groups S0 vs. S1 and S1 vs. S2 (P<0.05). The areas under the ROC curve were 0.971, 0.961, 0.969 and 0.908 for Vs predicting S≥S1, S≥S2, S≥S3 and S=S4 fibrosis respectively. Moderate correlation existed between Vs and inflammation grades (r=0.476, P=0.000).


Conclusion
Capable of staging liver fibrosis and preliminarily grading inflammation, VTQ is helpful for the early diagnosis of liver fibrosis and assessment of therapeutic follow-up and prognosis in patients with chronic hepatitis B.


Key words: 
Ultrasonography; Hepatitis B, chronic; Liver cirrhosis
Phase III APACT trial of adjuvant <i>nab-</i>paclitaxel plus gemcitabine (<i>nab</i>-P + Gem) versus gemcitabine (Gem) alone for patients with resected pancreatic cancer (PC): Outcomes by geographic region.
Authors: Michele Reni, Hanno Riess, Eileen Mary O'Reilly, Joon Oh Park, Hassan Hatoum, Berta Laquente Saez, Tapio Salminen, Helmut Oettle, Rafael Lopez, Scot D. Dowden, Meinolf Karthaus, Josep Tabernero, Eric Van Cutsem, Philip Agop Philip, David Goldstein, Jordan Berlin, Margaret A. Tempero
Journal: Journal of Clinical Oncology (2020)

4515 Background: The APACT trial was one of the largest and most geographically diverse trials of adjuvant chemotherapy for resected PC, allowing for comparison of outcomes by geographic region. In this analysis, we report updated overall survival (OS) results for the intent-to-treat (ITT) population and examine outcomes by geographic region. Methods: Treatment-naive patients with histologically confirmed PC, macroscopic complete resection, Eastern Cooperative Oncology Group performance status 0 or 1, and carbohydrate antigen 19-9 &lt; 100 U/mL were eligible. Stratification factors were resection status (R0/R1) and lymph node status (positive/negative). Treatment was initiated ≤ 12 weeks postsurgery. Patients received nab-P 125 mg/m 2 + Gem 1000 mg/m 2 or Gem 1000 mg/m 2 on days 1, 8, and 15 of six 28-day cycles. The primary endpoint was disease-free survival by independent review. Secondary endpoints were OS and safety. Results: The updated OS analysis (data cutoff date, January 2020) revealed a median OS of 41.8 months with nab-P + Gem compared with 37.7 months with Gem alone (hazard ratio [HR] 0.81; 95% CI, 0.68 - 0.97; nominal P = 0.047; Table). In each geographic region, the median OS with nab-P + Gem was numerically longer than with Gem alone. Conclusions: The updated OS analysis of the ITT population supports the previously reported trend favoring nab-P + Gem. The geographic regional analyses reveal numerically longer OS with nab-P + Gem vs Gem alone and variable outcomes by region; however, the differences do not support the trend observed in the ITT population, potentially due to limited sample sizes. Registration: EudraCT (2013-003398-91). Clinical trial information: NCT01964430 . [Table: see text]
办公室人群高血压的社区干预疗效
Authors: 于汶
Journal: BMJ (2008)

在办公室这样特殊环境中工作的人员,由于饮食不健康、吸烟、运动减少等高血压危险因素以及对高血压知识的匮乏,高血压已成为他们的隐身杀手.如何让这类人群对高血压的防治充分认识,社区医疗所起的作用是非常重要的。
68Ga-FAPI PET/CT Detects Gastric Signet-Ring Cell Carcinoma in a Patient Previously Treated for Prostate Cancer
Authors: Yizhen Pang, Haichao Huang, Li Fu, Liang Zhao, Haojun Chen
Journal: Clinical Nuclear Medicine (2020)

Abstract A 75-year-old man with a history of prostate cancer (T1N0M0, Gleason score 4 + 3) was referred to radionuclide bone scan and 68 Ga-PSMA PET/CT to detect recurrence. Multiple abnormal foci were observed in the axial and appendicular skeleton, which were suggestive of metastatic superscan from prostate cancer. However, histopathological examinations (from bone biopsy) did not support the metastases from prostate cancer. 68 Ga-FAPI PET/CT was then performed to detect the occult tumor, which showed intense activity in the gastric wall. Subsequent gastroscopy examination revealed the diagnosis of GSRCC (gastric signet-ring cell carcinoma). The diagnosis of GSRCC with widespread bone metastases was finally made.