tbuckley/cabot-search huggingface dataset:
A novel mathematical approach to predict outcome in adult Hodgkin lymphoma.
Authors: Manikandan Dhanushkodi, Tanmay Mitra, Rama Ranganathan, Venkatraman Radhakrishnan, Prasanth Ganesan, Krishna Rathnam, Selvaluxmy Ganesarajah, Swaminathan Rajaraman, Sagar Tenali Gnana, Sitabhra Sinha, Trivadi Ganesan
Journal: Journal of Clinical Oncology (2016)

e19016 Background: Currently, the prognosis of advanced Hodgkin’s lymphoma (HL) can be predicted by the International prognostic score (IPS). Although attempts have been made to validate this, the results are equivocal. Alternatively a mathematical approach using correlation measurements can be used in determining the prognostic factors and deriving a predictive model for outcome. Methods: 404 consecutive untreated patients with HL (2001-2010) were analysed for prognostic factors using the Cox proportional hazards model. The mathematical analysis was performed by measuring correlation matrix (CM) of all factors using their deviation from the normal range. Significant eigen values were used to derive noise free filtered CM. This was evaluated to identify prognostic factors and to design a weighted scoring system to predict outcome. Principle Component Analysis (PCA) of the filtered CM was done to evaluate the interdependance of the factors and the heterogeneity of the population.Results: The median age was 33 years (range 15 – 70 years; M:F 68%:32%). B symptoms were present in 49 % of patients. Stage I, II, III and IV constituted 16 %, 34 %, 36 % and 14 % respectively. Chemotherapy was ABVD (n = 235), COPP-ABV (n = 134) and COPP (n = 35) regimen. Consolidation radiotherapy was delivered to 25 %. The median follow up was 5.5 years. Complete (81.4%), partial remission (8.7%) and primary progressive disease (4.5%) was the outcome to initial treatment. 13.1 % have relapsed of their disease. The 10 year disease free (DFS) and overall survival (OS) was 64 % & 73 % respectively. In multivariate analysis age, stage and lymphocyte % were predictive of DFS and OS. The IPS factors were not validated for advanced HL patients (n = 159). The mathematical approach predicted that the key prognostic factors were age, B symptoms, number of nodal sites, hemogobin, WBC, lymphocyte count, ESR, albumin, LDH and creatinine. The PCA of the filtered CM revealed the interdependence of clinical factors whose grouping was different between male and female patients. Conclusions: The IPS for advanced HL was not validated in this dataset. The mathematical approach identified all the prognostic factors in IPS in addition to other novel ones. This approach can also be applied in other cancers.
Abstract 12899: Evaluation of Time Course of Left Ventricular Dysfunction by Cardiotoxicity of Anthracycline
Authors: Tatsuya Miyoshi, Hidekazu Tanaka, Akihiro Kaneko, Kensuke Matsumoto, Kazuhiro Tatsumi, Takuma Sawa, Yoshiki Yamadori, Junichi Imanishi, Yoshiki Motoji, Yasuhide Mochizuki, Yuko Fukuda, Hironobu Minami, Hiroya Kawai, Ken-ichi Hirata
Journal: Circulation (2013)

Background: Anthracyclines cause dose-dependent left ventricular (LV) myocardial dysfunction associated with a poor prognosis. Therefore, interest is high in the time course of LV dysfunction in th...
Cost variance analysis in treatment of advanced non-small cell lung cancer.
Authors: Prachi Kalamkar, Ariel Sandhu, Daniel Jung Lee, Matthew Bigbee, Gene Finley, David S. Parda, David G. Mayernik
Journal: Journal of Clinical Oncology (2018)

e18929 Background: There exists significant variation in lung cancer treatment depending on physician, payer and stage of disease without significant difference in survival or QoL (Quality of Life). We present a retrospective observational study of advanced stage non-small cell lung cancer (NSCLC) patients across Allegheny Health Network (AHN) to evaluate cost variation from a payer perspective. Methods: All stage III & IV NSCLC patients enrolled between Dec 2008-2012 with commercial or Medicare Advantage coverage, an AHN oncologist and claims data on or after the diagnosis date were reviewed. Patients were divided equally into four quartiles depending on PMPM (per member per month) cost. Total costs (inpatient, outpatient, labs, procedures, chemotherapy, radiation, imaging, etc.) per patient were calculated from diagnosis until disenrollment. Results: 166 patients were analyzed, 50 (30%) insured with commercial and 116 (70%) with Medicare Advantage. 102 patients were stage IV (61%), 24 were stage III B (14.4%) and 41 were stage IIIA (24.6%). Considerable variation in total per member (PM) cost was found between insurance products ($ 68,646 for commercial vs $ 47, 062 for Medicare Advantage) and among oncologists; spikes were seen near the end of life in all quartiles. The mean cost PM ranged from $ 3908 (Quartile 1) to $ 33,399 (Q 4). Each quartile consisted of patients in different stages with a majority of stage IV (31/102, 30%) in Q4 and stage IIIA in Q2 (15/ 41, 36.6%). Patients in Q4 had an average survival of 8 months whereas Q2 had 16 months. The majority of patients dying in the hospital were in Q4 (21/42, 50%) followed by Q3 (11/ 42, 26%). Non-trauma hospital admissions (34 % of total cost) and chemotherapy (39.7 % of total cost) were primary drivers of cost in both populations. Conclusions: Hospital admissions and chemotherapy were the major drivers of cost and are largely attributed to variation in provider practice patterns and insurance product. Our study provides a useful preliminary data for future investigation on the cost of care and budget impact in advanced stage NSCLC.
P05.75 Surgery followed by fractionated radiosurgery on the tumor bed in patients with single large brain metastases from solid tumor: preliminary results of a phase II study
Authors: P Navarria, E Clerici, F Pessina, C Franzese, L Bello, M Riva, L Toschi, G Masci, T Comito, M Scorsetti
Journal: Neuro-Oncology (2018)

Brain metastases (BMs) occur in 20%-40% of adult cancer patients, and their incidence has increased from 2 to 5 times over the past 40 years. Treatment options include surgery, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). As a single modality, none of these are able to obtain an adequate local control (LC) of large BMs (≥2.1 cm), and therefore a combined approach, is recommended. We designed a prospective phase II study aimed to assess the benefit of surgical resection followed by fractionated radiosurgery (FSRS) on the tumor bed, instead of postoperative WBRT, for patient with single large brain metastases from solid tumor. The potential advantage of this treatment is to improve local control and to reduce toxicity compared with WBRT after surgical resection. Primary endpoint was local control rate; secondary endpoints incidence of new brain metastases, and patients overall survival. Patients with age >18 years, KPS ≥70, oligometastatic disease, controlled primary tumor and extracranial metastases, single BM ≥ 2.1 cm, and estimated survival ≥3 months were enrolled. Patients underwent previous WBRT were excluded. Surgical resection was performed with the aim to maximally (>95%) remove the tumor. Within 1 month from surgery, a fractionated SRS was performed on the tumor bed for a total dose of 30 Gy in 3 daily fractions. Outcome was evaluated by neurological examination and MRI performed 2 months after treatment and every 3 months thereafter. Response in site of treatments was assessed according to RANO criteria. Between 2014 and May 2018, 122 patients were enrolled, 56 female and 66 male with a median age of 49 years. The most common primary tumor was Non-Small Cell Lung Cancer (47%), followed by breast cancer (27%) and melanoma (10%). The median follow-up was 22 months (range 7–48 months). The 1,2-year LC rate were 98%, and 98%. Forty-two (34%) patients had new BDP at a median time of 19 months. The median 1,2-year overall survival were 24 months, 91.3% and 73%. At the last observation time, 27 patients (22%) were dead and 95 patients (78 %) were alive. No detrimental effect on neurocognitive functions was recorded. Fractionated SRS after surgical resection is a safe and feasible option in patients with large brain metastases and oligometastatic disease.
Financial toxicity in adults with cancer: Adverse outcomes and potential areas of intervention.
Authors: Thomas Gregory Knight, Allison Mary Deal, Hyman B. Muss, Stacie Dusetzina, Seul Ki Choi, Jeannette T Bensen, Grant Richard Williams
Journal: Journal of Clinical Oncology (2016)

6624 Background: Financial toxicity (FT) has been shown to be associated with delays in care and treatment noncompliance (Khera et al. JCO 2014). The purpose of this study was to describe characteristics of individuals reporting FT and to identify rates of and patient-reported reasons for treatment noncompliance. Methods: Cancer patients aged ≥ 18 years who completed a survey ≥ 90 days from their diagnosis were identified from the Health Registry/Cancer Survivorship Cohort, a database designed to aid in survivorship research. FT was defined as agreement with the phrase "You have to pay for more medical care than you can afford" from the patient satisfaction questionnaire (PSQ-18). Logistic regression and fisher's exact tests were used to compare the groups. Results: Of the 1,992 patients: median age 60 yrs, 62% female, 81% white, 16% black, 3% non-English speaking, 32% unmarried, 55% less than a college degree, 56% within 2 years of diagnosis. 524 patients (26%) reported FT. These patients were more likely be aged ≤ 65 years, female, non-Caucasian, non-English speaking, not married, possess less education than a college degree, and diagnosed more recently (all p < 0.001). Patients with FT were more likely to report noncompliance due to inability to afford prescription medications (18% vs 3.7%), mental health care (5.7% vs 1.1%), dental care (23% vs 6.8%), doctor's visits (11.5% vs 2.9%), medical tests (6.3% vs 1.8%), and OTC medications (7.7% vs 2.4%) (all p< 0.001). The most highly endorsed reasons for delayed care were not having insurance coverage and being unable to afford general expenses. Table 1 shows differences in all the potentially intervenable factors that caused delays in care. Conclusions: Financial toxicity remains a major issue in cancer care, and this study identified several potentially intervenable contributing factors and concerning reasons for delays in care. Future research developing and evaluating interventions on these factors is necessary. Reason for Delay FT Pts (%) Non FT Pts (%) p value No transportation 5.4 2.1 <0.001 Cannot take time off of work 7.6 1.9 <0.001 Cannot afford travel expenses 6.5 2.1 <0.001 No health insurance 11.0 3.8 <0.001 Could not afford general expenses 18.0 4.9 <0.001
Early Initiation of Breastfeeding
Authors: M.J. Friedrich
Journal: JAMA (2018)

Globally, only 2 out of 5 newborns began breastfeeding within an hour of birth in 2017, leaving an estimated 78 million newborns to wait over 1 hour to be put to the breast, according to a new report from the United Nations Children’s Fund (UNICEF) and the World Health Organization (WHO).
Toll-like Receptor 3 Is a Therapeutic Target for Pulmonary Hypertension
Authors: Daniela Farkas, A. A. Roger Thompson, Aneel R. Bhagwani, Schuyler Hultman, Hyun Ji, Naveen Kotha, Grant Farr, Nadine D. Arnold, Adam Braithwaite, Helen Casbolt, Jennifer E. Cole, Ian Sabroe, Claudia Monaco, Carlyne D. Cool, Elena A. Goncharova, Allan Lawrie, Laszlo Farkas
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Pulmonary arterial hypertension (PAH) is characterized by vascular cell proliferation and endothelial cell apoptosis. TLR3 (Toll-like receptor 3) is a receptor for double-stranded RNA and has been recently implicated in vascular protection.To study the expression and role of TLR3 in PAH and to determine whether a TLR3 agonist reduces pulmonary hypertension in preclinical models.Lung tissue and endothelial cells from patients with PAH were investigated by polymerase chain reaction, immunofluorescence, and apoptosis assays. TLR3-/- and TLR3+/+ mice were exposed to chronic hypoxia and SU5416. Chronic hypoxia or chronic hypoxia/SU5416 rats were treated with the TLR3 agonist polyinosinic/polycytidylic acid (Poly[I:C]).TLR3 expression was reduced in PAH patient lung tissue and endothelial cells, and TLR3-/- mice exhibited more severe pulmonary hypertension following exposure to chronic hypoxia/SU5416. TLR3 knockdown promoted double-stranded RNA signaling via other intracellular RNA receptors in endothelial cells. This was associated with greater susceptibility to apoptosis, a known driver of pulmonary vascular remodeling. Poly(I:C) increased TLR3 expression via IL-10 in rat endothelial cells. In vivo, high-dose Poly(I:C) reduced pulmonary hypertension in both rat models in proof-of-principle experiments. In addition, Poly(I:C) also reduced right ventricular failure in established pulmonary hypertension.Our work identifies a novel role for TLR3 in PAH based on the findings that reduced expression of TLR3 contributes to endothelial apoptosis and pulmonary vascular remodeling.
PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers
Authors: Géraldine Gentric, Yann Kieffer, Virginie Mieulet, Oumou Goundiam, Claire Bonneau, Fariba Nemati, Ilse Hurbain, Graca Raposo, Tatiana Popova, Marc-Henri Stern, Valérie Lallemand-Breitenbach, Sebastian Müller, Tatiana Cañeque, Raphaël Rodriguez, Anne Vincent-Salomon, Hugues de Thé, Rodrigue Rossignol, Fatima Mechta-Grigoriou
Journal: Cell Metabolism (2018)

High-grade serous ovarian cancer (HGSOC) remains an unmet medical challenge. Here, we unravel an unanticipated metabolic heterogeneity in HGSOC. By combining proteomic, metabolomic, and bioergenetic analyses, we identify two molecular subgroups, low- and high-OXPHOS. While low-OXPHOS exhibit a glycolytic metabolism, high-OXPHOS HGSOCs rely on oxidative phosphorylation, supported by glutamine and fatty acid oxidation, and show chronic oxidative stress. We identify an important role for the PML-PGC-1α axis in the metabolic features of high-OXPHOS HGSOC. In high-OXPHOS tumors, chronic oxidative stress promotes aggregation of PML-nuclear bodies, resulting in activation of the transcriptional co-activator PGC-1α. Active PGC-1α increases synthesis of electron transport chain complexes, thereby promoting mitochondrial respiration. Importantly, high-OXPHOS HGSOCs exhibit increased response to conventional chemotherapies, in which increased oxidative stress, PML, and potentially ferroptosis play key functions. Collectively, our data establish a stress-mediated PML-PGC-1α-dependent mechanism that promotes OXPHOS metabolism and chemosensitivity in ovarian cancer.
Prostaglandin E Receptor EP4 (EP4) expression, survival and pattern of recurrence in locally advanced NSCLC (LANSCLC).
Authors: Neha Bhooshan, Paul Staats, Amy Fulton, Josephine Louella Feliciano, Martin J. Edelman
Journal: Journal of Clinical Oncology (2016)

e23249 Background: Elevated COX-2 expression has been correlated with inferior outcome in NSCLC. COX-2 catalyzes the transformation of PG to PGE-2. We and others have demonstrated that PGE-2 induces proliferation and metastatic spread and immunosuppression through the EP4 receptor (Breast Cancer Res Treat. 2014 143:19-3; J Immunother. 2012 ;35:179-88). We hypothesized that EP4 expression would correlate with outcome and patterns of relapse after treatment of LANSCLC stage IIIa (7th edition, N2+) . Methods: Tissue specimens from 41 pts treated for LANSC at UMGCC were obtained. A tissue microarray was prepared and immunohistochemical stained (Rabbit anti-human Polyclonal antibody,Lifespan Biosciences #LS-A3898) for EP4. Intensity of staining was scored semiquantitatively as 0-4 in both the nuclear and cytoplasmic compartments by a pathologist blinded to the clinical data. Results: Demographics: see table. EP4 nuclear staining 0-1 vs.2+ was associated with overall survival, (OS) (44.3 vs. 18 mo; HR = .41, p = .024) and numerically superior progression free survival (PFS) (16.4 vs. 10.2 mo, p = .16). EP cytoplasmic staining did not correlate with OS (0-1 vs 2+, 23.8 vs 28.8 mo; HR = 1.2 , p = .81). Relapse pattern (no relapse or local vs. systemic) did not correlate with EP nuclear staining (p = 1.0, X2 ). Conclusions: This is the first clinical study of EP4 expression in lung cancer. There was a significant correlation between OS and nuclear EP4 expression, indicating that this is a potential therapeutic target. Studies with AT-007, a specific inhibitor of EP4, are planned to commence this year.
The potential cost-effectiveness of first-line immunotherapy + chemotherapy for advanced non-squamous non-small cell lung cancer (NSCLC).
Authors: Joshua A. Roth, Trung Nguyen, Bernardo H. L. Goulart
Journal: Journal of Clinical Oncology (2018)

6612 Background: In May of 2017, the U.S. FDA granted accelerated approval for pembrolizumab + pemetrexed & carboplatin for previously untreated advanced non-squamous NSCLC—the only first-line indication for immunotherapy + chemotherapy (‘IO+Chemo’) in NSCLC. Preliminary value estimates are needed to inform decision making. Using data from the Phase II KEYNOTE-021 trial, we estimated the potential value of IO+Chemo from a U.S. payer perspective. Methods: We created a partitioned survival decision model to assess the cost-effectiveness of IO+Chemo vs. pemetrexed & carboplatin (‘Chemo’) in Stage IIIB/IV non-squamous NSCLC. One year overall (OS) and progression-free survival came from KEYNOTE-021 and were extrapolated with parametric curves. The base case used a Weibull curve for long-term OS (6% 5 year OS), and scenarios used Log-Logistic (21% 5 year OS) and Gompertz ( < 1% 5 year OS) curves to model more and less durable responses. First- and second-line therapy resource use and Grade 3/4 adverse event rates were derived from KEYNOTE-021. We applied 2017 Average Sales Price for drugs and 2017 CMS reimbursement for procedures. Utilities were derived from the literature. We estimated life years (LY), quality-adjusted life years (QALYs), and costs over a lifetime horizon. Outcomes were discounted at 3% per year. Results: In the base case, IO+Chemo and Chemo resulted in 2.23 and 1.43 LYs, 1.20 and 0.77 QALYs, and $328,640 and $147,418 cost, respectively. The IO+Chemo costs per LY and QALY gained were $227,149 and $422,313, respectively. The cost per QALY varied greatly in OS scenarios (See Table), showing the strong influence of durable responses on value. Conclusions: In the first cost-effectiveness analysis of frontline IO+chemo in advanced non-squamous NSCLC, we found that pembrolizumab-based therapy is unlikely to be cost-effective (ie < $150,000 per QALY) regardless of long-term OS assumptions. Future studies should reassess IO+chemo value with Phase III KEYNOTE-189 data. IO+Chemo: OS Curve Fit IO+Chemo: QALYs Gained IO+Chemo: Additional Cost Cost Per QALY Log Logistic 0.88 $189,830 $214,899 Weibull (Base Case) 0.43 $181,222 $422,313 Gompertz 0.09 $170,445 $1,891,845
A phase II prospective study of selumetinib in children with recurrent or refractory low-grade glioma (LGG): A Pediatric Brain Tumor Consortium (PBTC) study.
Authors: Jason R. Fangusaro, Arzu Onar-Thomas, Tina Young-Poussaint, Shengjie Wu, Azra H Ligon, Neal Ian Lindeman, Anuradha Banerjee, Roger Packer, Lindsay B. Kilburn, Ian Pollack, Regina Jakacki, Ibrahim A. Qaddoumi, Paul Graham Fisher, Girish Dhall, Patricia Ann Baxter, Susan G. Kreissman, L. Austin Doyle, Malcolm A. Smith, Ira J. Dunkel, Maryam Fouladi
Journal: Journal of Clinical Oncology (2017)

10504 Background: A greater understanding of the Ras-MAP kinase-signaling pathway in pediatric low-grade glioma (LGG) paired with the availability of potent selective inhibitors has enhanced the ability to target this pathway with therapeutic intent. Methods: The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/refractory LGG assigned to 6 strata and treated at 25 mg/m 2 /dose PO BID for up to two years. Here we present the data from three of these strata. The remaining strata are still accruing patients. Results: Stratum I included children with non-NF-1 and non-optic pathway recurrent/refractory pilocytic astrocytoma (PA) harboring BRAF aberrations (BRAF V600e mutation or the BRAF-KIAA 1549 fusion). Eight of 25 (32%) patients achieved a partial response (PR) with 2-year PFS of 66+/-11%. Two of 7 (29%) patient tumors with a BRAF V600e mutation and 6/18 (33%) with a BRAF KIAA-1549 fusion had a PR. Stratum 3 enrolled NF-1-associated LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Ten of 25 (40%) achieved PR with a 2-year PFS of 96+/-4%. Only one patient progressed while on treatment. Stratum 4 included children with non-NF-1 optic pathway/hypothalamic LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Two of 16 (12.5%) had a PR with a 2-year PFS of 65+/-13%. The BRAF aberration status of the responders in strata 3 and 4 is mostly unknown. All responses were confirmed centrally and seven patients remain on treatment. The most common toxicities were grade 1/2 CPK elevation, diarrhea, hypoalbuminemia, elevated AST and rash. Rare grade 3/4 toxicities included elevated CPK, rash, neutropenia, emesis and paronychia. Conclusions: Selumetinib was effective in treating children with recurrent/refractory LGG, including those with NF-1 associated LGG and PA harboring BRAF V600e mutation or BRAF-KIAA 1549 fusion. Larger prospective studies are necessary to determine the future, specific role of this agent in treating children with LGG harboring specific molecular aberrations. Clinical trial information: NCT01089101.
Tumor response assessment using diffusion weighted imaging (DWI) in patients with liver metastases treated with Aurora A and TORC1/2 inhibitors.
Authors: Natalie Julie Serkova, Debra J Singel, Elaine Tat Lam, Stephen Leong, Bradley Corr, Wells A. Messersmith, Jennifer Robinson Diamond
Journal: Journal of Clinical Oncology (2018)

e14573 Background: Commonly used radiological end-points in oncology are based on lesion size and lack sensitivity when monitoring response to molecular targeted therapies. The goal of this study was to evaluate the value of the apparent diffusion coefficients (ADC) from the diffusion weighted images (DWI) as physiological biomarkers for early treatment response in patients with liver metastases undergoing dual TORC1/2 (TAK-228) and Aurora A (MLN8237, alisertib) inhibitor treatment. Methods: DWI was performed in a subset of 5 patients (pts) enrolled in an expansion cohort of a Phase I study of TAK-228 and MLN8237 (n = 4 breast, n = 1 colorectal cancer). Pts had liver metastasis > 1.5 cm. DWI was performed at baseline, Cycle 1 Day 7 and Cycle 2 Day 7. Conventional T2-MRI, as well as DWI and ADC maps were acquired in the axial plane (with 5 b-values, TR = 3000ms, TE = 70 ms) at a Siemens 3T MR scanner. 1-3 target lesions per pt were identified on T2-MRI, their region of interests (ROIs) copied onto the ADC maps. Results: The ADC values of the liver lesions at baseline were 0.85 to 1.30 x10-3 mm3/s (n = 13); mean 1.01 x10-3 mm3/s. At Cycle 1 Day 7, 3 pts had increased ADC values (125%) indicating necrosis and decreased cell density (responders). One pt had no changes and one had decreased ADC values indicating increased cell density and vitality (non-responder). At Cycle 1 Day 7, resolution of one target lesion occurred in a responder and the remaining lesions resolved by Cycle 2 Day 7. Two other responders had high ADC with a decreased lesion size of up to 35% at Cycle 2 Day 7. The non-responder continued to reveal low ADCs, and increased lesion size at Cycle 2 Day 7. Conclusions: In this pilot study, the addition of DWI provides better early diagnostic performance in treatment monitoring of liver metastasis. DWI and ADC maps show the ability to detect an early treatment response in metastatic liver lesions based on tumor cell density and tumor necrosis. Increased ADC values in pts treated with alisertib in combination with a TORC1/2 inhibitor predict the clinical response as early as Day 7 of the initiation of treatment when no size shrinkage is present.