tbuckley/cabot-search huggingface dataset:
Do women who self-report cognitive symptoms after breast cancer treatment have more cognitive impairment than those who do not report symptoms? A mechanistic cohort study with functional brain MRI.
Authors: Janette L. Vardy, Myrle Stouten-Kemperman, Gregory Russell Pond, Christopher M. Booth, Sean Rourke, Haryana M. Dhillon, Anna Dodd, Adrian Crawley, Ian Tannock
Journal: Journal of Clinical Oncology (2016)

10097 Background: Some women report cognitive impairment after adjuvant chemotherapy (CTh) for breast cancer (BC). We explored underlying mechanisms with blood tests and functional imaging. Methods: 127 women within 5 years of early BC diagnosis were recruited: Gr A (n = 44) had received CTh and reported cognitive symptoms (FACT-COG < 85/156); Gr B (n = 53) had CTh but did not report cognitive problems ( > 100/156); Gr C (n = 30) had not received CTh. Clinical neuropsychological (NP) tests and computer-based CANTAB tests were performed. Bloods included sex hormones, coagulation factors, 10 cytokines, and apo-E genotype. Functional MRI scans were obtained on 102 subjects while they performed an n-back (1-,2-,3-) memory task. Results: Median age 50 (29-60 years); median 17 months post-diagnosis. On clinical NP tests 19% had cognitive impairment using Global Deficit Score (GDS), and 34% on ICCTF criteria. No significant differences in cognitive impairment rates were found between the 3 groups on clinical or CANTAB batteries using GDS (Gr A 26% and 69%, Gr B 14% and 52%, Gr C 18.5% and 60% respectively); or between Gr (A+B) vs C. Gr A had significantly more fatigue, anxiety/depression and poorer QOL. No association was found between total FACT-COG score and NP scores (clinical rho = -0.13; CANTAB rho = -0.15). Across groups, fMRI results showed a main task-effect for all contrasts in frontal and parietal areas (p < 0.001). Gr C had hyperactivation compared to CTh groups: Gr C vs A more activation in temporal, parietal and frontal regions. Gr C vs B more activation in parietal and temporal regions. Gr C vs (A+B) had hyperactivation in right precentral gyrus, left putamen and amygdala and bilateral cerebellum. Gr A had more frontal activation than Gr B. Elevated IL-1,-2 and -8 were associated with NP impairment (rho > .20). There was no difference based on apoE status. Conclusions: There were no differences in rates of global cognitive impairment between groups. Cognitive symptoms were associated with fatigue, anxiety and depression, but not with objective cognitive impairment. Women who received CTh had hypoactivation on fMRI in various brain regions.
Allogeneic stem cell transplant (AHCT) in the eighth decade: Age is just a number.
Authors: Ravi Kishore Narra, Saurabh Chhabra, Swapna Narayana, Nirav Niranjan Shah, Mehdi Hamadani, Aniko Szabo, Marcelo C. Pasquini, Parameswaran Hari
Journal: Journal of Clinical Oncology (2017)

7045 Background: Allogeneic hematopoietic cell transplant (AHCT) is a curative treatment for hematological malignancies but older adults ( &gt; 70 years) have been historically excluded due to age-related comorbidities and concern for increased non-relapse mortality (NRM). Reduced intensity conditioning (RIC) regimens, and improvements in supportive measures have broadened AHCT to older adults. Limited data exist regarding AHCT in their eighth decade ( &gt; 70). Methods: We evaluated 24 consecutive pts aged &gt; 70 years receiving AHCT for various hematological malignancies between 2012 and 2016 at the Medical College of Wisconsin. Results: Median age was 72 (range, 70-76), and 62% were male. Disease indications included 11 AML, 6 CMML, 1 MDS, 1 NHL, 1 MM with only 11 patients (46%) in CR at transplant. 15 patients (62%) had normal karyotype, while other 9 had complex karyotype (n = 4), trisomy 11 (n = 1), trisomy 8 (n = 1). 6 patients (26%) had low-risk DRI score, 9 (39%) intermediate and 8 (35%) had high-risk score. Median HCT-CI score was 1.5 (range, 0-5) and 79% patients had a score of ≤2. Donors were related in 50% cases (3 haploidentical, 7 matched siblings and 2 syngeneic). Conditioning was RIC in 23 pts and all peripheral blood grafts. Median follow up was 14.2 months (range, 1.5-42.3). At day 28, 92% had neutrophil engraftment and 87% platelet engraftment. 2 patients had primary graft failure. 4 patients had acute GVHD, 4 had chronic GVHD,1 had both. Median CD3 chimerism was 99% (range, 74-100), CD33 was 100% (range, 78-100). Median of hospital-free days in the first 100 days was 80 and 160 days in the first 6 months after AHCT. 4 pts (17%) underwent AHCT entirely in outpatient setting. 6 patients relapsed at a median of 145 days (range 40-195). Survival at 2 years was 67% with relapse-free survival of 56% and NRM of 14%. Causes of death included sepsis (n = 1), fungal pneumonia (n = 1), cardiac (1), IPS (1), relapse (3). Conclusions: This experience with septuagenarians undergoing AHCT demonstrated an excellent 2 yr survival of 67% and that they can receive AHCT in the outpatient setting with a median hospital-free period of 80 days within the first 100 days. In carefully selected patients NRM with AHCT is manageable. Age alone should not determine eligibility for AHCT.
Toxicity profile of immune checkpoint inhibitor treatment of older metastatic melanoma patients from a single institution cohort.
Authors: Upendra P. Hegde, Bruce Mark Brenner, Sophie Masternak, Roy Sittig, June Lu, Katie Ferenczi, Phil Kerr, Jane grant-Kels
Journal: Journal of Clinical Oncology (2016)

e21005 Background: Melanoma is an immunogenic tumor incidence of which is rising at a rapid rate in the aging population that harbors a weakened and dysregulated immune system. Success of immune checkpoint inhibitor (ICI) treatment of metastatic melanoma (MM) is complicated by autoimmune toxicity (AIT). We report from our Institute an AIT profile in older patients (pts) following ICI treatment of MM. Methods: Between 2011 and 2015, we treated 16 pts aged 60 years or more diagnosed with mm with ICI. Nine pts received anti CTLA-4 antibody Ipilimumab (Ipi) and upon tumor progression 4 of them also received anti PD-1 antibody Pembrolizumab (Pembro). Seven other pts received Pembro as first line treatment of metastatic melanoma. All pts provided written consent and received FDA approved doses of ICI on a standard treatment protocol. Retrospective assessment was done of their responses and toxicity to ICI treatment following IRB approval. Results: The median age of the 16 patients was 71 years, (range 60-88), 11 males and 5 females. Median doses of Ipi and Pembro administered till end of January 2016 are 4 and 5 respectively. Two out of 9 pts who received Ipi treatment achieved durable responses while disease progressed in 7 pts (of these 7, 2 pts died of progressive disease and one died of pulmonary embolism). Of the11 pts who received Pembro, clinical benefit was observed in 5 pts that included one complete response, 3 partial responses and one stable disease. Disease progressed in three pts of whom two died and one is alive with disease. Treatment response is not evaluated in three pts. AIT of grade II or more was noted in 8 out of 20 pts that received either Ipi (9pts) or Pembro (11pts). AIT in 4 out of 9 pts receiving Ipi included colitis in two, hepatitis in one and dermatitis in one. AIT in 4 out of 11 pts receiving Pembro treatment included in one patient pneumonitis, hyperglycemia and polymyalgia rheumatica while myasthenia gravis, pneumonitis and bullous pemphigoid developed in one each. Conclusions: Our observations of AIT in older mm patients following ICI treatment are concerning and suggest their verification be done in a larger patient cohort and compared to their younger counterparts
Dartmouth College professor resigns after plagiarism finding
Authors: Owen Dyer
Journal: BMJ (2018)

A leading health policy scholar has resigned his post at the Dartmouth Institute for Health Policy and Clinical Practice in Lebanon, New Hampshire, citing his unwillingness to cooperate further with an internal disciplinary process that found that he had plagiarised a junior colleague.

H Gilbert Welch, who was a professor of medicine at the institute and at Dartmouth’s school of medicine, is a prominent critic of routine cancer screening who has written extensively on the perils of overdiagnosis.

The plagiarism allegation arose from an article on breast cancer overdiagnosis that appeared in the New England Journal of Medicine in October 2016.1 Samir Soneji, an associate professor at Dartmouth, claimed that Welch had borrowed key ideas from him and his research partner, Hiram Beltran-Sanchez of the University of California, Los Angeles.2

Welch had emailed Soneji asking for …
Metastatic patterns and prognostic significance of signet ring cell carcinoma of the colon: Retrospective analysis of SEER database.
Authors: John Khoury, Rebecca Chacko, David Macari, Bolanle Gbadamosi, Daniel Ezekwudo, Leann Blankenship, Joseph M Anderson, Ishmael A. Jaiyesimi
Journal: Journal of Clinical Oncology (2019)

488 Background: Signet ring cell carcinoma of the colon (SRCC) represents less than 1% of all colon carcinomas. We retrospectively examined the metastatic patterns and prognosis of SRCC in comparison to adenocarcinoma (AC) of the colon. Methods: A total of 763 patients diagnosed with SRCC and 42,875 patients with AC of the colon from 2010 to 2012 were identified from the Surveillance, Epidemiology and End Results (SEER) database. Age, race, gender, primary site, grade, stage, metastatic site and survival data were collected. Results: Out of 43,638 patients, 78.7% were white, 12.5% black and 8.8% other races. Median age of diagnosis was 67.5 years for SRCC as compared to 69.1 years for AC . SRCC was more likely to be grade III or IV (92% vs 21.6%; p &lt; 0.001), to be found in the right colon (63.7% vs 49.4%; p &lt; 0.001) and to present as advanced stage (40.2% vs 29.4% for stage III and 37.1% vs 22.3% for stage IV; p &lt; 0.001). SRCC was more likely to present with metastases to the brain (11.0% vs 1.3%; p &lt; 0.001) and bone (6.4% vs 4.1%; p &lt; 0.001), while AC subjects were more likely to present with metastases to the liver (77.0% vs 22.1%; p &lt; 0.001) and lung (21.2% vs 5.8%; p &lt; 0.001). The 5 year overall survival rate (5-YSR) was 28.2% (CI, 24.5% to 32.4%) for SRCC compared to 50.8% (CI, 50.1% to 51.6%) for AC (Hazard ratio for death, 1.38; CI, 1.26 to 1.52; P &lt; 0.001). The differences in stage specific 5-year survival rates for SRCC and AC were not statistically significant for stage I and stage II. However, SRCC had a lower 5-YSR for stage III (34.5% vs 55.4%) and stage IV (3.3% vs 10.8%). Conclusions: SRCC of the colon has worse survival rates for advanced stages when compared to AC. SRCC presents at earlier age, with advanced tumor grade and stage at diagnosis. The metastatic behavior of SRCC is different than AC with a higher incidence of brain and bone metastases at diagnosis.
Abstract 19250: Importance of Considering Competing Risks in Patients With a Left Ventricular Assist Device (LVAD)
Authors: Ramsey M Wehbe, Alexander J Rodriguez, Allen S Anderson, Kambiz Ghafourian, Esther E Vorovich, Jane E Wilcox, Clyde W Yancy, Duc T Pham, Jonathan D Rich
Journal: Circulation (2016)

Introduction: Whereas a competing risk analysis has discriminated causes of death after heart transplantation, a similar analysis of outcomes after LVAD implant is not well established. Patients (p...
Evaluation of homeobox (HOX) gene expression as a prognostic biomarker of time to recurrence (TTR) in high grade serous ovarian cancer (HGSOC) patients treated with adjuvant carboplatin plus paclitaxel (A-C/P).
Authors: Jai Narendra Patel, Katherine Rose Miller, James Thomas Symanowski, Jalid Sehouli, Chad Michener, Ioana Braicu, David L. Tait, Wendell Jones, Qing Zhang, Chad Livasy, Charles Biscotti, Mahrukh Karkaria Ganapathi, Ram N. Ganapathi
Journal: Journal of Clinical Oncology (2016)

e17046 Background: Aberrant HOX gene expression has been observed in various malignancies, including HGSOC. However, their role as a prognostic biomarker for TTR in HGSOC patients treated with A-C/P is unknown. Methods: RNA sequencing was conducted to determine HOX gene expression in a discovery cohort of primary tumors from 19 HGSOC patients treated with A-C/P. HOX genes associated with TTR in the discovery cohort and/or overall or disease-free survival in The Cancer Genome Atlas HGSOC data sets were selected for further testing by RT-PCR using the Fluidigm platform in an independent training cohort of primary tumors from 73 HGSOC patients treated with A-C/P. Univariate Cox proportional hazards models were used to identify HOX genes individually associated with TTR. Significant HOX genes (P<0.10) in the univariate analysis were included in a multivariable model applying backward elimination followed by forward selection. Risk groups were created by defining quartile cutoffs of the linear predictor from the final Cox model and analyzed using Kaplan-Meier techniques and Cox proportional hazards models. Results: Of the 37 HOX genes analyzed in the discovery cohort, 23 were selected for further analysis. Of these, HOXA2, A4, A7, A10, B2, B3, and D3 were individually associated with TTR in the training cohort. Multivariable analyses yielded HOXA4 and B3 in the final model (P=0.001 and P=0.016, respectively) with increasing expression levels associated with increased risk of recurrence. The prognostic index for HOXA4/B3 was significantly associated with TTR (Table 1, P=0.008). Conclusions: HOXA4/B3 gene expression was significantly associated with TTR in HGSOC and may serve as a potential prognostic biomarker. Ongoing studies include validation in larger patient cohorts treated with A-C/P and correlation of HOXA4/B3 expression with chemotherapy resistance and tumor recurrence. Median TTR classified by linear predictor quartiles for HOXA4/B3. Risk group Median TTR (months) HR 95% CI Q1 (reference group) 72.0 – – Q2 19.4 2.33 1.01–5.36 Q3 17.0 3.20 1.40–7.31 Q4 13.8 4.11 1.74–9.68
Early assessment of therapy response in non-small cell lung cancer (NSCLC) via longitudinal ctDNA analysis.
Authors: Xiaoju Max Ma, Christine Ju, Corinna Woestmann, Liu Xi, Stephanie J. Yaung, Bernd Hinzmann, Michael Thomas, Claus Peter Heussel, Felix Lasitschka, Michael Meister, Marc Schneider, Felix Herth, Thomas Muley, Birgit Wehnl, John F. Palma
Journal: Journal of Clinical Oncology (2019)

e20701 Background: Quantifying circulating tumor DNA (ctDNA) is an emerging method to non-invasively assess treatment effect for solid tumors. Despite disease heterogeneity in NSCLC, we set out to identify a broadly applicable ctDNA-based method for disease monitoring. By employing plasma taken during early treatment cycles, we tested whether early response assessed by ctDNA level could predict treatment effect. Methods: Using a 197-gene NGS assay, the AVENIO ctDNA Surveillance Kit (For Research Use Only, not for use in diagnostic procedures), we measured ctDNA levels in post-treatment plasma samples based on variants identified at baseline. We used samples from an observational German Lung Cancer Multi-Marker Study. In a cohort of 83 stage IV lung adenocarcinoma treated with first-line chemo or chemoradiation therapies, we evaluated the association between survival and ctDNA levels in the first available post-treatment plasma sample (median number of days after start of treatment = 23). We used a ctDNA-based monitoring algorithm, and applied it to an independent set of 22 late stage lung squamous cell carcinoma (SCC) that also underwent chemo or chemoradiation therapies to further evaluate the algorithm in different histology subtypes. Results: We divided the 83 adenocarcinoma cohort into training (n = 53) and test (n = 30) sets. We found that subjects with longer progression free survival (PFS) had mean allele fraction (AF) &lt; 1% in the training set. We applied the classifier to our validation set and found that subjects with mean AF &lt; 1% had longer PFS (HR 0.35; 95% CI 0.12 - 0.93; log-rank P = 0.028) and overall survival (OS) (HR 0.29; 95% CI 0.09 - 0.89; log-rank P = 0.021). Using cutoffs identified in adenocarcinoma, we applied the same algorithms to the SCC cohort. Subjects with mean AF &lt; 1% had longer PFS (HR 0.26; 95% CI 0.10 - 0.71; log-rank P = 0.005) and OS (HR 0.12; 95% CI 0.05 - 0.51; log-rank P = 0.001). Conclusions: Even in heterogeneous diseases such as NSCLC, changes in ctDNA levels in response to treatment may prove to be a valuable way of identifying subjects who may not benefit, which is earlier than current standard of care methods like computed tomography (CT) scan. Future prospective studies to confirm these results are warranted.
Mesenchymal glioblastoma constitutes a major ceRNA signature in the TGF-β pathway
Authors: Qixue Wang, Jinquan Cai, Chuan Fang, Chao Yang, Junhu Zhou, Yanli Tan, Yunfei Wang, Yansheng Li, Xiangqi Meng, Kai Zhao, Kaikai Yi, Sijing Zhang, Jianning Zhang, Chuanlu Jiang, Jing Zhang, Chunsheng Kang
Journal: Theranostics (2018)

Rationale: Competitive endogenous RNA (ceRNA) networks play important roles in posttranscriptional regulation.Their dysregulation is common in cancer.However, ceRNA signatures have been poorly examined in the invasive and aggressive phenotypes of mesenchymal glioblastoma (GBM).This study aims to characterize mesenchymal glioblastoma at the mRNA-miRNA level and identify the mRNAs in ceRNA networks (micNET) markers and their mechanisms in tumorigenesis.Methods: The mRNAs in ceRNA networks (micNETs) of glioblastoma were investigated by constructing a GBM ceRNA network followed by integration with a STRING protein interaction network.The prognostic micNET markers of mesenchymal GBM were identified and validated across multiple datasets.ceRNA interactions were identified between micNETs and miR181 family members.LY2109761, an inhibitor of TGFBR2, demonstrated tumor-suppressive effects on both primary cultured cells and a patient-derived xenograft intracranial model.Results: We characterized mesenchymal glioblastoma at the mRNA-miRNA level and reported a ceRNA network that could separate the mesenchymal subtype from other subtypes.Six genes (TGFBR2, RUNX1, PPARG, ACSL1, GIT2 and RAP1B) that interacted with each other in both a ceRNA-related manner and in terms of their protein functions were identified as markers of the mesenchymal subtype.The coding sequence (CDS) and 3'-untranslated region (UTR) of TGFBR2 upregulated the expression of these genes, whereas TGFBR2 inhibition by siRNA or miR-181a/d suppressed their expression levels.Furthermore, mesenchymal subtype-related genes and the invasion phenotype could be reversed by suppressing the six mesenchymal marker genes.Conclusions: This study suggests that the micNETs may have translational significance in the diagnosis of mesenchymal GBM and may be novel therapeutic targets.
When the loss of spirituality leads to the loss of the path: The moderating role of spirituality in a multiple-step-mediation process from physical suffering to distress.
Authors: Alessandro Rossi, Maria Marconi, India Minelli, Stefania Mannarini, Maria Monica Ratti, Chiara Rossini, Giuseppe Di Lucca, Claudio Verusio
Journal: Journal of Clinical Oncology (2018)

e22160 Background: A diagnosis of Cancer often leads patients to experience a breakdown in spirituality that could undermine his/hers life. Spirituality troubles seem to be related with emotional problems – triggered by physical and practical difficulties – that lead to experience psychological distress. However, there aren’t definitive results on these relationships. This study aimed to test a multiple step mediation moderated analysis in which spirituality moderates the process that leads to distress. Methods: Patients (N = 250, 54.6% female, mean age = 64.3, SD = 12.3) were consecutively enrolled at “Presidio Ospedaliero” of Saronno, ASST Valle Olona, Italy – Department of Medical Oncology. Patients were tested with NCCN’s Distress Thermometer and Problem List (DT&PL; NCCN, 2003) assessing: (A) distress and (B) physical (α = .77), (C) practical (α = .68), (D) social (α = .70), (E) emotional (α = .85) and (F) spirituality problems. Results: First, a CFA was performed to test the factorial structure of the PL. The factor structure was confirmed: RMSEA = .064; CFI = .904. Then, a multiple step mediation moderated analysis (5000 bootstrap resampling) shows model’s significance [F = 59.9; p < .001; R2= .49; Eff.Size = .364]. Surprisingly, in absence of spiritualty problems, the relationship between physical problems and distress was partially mediated (path c’: β = .118, p = .016) by practical problems (path a1: β = .061, p = .001) by relationships problems (path d1: β = .281, p < .001) and by emotional problems (path d2: β = .612, p = .013; and path b3: β = .889, p < .001). Opposite, in presence of spiritualty problems, none of these relationships reached statistical significance (p > .05) – showing effects of interaction on each of these paths. Conclusions: These surprising results highlight the role of spirituality. The process from physical difficulties to psychological distress follows a specific path only in absence of spirituality issues. These findings suggest new ways in which psycho-oncologists should structure interventions to improve quality of life and reduce psychological suffering paying attention to the spirituality sphere of the oncological patient.
Forecasting financial impact of alternative payment models to cancer drug manufacturers.
Authors: Jennifer M. Hinkel, Daniel B. Sexton, William T McGivney
Journal: Journal of Clinical Oncology (2017)

6549 Background: Payers are moving from fee-for-service (FFS) reimbursement models towards value-based Alternative Payment Models (APMs). In Medicare, this trend has emerged via MACRA legislation and the Oncology Care Model (OCM). Reimbursement changes carry financial implications for payers, providers, and drug manufacturers. Methods: Financial impact of APMs was modeled as a function of Volume Factors and Price Factors in sales of a cancer drug product. Volume Factors included utilization patterns and market share. Price Factors included launch price, price increases, and both mandated and negotiated discounts. The model described three APM categories: Buy &amp; Bill Plus (similar to OCM), Episode-Based Payment, and Third-Party Buy &amp; Bill. The model included assumed timelines of APM implementation and the share of commercial insurer and Medicare markets implementing. Assumptions were generated in a multi-stakeholder workshop applying a modified Delphi method and Nominal Group Technique to arrive at consensus. The model included input ability for existing product forecast data including expected patient numbers, market share, payer mix, channel mix, price, 340B discount parameters, and additional concessions. Combinations of inputs and assumptions were run through the model as scenarios to generate results. Results: Across all scenarios, Episode-Based Payment resulted in revenues averaging 34% below baseline forecast at the ten-year mark. Third-Party Buy and Bill resulted in revenues averaging 100% of baseline at the ten-year mark. Buy and Bill Plus resulted in revenues averaging 66% below baseline at the ten-year mark. Market share as a function of clinical differentiation appeared to be a significant factor influencing revenue impact, with highly differentiated products outperforming others in all APMs. Conclusions: While much attention is paid to the impact of reimbursement reform on oncology provider economics, with subsequent impacts to patient access, less attention has been focused on impact to drug manufacturers. APM implementation could significantly impact manufacturer revenues, which in turn may impact both access to such therapies and research investment towards new anti-cancer therapies.