tbuckley/cabot-search huggingface dataset:
Assessing a prognostic model for predicting VTE occurrence in cancer patients.
Authors: Deesha Sarma, So Yeon Kim, David H. Henry
Journal: Journal of Clinical Oncology (2012)

1577 Background: Venous thromboembolism (VTE) poses a significant health risk to cancer patients and is one of the leading causes of death among this population. The most effective way to prevent VTE and reduce its prominence as a public health burden is by identifying high-risk patients and administering prophylactic measures. In 2008, Khorana et al. developed a model that classified patients by risk based on clinical factors. Methods: We conducted a retrospective study to test this model’s efficacy, on 150 patients with cancer receiving chemotherapy at an outpatient oncology clinic between January 1 and August 1, 2011. We aggregated data and assigned points based on the five factors in the Khorana model: site of cancer with 2 points for very high-risk site and 1 point for high-risk site, 1 point each for leukocyte counts more than 11 x 10 9 /L, platelet counts greater than 350 X 10 9 /L, hemoglobin levels less than 100 g/L and/or the use of erythropoiesis-stimulating agents, and BMI greater than 35 kg/m 2 (Khorana et al., Blood 2008). Based on this scoring system, patients with 0 points were grouped into the low-risk category, those with 1-2 points were considered intermediate-risk, and those with 3-4 points were classified as high-risk. Results: As shown in the table, VTE incidence for the low-risk group was 1.9%, intermediate-risk group was 3.9%, and high-risk group was 9.1%. Conclusions: High-risk patients were about 4.5 times more likely to develop a VTE than low risk patients. These results provide valuable insight in determining which patients might benefit from prophylaxis and in motivating the design of prospective clinical trials that assess the VTE predictive model in various ambulatory cancer settings. [Table: see text]
Acral melanoma in the Asian/Pacific Islander population: Analysis of +8q and 8q24 chromosomal aberrations.
Authors: Shane Young Morita, Iris H. Kim, Christopher A. Lum
Journal: Journal of Clinical Oncology (2013)

e20029 Background: Acral melanoma (AM) is a distinct subtype of melanoma that displays a higher proclivity in the minority population. AM is associated with a worse outcome in comparison to conventional cutaneous melanoma (CM). Asian/Pacific Islanders with AM in particular, exhibit the poorest survival amongst all ethnic groups. Recent studies have profiled the importance of +8q and 8q24 as markers for an adverse prognosis in CM. However, a focused chromosomal analysis of minority patients with AM at this locus has not been previously described. Methods: IRB approval was obtained for this retrospective analysis. From 2004 to 2012, 14 Asian/Pacific Islander patients histologically confirmed to have invasive AM were evaluated at a tertiary institution. Data including age, gender, tumor location, Breslow thickness, ulceration, and mitoses per mm squared were compiled. In situ hybridization was performed targeting the centromeric region of chromosome 8 (Vysis CEP 8-FITC) and the myelocytomatosis viral oncogene homolog locus (MYC; 8q24.12 q24.13, Vysis LSI-Spectrum Orange). The overall ratio of signals and individual spot counts for CEP8 and 8q24 was recorded. Results: Our findings demonstrated that +8q chromosomal aberrations were highly prevalent (8/14; 57%). The majority of our entire cohort (7/14; 50%) exhibited thick primary lesions (>4.0 mm) with a high propensity for ulceration. There were no copy number gains in 8q24. Demographics of the Asian/Pacific Islander cohort included mean age of 67.4 years old (range 43-86) and male gender 9/14 (64%). Tumor location principally involved the foot 11/14 (79%); mean Breslow thickness was 4.6 mm (range 0.9-11.0), ulceration 7/14 (50%), and mean mitoses per mm squared was 3.4 (range 0-9). Conclusions: Asian/Pacific Islanders with AM were found to have a high frequency of +8q chromosomal alterations. There appeared to be an association with a thicker Breslow and presence of ulceration. This is the first study to our knowledge that has examined chromosomal aberrations of +8q and 8q24 in a non-Caucasian population of AM patients. This is compelling data that may be applied to future prognostic classifications.
Treatment outcomes of patients with primary central nervous system lymphoma: Single center experience from south India.
Authors: Krishna Mohan V T Mallavarapu, Santa Ayyagari, Senthil Jagannathan Rajappa, Krishnam Raju Alluri, Sudha Murthy S
Journal: Journal of Clinical Oncology (2013)

e13010 Background: Primary CNS Lymphoma (PCNSL) is a rare neoplasm of the brain accounting for 1-2% of all brain tumours. Incidence and histopathologic features of PCNSL in India has been reported; however, reports on therapy outcomes of the disease are lacking. We report treatment outcomes of patients with PCNSL at our institute. Methods: Case records of all patients treated for PCNSL between 2008 and 2012 were retrospectively analysed. Epidemiologic details, treatments given, progression free and overall survival were calculated. Patients who completed at least high dose methotrexate (1.5 gram/ m 2 ) for 5 courses with or without RT were included for analysis. Overall survival (OS) was defined as time from diagnosis till death/lost to follow up. Results: A total of seventeen patients were analysed. The median age at diagnosis was 58 years and M: F ratio was 1.14:1. Thirteen out of seventeen patients were eligible for analysis; six could complete the total treatment protocol which included methotrexate, vincristine, procarbazine, Dexamethasone, Radiation therapy followed by high dose cytarabine. Median overall survival was 20 months (range 2-54 months). Among those who completed the protocol, median survival at 21 months was not reached with 66% survival. Conclusions: Treatment of PCNSL with at least high dose methotrexate with or without whole brain radiation offers moderate results. Completion of treatment protocol is associated with better overall survival.
Prognostic and predictive value of hedgehog (Hh) signaling in advanced non-small cell lung cancer (NSCLC).
Authors: Rossana Berardi, Alfredo Santinelli, Azzurra Onofri, Miriam Caramanti, Agnese Savini, Silvia Chiorrini, Tommasina Biscotti, Zelmira Ballatore, Maria Grazia De Lisa, Alessandra Mandolesi, Simona Biagetti, Simona Alfonsi, Cecilia Pompili, Michele Salati, Alessandro Brunelli, Paola Mazzanti, Chiara Pierantoni, Armando Sabbatini, Italo Bearzi, Stefano Cascinu
Journal: Journal of Clinical Oncology (2012)

e21070 Background: Advanced NSCLC still represents a medical challenge in cancer therapy. The Hh pathway is critical for cell growth and differentiation. The aim of our study is to evaluate the role of the Hh signaling pathway in determining the clinical outcome of NSCLC patients. Methods: The expressions of Hh-related molecules including Ptch1 and Gli1 (nuclear and cytoplasmic) were determined by immunohistochemistry in 35 histologic samples (biopsies and surgical specimens) of advanced NSCLC patients. All the neoplastic area presents in the slides was considered and both cytoplasmic and nuclear stainings were evaluated, according to the positive neoplastic cells. The intensity of the staining was considered and scored as 0 (absent), 1+ (low), 2+ (medium) and 3+ (high). Results: 18 adenocarcinomas and 17 squamous cell carcinomas were analysed. Positivity of Gli1-cytoplasmic expression and Gli1-nuclear expression were expressed in adenocarcinoma at a significantly higher level and more frequently than compared to squamous cell carcinoma (p&lt;0.05), while Ptch1 did not differ significantly in the two histotypes. Overall survival was higher in Gli1 and Ptch1 negative tumor samples compared to the positive group (p=0.02). The 18 patients with adenocarcinoma received erlotinib as second line therapy and those presenting a lower Gli1 and Ptch1 expression experienced a significantly better progression free survival. Conclusions: These results suggest that the Hh pathway might play a major prognostic role in NSCLC with significant differences between the histotype. Furthermore it might predict the efficacy of erlotinib as second-line treatment in patients with advanced lung adenocarcinoma.
Phase II study of dacarbazine for metastatic colorectal cancer: Final results with MGMT analysis.
Authors: Alessio Amatu, Andrea Sartore Bianchi, Catia Moutinho, Katia Bencardino, Erica Bonazzina, Lisa Pietrogiovanna, Filippo Venturini, Alessandra Gambaro, Giovanna Marrapese, Alessandro Belotti, Manel Esteller, Salvatore Siena
Journal: Journal of Clinical Oncology (2013)

3581 Background: O 6 -methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein removing mutagenic and cytotoxic adducts from O 6 -guanine in DNA. Approximately 40% of colorectal cancers (CRCs) display MGMT deficiency due to promoter hypermethylation leading to silencing of the gene. Alkylating agents, such as dacarbazine, exert their antitumor activity by DNA methylation at the O 6 –guanine site, inducing base pair mismatch, therefore activity of dacarbazine could be enhanced in CRCs lacking MGMT. We conducted a phase II study with dacarbazine in CRCs who had failed standard therapies (oxaliplatin, irinotecan, fluoropyrimidines, and cetuximab or panitumumab if KRAS wild type). Methods: All patients had tumor tissue assessed for MGMT as promoter hypermethylation in double-blind for treatment outcome. Patients received dacarbazine 250 mg/m 2 i.v. qd for 4 consecutive days q21 until PD or intolerable toxicity. We employed a Simon two-stage design to determinate if the ORR would be ≥ 10%. Secondary endpoints included association of response, PFS and disease control rate with MGMT status. Results: Sixty-eight patients were enrolled from May 2011 to March 2012. Patients received a median of 3 cycles of dacarbazine [range 1-12]. Grade 3-4 toxicities included: fatigue (41%), nausea/vomiting (29%), constipation (25%), platelet count decrease (19%), anemia (18%). Overall, 2 patients (3%) achieved partial response (PR) and 8 patients (12%) had stable disease (SD). Disease control rate (PR+SD) was significantly associated with MGMT promoter hypermethylation in the corresponding tumors. Conclusions: Objective clinical responses to dacarbazine in metastatic CRC patients are confined to those tumors harbouring epigenetic inactivation of the DNA repair enzyme MGMT. Clinical trial information: 2011-002080-21.
Does paid sick leave affect the unmeasured costs of colorectal cancer treatment?
Authors: Christine Marie Veenstra, Scott E. Regenbogen, Sarah T. Hawley, Jennifer J. Griggs, Arden M. Morris
Journal: Journal of Clinical Oncology (2015)

6590 Background: For working patients, the financial impact of colorectal cancer (CRC) diagnosis and treatment can be substantial. Unmeasured costs can include unpaid time away from work and job loss. Although not a provision of the Affordable Care Act or FMLA, paid sick leave may help CRC patients retain their jobs and alleviate some financial burden. Methods: In 2011-13, we surveyed Stage III colorectal cancer patients from Detroit and Georgia SEER registries 4-12 months after diagnosis. The analytic sample was restricted to respondents who were working at the time of diagnosis. We assessed two outcomes, job retention and personal financial burden. We measured personal financial burden using a validated 6-item scale and categorized it as a binary measure indicating low vs. high burden. We assessed associations between 1) paid sick leave and job retention and 2) job retention and personal financial burden in separate models, using logistic regression to control for age, sex, race, education, and income. Results: Among 1469 patients who returned surveys (RR 68%), 38% were working for pay at the time of CRC diagnosis. Overall, 46% of patients did not retain their jobs and 32% reported high financial burden during CRC treatment. In adjusted analyses, availability of paid sick leave was significantly associated with job retention (OR 2.59, 95% CI 1.68–3.98). After adjustment, job retention was inversely associated with high personal financial burden (OR 0.25, 95% CI 0.160.38). Compared with respondents who had paid sick leave available, those without paid sick leave were more likely to be older, have a high school education or less, and have an income of under $50,000 (all p < 0.001). Conclusions: In a robust, population-based study, we found that the availability of paid sick leave during CRC treatment was positively associated with job retention. Furthermore, personal financial burden was reduced when working patients were able to retain their jobs throughout CRC treatment. Millions of working Americans do not have access to paid sick leave, but our results indicate that an investment in paid sick leave by employers and government may provide long-term societal dividends.
Safety and Efficacy of the CD95-Ligand Inhibitor APG101 in Transfusion-Dependent Patients with Low Risk MDS: Results from a Phase I Study
Authors: Tobias Boch, Thomas Luft, Maximilian Mossner, Johann-Christoph Jann, Daniel Nowak, Christine Folz, Jennifer Klemmer, Susanne Brendel, Harald Fricke, Claudia Kunz, Wolf-Karsten Hofmann, Florian Nolte
Journal: Blood (2016)
Transcriptional gene expression profile in hepatocarcinoma cells induced by acetylsalicylic acid (ASA) in hepatitis C virus (HCV)-subgenomic replicon system.
Authors: Clara Patricia Rios Ibarra, Barbara Verduzco Garza, Rocio Ortiz Lopez, Yohann Grondin, Sonia Lozano Sepulveda, Arturo Quintanilla Guzman, Ana Maria Rivas Estilla
Journal: Journal of Clinical Oncology (2013)

e22016 Background: It has been demonstrated that ASA treatment could down-regulate in vitro HCV expression in hepatocarcinoma cells (~50%, p 0.05). However, the signaling pathway induced during ASA antiviral effect has not been elucidated. We analyzed the transcriptional expression profile of Huh-7-HCV-subgenomic replicon cells in presence or absence of ASA in order to identify the signaling pathway and the molecular mechanisms involved in the antiviral effect induced by ASA on HCV expression. Methods: Huh-7-HCV-replicon cells (hepatocarcinoma) were exposed to 4 mM ASA from 24 to 72 hours. Total RNA was isolated, quantified and validated by capillary electrophoresis. After that, we performed a retrotranscription in vitro. Synthesized transcripts were marked with biotin, purified, fragmentized and hybridized in HG-U133 Plus 2 Gene Expression. Hybridization signals were captured with Gen Chip 3000 7G Scanner and analyzed by Expression Console and Dchit Software. Results: After normalization, we obtained hierarchical maps with differentially-expressed genes. Among genetic targets over-expressed, the following stood out CCAAT-enhancer-binding proteins (C/EBP), interleukine-8 (IL-8), cytochrome P450 (CyP450) and methallothioneins (MT) genes were found. Among down-regulated genes we identified ribonucleotide reductase (RR) and superoxide dismutase (SOD) genes. Some of these genes have been previously associated with oxidative stress regulation. All results were validated by real time PCR. Conclusions: We observed that ASA modulates the expression of genes associated with antioxidant role as SOD and methallothioneins. Antioxidant agents can inhibit virus proliferation. HCV decreased antioxidant defense, which promotes the development of hepatic complications caused by HCV infection, including liver cancer. Therefore, ASA could be inducing an antioxidant environment regulating HCV replication. This study provides a tool for identifying novel host factors in hepatocarcinoma cells involved in the antiviral effect regulated by ASA against HCV and improves our understanding of the regulatory mechanism of HCV replication.
A first-in-human study of LOXO-101, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family.
Authors: Howard A. Burris, Marcia S. Brose, Alice Tsang Shaw, Todd Michael Bauer, Anna F. Farago, Robert Charles Doebele, Steven Smith, Michele Fernandes, Scott Cruickshank, Jennifer A. Low
Journal: Journal of Clinical Oncology (2015)

TPS2624 Background: TheTRK family of neurotrophin receptors, TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3 genes, respectively) and their neurotrophin ligands regulate growth, differentiation and survival of neurons. Translocations involving the NTRK1/2/3 kinase domain, mutations involving the TRK ligand-binding site, amplifications of NTRK, TRK splice variants, and autocrine/paracrine signaling have been described in a diverse number of tumor types and may contribute to tumorigenesis. Recently NTRK1 fusions were described in a subset of adenocarcinoma lung cancer patients (Vaishnavi, 2013) and NTRK2 and NTRK3 fusions have been described in multiple tumor types (Skalova, 2014; Ricarte-Filho, 2013; Vaishnavi, 2014). LOXO-101 is a potent, oral, ATP-competitive pan-TRK inhibitor with IC50 values in the low nanomolar range for inhibition of TRK family members in binding and cellular assays, with 100x selectivity over other kinases. LOXO-101 has demonstrated tumor inhibition in preclinical models. Methods: This study (NCT02122913) is an ongoing phase Ia/Ib dose escalation plus expansion trial in adults with advanced solid tumors. The phase Ia component is an open-label, multicenter, dose escalation trial. Patients with solid tumors refractory to standard therapy, with normal hematopoietic and major organ function are eligible for study. LOXO-101 is administered orally QD or BID for continuous 28-day cycles. This component of the trial will determine the MTD for LOXO-101. The phase Ib component is an open-label, multicenter, global, dose expansion study. In addition to the Phase Ia eligibility criteria, patients must have a demonstrated alteration in one of the three NTRK genes or three TRK proteins. The number of expansion cohorts will be determined by the molecular characteristics of the tumors in the patients enrolled. Data will provide initial evidence of tumor activity of LOXO-101, stratified by the type of NTRK or TRK alteration or tumor type, as well as further elucidation of the safety profile of LOXO-101 in cancer patients. Archival tissue is required for further characterization of molecular abnormalities. Clinical trial information: NCT02122913.
Systematic assessment of intra- and peri-metastatic tumor budding in patients with stage IV colorectal cancer.
Authors: Annika Blank, Sandra Burren, Inti Zlobec, Heather Dawson, Alessandro Lugli
Journal: Journal of Clinical Oncology (2017)

626 Background: Tumor budding is a strong independent prognostic factor in primary colorectal cancer (CRC). The prognosis of stage IV CRC is still poor and there is need for biomarkers to facilitate the clinical management. Data on tumor budding in colorectal cancer distant metastases (CRDM) are still missing. Therefore, the aim of this study was to analyze its role in tumor progression. Methods: 73 stage IV CRC with clinico-pathological data were retrieved from a cohort of 331 CRC patients, surgically treated between 2002 and 2013 at the University Hospital of Bern. Tumor budding was visualized immunohistochemically by pan-cytokeratin staining. Tumor budding was defined as intra- and peri-tumoral budding in the primary tumor (ITB = buds in the tumor center; PTB = buds at the tumor margin), intra- and perinodal budding (INB and PNB) and intra- and peri-metastatic tumor budding (IMB and PMB). Overall tumor budding was defined as tumor buds independent of the center and margin (OTB, ONB, OMB). The tumor bud count was assessed by calculating the mean number of tumor buds in 10 high power fields. For survival analysis a cut off of 10 tumor buds was applied to subdivide the tumors with low and high numbers of tumor buds. Results: In lymph nodes and CRDM, the tumor bud count was lower compared to primary tumors (PNB: 13; INB: 18; ONB: 21 vs PMB: 10; IMB: 21; OMB: 22 vs PTB: 23; ITB: 24; OTB: 33). For PTB/PNB and OTB/ONB, there were significant differences between primary tumor and lymph node metastasis (PTB/PNB: p &lt; 0.001; OTB/ONB: 0.008) and primary tumor and distant metastases (PTB/PMB: p &lt; 0.001; OTB/OMB: 0.007). The presence of PMB was predicted by INB, PNB and V1 (p = 0.032, p = 0.001 and p = 0.003). A trend towards a worse prognosis in patients with a high OMB number was observed. Conclusions: Tumor budding is present in lymph node and distant metastases of CRC, but its number is lower compared to the corresponding primary tumor. As tumor budding in local and distant metastases seems to be a predictor of tumor progression, these novel data should be considered as a basis for further analysis in large and multicentric clinical trials.
A Phase II multicenter trial to evaluate combination ipilimumab and high-dose IL-2 in patients with unresectable stage III and IV melanoma.
Authors: Howard Kaufman, Jiafeng Wang, Brendan D. Curti, Joseph Clark, Marc S. Ernstoff, Ann Silk, Janice M. Mehnert, Andrew Zloza, Joe Shih, David F. McDermott
Journal: Journal of Clinical Oncology (2015)

TPS3095 Background: High-dose (HD) IL-2 (600,000 IU.kg) and ipilimumab (3 mg/kg) are approved immunotherapy agents for selected patients with advanced melanoma and both are associated with durable responses in a small number of patients. Previous studies in a pre-clinical melanoma tumor models and in a small phase I/II dose escalation clinical trial suggested that concurrent combination treatment was associated with improved response rates, including a 17% complete response rate in the clinical trial, without an increase in toxicity. Data has also suggested that higher doses of ipilimumab may improve response rates as shown in clinical trials comparing 3 to 10 mg/kg dosing. To better define the potential benefit of this combination in patients with melanoma, this phase II multicenter, open-label, single arm trial, is being conducted (NCT02203604). Methods: The primary goal of this trial is to determine the clinical OR rate within the first 24 weeks. Secondary end points include safety, feasibility, overall survival, one- and two-year survival, progression-free survival, best overall response, and frequency of effector CD8+ T cells and CD4+FoxP3+ regulatory T cells in peripheral blood, and when possible in the tumor microenvironment. Adults with advanced unresectable stage III and IV melanoma and who meet criteria for high-dose IL-2 therapy are eligible. Main exclusion criteria are active brain metastases, active autoimmune diseases, concurrent systemic immunosuppressive therapy as well as prior immunotherapy with IL-2 or impilimumab. Up to 82 patients will be enrolled and receive ipilumimab (10 mg/kg) for 4 cycles (Days 1, 22, 43, 64) and high-dose IL-2 (600,000 IU/kg) for 2 cycles (Days 22-26, 43-47) followed by maintenance ipilimumab. Preliminary safety assessment will be performed on the first 6 patients before other patients are allowed to enter the study. If significant toxicity occurs in the first 6 patients ipilimumab will be dose reduced to 3 mg/kg. As of Feb 4, 2015 3 patients have been enrolled. Clinical trial information: NCT02203604.