tbuckley/cabot-search huggingface dataset:
Medicare Spending and the Adequacy of Support With Daily Activities in Community-Living Older Adults With Disability
Authors: Jennifer L. Wolff, Lauren H. Nicholas, Amber Willink, John Mulcahy, Karen Davis, Judith D. Kasper
Journal: Annals of Internal Medicine (2019)

Identifying factors that affect variation in health care spending among older adults with disability may reveal opportunities to better address their care needs while offsetting excess spending.To quantify differences in total Medicare spending among older adults with disability by whether they experience negative consequences due to inadequate support with household activities, mobility, or self-care.Observational study of in-person interviews and linked Medicare claims.United States, 2015.3716 community-living older adults who participated in the 2015 NHATS (National Health and Aging Trends Study) and survived for 12 months.Total Medicare spending by spending quartile in multivariable regression models that adjusted for individual characteristics.Negative consequences were experienced by 18.3% of participants with disability in household activities, 25.6% with mobility disability, and 20.0% with self-care disability. Median Medicare spending was higher for those who experienced negative consequences due to household ($4866 vs. $4095), mobility ($7266 vs. $4115), and self-care ($10 935 vs. $4436) disability versus those who did not. In regression-adjusted analyses, median spending did not differ appreciably for participants who experienced negative consequences in household activities ($338 [95% CI, -$768 to $1444]), but was higher for those with mobility ($2309 [CI, $208 to $4409]) and self-care ($3187 [CI, $432 to $5942]) disability. In the bottom-spending quartile, differences were observed for self-care only ($1460 [CI, $358 to $2561]). No differences were observed in the top quartile.This observational study could not establish causality.Inadequate support for mobility and self-care is associated with higher Medicare spending, especially in the middle and lower ends of the spending distribution. Better support for the care needs of older adults with disability could offset some Medicare spending.The Commonwealth Fund.
Rare tumor with matched germline whole exome sequencing to identify somatic and inherited variants of clinical significance.
Authors: Bryce Perkins, Ryan Sprissler, Hani M. Babiker, Pavani Chalasani, Laurel Johnstone, Brandon Lau, Kenneth Ramos, Crystal Placencia, Ryan Gutenkunst, Michael Hammer, Daruka Mahadevan
Journal: Journal of Clinical Oncology (2019)

1523 Background: Rare cancer incidence is defined as &lt;6/100,000 cases. These cases are challenging due to delays in diagnosis, late stage at diagnosis, lack of standard of care and poor outcomes. We present molecular profiling of 28 rare tumor cases analyzed by whole exome sequencing (WES) seen in the Early Phase Therapeutics Program. Methods: We performed WES on 15 rare tumors with matched germline DNA, as well as tumor only on 2 additional cases. We sequenced a panel of 500 candidate cancer genes in 6 tumor/normal and 6 tumor only cases. Copy number alterations (CNAs) were assessed for the tumor-normal WES cases with SNVs and small indels for all cases. Caris (AZ) (tumor only) and liquid biopsy (Gaurdant360, CA) were also conducted in these patients for comparison. Results: Rare tumors affected 18 different tissues of the body with 1 case affecting tissue typical of common cancers. The rare tumor group contained 25% pathogenic or likely pathogenic germline variants compared to 7.1% for common tumors. This increased rate of inherited pathogenic variants met statistical significance: Fisher exact test (p = 0.0118). A total of 69 sequence variants and 8 CNAs were identified, 37 were actionable. For all but 3 patients, there was at least one variant associated with an actionable outcome given off-label use or clinical trial participation. There was excellent concordance with results from commercial sequencing; however, our tumor/germline sequencing identified additional germline variants of clinical significance, all were loss-of-function variants in tumor suppressors. Tumor vs. normal analysis showed that the majority of the commercially reported VUS were in fact germline VUS. In one case, a reported pathogenic variant we found to be an inherited pathogenic germline variant. 15 patients received at least 1 line of therapy indicated by genomic sequencing. For these patients the PFS ratio when compared to the most recent line of therapy prior to targeted therapy was 2.02, with 10/15 (67%) patients having a PFS ratio of &gt;1.0, and 6/15 (40%) of patients having PFS ratio &gt;1.3. Conclusions: We demonstrate the importance of tumor-normal analysis, especially in the context of rare tumors. Rare tumor patients may disproportionately benefit from tumor vs. normal WES at diagnosis to improve PFS within targeted therapy trials, guided by genomics.
Translating transcriptome to immunophenotype in head and neck squamous cell carcinoma (HNSCC) to identify pathways promoting T-cell infiltration.
Authors: Theodoros Rampias, Christos K. Kontos, Alexandros Polyzos, Aris Giotakis, Evangelos Giotakis, Andreas Scorilas, Euthymios Kirodimos, Periklis Foukas, Amanda Psyrri
Journal: Journal of Clinical Oncology (2019)

e17542 Background: We sought to analyze the transcriptional landscape of HNSCC in an attempt to identify tumor-intrinsic oncogenic pathways that appear to mediate T-cell infiltration of tumor tissue. In this direction, we employ a methodology that integrates histopathology data of the tumor microenvironment with its corresponding transcriptome. Methods: 32 frozen HNSCCs were subjected to RNA-seq and corresponding FFPE were scored for plasma cells, tertiary lymphoid structures and CD8a + TILs (center, invasive margin). RNA-seq data were analyzed to identify differentially expressed genes (DEGs) between tumors scored by immunohistochemistry (IHC) as CD8a high and CD8a low. Gene ontology analysis (GO) was performed based on DEGs &gt; 1.5 fold expression change between CD8a high and CD8a low groups. Candidate genes were investigated by hierarchical clustering in TCGA RNA-seq data and further validated by IHC and quantitative RT-PCR in our cohort. Results: 32 HNSCCs were either scored as CD8a high or CD8a low based on IHC detection of CD8a + cells in invasive margin of tumors. Comparative analysis of mRNA expression data between CD8a high and CD8a low groups in our cohort revealed that Muc1/16 overexpression and glycosylation was highly enriched in T cell infiltrated group of tumors. This finding was further validated using antibodies that detect glycosylated epitopes for both mucins. Analysis of TCGA RNA-seq data indicated that Muc1/16 overexpressing tumors share signatures of early keratinocyte differentiation and stem cell identity and co-express high levels of enzymes that promote Muc1/16 glycosylation. Interestingly, loss of CDH1 and acquisition of epithelial mesenchymal transition (EMT) markers in the cluster of Muc1/16 overexpressing tumors is strongly correlated with elevated CD8a, IDO1, CD274 and CXCL10 mRNA levels (P &lt; 0.0001). Conclusions: Muc1/16 overexpressing tumors represent a very immunogenic HNSCC cluster. Previous studies have shown that mucins 1 and 16 in cancer cells expose glycosylated-specific epitopes that are recognized by T cells as cancer antigens. To this end, MUC1/16 expression may serve as predictive biomarkers for response to immunotherapy and MUC-targeted immunotherapy may function as an attractive partner to checkpoint inhibitors in HNSCC.
Examining predictors of female cancer treatment delay in Appalachian women.
Authors: Rajesh Balkrishnan, George P Batten, Raj Piyush Desai, Zachary H Daniels, Lydia Novruzov, Susan J Mole, Nonna J Stepanov, Anderson Roger
Journal: Journal of Clinical Oncology (2019)

e18107 Background: Appalachian women have a higher burden of both morbidity and mortality from female cancers of the breast, ovary and cervix, and have documented treatment delay and poor adherence. The environmental and sociobehavioral risk factors that could contribute towards these issues such as patient non adherence and treatment delay have not been studied. Methods: We conducted a detailed survey of women seeking cancer related preventative care in a tertiary care cancer center in the Appalachian region of Virginia. Survey questions included health behaviors, financial issues, and past health history. The survey was administered to 200 women and a total of 158 complete responses (42 in women with cancer in the recent past) were obtained. Results: There were significant differences between women with and without female cancers with the cancer group being older, less likely to be married, be unemployed and more likely to have received mammograms (All p &lt; 0.05). In multivariate analyses , the major risk factor associated with delaying treatment was the lack of health insurance in the previous year (RR: 0.25, 95% CI: 0.082-0.73). Conclusions: Women in Appalachia face significant barriers in receiving diagnoses and treatment for female cancer including lack of employment, health care insurance and social support. These factors need to be considered while designing interventions to improve access and adherence to cancer treatments in this population.
Breast cancer screening adherence at multiple timepoints over eight years among women in a familial cohort.
Authors: Marcy L. Schaeffer, Betty J May, Brenna C. Hogan, Mikiaila M. Orellana, Michelle C. McCullough, Deborah Kay Armstrong, Kelly Myers, Kala Visvanathan
Journal: Journal of Clinical Oncology (2019)

1557 Background: Since 2007, U.S. guidelines recommend cancer-free women with ≥20% lifetime breast cancer (BC) risk undergo BC screening with mammogram and breast MRI. There is limited long-term data on BC screening adherence among young, high-risk women. To address this knowledge gap, we examined utilization of multiple BC screening modalities over time. Methods: Eligible women were ≥ 30 years old, had no history of BC/ovarian cancer, an intact breast, are enrolled in the Breast and Ovarian Surveillance Service (BOSS) Cohort, and visited the Johns Hopkins Cancer Genetics Clinic for risk assessment within 2 months of cohort enrollment (N = 374). All screening was self-reported at baseline, 4, and 8 years. A subset has been validated. We categorized women by BC risk (Tyrer-Cuzick version) obtained at the clinic. We examined frequency of screening over follow-up, and defined adherence to annual mammography and breast MRI based on age- and risk-based guidelines. We modeled the association between BC risk and adherence at 4 and 8 years using logistic regression. Results: At baseline, the median age was 47 years, 31% had lifetime risk &lt; 20%, and 69% had risk ≥20%. Frequency of mammography and clinical breast exam over follow-up was &gt; 60%, while frequency of breast MRI and breast ultrasound was &lt; 40%. Twenty-five percent of high-risk women at 4 years and 40% at 8 years did not report any mammography, breast MRI, or breast ultrasound. At 4 years, high-risk women were 85% less adherent [multivariable adjusted OR = 0.15; 95%CI = 0.07, 0.34] to BC screening guidelines compared to women with a risk of &lt; 20% due to low uptake of breast MRI, while at 8 years, high-risk women were also less adherent to mammography [multivariable adjusted OR = 0.42; 95%CI = 0.18, 0.95]. We observed similar associations among women at high-risk at 5- and 10-years. Adherence at 4 years predicted adherence at 8 years. Interestingly, women who did not uptake MRI complied with other health screening including for colorectal cancer. Conclusions: High-risk women were not adherent to risk-appropriate BC screening, and adherence did not improve over time. Low adherence appears specific to BC screening. New approaches to BC screening are urgently needed for this high-risk group.
RELAY: A multinational, double-blind, randomized Phase 3 study of erlotinib (ERL) in combination with ramucirumab (RAM) or placebo (PL) in previously untreated patients with epidermal growth factor receptor mutation-positive (EGFRm) metastatic non-small cell lung cancer (NSCLC).
Authors: Kazuhiko Nakagawa, Edward B. Garon, Takashi Seto, Makoto Nishio, Santiago Ponce Aix, Chao-Hua Chiu, Keunchil Park, Silvia Novello, Ernest Nadal, Fumio Imamura, Kiyotaka Yoh, Jin-Yuan Shih, Kwok Hung Au, Denis Moro-Sibilot, Sotaro Enatsu, Annamaria H. Zimmermann, Bente Frimodt-Moller, Carla M. Visseren Grul, Martin Reck
Journal: Journal of Clinical Oncology (2019)

9000 Background: Dual blockade of EGFR and VEGFR pathways in EGFRm NSCLC augments anti-tumor efficacy versus (v) EGFR inhibition alone. RELAY (NCT02411448) evaluated efficacy and safety of ERL, an EGFR TKI standard-of-care, plus RAM, a human IgG 1 VEGFR2 antagonist, or PL in 1L EGFRm metastatic NSCLC. Methods: Eligibility included untreated metastatic NSCLC pts with Exon 19 deletion (del) or L858R and no CNS metastasis. Randomized (1:1) pts received ERL (150 mg/day) + RAM (10 mg/kg q2w) or ERL + PL, stratified by gender, geographic region (East Asia v other), EGFRm type (Ex19del v L858R) and EGFR testing method (Therascreen/Cobas v other). The primary endpoint was Investigator assessed progression free survival (PFS). Other objectives included ORR, DoR, PFS2, OS, safety, and plasma T790M mutation (Guardant NGS). Results: 449 pts were randomized characteristics were balanced between treatment arms: Asian 77%, Females 63%, Ex19del 54%. RAM + ERL significantly prolonged PFS, DoR, and PFS2 (Table). Grade &gt;=3 TEAEs were greater with RAM (72%) v PL (54%), largely driven by hypertension (24 v 5%, no Gr4); with 1 treatment related on study death (hemothorax) in RAM v 0 PL. EGFR T790M+ rates at progression are forthcoming. Conclusion: RAM + ERL led to superior PFS in 1L EGFRm metastatic NSCLC. Safety was consistent with the established safety profiles of the individual compounds. Clinical trial information: NCT02411448. [Table: see text]
KLF4 p.A472D mutation: An acquired resistant mutation to cetuximab in colorectal cancer.
Authors: Liu Yang, Jiahong Jiang, Lianpeng Chang, Yaping Xu, Chao Ni, Dongsheng Huang
Journal: Journal of Clinical Oncology (2019)

e15077 Background: With the increase of treatment course, acquired resistance of epidermal growth factor receptor (EGFR) blockade is inevitable in patients with metastatic colorectal cancer (mCRC). KRAS mutations have been considered to be primary drivers of this acquired resistance; however, the potential function of other genes has not been extensively investigated. Methods: This study included 17 mCRC patients with acquired cetuximab resistance, and mutations in circulating tumor DNA (ctDNA) from plasma samples were identified using target-capture deep sequencing. Analysis of mutational prevalence in ctDNA, three CRC tissue-based datasets and one ctDNA dataset was performed. Mutation predicted with significant effect on acquired resistance was selected and the functional analysis was validated in CRC cells. Results: The prevalence of mutations identified in ctDNA was consistent with CRC tissue-based and ctDNA datasets. Clonal analysis revealed that 41.2% of patients were positive for at least one subclonal. Multiply resistance mechanisms of cetuximab were co-existed in individual patient, with one of them even harbored nine distinct mutations. In particularly, function analysis of Krüppel-like factor 4 (KLF4) mutation p.A472D revealed increased cetuximab resistance in CRC cells, which was associated with the increased phosphorylation of downstream EGFR signaling proteins. Conclusions: The KLF4 mutation p.A472D contributes to acquired cetuximab resistance in patients with mCRC and it may serve as a new biomarker useful in clinical application. Monitoring somatic mutations related to acquired cetuximab resistance in mCRC patients through ctDNA is an appropriate means of providing real-time insights useful for clinical reference and treatment planning.
Preliminary safety, efficacy, and pharmacokinetics (PK) results of KN046 (bispecific anti-PD-L1/CTLA4) from a first-in-human study in subjects with advanced solid tumors.
Authors: Jermaine Coward, Vinod Ganju, Ramin Behzadigohar, Kenneth Kwong, June Xu, Hardy Van, Paul Kong, Fei Yang, Lisa Chen, Kangping Guo, Mei Liu, Danming Zhu, Lara Kristina Donato, Ting Xu, Gary Edward Richardson
Journal: Journal of Clinical Oncology (2019)

2554 Background: KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD1 and CTLA-4 interaction with CD80/CD86. KN046 has a wild type IgG1 Fc portion that preserves intact effector functions, such as depletion of T regs in tumor microenvironments. This first-in-human study evaluated the safety, tolerability, PK and preliminary efficacy of KN046 in subjects with advanced solid tumors. Methods: This traditional “3+3” dose-escalation design study enrolled patients (pts) with advanced unresectable or metastatic solid tumors refractory or intolerant to standard therapies. Previous treatment from PD1 or PD-L1 immune checkpoint inhibitors was allowed. KN046 was administered intravenously Q2W. Dose limit toxicity (DLT) evaluation period is 28 days. The planned dose levels (DL) were 0.3, 1, 3, 5 and 10 mg/kg. Efficacy evaluation was performed by RECIST 1.1 every 8 weeks. Results: As of Dec 13, 2018, 10 pts had been enrolled (0.3 mg/kg, n = 1; 1 mg/kg, n = 3; 3 mg/kg, n = 3; and 5 mg/kg, n = 3). Median duration of treatment was 8 (range: 2-24) weeks. 1 DLT was observed at 5 mg/kg dose (a grade 3 immune-related hepatitis without elevation in total bilirubin; reversible in two weeks). The most common (≥30%) treatment-emergent AEs (TEAE) were Fatigue, Diarrhea, Nausea, Vomiting. Six immune-related TEAEs (Abdominal pain lower, Arthralgia, Hepatic function abnormal, Hyperthyroidism, Nausea and Transaminitis) were observed in 3 pts. One pt with NSCLC from 3 mg/kg cohort had confirmed completed response. Two pts (TNBC and nivolumab refractory RCC) from 1 mg/kg cohort had shown long-term stable disease ( &gt; 12 weeks). Faster clearance of KN046 was observed at lower dose might be due to target-mediated clearance. T1/2 is approximately 7~9 days at doses of 3 mg/kg and above when saturation occurs. Conclusions: Single agent KN046 has an acceptable safety profile and is in line with previously reported safety data from other immune checkpoint inhibitors. Preliminary efficacy results are promising. PK data from initial 4 cohorts support Q2W schedule. The study is currently ongoing at dose level of 5 mg/kg Q2W. Clinical trial information: NCT03529526.
Case 20-1987
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely
Journal: New England Journal of Medicine (1987)

Presentation of Case A 45-year-old man was admitted to the hospital because of plasma-cell leukemia and renal failure. He was well until 21 months earlier, when he incurred a compression fracture of the third lumbar vertebra in a fall. Evidence of a pathologic fracture was found. A peripheral-blood smear showed rouleaux formation. A bone marrow aspiration revealed sheets of mature and immature plasma cells (Fig. 1). A diagnosis of multiple myeloma was made. Radiation treatment was administered to the spine, and the patient received cyclic chemotherapy with vincristine, melphalan, cyclophosphamide, doxorubicin, and prednisone. His condition was satisfactory during the next . . .
Patient satisfaction with oncology clinical decision support in South Korea.
Authors: Kyounga Lee, Seon Heui Lee, Anita Preininger, JungHo Shim, Gretchen Jackson
Journal: Journal of Clinical Oncology (2019)

e18329 Background: Watson For Oncology (WFO) is an artificial intelligence (AI) tool that presents therapeutic options to oncologists and patients at 9 hospitals in Korea. The earliest user is Gachon University Gil Medical Center (GMC), where the tumor board (MDT) is fully integrated with WfO (MDT-WfO). GMC patients and oncologists may select one of the treatment choices presented by MDT-WfO or choose to follow recommendations of one or more oncologists at GMC augmented by WfO (non-MDT-WfO). This study is aimed at determining the satisfaction of patients who pursue shared decision-making through the MDT-WfO approach. Methods: Cancer patients enrolled in this IRB-approved study and treated at GMC between March and September of 2018 were surveyed. All patients rated satisfaction levels from 1-10 after treatment decision-making was completed, with 1 indicating the lowest level of satisfaction and 10 the highest. For each question, the average satisfaction score for patients in the MDT-WfO group was compared to the mean for patients in the non-MDT-WfO group, with a t-test for significance. Results: There were 9 cancer types treated at GMC from March through September of 2018. Of the of 290 patients enrolled in this study, 130 (44.8%) selected MDT-WfO and 160 (55.2%) did not. Overall, patients that interacted with MDT-WfO viewed GMT more positively (86.9%) after treatment decisions had been made than patients in the non-MDT-WfO group (71.3%).Although patients did not report significantly differing levels of satisfaction for most survey questions, there was a significant difference in terms of satisfaction with the explanation they received from the medical staff. Satisfaction level for this item was 9.52 with MDT-WfO and 9.22 points without ( p = 0.029). Conclusions: Patients reported greater satisfaction in the explanations they received in the MDT-WfO group, consistent with their more positive impression of GMT after treatment decisions were made. More studies are needed to determine if the increase in the level of satisfaction for this item is due to explanations from MDT unrelated or related to WfO. More studies on how WfO is used differently by the tumor board and individual oncologists may provide a unique perspective on how WfO is integrated into the MDT.