tbuckley/cabot-search huggingface dataset:
<i>KRAS</i> G12C mutation associated outcomes among patients with locally advanced non-small cell lung cancer.
Authors: David Qian, Madhusmita Behera, Conor Ernst Steuer, Suchita Pakkala, Jennifer W Carlisle, Taofeek Kunle Owonikoko, Benjamin Walker Fischer-Valuck, Aparna Hemant Kesarwala, Jeffrey Bradley, Walter J Curran, Suresh S. Ramalingam, Kristin Ann Higgins
Journal: Journal of Clinical Oncology (2020)

e21079 Background: Recent progress in targeted therapy includes the demonstration of promising anti-tumor activity and safety of a KRAS inhibitor in patients with advanced malignancies harboring the G12C somatic mutation ( KRAS G12C ). KRAS mutations are present in one-third of all non-small cell lung cancers (NSCLCs), of which KRAS G12C comprises about 40%. In this study we characterize the outcomes of patients with stage III NSCLC who received radiotherapy, stratified by KRAS G12C status. Methods: Level 3 data for NSCLC patients were downloaded from The Cancer Genome Atlas (TCGA). Clinical and somatic mutation data were analyzed for the 118 NSCLC patients with stage III disease whose treatment included radiotherapy with or without chemotherapy. Overall survival (OS) and progression-free survival (PFS) were then compared between patients whose tumors possess versus lack KRAS G12C using Cox proportional hazards regression. Results: This TCGA cohort study consists of 75 males and 43 females with stage III NSCLC (57 adenocarcinomas and 61 squamous cell carcinomas) enrolled between February 2010 and November 2014. Presence of KRAS G12C was detected in 7 patients (6%) and conferred poorer OS (HR 3.14, 95% CI 1.12–8.84, P = 0.030) as well as PFS (HR 3.74, 95% CI 1.46–9.56, P = 0.0059) compared to absence of KRAS G12C , with median survival of 9.0 versus 28.9 months and median time to progression of 8.5 versus 16.8 months. All 7 patients with KRAS G12C had lung adenocarcinomas (ACs). Inferior survival of patients with KRAS G12C persisted on subgroup analyses of AC and KRAS mutation status (Table). Conclusions: Among patients with stage III NSCLC in TCGA treated by radiotherapy, those with KRAS G12C had significantly worse OS and PFS. Clinical trial of a KRAS inhibitor is a rational next step toward improving outcomes for this patient population, which has yet to be remarkably impacted by existing precision oncology approaches. [Table: see text]
Comparison of baseline patient characteristics in immunotherapy versus targeted therapy trials for advanced melanoma.
Authors: Shivani Handa, Giulia Petrone, John R Rutledge, Philip Adam Friedlander
Journal: Journal of Clinical Oncology (2020)

e22012 Background: Immune checkpoint inhibitors (ICI) or BRAF/MEK targeted therapy are both FDA approved first line options for BRAF mutant advanced melanoma. However, the optimal sequencing of these approaches and the profile of patients who benefit the most from one treatment over the other is suboptimally defined. Methods: We compared the baseline characteristics of the participants enrolled in the immunotherapy (IT) and targeted therapy (TT) trials quoted in the NCCN guidelines as the guidelines are used by many oncologists who do not subspecialize in melanoma to formulate treatment plans. Data was gathered about age, sex, race, ECOG score, LDH levels, stage, BRAF mutation status, PD-L1 expression and prior lines of therapy. Results: Median age range was younger in the TT population (48-57 y) as compared to the IT population (56-65 y); &gt; 50% were males. 54-82% patients in the IT trials had an ECOG score of 0. Relatively more patients (pts) with ECOG score of 1 were included in Dabrafenib/ Trametinib and Vemurafenib/Cobimetinib trials (62-65%). Most pts had stage IV M1c disease. LDH levels were similar in IT and TT trials. V600E mutation was uniformly more common in the TT trials as expected. PD-L1 expression varied widely; from 23% to 81% patients with a high PD-L1 expression. Trials evaluating pembrolizumab included patients (7-26%) who were previously treated with BRAF/MEK inhibitor, however TT trials did not include as many pts exposed to ICI. Conclusions: Age range and sex ratio of the pts included in the trials were representative of the epidemiology of melanoma, but race was underreported. TT studies trended towards a younger median age range than patients treated in the IT studies. However optimal biomarkers for initial treatment choice cannot be determined by the patient demographics and characteristics presented in the studies discussed in the NCCN guidelines. Studies randomizing treatment sequence and identification of biomarkers prognostic of patient specific treatment efficacy are needed. Comparison of the IT and TT studies support the choice of either approach as initial treatment in pts with BRAF mutant melanoma lacking contraindications.
亚临床甲状腺功能亢进症的诊断与治疗
Authors: 蔡晓频
Journal: BMJ (2012)

亚临床甲状腺功能亢进症(甲亢)是常见的轻微的甲状腺功能紊乱,诊断基于实验室甲状腺功能检测结果[血清TSH水平低于正常参考值下限,而游离T4(FT4)和游离T3(FT3)水平在正常参考值范围内],诊断应除外其他引起TSH下降的原因,还需明确亚临床甲亢的病因.临床上基于亚临床甲亢的病因、患者年龄、是否并发心血管疾病或骨质疏松以及TSH下降水平,选择治疗或随访。
脂联素、高敏C反应蛋白和神经元烯醇化酶在急性脑梗死预测中的临床意义
Authors: 黄友敏, 褚福第
Journal: BMJ (2006)

脂联素(adiponectin)是近年来新发现的由脂肪组织特异性分泌的脂肪细胞因子,具有抗动脉粥样硬化、抗高血糖及抗炎症等作用,它在能量代谢、血脂代谢及动脉粥样硬化形成的过程中发挥重要作用[1]。
Management window for patients with atrial fibrillation in community health center
Authors: Jiang-tao Gu, Huan Song, Wei-hua Gong, Ying Zhou, Wei Cheng, Lie Dai
Journal: BMJ (2013)

A management window model for patients with atrial fibrillation (AF) was established in Tilanqiao Community Health Service Center cooperated with tertiary hospitals. Patients were screened and treated in the community health service center, and a comprehensive management plan was conducted and patients were followed-up. A total of 105 patients with atrial fibrillation (97.2%) were effectively managed with an average follow-up of 10.6 months. The CHADS2 score ≥ 2 in 78 cases, including 11 cases with administration of warfarin (14.1%) and 26 cases with paroxysmal AF without transition to persistent atrial fibrillation. Compared to the data before management, the rate of taking aspirin and warfarin in managed patients was increased (all P<0.05), the international normalized ratio (INR) of patients receiving warfarin was improved (P<0.05); the ratio of receiving comprehensive treatment program, standardized treatment and health education were significantly increased (P<0.05); the awareness of the disease, treatment compliance and satisfaction of patients were improved significantly (all P<0.05). The results suggest that the management widow model is feasible and effective for management of patients with atrial fibrillation in community health service centers.


Key words: 
Atrial fibrillation; Disease management
Post-transplant lymphoproliferative disorder (PTLD) after solid organ transplant (SOT): A multicenter real world analysis (RWA) of 877 patients (pts) treated in the modern era.
Authors: Deepa Jagadeesh, Donald Edward Tsai, Wei Wei, Jean Alvarez Bustamante, Nina D. Wagner-Johnston, Stephanie Berg, Seo-Hyun Kim, Nishitha M. Reddy, Deepika Sriram, Craig Portell, Paola Ghione, Timothy Voorhees, Manali K. Kamdar, Jean Louise Koff, Vikas Dharnidharka, Andrew M. Evens
Journal: Journal of Clinical Oncology (2020)

e20026 Background: Historically, SOT PTLD have modest outcomes in part due to heterogeneous treatment approaches. Additionally, there remains an absence of a large data repository in PTLD to help delineate contemporary pt outcomes &amp; prognostic factors. We conducted a large, multicenter RWA to study outcomes &amp; prognostication of SOT PTLD in the modern era. Methods: Retrospective data on 877 untreated SOT PTLD pts ages ≥18 years (yrs) (2000-2018) were analyzed from 15 academic centers. Prognostic factors for relapse free survival (RFS) &amp; overall survival (OS) were assessed by Cox model. Results: The median age at diagnosis was 54 yrs (range 18-84). The majority of pts were white (78%) &amp; male (67%). Median time from SOT to PTLD diagnosis was 57 months (range 0.23-470). SOT types: kidney (41%) liver (19%), lung (16%), and heart (11%); 11% multi-organ. Tumor was EBV+ in 52%. Graft involvement (18%) and rejection (21%) were seen in a proportion of pts. Most pts had reduction in immunosuppression (79%) and rituximab (R)-containing regimen (61%) as part of 1 st line therapy (Tx). Most common Tx: R monotherapy (34%), R+chemotherapy (29%) &amp; chemotherapy without R (8%). Maintenance R use was infrequent (6%). Overall response rate was 63% [51% complete response (CR) and 12% partial response (PR)] and 19% of pts had primary refractory disease. With 44-month median follow-up (0.1-304), 62% of pts were alive. Median OS &amp; RFS for all pts were 12 &amp; 9 yrs, respectively, while differential survival rates were identified for several pt subsets (Table). On univariate analysis, lung SOT was associated with borderline RFS (HR 0.68 [95% CI 0.44-1.03], P= 0.07) and inferior OS (HR 0.67 [95% CI 0.49-0.91], P= 0.012), while EBV negative PTLD was associated with poorer RFS (HR 1.51 [95% CI 1.12-2.04, P= 0.006). In addition, achievement of PR to 1 st line Tx vs CR was strongly prognostic for inferior RFS (HR 2.58 [95% CI 1.88-3.54], P&lt; .0001) and OS (HR 2.30 [95% CI 1.60-3.29], P&lt; .0001). Conclusions: In this large, multicenter PTLD RWA, type of SOT was strongly associated with long-term RFS and OS and EBV status predicted RFS. Furthermore, depth of response to 1 st line Tx was a critical determinant for long-term pt survival. [Table: see text]
Substantial ninety-nine percent reduction of turnaround time for QTc diagnostics using smartphone-based tele-cardiology.
Authors: Lena-Sophie Fink, Timo Schinkoethe, Rachel Wuerstlein, Nadia Harbeck
Journal: Journal of Clinical Oncology (2020)

e14155 Background: Numerous anti-cancer drugs may lead to long QT syndrome as a cardiotoxic side effect, which could lead to sudden cardiac death. But the outcome of a long QT syndrome is not necessarily fatal. When diagnosed and managed in time, prolongation of the QT interval is reversible. Regular QT interval assessment is, therefore, necessary to ensure the optimal care for these patients. Evaluation of the QT interval requires timely support of the attending oncologist by a cardiologist. The idea for the presented solution was to replace the conventional interaction between oncologists and cardiologists by a smartphone APP solution supporting single-lead ECG records directly at the cancer center and sent from APP to APP to a cardiologist for immediate diagnostic (named as ‘QTc Tracker’). Methods: 54 cancer centers in Germany were equipped with the ‘QTc Tracker’ and a connected single-lead ECG device. Before implementation, all participants were asked in a structured interview about their routine ECG workflow, turnaround time, and satisfaction. After implementation, the centers were contacted again for a comparative evaluation of the turnaround time and satisfaction. Results: The mean total turnaround time of the routine QT/QTc evaluation was 140 h (± 333 h, range 0.3 - 1993 h). 25 cancer centers had direct access to a cardiologist. In these centers, the mean turnaround time was 1.2 h (± 1.3 h, range 0.33-6.5 h), whereas 9 centers with a cardiologist but no direct access needed a mean of 78 h (± 74 h, range 24-192 h). Centers without a cardiologist needed a mean of 354 h (± 490 h, range 24-1993 h) to receive their ECG report. Using the QTc Tracker APP, the mean turnaround time for all centers went down to 47 minutes. Conclusions: A reduction of the mean ECG turnaround time from 140 h down to 47 minutes equals a reduction of 99 %. This also enables centers without a cardiologist on site to provide the QT/QTc report within a single patient visit. Having the ECG result on the same day reduces uncertainties for the patients, and increases treatment continuity and patient safety. In particular as a regular side-effect monitoring, this application promises more convenience for patients and their physicians. The tool is currently integrated in several phase III-IV clinical trials in Germany.
BXQ-350 to target to the lysosome and kill glioblastoma (GBM) cells via activation of apoptotic caspases in vitro.
Authors: Laura Felix, Timothy J Stephens, Nikhil J Wilkins
Journal: Journal of Clinical Oncology (2020)

3639 Background: Apoptosis is a programmed cell death mechanism where cells respond to internal or external stimuli by initiating a cascade of events and enzymes leading to cell death. One of the hallmarks of cancer is the ability of tumor cells to resist these apoptotic stimuli. This allows tumor cells to have aberrant metabolisms, such as sphingolipid metabolism in tumor cell lysosomes, or mutations which would normally commit cells to death. Saposin C, the protein component of BXQ-350, Bexion Pharmaceuticals’ proprietary biotherapeutic, is involved in normal lysosomal sphingolipid metabolism. Removing resistance, shortcutting steps leading to apoptosis, or correcting sphingolipid metabolism can result in the death of these tumor cells. Methods: The GBM cell line Gli36ΔEGFR was plated in 96 well plates at a density of 1x10 4 cells per well in Dulbecco’s Modified Eagle Media with 10% FBS overnight at 37 o C for caspase and cytotoxicity assays. Cells were treated with 9uM to 30uM BXQ-350 in triplicate and incubated for 24 hours at 37 o C. Promega’s Caspase-Glo 9 or Caspase-Glo 3/7 reagent was added to appropriate wells and the plates were incubated at room temperature in the dark for 3 hours then luminescence was read. The parallel cytotoxic assay was run under the same conditions except Roche’s MTT labeling reagent was added to the appropriate wells after 24 hours and incubated at 37 0 C for 4 hours. Solubilization solution was added to each well and the plate was incubated at 37 o C overnight then absorbance was read. The GBM cell line U87 MG was used to determine lysosomal targeting. U87 MG cells were treated with 10uM BXQ-350 and incubated at 37 o C overnight. They were stained with anti-SapC (RFP) and anti-LAMP1 (GFP) antibodies and images were taken. Results: BXQ-350 mediated cell death is correlated with a rise in Caspase 3, Caspase 7 and Caspase 9 activity. The caspase activity levels did not rise until after BXQ-350 passed its IC50 and stayed elevated. Caspases 3/7 levels showed higher activity compared to untreated than Caspase 9. In addition to this, BXQ-350 was seen to colocalize to LAMP1, a lysosomal membrane protein. Conclusions: BXQ-350 tracks to the lysosomal membrane where it initiates the cascade of enzymes necessary to cause apoptosis. Caspases 3/7 are the effector caspases and are necessary for the completion of the apoptotic pathway. The higher activity levels of these caspases show the cells are committed to cell death not allowing these cells to subvert apoptosis. This removes one of the major barriers to fighting cancer.
Breast cancer pathology patterns in Armenia.
Authors: Davit Zohrabyan, Samvel Bardakhchyan, Sergo Mkhitaryan, Liana Safaryan, Jemma Arakelyan, Gevorg Tamamyan, Lilit Harutyunyan, Armen Avagyan, Armen Mkhitaryan, Gohar Mkrtchyan, Marine Rushanyan, Martin Harutyunyan
Journal: Journal of Clinical Oncology (2020)

e12586 Background: Breast cancer (BC) is the most common malignancy among the women in Armenia (AM). Currently there is a knowledge gap regarding the morphology distribution of the BC in AM. Methods: The data on patients with BC diagnosed in 2015-2016 in the pathology lab “Davidyants Labs” in AM were retrospectively reviewed. Pts with Her2+ results by IHC were excluded from the study, due to unavailability to perform FISH or CISH analyses. Overall 361 pathology reports were evaluated. Results: The median age was 54 years; range [19-82]. Histopathological subtypes were defined for 305 pts, from which lobular carcinoma 57.4% of cases (175/305), ductal carcinoma 26.9% (82/305), mucinous carcinoma 2.6% (8/305), mixed type carcinoma (lobular and ductal) 2.6% (8/305), DCIS 2% (n = 6/305), non specified carcinoma 2% (6/305), medullary carcinoma 1% (n = 3/305) and others 5.6% (17/305). Within the cohort 8.5% (23/270) were grade 1, 65.9% grade 2 (178/270); 25.6% grade 3 (n = 69/270). Vascular or lymphatic invasion was present in 59.5% (50/84) and 64.7% (55/85), respectively. Staging distribution, based on pT pN data for 92 pts who went to primary surgery, was: 0 stage 7.6% (7/92), I stage 22.8% (21/92), II stage 41.3% (38/92), III stage 28.3% (26/92). Staging distribution based on ypT ypN data for 27 pts who went to surgery after neoadjuvant chemo was 0 stage 25.9% (7/27), I stage 18.5% (5/27), II stage 29.6% (8/27), III stage 25.9% (7/27). ER and PR were defined for 244 patients. ER positive 89.8% (219/244) of cases, PR pos. 73% (178/244), ER/PR pos. 72.5% (177/244) cases. Her receptor was defined for 237 patients. Her3+ 16.9% (40/237); Her2+ 12.7% (30/237); Her1+ 38% (90/237); Her0 32.5% (n = 77/237). We could not evaluate Her2+ status by FISH or CISH, so these results were excluded from the analysis. Ki67 was low (≤20) in 42.1% (101/240) of cases and high ( &gt; 20) in 57.9% (139/240). Within the group Luminal A type was 41.4% (84/203); Luminal B 32.5% (66/203); Her positive 19.7% (40/203) and triple negative 6.4% (13/203). p53 and perineural invasion (Pn) was present in 32% (16/50) and 52% (26/50), respectively. Tumor leukocyte infiltration was determined for 16 patients. Leukocyte infiltration was positive in 43.7% (7/16) cases, negative in 25% (4/16) cases, minimal in 31.3% cases (5/16). Conclusions: BC in Armenian women presents with different epidemiological characteristics in comparison with other ethnicities. Lobular type BC is the most frequent type among Armenian women, however, differential diagnosis between lobular/ductal carcinomas was done without IHC (E-Cadherin), which rises the need for further studies on that regard.
Use of pulse steroids to treat renal IRAE to maintain patients with metastatic non-small cell carcinoma cancer on pembrolizumab.
Authors: Ala Abudayyeh, Maen Abdelrahim, Frank V. Fossella
Journal: Journal of Clinical Oncology (2020)

e21589 Background: Immune checkpoint inhibitor (ICI) has a major clinical success in many cancers including non-small cell lung cancer. Renal Immune related adverse events is one of the rare IRAE’s with a reported incidence of 3-5%. In this abstract we present two cases of patients with metastatic NSCL cancer with biopsy proven acute interstitial nephritis and maintained on pembrolizumab with co-treatment of steroids. Methods: We reviewed all patients diagnosed with NSCL cancer and treated with ICI who have been diagnosed with biopsy proven AIN. We selected only the patients who were re-challenged with ICI and co-treated with steroids. Results: Two patients were identified. First patient a 40 y.o. female who was diagnosed with metastatic NSCLC. Patient was started on carboplatin, alimta, and pembrolizumab. After cycle 4 she acute kidney injury where creatinine increased to 3.26mg/dl from baseline 0.69mg/dl she was initially pulsed with steroids due to suspected renal IRAE. A kidney biopsy that indicated acute tubular necrosis which is likely related to pemetrexed and/or carboplatin. In addition, she did have acute tubular interstitial nephritis related to pembrolizumab. Creatinine stabilized at 2.0mg/dl and was continue only on pembrolizumab for the last 5 months with prednisone 40mg daily tapered off over 4 days. She has maintained her creatinine at 2.0mg/dl with continued excellent disease control. Second patient diagnosed with poorly differentiated non-small cell carcinoma with metastatic disease and PD-L1 expression is 80-90%. She was initially started on carboplatin, alimta, and pembrolizumab with complete response after 4 cycles. Her creatinine peaked to 1.84mg/dl from baseline of 0.67mg/dl. A kidney biopsy revealed chronic active interstitial nephritis. She was treated with a prednisone taper and creatinine improved to 1.1mg/dl. Patient was continued on pembrolizumab and maintained for 14 months on prednisone (as above) and sustained complete tumor response. Conclusions: Steroids in patients with persistent AIN after re-challenge may provide an excellent option to continuation of treatment. As demonstrated above, use of steroids is controversial since concern of impact on tumor response; however, smaller doses for short duration maybe efficacious in treatment of renal IRAE without impact on tumor response. Further studies need to be initiated to evaluate this intervention and its long term effects.
Work loss and activity impairment due to duration of nausea and vomiting in patients with breast cancer receiving CINV prophylaxis.
Authors: Lee S. Schwartzberg, Rudolph M. Navari, Kathryn Jean Ruddy, Thomas William LeBlanc, Rebecca Anne Clark-Snow, Rita S. Wickham, Gary Binder, William Bailey, Marco Turini, Ravi C. Potluri, Luke M. Schmerold, Eric Roeland
Journal: Journal of Clinical Oncology (2020)

e24133 Background: The impact of chemotherapy-induced nausea and vomiting (CINV) on work loss and activity impairment is important to patients yet not well described in literature. We sought to evaluate CINV-related work loss and activity impairment and their associations with CINV duration. Methods: In a prospective CINV prophylaxis trial of oral or intravenous netupitant/palonestron (NEPA) + dexamethasone (DEX) (12mg day 1 only) for patients with breast cancer receiving anthracycline + cyclophosphamide (AC), we defined CINV as vomiting or use of rescue medication during days 1-5 after AC. Pre-specified endpoints included CINV duration (0-5 days), patient reported CINV-associated work loss (Work Productivity and Activity Impairment survey), and CINV-related impaired activity [0 (none) - (worst) Likert scale] for chemotherapy cycles 1 and 2. CINV-related work loss and activity impairment could involve nausea with or without vomiting or rescue medication use. We categorized CINV duration as 1-2 days (d) or ≥3 d, and compared results using the chi-squared test. We report here on the first 2 cycles. Results: Survey data was captured for 792 cycles in 402 female patients including 132 (32.8%) employed patients. Mean age was 55.4. CINV was observed in 173 (21.8%) of total cycles. CINV-related work loss was reported in 26 (3.3% of all cycles, 15.0% of cycles with CINV, 38.2% of employed patient cycles with CINV) while 142 had related activity impairment. When we categorized cycles by CINV duration, CINV-related work loss was seen in 25.9% of 81 cycles with ≥3 d CINV duration vs. 5.4% for 92 cycles of 1-2 d of CINV (p &lt; 0.001); mean scores of CINV-related impaired activity were 5.0 for ≥3 d CINV vs 3.0 for 1-2 d CINV (p &lt; 0.001). Conclusions: Despite guideline recommended prophylaxis, CINV occurred in &gt; 20% of AC cycles. In cycles with CINV, CINV-related work loss occurred in 38.2% for employed patients while activity impairment occurred in 82.1% for all patient cycles. The majority of CINV lasted 1-2 d. Notably, ≥3 d of CINV was associated with considerably higher levels of work loss and activity impairment suggesting that duration may be a meaningful measure of CINV impact. Clinical trial information: NCT03403712 . [Table: see text]