tbuckley/cabot-search huggingface dataset:
Biomarker utilization in non-small cell lung cancer, are we treating after testing?
Authors: Elias Makhoul, Jong Taek Kim, Wenjuan Zhang, Jean Raphael Lopategui, Ani Sarkis Balmanoukian, Eric Vail
Journal: Journal of Clinical Oncology (2020)

9609 Background: Targeted therapy in EGFR and ALK mutated non-small cell lung cancer (NSCLC) has been the standard of care for nearly a decade with subsequent FDA approvals for ROS1 and BRAF V600 mutated NSCLC occurring in 2016 and 2017. However, recent studies have shown suboptimal utilization of genomic profiling results in these patients. In 1 recent study of community oncologists, ~70% of EGFR/ALK+ patients received appropriate targeted therapy, while patients with other gene mutations (including BRAF and ROS1) only received targeted therapy ~30% of the time. Left unanswered was what patients were receiving instead and why. Additionally, it is unknown if this finding is generalizable to the academic setting. We aimed to investigate whether in our patient population, NSCLC patients with actionable mutations received associated FDA approved therapies and if not why. Methods: The pathology database was queried for all NSCLC with molecular testing (including qPCR, FISH and NGS) from 2009 to 2019. Patients with sensitizing EGFR, ALK, ROS1 or BRAF mutations that were detected after the first FDA approval for their respective targeted therapies were included for analysis with those lost to follow up subsequently excluded. Basic demographic and clinical variables were collected as well as treatment records. Results: 2160 NSCLC patients were evaluated (2160 EGFR, 1417 ALK, 810 ROS1, 589 BRAF). 468 patients were identified with targetable mutations (411 EGFR, 46 ALK, 5 ROS1, 6 BRAF). No patient had more than 1 targetable mutation. Of those patients, 248 were at an advanced stage and had clinical follow up (202 EGFR, 37 ALK, 4 ROS1, 5 BRAF). Of those patients 197/202 (97.5%), 33/37 (89.2%), 3/4 (75%) and 1/5 (20%) received EGFR, ALK, ROS1 or BRAF targeted therapy respectively. Across biomarkers 14/248 patients (5.6%) did not receive subsequent targeted therapy. 10 patients (5 EGFR, 3 ALK, 1 ROS1 and 1 BRAF) passed away before targeted therapy could be initiated. Physician choice and missed findings accounted for the remaining four cases. Conclusions: The vast majority of advanced NSCLC patients analyzed in this study received appropriate targeted therapy matched to genomic findings. The main reason (~4% of total cases) that patients did not receive therapy was due to rapidly progressive disease and death before it could be initiated. These findings are at odds with those published from the community setting. This may be due to multiple factors, including clinician education, ease of access to targeted therapies across patient populations and incomplete data in the previous study populations.
Phase II study of TAK228 in patients with advanced non-small cell lung cancer (NSCLC) harboring NFE2L2 and KEAP1 mutations.
Authors: Paul K. Paik, Linda Su Hyun Ahn, Andrew J. Plodkowski, Pang-Dian Fan, Charles M. Rudin
Journal: Journal of Clinical Oncology (2020)

9607 Background: Despite past efforts, no targeted therapies exist for squamous cell lung cancer (LUSC) pts. We identified a heretofore untargeted oncogene (NFE2L2)/tumor suppressor (KEAP1) pair, each mutated in ~15% of LUSCs. NFE2L2 encodes NRF2, a transcription factor involved in the oxidative stress response and targeted for degradation by KEAP1. NFE2L2 mutations (mut) occur only in an exon 2 hotspot (Neh2 domain), which is the binding site for KEAP1. Mutations in this region disrupt KEAP1 binding, leading to NRF2 nuclear translocation and increased mTOR signaling via RagD. We report translational studies and results from a phase 2 trial of the oral TORC1/2 inhibitor TAK228 in biomarker-selected pts. Methods: Cell line and xenograft experiments were performed using LK-2 LUSC (NFE2L2 E79K mut), A549 ADCL (KRAS G12S + KEAP1 loss), and SK-MES-1 LUSC cells (NFE2L2/KEAP1 WT) treated with TAK-228, everolimus, rapamycin, or deforolimus. Pts with stage IV LUSC harboring NFE2L2 or KEAP1 mut and ADCL harboring KRAS + KEAP1 co-mut were treated on an NCI CTEP phase 2 study of TAK228 3mg po qd (NCT02417701). Primary endpoint: ORR. Secondary endpoint: PFS. The study used a Simon 2-stage design for each cohort with H0 = 5% (N≥1/5 responses), HA = 40% (N≥2/10 responses). Results: TAK228 exhibited differential anti-tumor activity over TORC1 rapalogs in LK-2 and A549 cells. TAK228 alone was cytotoxic at sub-[μM] (IC50 68nM) in LK-2 cells; all other rapalogs had IC50s &gt; 10μM. This was associated with marked decrease in TORC1/2 &amp; MAPK signaling (decreased pS6, pAKT, pERK). Anti-tumor response was seen in LK-2 and A549 xenografts treated with TAK228. No anti-tumor/growth inhibitory responses were seen with any other rapalog. N = 21 evaluable pts have been treated (10 NFE2L2, 6 KEAP1, 5 KRAS+NFE2L2/KEAP1). Median age = 70; median prior lines tx = 2, smokers = 100%, median pack yrs = 39. Most common AEs included hyperglycemia (72%), fatigue (32%), diarrhea (32%), decreased appetite (32%). In NFE2L2 mut LUSC pts, ORR = 20% (2/10 confirmed PR), DCR = 100% with median PFS = 8.9mos (95%CI 7-NR). In KEAP1 mut LUSC pts, ORR = 17% (1/6 confirmed PR), DCR = 67% with PFS range = 1.8-8.6 mos. In KRAS + NFE2L2/KEAP1 mut ADCL pts, ORR = 0% and DCR = 0%. Conclusions: TAK228 is tolerable with differential activity in NFE2L2 (primary endpoint met) and KEAP1 mutant LUSC. A randomized phase 2 trial of TAK228 + docetaxel vs. SoC chemotherapy in advanced LUSC pts with NFE2L2/KEAP1 mut is in development (LungMAP S1900D) as is an NCI CTEP phase 1/1b trial of TAK228 + CB-839 in advanced NSCLC patients with NFE2L2/KEAP1 mut (NCI #10327). Clinical trial information: NCT02417701 .
Correlation of family environment with quality of life in patients with alcohol-induced mental disorder
Authors: Jin-cai Zhu, Qing-feng Wu, Ai-qun Lai, Jian-xiong Xu, Ji-tian Li, Shan-na Su, Xiao-ling Li, Xiu-ying Qiu, Su-fang Liu
Journal: BMJ (2011)

Fifty five patients with alcohol induced-mental disorder (study group) and 43 local inhabitants without history of alcohol abuse (control group) were surveyed with family environment scale (FES-CV) and generic quality of life inventory-74 (GQOLI-74). The total score and the scores of all dimensions except material life in GQOLI-74 of study group were significantly lower than those of control group(P ＜0. 05). Compared with control group, the scores in FES of study group were lower for factors of cohesion, expressiveness, active-recreational orientation, moral-religious emphasis and organization in the patient's family, while the scores for conflict and control were higher( P ＜ 0. 05 or P ＜ 0. 01 ). The results indicate that family environment is closely correlated with quality of life in patients with alcohol-induced mental disorder, and family therapy would improve their quality of life.

Key words: 
Psychoses, alcoholic;  Quality of life
Effects of initial trophic versus full enteral feeding on patients with acute lung injury
Authors: Shaohua Lin, Xiaowen Yan, Guangyuan Guo, Bo Jiang, Xuejun Dai, Cunkun Chu, Hongsheng Zou
Journal: BMJ (2014)

A total of 99 patients with acute lung injury (ALI) were randomly divided into initial trophic f and full enteral feeding groups.The regime was maintained for 28 days.The changes were evaluated in the number of ventilator-free days, 28-day mortality and incidence of ventilator-associated pneumonia (VAP). And vomiting, gastric residual volumes, constipation and intensive care unit (ICU) stay duration, enteral nutrition costs and total costs were recorded and compared.The number of ventilator-free days(χ2=0.417, P=0.81; χ2=0.629, P=0.36), 28-day mortality (χ2=0.211, P=0.14) , VAP(χ2=0.235, P=0.16) and ICU stay duration (t=0.591, P=0.17) had no significant increases in lower-volume trophic enteral feeding group. The incidence of vomiting (χ2=3.417, P=0.004), gastric retention rate (χ2=3.592, P=0.003), incidence of diarrhea frequency (χ2=2.147, P=0.007), incidence of abdominal distension (χ2=3.915, P=0.001) and use frequency of gastrointestinal prokinetic drug (χ2=2.316, P=0.002) in fully enteral nutrition (EN) group were higher than those of low volume EN group.There was statistically significant difference. While fully EN patients daily monitoring of the average blood glucose value (t=1.259, P=0.003) and insulin usage (t=1.479, P=0.001) were significantly higher than the low volume EN group, nutritional costs (t=3.441, P=0.001), total cost of hospitalization (t=2.379, P=0.03) were significantly higher than those of low volume EN group. There was statistically significant difference. As compared with full enteral feeding, an initial regime of trophic enteral feeding for up to 6 days did not improve ventilator-free days, 28-day mortality, infectious complications or ICU stay duration in ALI patients. However, it was associated with more gastrointestinal tolerance, less enteral nutrition and lower total costs.


Key words: 
Respirataty distress syndrome; Enteral nutrition
The significance of beta-II microglobulin (β2M) and International Staging System (ISS) in multiple myeloma (MM) patients (pts.) with renal impairment (RI).
Authors: Gloria Lin, Parameswaran Hari, Saurabh Chhabra, Mehdi Hamadani, Anita D'Souza, Aniko Szabo, Binod Dhakal
Journal: Journal of Clinical Oncology (2020)

8544 Background: ISS stage which underlies prognostic models used in MM, is derived from albumin and β 2 M at diagnosis. β 2 M, a low molecular polypeptide, is present on all nucleated cells and is elevated in pts. with RI. In MM, although the association between β 2 M and prognosis has been interpreted to reflect a higher tumor burden, RI by itself may explain at least in part the higher levels of β 2 M seen with this disease. Historically, those presenting with MM and severe RI had a poor prognosis and quite likely the β 2 M elevation irrespective of kinetics predicted poor prognosis. In this study, we investigated the significance of β 2 M and ISS staging in MM patients in the setting of RI in the modern era when renal recovery is more common after induction. Methods: MM pts. treated at our institution from 2012-2014 were included and divided into two groups by creatinine (Cr) level at diagnosis: &lt; 2 and ≥2 mg/dl. Demographic and disease characteristics were compared between the two groups using ANOVA and chi-square tests as appropriate. COX regression was used for the multi-variate analysis for survival and the effect of β 2 M levels, adjusting for albumin levels, on survival was allowed to vary by Cr level to evaluate potential interaction. Results: Of 201 total pts., 163 (81.6%) had Cr &lt; 2 mg/dL and 38 (18.4%) ≥ 2mg/dL at diagnosis with higher β 2 M and ISS stage in Cr≥2 group. On adjusted analysis, albumin was significantly associated with overall survival (OS) (hazard ratio, HR 0.60; 95% CI 0.36-1; p = 0.04); however, β 2 M was associated with OS only when Cr &lt; 2 mg/dl (HR 1.13, 95% CI 1.06-1.19; p &lt; 0.0001) but not when Cr≥2 mg/dl (HR 0.98, 95% CI 0.91-1.06; p = 0.65) with significant interaction (p = 0.004). Likewise, the effect of β 2 M on progression-free survival was significant when Cr &lt; 2 (HR 1.1, 95% CI 1.05-1.19; p = 0.0002), but not Cr≥2 (HR 1.02; 95% CI 0.97-1.08; p = 0.42) with significant interaction (p = 0.03). Conclusions: Our results show that in the era of modern induction therapy and rapid improvement in kidney function, a high β 2 M may not impact prognosis as adversely, at least in those with RI, since an elevated β 2 M may be disproportionate to true tumor burden. Thus, ISS staging in these patients should be reevaluated after induction and potential renal recovery. Novel biomarkers may refine MM staging independent of the level of kidney function.
青年人肺癌误诊16例
Authors: 邓红霞, 李克明, 张丽
Journal: BMJ (2004)

对我院1993年3月～2003年3月收治的青年人肺癌16例进行临床病理分析. 1.临床资料:16例均为原发性支气管肺癌,并经细胞学和/或病理学证实.其中男10例,女6例,男女之比为1.6∶ 1.年龄20～36岁,平均30岁.确诊时间＜3个月6例,3～6个月4例,大于6个月～1年4例,＞1年2例,平均确诊时间6.2个月。
Artificial intelligence model to predict slow progression for advanced non-small cell lung cancer (aNSCLC) patients receiving second-line therapies.
Authors: Francois Charest, Samuel P Heilbroner, Karl Rudeen, Jitesh Chawla, Somasekhar Suryadevara, Babu Narayanan
Journal: Journal of Clinical Oncology (2020)

e21596 Background: There are ongoing efforts to understand and predict exceptional response to existing cancer therapies, but few clinical characteristics of these patients are known. We trained a machine learning model using the Concerto HealthAI database of oncology EMR data that includes clinical data from CancerLinQ Discovery to predict slow progression, a proxy for exceptional response, in aNSCLC in the second line setting. Methods: We trained an XGBoost model to predict patients with a progression free survival (PFS) greater than 180 days from the start of second line therapy (index date). This cutoff approximately determines the top 20% of PFS values in our database (median PFS = 86 days). Patients were included from the study if they (1) were pathologically confirmed aNSCLC without other primary cancer diagnoses and (2) started their second-line therapy between 2013 and 2017. Patients were labeled as slow progressors if they (1) had no evidence of progression or death within 180 days of index and (2) were evaluated for progression for at least 180 days post-index. The model considered data up to 120 days prior to index date. Risk factors in the model included demographics, vitals, common labs, common medical conditions, ECOG performance status, stage, histology, prior cancer treatment patterns, prior progression/response assessments, and medication history. Feature importance was evaluated using SHapley Additive exPlanations (SHAP). Results: 2205 patients met selection criteria of the study. Of these, 420 were labeled as slow progressors. 1776 patients were used for model training and 429 were set aside for model validation. The final model was able to predict slow progression with an AUCROC of 0.75 (F-score 0.48, precision 0.39, recall 0.6). The performance compares favorably to that of a logistic regression model (0.66 AUCROC). Top features that indicated slow progression included a low number of prior progression events or regimens, absence of metastatic disease, lower stage/t-stage/ECOG, absence of COPD, previous treatment with an EGFR inhibitor, normal Alk-Phos/WBC (versus elevated), absence of tachycardia, and a normal BMI (versus low). Conclusions: Machine learning and real world-data provided promising results in predicting slow progression in aNSCLC and may be useful in discovering novel drivers of favorable response.
<i>Detect Early Be Safe–Care for Mother</i> (DEBS-CaM) project: School-based interventions to improve awareness and screening for breast cancer among the young mothers of Kerala.
Authors: Narayanankutty Warrier, Uma V Sankar, Sreedharan P S, Nirmal V, Sajeevan K V, Ajmal Sherif
Journal: Journal of Clinical Oncology (2020)

e13570 Background: The prognosis rate among the breast cancer patients was less than 50% in India when compared to European countries due to the late diagnosis and most of them diagnosed at an advanced stage of disease. Early detection can reduce the risk of advancement of disease by 30%. There is an immediate need to target both younger population to empower the women with the knowledge on their breast cancer risk and self-breast examination (SBE). So the project aimed to examine the efficacy of a Brief Motivational Intervention (BMI) and Student based Parental intervention (SBPI) based on motivational interviewing as a universal preventive and early diagnosis interventions to fight against breast cancer among the school students using a randomized factorial design. Methods: Daughters and Mothers are always a good dyads for doing an personal health intervention. Since it is a ‘matter of closeness’, a mother and a daughter can easily communicate, intervene and ensure the act of doing in self breast examination.We identified 85 schools (including the Junior high and senior high schools in the northern region of Kerala. The female resource person from the MVR Cancer Centre &amp; Research Institute delivered the awareness session on risk factors of breast cancer breast and SBE. So the attendees demonstrated the SBEs to their mothers and ensure the act of doing monthly. The study utilized a 2 × 2 × 3 factorial design, crossing a BMI; (yes, no) and SBPI (yes, no), with one within-subjects factor (Time; baseline and 10 months). Over 10 months, we recruited cohorts of parent-student dyads and randomize by dyad to one of four experimental conditions: BMI only and BMI and SBPI only. We did the randomization by computer algorithm to ensure that the experimental conditions will balance on prognostic indicators of students and their mother’s on breast cancer risk and including waist to hip ratio, frequency of SBE, healthy dietary intake and physically active. Results: Baseline data collected from students and parents during the summer prior to college matriculation. Follow-ups occurred at 10 months post-baseline for parents in the face to face interview with students at their schools. We found 17% of mothers detected any kind of breast abnormalities and among that, 68% of mothers went for further detailed diagnostic tests. Conclusions: It is an innovative approach incorporating the principles of primary prevention and early detection for the breast cancer among the young mothers of Kerala.
Challenges and Lessons for Managing Glaucoma during COVID-19 Pandemic: Perspectives from Asia
Authors: Rahat Husain, Xiulan Zhang, Tin Aung
Journal: Ophthalmology (2020)

Since late last year, Asia has faced the mounting challenge of the coronavirus disease 2019 (COVID-19) pandemic. The first cases were reported in China in late 2019, whereas Singapore saw their first imported case in late January 2020. Over the last few months, we have experienced many challenges in the clinical management of patients with glaucoma. In this commentary, we provide perspectives from China and Singapore on how glaucoma practice has adapted during this crisis.
The impact of clinical trial (CTr) participation on savings performance in the oncology care model (OCM).
Authors: Kerin B. Adelson, Maureen Canavan, Sophia Mun, Cary Philip Gross, Naralys Sinanis, Amy J. Davidoff
Journal: Journal of Clinical Oncology (2020)

e19367 Background: The OCM is a Centers for Medicare and Medicaid Services (CMS) alternative payment model, which seeks to curb costs while improving care for patients receiving systemic cancer therapy. CMS models the expected total cost (spending target) for each 6-month episode using historical, geographic and clinical factors including CTr participation. We evaluated the relationship between CTr participation, actual cost of care and performance in the OCM. Methods: We used claims for OCM episodes attributed to the Yale Cancer Center between July 2016 and July 2018. We stratified episodes by CTr participation and used t-tests and chi-square tests to compare total cost, drug costs (Part B and D) and whether actual episode costs were above or below CMS targets. Analyses were conducted for the total sample, and among the most common cancer types. Results: Among 9,387 OCM episodes (5,270 unique patients), 815 (8.7%) episodes involved a CTr. Among non-CTr patients, the mean Medicare cost per episode ($32,909) was modestly higher than the mean episode spending target ($31,746; p &lt; 0.001), while in the CTr group, the mean Medicare cost per episode ($36,590) was substantially lower than the mean episode spending target ($48,124 p &lt; 0.001). Mean drug cost was lower with CTr vs without ($15,650 vs $19,587, p &lt; 0.001). Drug costs also accounted for a lower percentage of total costs for episodes with CTr vs not (41% vs 57%). CTr episodes were more likely to meet spending targets than non-CTr episodes (66% vs 56%, p &lt; 0.001) overall and in breast, lung, and myeloma cancers, although only statistically significant for lung cancer (76% CTr vs 48% non-CTr, p &lt; 0.001). Mean difference between target and actual costs was greater for episodes with CTr (- $11,534) than for episodes without CTr (+ $1,163) (p &lt; 0.001). Conclusions: On average, episodes with CTr participation had substantially lower costs compared with their spending targets, while non-CTr episodes had slightly higher costs compared with their spending targets. While total cost of care was higher for episodes with CTr (as the CMS model predicts), drug costs were significantly lower. As drugs comprise a large proportion of total cost, lower drug costs in CTr episodes likely contribute to savings. Additional research should explore whether other OCM centers with higher rates of CTr participation are more likely to meet spending targets in value-based payment models.
DPD Quantification in Cardiac Amyloidosis
Authors: Paul R. Scully, Elizabeth Morris, Kush P. Patel, Thomas A. Treibel, Maria Burniston, Ernst Klotz, James D. Newton, Nikant Sabharwal, Andrew Kelion, Charlotte Manisty, Simon Kennon, Muhiddin Ozkor, Michael Mullen, Neil Hartman, Perry M. Elliott, Francesca Pugliese, Philip N. Hawkins, James C. Moon, Leon J. Menezes
Journal: JACC. Cardiovascular imaging (2020)

To assess whether single-photon emission computed tomography (SPECT/CT) quantification of bone scintigraphy would improve diagnostic accuracy and offer a means of quantifying amyloid burden.Transthyretin-related cardiac amyloidosis is common and can be diagnosed noninvasively using bone scintigraphy; interpretation, however, relies on planar images. SPECT/CT imaging offers 3-dimensional visualization.This was a single-center, retrospective analysis of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scans reported using the Perugini grading system (0 = negative; 1 to 3 = increasingly positive). Conventional planar quantification techniques (heart/contralateral lung, and heart/whole-body retention ratios) were performed. Heart, adjacent vertebra, paraspinal muscle and liver peak standardized uptake values (SUVpeak) were recorded from SPECT/CT acquisitions. An SUV retention index was also calculated: (cardiac SUVpeak/vertebral SUVpeak) × paraspinal muscle SUVpeak. In a subgroup of patients, SPECT/CT quantification was compared with myocardial extracellular volume quantification by CT imaging (ECVCT).A total of 100 DPD scans were analyzed (patient age 84 ± 9 years; 52% male): 40 were Perugini grade 0, 12 were grade 1, 41 were grade 2, and 7 were grade 3. Cardiac SUVpeak increased from grade 0 to grade 2; however, it plateaued between grades 2 and 3 (p < 0.001). Paraspinal muscle SUVpeak increased with grade (p < 0.001), whereas vertebral SUVpeak decreased (p < 0.001). The composite parameter of SUV retention index overcame the plateauing of the cardiac SUVpeak and increased across all grades (p < 0.001). Cardiac SUVpeak correlated well (r2 = 0.73; p < 0.001) with ECVCT. Both the cardiac SUVpeak and SUV retention index had excellent diagnostic accuracy (area under the curve [AUC]: 0.999). The heart to contralateral lung ratio performed the best of the planar quantification techniques (AUC: 0.987).SPECT/CT quantification in DPD scintigraphy is possible and outperforms planar quantification techniques. Differentiation of Perugini grade 2 or 3 is confounded by soft tissue uptake, which can be overcome by a composite SUV retention index. This index can help in the diagnosis of cardiac amyloidosis and may offer a means of monitoring response to therapy.