tbuckley/cabot-search huggingface dataset:
Therapeutic impact of mutation subtypes and concomitant <i>STK11</i> mutations in <i>KRAS</i>–mutated non-small cell lung cancer (NSCLC): A result of nationwide genomic screening project (LC-SCRUM-Japan).
Authors: Yutaro Tamiya, Yoshitaka Zenke, Shingo Matsumoto, Naoki Furuya, Tomohiro Sakamoto, Terufumi Kato, Kazumi Nishino, Masato Shingyoji, Shingo Miyamoto, Chigusa Shirakawa, Ryo Toyozawa, Kadoaki Ohashi, Takaya Ikeda, Kaname Nosaki, Hibiki Udagawa, Keisuke Kirita, Kiyotaka Yoh, Seiji Niho, Koichi Goto
Journal: Journal of Clinical Oncology (2020)

9589 Background: KRAS mutations are one of the common oncogene drivers in non-small cell lung cancer (NSCLC), and the development of several targeted drugs for KRAS-mutated NSCLC is now ongoing. However, the clinical impact of KRAS mutation subtypes or concomitant other gene mutations in NSCLC patients (pts) remains unclear. Methods: In a nationwide genomic screening project (LC-SCRUM-Japan), we have prospectively analyzed lung cancer pts for genetic alterations and tumor mutation burden (TMB) by next-generation sequencing system, and for PD-L1 expression by immunohistochemistry (22C3 antibody). The therapeutic efficacy and survival of KRAS-mutated non-squamous (non-sq) NSCLC pts were evaluated using a clinico-genomic database of the LC-SCRUM-Japan. Results: A total of 5166 non-sq NSCLC pts enrolled from 2015 to 2019. KRAS mutations were detected in 794 pts (15%; G12C/G12D/G12V/G12A/G13X/others = 232/186/165/66/61/84). Among the 794 pts, TMB and PD-L1 expression were analyzed in 128 and 79, respectively, and 218 received PD-1/PD-L1 inhibitors (IO) after 1st-line chemotherapy. The median age was 66 years (range, 29-89). 142 pts (65%) were male and 172 (78%) were smokers. Concomitant STK11 mutations were detected in 33 pts (15%) with no difference in the mutation frequency among KRAS mutation subtypes. KRAS G12C was significantly associated with high TMB (≥ 10 mut/Mb) (p = 0.03), and KRAS G12C or G12V with high PD-L1 expression (≥ 50%) (p = 0.02). In pts who received IO, median progression-free survival (mPFS) was significantly longer in pts with KRAS G12C or G12V than in those with other KRAS mutations (4.7 vs 2.0 months, hazard ratio (HR) 0.58 [95%CI 0.43-0.78], p &lt; 0.01). Among pts with KRAS G12C or G12V, mPFS of IO was significantly shorter in pts with concomitant STK11 mutations than in those without (1.8 vs. 5.7 months, HR 1.97 [95%CI 1.06-3.41], p = 0.02). These correlations were not observed in platinum-containing chemotherapy (Plt-CTx). There were also no significant differences in IO and Plt-CTx efficacies between with and without other concomitant mutations, such as TP53, RB1, CDKN2A and PTEN mutations. Conclusions: Non-sq NSCLC pts with KRAS G12C/V were more sensitive to IO therapies than those with other KRAS mutations, but KRAS G12C/V-positive pts with concomitant STK11 mutations were less sensitive than those without. These results could be highly informative in the development of novel targeted therapies for KRAS-mutated NSCLC.
A first-in-class ex vivo combination between cytokine-induced memory like (CIML) NK cells and a CD38 targeting antibody recruiting molecule (ARM) as a novel approach to target NK cells without cellular engineering for the treatment of multiple myeloma.
Authors: Luca Rastelli, Maqbool Mohsin, Ann Marie Rossi, Enrique Alvarez Sotomayor, Lawrence Iben, Ada Vaill, Matthew Welsch, Rizwan Romee, Anna Bunin
Journal: Journal of Clinical Oncology (2020)

8523 Background: Cytokine-induced memory-like (CIML) NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for several weeks to months. Antibody Recruiting Molecules (ARM) are bifunctional molecules that simultaneously bind a given tumor marker and engage endogenous IgG antibodies, therefore binding and activating NK cells via their FcR and targeting them to kill tumors cells. A first in class therapy that has the potential to improve the activity of CIML NK cells by combining them with KP1237, a CD38-ARM is presented for the treatment of newly diagnosed multiple myeloma (MM) patients who are minimal residual disease positive (MRD+) and eligible for autologous stem cell transplant (ASCT). Methods: Specific killing of CD38 expressing MOLP-8 cells by CIML NK cells alone or in combination with KP1237 was measured. Additionally, NK and CIML NK cells from healthy volunteers and MM patients at various stages of the disease were tested for activity against autologous and allogeneic tumor cell targets. In these experiments, surface phenotype and activation status of NK cells were determined. Results: A statistically significant increase in specific killing was observed when KP1237 was used in combination with CIML NK cells in an ADCC assay against CD38 expressing MOLP-8 (p = 0.0105, mean 61.8 ± SD 9.1 and mean 83.7 ± SD 13.58 for CIML NK alone and CIML NK+KP1237, respectively). This effect was accompanied by an increase in plasma membrane retention of CD107a. Surface phenotype of NK and CIML NK cells from healthy volunteers and MM patients was compared since the functional activity of NK cells from such patients is debated. We report surface expression of CD56, CD16, CD57, NKG2D, Nkp44, Nkp46, CD107a, KIR2DL2/3/DS2, and CD69 as well as frequencies of CD57hi CD56+ mature versus CD57lo CD56+ immature NK cell subsets. Further, autologous CIML NK cells + KP1237 exhibit cytotoxicity towards patient plasma cells. Conclusions: The activity of CIML NK cells towards CD38 expressing MM target cells is improved by the addition of KP1237 avoiding the need for cellular engineering with chimeric antigen receptors. This led to the development of the combination drug product consisting of patient autologous CIML NK cells, KP1237 and IVIG. Clinical development is under way for (MRD+) MM patients eligible for ASCT.
Survey on knowledge of obstructive sleep apnea among general practitioners in community medical institutions in Beijing Fengtai district
Authors: Xiangqian Yin, Hao Wu
Journal: BMJ (2019)

Objective
To survey the knowledge levels of obstructive sleep apnea (OSA) among general practitioners in community medical institutions run by the Fengtai District government.


Methods
One hundred and eighteen general practitioners from 13 government-run community health service centers in Fengtai District were selected for a questionnaire survey on OSA awareness and attitude in December 2016.


Results
One hundred and nine valid questionnaires were recovered. The survey showed that the overall accuracy rate of cognitive problems was 68.6% (1 345/1 962), the accurate rates for etiology and pathogenesis, diagnosis, epidemiology, clinical manifestations and complications, and treatment were 84.7% (277/327), 75.9% (331/436), 59.0% (193/327), 79.1% (345/436) and 45.6% (199/436), respectively. Very few participants (0.9%,1/109) thought that OSA was not an important clinical disorder and not important for identification, while quite a few participants felt uncertain confidence in the identification (39.4%,43/109), management (62.4%,68/109) and treatment (65.1%,71/109) of the disease. The knowledge scores of general practitioners who had attended OSA related training were higher than those who had not [14 (13, 15) vs. 12 (10, 14), Z=-2.712, P=0.007].


Conclusion
General practitioners in community medical institutions of Beijing Fengtai District generally have a positive attitude towards OSA, but are lack in the ability of diagnosis, management and treatment of the disease, indicating that further training is necessary.


Key words: 
Sleep apnea, obstructive; Questionnaires; General practitioner
A process mining approach to real-world advanced melanoma treatments.
Authors: Camille Lea Gerard, Erica Tavazzi, Roberto Gatta, Julie Delyon, Michel A Cuendet, Olivier Michielin
Journal: Journal of Clinical Oncology (2020)

e22040 Background: Process Mining (PM) is an emerging discipline with promising potential in oncology, which offers a time-oriented perspective on the clinical events that define the patient’s (pts) path of care, from diagnosis to follow-up. PM enables us to 1) build unsupervised models that automatically discover frequent patterns and detect unexpected behaviors, and 2) show the pts flow through predefined models, allowing quantitative assessments of conformance/divergence between reality and expected behaviors or medical guidelines. Methods: We explored the potential of PM to analyze treatments in a real-world melanoma cohort of 212 advanced melanoma pts treated with tyrosine kinase inhibitors (TKI), chemotherapy, or immunotherapy (IO) since 2010. 44% of pts are BRAF mutated, 24% NRAS mutated, and 16% WT. Using PM, we characterize the sequences of treatment according to type of drugs, order and timing of consecutive lines. We use kernel density estimations, Fisher or Wilcoxon tests to assess differences between groups. As main endpoint we assess the overall survival (OS) with respect to specific patterns of care followed by the pts using Kaplan-Meier analysis with log-rank test. Results: This approach provides important self-consistency checks for data and reveals the most frequent treatment sequences, and the associated outcome. The 324 administered treatments, characterized in terms of type and occurrence, are: TKI (23%), antiCTLA4 + antiPD1 (22%), antiPD1 (21%), and antiCTLA4 (20%). The overall 3-year OS is 56.9% (95% CI: 49.2 – 65.8). We identified 50 distinct patterns, which can be further aggregated into relevant cohorts to provide real-world answers to medical questions. Among others, we probed the influence of treatment order: IO single (any BRAF status), IO → TKI, TKI → IO (see table). Preliminary results suggest that pts treated with TKI → IO had shorter OS despite balance prognostic factors to IO → TKI group. IO → TKI provides short-term benefits with 1.5-year OS similar to IO alone, but degraded 3-year OS. Conclusions: The PM approach enables fast and efficient visual inspection of the data, emphasizing treatment sequences over time and allowing stratification at different levels. More population attributes and outcomes will be included to further characterize treatment sequences and provide real-world insights into future personalized care options. [Table: see text]
Clinical analysis of 129 Young patients with lung cancer
Authors: Ying-kai Zhang, Hai-lian Du, Yi-kai Niu, Xia Li, Xiu-li Zhang
Journal: BMJ (2008)

Clinical data of 129 young pafienm with lung cancer were analyzed retrospectively.Adenocarcinoma was the main pathologic type of lung cancer(n=62,48.1%),followed by undifferentiated small cell carcinoma(n=35,27.1%),squamous carcinoma(n=20,15.5%).Forty four cases were misdiagnosed at first consultation with a misdiagnosis rate of 34.1%.To avoid misdiagnosis seems to be the key issue for improvement of prognosis in young patients with lung cancer.

Key words: 
Lung neoplasms; Diagnostic errors
Clinical characteristics of aortic dissection and analysis of factors related to misdiagnosis
Authors: Hong Shen, Yu Kang, Zhi-feng Yao, Yong-le Chen, Jing Shi, Chen-ling Yao, Chao-yang Tong, Lai Wei, Chun-sheng Wang
Journal: BMJ (2013)

The clinical data of 361 patients aged from 16-77 y with aortic dissection (AD) admitted from January 2003 to June 2008, including 273 males and 88 females, were retrospectively reviewed. The symptoms and physical signs of the AD were diverse, major clinical manifestation was pain (87.8%) and the painless diseases were seen in 12.2% of cases. The misdiagnosis occurred in 51 patients (14.1%), including 43 male patients and 8 females, aged from 25-77 y before admission; 45 painful cases (88.2%) were misdiagnosed as acute coronary syndrome, acute pancreatitis, acute cholecystitis and cholelithiasis and 6 painless patients (11.8%) were misdiagnosed as pulmonary infection and congestive heart failure. The data indicate that AD may demonstrate diverse manifestations and severity leading to misdiagnosis and the symptom of pericardial effusion is helpful for accurate diagnosis.


Key words: 
Aortic aneurysm; Diagnositic errors
Evaluating sexual function in adolescent and young adult childhood cancer survivors.
Authors: Jenna Sopfe, Rebekah Marsh, Leslie C. Appiah, James L. Klosky, Pamela N Peterson, Brooke DorseyHolliman
Journal: Journal of Clinical Oncology (2020)

e24180 Background: Up to half of adolescent and young adult (AYA) childhood cancer survivors (CCS) experience sexual dysfunction (SD) as a result cancer or its treatment. SD in CCS is under-recognized, with low levels of routine screening due to barriers such as discomfort, time, and awareness. This study explores solutions to these barriers by describing AYA CCS preferences for implementation of screening for SD and evaluating the utility of a validated adult screening tool (PROMIS SexFS Brief) in this population. Methods: 16 AYA CCS (aged 15-24 years) completed semi-structured interviews followed by questionnaire completion. Interviews explored patients’ prior experiences with SD screening, along with preferences for screening type (e.g., discussion, screening tool), delivery modality, and timing. Patients then completed the PROMIS SexFS Brief while verbalizing their thoughts and providing open-ended responses to each item. Transcribed interviews were inductively coded and analyzed, guided by content analysis methodology. Results: This analysis represents 2/3 of planned interviews, and all will be completed by April 1, 2020. Interviews were performed with 11 females and 5 males (median age 21). Preliminary analysis demonstrates that participants had minimal experience with SD conversations, but had preferences regarding by whom, how, and when screening/education should occur. Who: Participants felt providers should have preexisting rapport with their patients; preferences existed for provider role and sex/age. How: A combination of written materials and in-person conversations was preferred. Several acknowledged a desire to have a “warning” that the conversation would happen, such as through a questionnaire. Participants did not have a preference regarding delivery modality (paper vs. online). The PROMIS SexFS Brief appeared to demonstrate content validity and acceptability in AYA CCS. When: Participants wanted education and screening to occur regularly throughout cancer therapy and survivorship. SD conversations should be tailored developmentally to the patient. Conclusions: Our results demonstrate a theme throughout interviews of the importance of patient/provider rapport. Further, while AYA CCS prefer in-person conversations about SD, conversations should be preceded by written information or a questionnaire to increase patient preparedness/comfort. Preliminary findings suggest that the PROMIS SexFS Brief is a promising tool for screening SD in this population; further studies evaluating use in clinical settings is warranted.
Serum uric acid level is a risk factor for the progress of diabetic nephropathy
Authors: Yun-qiu Qi, Gui-jun Qin
Journal: BMJ (2011)

Total 306 patients with early stage diabetes were enrolled in the study, after follow-up for 67 ± 8 months, the data of 288 cases were analyzed with survival analysis method. At the end of study 64 out 288 patients had high serum uric acid and the remaining 224 had normal uric acid levels. The prevalence of dominant proteinuria and reduced GFR were significantly higher in patients with high serum uric acid than those with normal serum uric acid (47. 36% vs 30. 29% and 66. 14% vs 37.72%, respectively, both P <0. 05). The results suggest that high level of serum uric acid is a risk factor for the progress of diabetic nephropathy. 

Key words: 
Uric acid;  Prognosis
Direct Angioplasty for Acute Myocardial Infarction
Authors: Mark H. Eckman, John B. Wong, Deeb N. Salem, Stephen G. Pauker
Journal: Annals of Internal Medicine (2020)

Abstract ▪Purpose:To review the usefulness of angioplasty done early in the course of an acute myocardial infarction without preceding thrombolytic therapy. ▪Data Sources:The English-language liter...
Tolerability of dual checkpoint blockade with nivolumab and ipilimumab: A meta-analysis.
Authors: Alejandro Ramon Carvajal, Judy Huang, Shenhong Wu
Journal: Journal of Clinical Oncology (2020)

e15149 Background: The dual checkpoint blockade of PD-1 and CTLA-4 with nivolumab and ipilimumab have been used extensively for cancer immunotherapy in clinical practice and trials due to its efficacy. A critical concern is the tolerability of the combination due to the increased risk of severe immune-mediated adverse events. A meta-analysis of clinical trials was performed to assess the treatment tolerability measured as discontinuation due to adverse events. Methods: A search through PubMed as well as abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until December 2019 was performed to identify clinical trials in which the combination of nivolumab and ipilimumab was given to cancer patients. Eligible clinical trials reported a discontinuation rate due to adverse events for the groups of patients receiving nivolumab and ipilimumab. A random or fixed effects model was used to determine summary incidences, relative risks, and 95% confidence intervals. Results: Seven clinical studies which included a total of 3,213 patients (combo: 1746, control: 1467) with various cancers were selected. Overall, the intolerability of nivolumab and ipilimumab measured as the summary incidence of discontinuation due to adverse events was 25.1% (95% CI: 17.8-34.1%). The rate varied significantly with the type of cancer (P &lt; 0.001). The lowest discontinuation rate was in uveal melanoma, with a rate of 11% (95% CI: 2.9-34.2%), and the highest discontinuation rate was in melanoma at 46.3% (95% CI: 36.6-56.4%). In comparison with chemotherapy controls from randomized controls, the intolerability was significantly higher with an relative risk of 2.1 (95% CI: 1.78-2.84) for the combination. Conclusions: There is a substantial risk for intolerability in cancer patients receiving the combination nivolumab and ipilimumab. Further studies are needed for risk mitigation.
Phase I study of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Andrew L. Coveler, David Lawrence Bajor, Ashiq Masood, Emrullah Yilmaz, Anthony Frank Shields, Milind M. Javle, Ravi Kumar Paluri, Gina M. Vaccaro, Mark Zalupski, Juneko E. Grilley-Olson, Hedy L. Kindler, Michael W. Schmitt, Martin Gutierrez
Journal: Journal of Clinical Oncology (2020)

TPS4671 Background: SEA-CD40 is an investigational non-fucosylated, humanized IgG1 monoclonal antibody directed against CD40, a co-stimulatory receptor expressed on antigen-presenting cells (APCs). Activation of CD40 on APCs upregulates cytokine production and co-stimulatory receptors, enhancing tumor antigen presentation to T cells. Preclinical data indicate that treatment of PDAC with chemotherapy in conjunction with a CD40 agonist could enhance antigen presentation and initiate an antitumor immune response (Byrne KT and Vonderheide RH, Cell Rep 2016;15, 2719–32). An ongoing Phase 1 study (SGNS40-001) is evaluating SEA-CD40 as monotherapy and in combination with pembrolizumab in patients with advanced solid or hematologic malignancies. A new cohort is enrolling to evaluate the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in PDAC. Methods: The cohort consists of patients with metastatic PDAC who have had no prior therapy for metastatic disease. Patients must be ≥18 years old, with (neo)adjuvant therapy completed &gt;4 months prior to enrollment, ECOG status ≤1, adequate renal, hepatic, and hematologic function, and measurable disease per RECIST v 1.1 criteria. A standard regimen of gemcitabine and nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle is administered with SEA-CD40 IV on Day 3. Pembrolizumab is administered every 42 days starting on Day 8. The primary objective is antitumor activity; secondary objectives are safety and tolerability and SEA-CD40 and pembrolizumab pharmacokinetics. Efficacy endpoints are confirmed RECIST ORR per investigator (primary), disease control rate (response or stable disease ≥16 weeks), duration of response, PFS, and OS. Disease is assessed every 8 weeks using RECIST and immune-based RECIST (iRECIST). Treatment continues until occurrence of unacceptable toxicity, progressive disease per iRECIST, consent withdrawal, or study closure. Assessment of dose-limiting toxicity will occur initially in groups of 6 patients to identify the recommended phase 2 dose of SEA-CD40 for the cohort. Enrollment to this cohort began in November 2019. Clinical trial information: NCT02376699 .
Spatiotemporal modeling with SimBioSys TumorScope to predict chemotherapeutic response in breast tumor microenvironments.
Authors: Chaitanya K Mamillapalli, Timothy K Markwell, Jason K Ellis, John Pfiefer, Tushar Pandey, John A Cole, Joseph R Peterson, Daniel J Fox
Journal: Journal of Clinical Oncology (2020)

e12656 Background: Predictive models of the efficacy of different tumor therapies will provide significant enhancements to current standard of care practices. Predicting a given tumor’s growth and treatment response, however, is an intricate process that requires not only an understanding of the tumor's intrinsic characteristics, but also spatial- and temporal-resolved tumor shape descriptions, surrounding tissue dynamics, and a complete account for the milieu of diffusible molecules that drive tumor behaviors and interactions. Here we report an ongoing retrospective study designed to validate SimBioSys TumorScope as a computational tumor therapy prediction model in a real-world clinical setting. Methods: Fully-deidentified and HIPAA-compliant data were assessed from real-world clinical records and cases. Subjects comprised early stage breast cancer patients who were treated with neoadjuvant chemotherapy (NACT) and subsequent surgical resection. Data fields included imaging data, biomarker status, tumor sizing, demographic data, digital pathology, and genetic lab test data. Half of the data, including all data fields, were used as a training dataset for TumorScope. The second half of the data, with blinded diagnoses and results, will be used to test TumorScope’s prediction accuracy. Simulations will be initialized with pre-treatment MRI data and processed through the entirety of each patient's specified treatment regimen. Predicted tumor volume and longest dimension will be compared against measured values at several time-points after therapy initiation. Overall accuracy will be statistically assessed by the Pearson correlation coefficient between predicted and measured tumor volume and longest dimension at each time-point, as well as their root-mean-squared-errors. Results: Final statistical analysis is currently underway. Thus far, SimBioSys TumorScope has trended high accuracy levels with the non-blinded “training” cohort just as it has in previous database studies, with a Pearson correlation coefficient greater than 0.94. Conclusions: SimBioSys TumorScope for Breast Cancer accurately predicts patient NACT responses via spatio-temporal modeling of drug and nutrient perfusion, metabolic behavior, and the physio-chemical interactions between surrounding tissues. Future prospective studies may assess TumorScope’s capacity to support efficient patient treatments and enhance overall standard of care.