tbuckley/cabot-search huggingface dataset:
A prostate cancer clinical trials consortium trial of disulfiram (D) in men with nonmetastatic recurrent prostate cancer (PCa).
Authors: Michael Thomas Schweizer, Aditya Bardia, Amanda L. Blackford, Jianqing Lin, Andrew J. Armstrong, Serina King, Michelle A. Rudek, Srinivasan Thomas Yegnasubramanian, Michael Anthony Carducci
Journal: Journal of Clinical Oncology (2013)

219 Background: Epigenetic silencing of tumor suppressor genes (TSG) by promoter methylation contributes to carcinogenesis and progression. Targeting these epigenetic changes in PCa has been hindered by a paucity of available agents. D potently inhibits PCa growth in vitro and can cause demethylation and re-expression of known TSGs in PCa cells lines. Methods: To determine if D leads to demethylation changes [i.e. decreased global 5 me C DNA content from peripheral blood mononuclear cells (PBMC)] we conducted an open-label, dose escalation trial of D in men with non-metastatic recurrent PCa after local therapy. Dose escalation occurred if a demethylating “response” (i.e. &gt;10% decrease in global 5 me C content) in &lt;3 patients was observed in cohort 1. Cohort 1 and 2 received D 250 mg and 500 mg daily respectively; 1 cycle equaled 4 weeks. The primary endpoint was the proportion of subjects with a demethylation response. Secondary endpoints included rate of PSA progression at 6 months (i.e. confirmed &gt;50% rise over baseline and &gt;2 ng/mL above nadir), changes in PSA doubling time (PSADT) and safety/tolerability. Results: Two patients out of 9 (22.2%) in cohort 1 met our primary endpoint. Cohort 2 accrued a total of 10 patients, 3 (30.0%) of which had &gt;10% decrease in global 5 me C content. Only 5 subjects were on trial for ≥6 months, all were in cohort 1 and all had PSA progression by 6 months. Median PSADT change post-treatment was not significantly different between responders and non-responders (266.9 vs -7.8 days, P=0.18) or between cohorts 1 and 2 (22.5 vs -39.7 days, P=0.54). While there were no grade (G) 4 adverse events (AE), the drug was poorly tolerated with 6 patients experiencing G3 AE (3 per cohort). There was a trend toward fewer median number of completed cycles in cohort 2 vs cohort 1 (5 vs 9 cycles, P=0.12). Common AE included: fatigue, GI toxicity, ataxia/dizziness, and constitutional symptoms. Conclusions: A minority of patients had global PBMC demethylation changes, consistent with D acting as a probable demethylating agent in those individuals. Given the toxicities associated with D and no significant clinical benefits, further development of this agent should not be pursued in this population. Clinical trial information: NCT01118741.
Nimotuzumab in combination with preoperative concurrent chemoradiotherapy for locally advanced esophageal squamous cell carcinoma: A prospective trial.
Authors: Xiaoyuan Wu, Yongshun Chen, Yuanyuan Yang, Daxuan Hao, Xue Li, Chunyu He, Jinsong Liu, Jianhua Wang
Journal: Journal of Clinical Oncology (2016)

101 Background: Preoperative chemoradiotherapy is an accepted standard treatment for patients with locally advanced esophageal cancer. Nimotuzumab is a monoclonal antihuman EGFR IgG1 antibody that has demonstrated synergistic activity with both radiotherapy and platinum-based chemotherapy in some solid tumors. The aim of this study is to investigate the safety and efficacy of nimotuzumab in combination with preoperative concurrent chemoradiotherapy for locally advanced esophageal squamous cell carcinoma (ESCC). Methods: Previously untreated patients with stage II-III ESCC received nimotuzumab (200mg per week in weeks1-5), paclitaxel(45 mg/m 2 per week in weeks 2-5), cisplatin(20 mg/m 2 per week in weeks 2-5) and radiotherapy at a total dose of 40 Gy (2.0Gy/d,5 days per week in weeks 2-5). Esophagectomy was performed 4 weeks after the completion of preoperative strategies. Results: Eighteen eligible patients were enrolled. All patients completed the preoperative regimen, and seventeen patients underwent surgery. The clinical response rate was 94.4% (17/18). The most frequent Grade 1/2 toxicities were esophagitis(12/17), leukocytopenia(14/17), nausea/vomiting(8/17) and fatigue(4/17). Grade 3 leukocytopenia was observed in 11.8 % of patients (3/17). The rate of radical resection was 100%, and the pathological complete response rate was 41.2%(7/17). Downstaging occurred in 15/17 (88.2 %) patients by T stage and 8/17 (47.1%) by N stage. The incidences of postoperative anastomotic leak, pulmonary infection, hoarseness and arrhythmia were 11.8%, 11.8%, 5.9%, and 5.9%, respectively. No perioperative deaths occurred in the study. Conclusions: The regimen of nimotuzumab in combination with preoperative concurrent chemoradiotherapy is safe for locally advanced ESCC. The preoperative strategy is able to achieve substantially high clinical response rate and pathological complete response rate.
Leukocyte-mediated Delivery of Nanotherapeutics in Inflammatory and Tumor Sites
Authors: Xinyue Dong, Dafeng Chu, Zhenjia Wang
Journal: Theranostics (2017)

Nanotechnology has become a powerful tool to potentially translate nanomedicine from bench to bedside.Nanotherapeutics are nanoparticles (NPs) loaded with drugs and possess the property of tissue targeting after surfaces of NPs are bio-functionalized.Designing smaller size of nanotherapeutics is presumed to increase tumor targeting based on the EPR (enhanced permeability and retention) effect.Since the immune systems possess a defence mechanism to fight diseases, there is an emerging concept that NPs selectively target immune cells to mediate the active delivery of drugs into sites of disease.In this review, we will focus on a key question of how nanotherapeutics specifically target immune cells and hijack them as a delivery vehicle to transport nanotherapeutics into disease tissues, thus possibly improving current therapies in inflammation, immune disorders and cancers.We will also discuss the challenges and opportunities for this new strategy of leukocyte-mediated delivery of nanotherapeutics.
Predictive value of preoperative peripheral lymphocyte count on recurrence of resectable non-small cell lung cancer.
Authors: Jian Zhang, Shaohong Huang, Hui Li, Xiuling Chen, Yun Li, Cuiping Wang, Lijia Gu
Journal: Journal of Clinical Oncology (2012)

81 Background: Recently, the prognostic value of cancer-related inflammatory response has been revealed. Previous studies showed that peripheral neutrophils and lymphocytes had significant impact on the prognosis of advanced and early node-negative non-small cell lung cancer (NSCLC). The purpose of this study was to investigate the prognostic value of preoperative lymphocyte and neutrophil counts in patients with NSCLC who underwent radical surgery and adjuvant chemotherapy. Methods: Retrospective analyses were performed to examine the impact of preoperative peripheral lymphocyte and neutrophil counts on disease-free survival (DFS) and overall survival (OS) and to analyze the relationships of these factors to clinicopathological factors. Results: 142 patients with NSCLC were evaluated totally. 57 (40.1%) patients had local recurrence or metastasis. Multivariate analysesrevealed that peripheral lymphocyte count was an independent favorable prognostic factor of DFS (hazard ratio: 0.548; 95% confidence interval: 0.351-0.857; p=0.008) but not OS (p=0.164). The maximum log-rank statistical value was 9.504 (p=0.002) when the cutoff value of lymphocyte was 1800mm -3 . The median DFS were 318.0 days (95% confidence interval: 226.0-410.0) for lymphocyte≤1800mm -3 group and 669.0 days (95% confidence interval: 0.0-1431.0) for lymphocyte&gt;1800mm -3 group. Low lymphocyte count was related with lymphatic invasion (p=0.012) and recurrence of NSCLC (p=0.022). Peripheral neutrophil count had no impact on DFS or OS when analysis included all the 142 patients. In addition, T stage (p=0.001), N stage (p=0.001) and vascular invasion (p=0.021) were also independent unfavorable prognostic factors of DFS. Pathological stage (p=0.001), vascular invasion (p=0.011), and ECOG score (p=0.009) were independent unfavorable prognostic factor of OS. Conclusions: Preoperative peripheral lymphocyte count, which is related with lymphatic invasion, is an independent favorable prognostic factor of DFS in patients with NSCLC who underwent radical surgery and adjuvant chemotherapy.
CYFRA 21-1 as a novel diagnostic serum biomarker in pancreatic cancer.
Authors: Jung Hoon Kim, Joon Cheol Song, Jung Hyun Kwon, Dae Kyun Kim, Dong Wook Jekarl, Jeong Won Jang, Young Chul Yoon
Journal: Journal of Clinical Oncology (2014)

191 Background: CYFRA 21-1 is a fragment of cytokeratin 19, a structure protein and part of intermediate filament proteins contributing to stability of epithelial cells. Serum concentration of CYFRA 21-1 is known to be elevated in many types of epithelial malignancies, and especially it has a prognostic and predictive value in patients with non-small cell lung cancer. We assessed serum CYFRA 21-1 and studied its clinical significance in patients with pancreatic cancer. Methods: The sera from 52 patients diagnosed with pancreatic cancer was collected between May 2012 and August 2013 at Incheon St. Mary’s hospital, Catholic University of Korea, School of Medicine and was measured for CYFRA 21-1 and CA 19-9. 48 patients had an advanced disease at presentation, 2 patients had a locally advanced disease, and 2 patients presented with a local disease. Control blood samples were obtained from 31 healthy individuals and 48 patients with nonmalignant hepatic or pancreatobiliary disease. We measured CYFRA 21-1 using two-step sandwich, chemiluminescent microparticle immunoassay, Architect i2000SR (Abbott Laboratories, Ltd., Il, USA). Results: Serum concentration of CYFRA 21-1 was significantly elevated in patients with pancreatic cancer compared with control group. (p=.000) CYFRA 21-1 ( &gt;1.96 ng/ml as determined by the ROC curve) had a sensitivity, specificity, positive predictive value, and negative predictive value of 86.5%, 79.7%, 73.8%, 90% for the diagnosis of pancreatic cancer. Additionally, CA 19-9 ( &gt;35 U/ml determined by our institute’s criteria) had a sensitivity, specificity, positive predictive value, and negative predictive value of 67.3%, 89.9%, 69.1%, 81.6%. The area under curve for CYFRA 21-1 and CA 19-9 was 86.3% and 81.5%, respectively. Conclusions: CYFRA 21-1 has a potential to become a novel serum biomarker for the diagnosis of pancreatic cancer. Serum concentration of CYFRA 21-1 in combination with CA 19-9 can be useful in clinical practice to diagnose pancreatic cancer.
Effect of rapid genetic testings on the rate of bilateral prophylactic mastectomy in BRCA1/2 mutation carriers.
Authors: L. Cortesi, E. De Matteis, E. Razzaboni, V. Medici, G. Tazzioli, A. Andreotti, M. Federico
Journal: Journal of Clinical Oncology (2011)

1511 Background: The life-time risk to developing breast cancer in BRCA1/2 mutation carriers is 43% and 46%, respectively, whereas the ten years risk of developing a contralateral breast cancer is 25%. The bilateral prophylactic mastectomy (BPM) can reduce the risk of developing a breast cancer in BRCA1/2 mutation carriers up to 95%. Since Italian women show a low acceptability rate of this procedure a rapid genetic testing was developed, aimed to increase the number of BPM. Methods: Since 1995, at the Modena Centre for Hereditary Breast and Ovarian Cancer (Italy), by performing a standard oncogenetic counselling, 1929 mutational analysis have been carried out, identifying 342 (18%) mutation carriers. Among the 342 carriers, 195 are affected by breast and/or ovarian cancer, whereas 147 are healthy people. When a positive result is disclosed, a BPM or a contralateral prophylactic mastectomy is offered, respectively, to healthy people or to patients previously affected by breast cancer. From January 2008, a rapid genetic testing for people with hereditary profile was proposed at the time of breast cancer diagnosis. The entire oncogenetic counselling path is completed within three weeks. So BRCA1/2 carriers have the opportunity to immediately undergo BPM. Results: The rate of BPM significantly differs between the conventional genetic counselling and the rapid one. In fact, in the first case only ten healthy women among 147 BRCA1/2 mutation carriers (6.8%) accepted to undergo BPM. In the last case, 71 mutational analyses were performed and 25 (35%) patients were mutated. Among the 25 patients with a positive result, 13 (52%) had a BPM at the surgery time for the breast cancer. Conclusions: Our study shows that a rapid genetic testing in patients with a hereditary profile can significantly improve the rate of BPM at the surgery time for breast cancer. This oncogenetic counselling model was allowed thanks to new automated diagnostics methodologies. Finally it was due to a multidisciplinary organization in which different health professional figures, such as oncologists, psychologists, and surgeons, cooperate within the same unit.
Final results of a pilot study using sunitinib malate in patients with stage IV uveal melanoma.
Authors: L. A. Tijani, M. Luadadio, M. J. Mastrangelo, T. Sato
Journal: Journal of Clinical Oncology (2010)

8577 Background: The prognosis of metastatic uveal melanoma is poor; the median overall survival is reportedly less than 6 months. A significant proportion of metastatic uveal melanomas express C-kit receptors (CD117). They also produce stem cell factor. Autocrine stimulation through C-kit receptors might play a critical role in disease progression. Sunitinib is a multitargeted receptor tyrosine kinase inhibitor of C-Kit, vascular endothelial growth factor and platelets-derived growth factor receptors; therefore, sunitinib might be effective in treatment of metastatic uveal melanoma. Methods: Patients with stage IV uveal melanoma whose metastases have at least 10% C-kit expression were treated. The initial dose of sunitinib was 37.5 mg daily over a 28-day cycle. The treatment was continued until disease progression or grade 3 or greater toxicity after dose reduction to 25 mg. The primary objectives were assessment of safety and potential efficacy of sunitinib. Clinical response was evaluated every 8 weeks using RECIST criteria; toxicity was assessed every 4 weeks. Results: Twenty patients aged 29-78 years including 17 patients who received at least one previous treatment were enrolled. One patient had partial response (PR), 12 stable diseases (SD), 5 progressive diseases (PD), and 2 non- evaluable due to withdrawal before response assessment. The clinical benefit rate (CR+PR+SD) for intent-to-treat patients was 65.5%. Median overall and progression-free survivals were 8.2 months (range 0.9-33.8 months) and 4.0 months (0.6-29.2 months), respectively. Eight patients survived more than 12 months. Three patients have no PD for more than 12 months. The most common side effect was grade 1-2 fatigue, occurring in 90% of the patients. Eleven patients required a dose reduction to 25mg due to grade 3 adverse events: diarrhea (n = 2), fatigue (n = 3), pneumonia (n = 1), neutropenia (n = 1), cardiac dysfunction (n = 1), thrombocytopenia (n = 1), hand-foot syndrome (n = 1), and headache (n = 1). Patients who needed a dose reduction were able to maintain their best response with the lower dose. Conclusions: Sunitinib at 37.5 mg daily is a feasible treatment with an acceptable safety profile and potential efficacy in metastatic uveal melanoma. No significant financial relationships to disclose.
Off-label prescriptions in cancer: Who should pay for them?
Authors: A. Negro, E. G. J. Rivarola, E. Gil Deza, M. Muino, E. L. Morgenfeld, D. Juarez, S. Aguirre, F. Negro, M. L. Fischer, M. J. Nacul, M. Abal, S. L. Ares, C. Garcia Gerardi, M. Montiel, F. G. Gercovich
Journal: Journal of Clinical Oncology (2011)

e16559 Background: At the 2007 ASCO meeting we presented the results of the first 26 months of our team's work in a paper entitled: Standard therapy deviations in the practice of clinical oncology (JCO, Vol 25, No. 18S (June 20 Supplement), 2007: 6504). The current paper was designed to evaluate with the same methodology, during 72 months, the off label prescription (OLP) rate, the correction rate of each deviation and the economic impact of these corrections on the Argentinean public health system. Methods: Between October 2004 and December 2010, 119.656 oncological prescriptions (Tx) were carried out on 15.129 patients treated in 61 locations and progressively entered into a database and compared with the national and international guidelines (evidence-based oncology). The OLPs were identified and pointed out to the attending physician, whose response was catalogued as: "A" (correction), 'B' (No correction). Results: Three thousand one hundred and seventy seven OLPs were identified in 15.129 patients (21%). There was a noticeable difference in the OLP rate (between 0 and 90%) in the studied locations. Comparison between the 2004-2006 and 2007-2010 periods showed a marked increment in the deviations related to the appearance of new target therapies (from 13% to 27%, Chi square p=0.0001). The correction rate (A) was 72% (between 50-100%) and remained stable throughout the period. The calculated savings brought by the corrections of the 8 most expensive drugs in this cohort was U$S 31,850,960 during this period. Conclusions: A great difference in the off-label prescription rate, which is unlikely to be related to patient characteristics, was observed in the different regions of our country. These deviations have an unacceptable economic impact to the public health system and represent a risk for the patients' health while providing no therapeutically benefits.
Thrombosis Treatment: Development of Polymer Microcapsules Functionalized with Fucoidan to Target P-Selectin Overexpressed in Cardiovascular Diseases (Adv. Healthcare Mater. 4/2017)
Authors: Bo Li, Maya Juenet, Rachida Aid‐Launais, Murielle Maire, Véronique Ollivier, Didier Letourneur, Cédric Chauvierre
Journal: Advanced Healthcare Materials (2017)

To reduce cardiovascular mortality, early diagnosis and effective treatments are needed. Cédric Chauvierre and co-workers demonstrate the functionalization with fucoidan of polymer microcapsules on the surface to specifically target P-selectin overexpressed at initial stages of vascular diseases in article number 1601200. The organic core of microcapsules provides a loading space for imaging probes and/or for hydrophobic drugs. This innovative microstructure appears to be a promising theranostic tool for cardiovascular diseases.
Identification of susceptibility loci in hereditary prostate cancer families using copy number variation and linkage analysis.
Authors: Elisa M. Ledet, Joan Bailey-Wilson, Oliver Sartor, Marilyn M. Li, Diptasri Mandal
Journal: Journal of Clinical Oncology (2015)

232 Background: Family history is one of the most significant predictor of prostate cancer risk. With approximately 10% of prostate cancer cases attributable to inheritable genetic factors. However, disease gene identification for prostate cancer has been extremely challenging due to both disease and genetic heterogeneity. Therefore, the goal of this study was to employ an array of genetic tools in order to characterize germline variants in seven high-risk families with prostate cancer. Methods: To overcome the effects of ethnic disparity, genetic heterogeneity, incomplete penetrance, and missing heritability, we utilized a comprehensive approach that combines both array comparative genomic hybridization (aCGH) analysis and linkage analysis to identify genetic components of prostate cancer. Seven prostate cancer cases were studied using aCGH to search for germ-line copy number variants (CNVs) associated with hereditary prostate cancer. The study subjects were from 7 large, high-risk, clinically homogenous families with European ancestry from Southern Louisiana. Genotyping for linkage analyses was done using Illumina Infinium II SNP HumanLinkage-12 panel. Results: Three novel regions of CNVs were identified: 16q23, 11q22, and 2q22 in all 7 prostate cancer cases from high-risk families. Both model-based and model-free linkage analyses were performed on 4 of the most informative families (≥5 prostate cancer patients per family). Suggestive evidence of linkage was obtained at 2q14 (HLOD score of 1.94). Using aCGH, a 68 kb duplication was observed in this region in all 7 hereditary prostate cancer cases. Conclusions: These genetic findings, which were identified in multiple large, well-characterized families, provide new insight into hereditary prostate cancer. A combination of future fine mapping of the 2q14 region in a larger cohort of patients, confirmation of these novel CNVs in additional subjects, and use of next-generation sequencing approaches to search for potential disease-associated genetic alterations are needed to provide further characterization of these prostate cancer associated susceptibility loci.
Clinical, pathologic, and genomic profiles of exceptional responders to anti−PD1 therapy in renal cell carcinoma.
Authors: Mark Wayne Ball, Michael Hiroshi Johnson, Michael A. Gorin, Maria Rodriguez, Luis A. Diaz, Michael Haffner, George J. Netto, Charles G. Drake, Mohamad E. Allaf
Journal: Journal of Clinical Oncology (2016)

625 Background: Previous studies have correlated response to PD−1 blockade with PD−L1 over−expression, as well as cell−mediated immune transcripts). However, factors associated with long−term, durable response to nivolumab in patients with RCC have not yet been elucidated. To better understand these factors, we conducted a study to characterize the two extremes of response to therapy – exceptional responders who had durable, complete response and patients who had primary refractory disease. Methods: Patients with durable, complete response (“exceptional responders”) (n=4) and primary refractory disease (n=3) were analyzed. Immunohistochemical staining for PD−L1, CD8 and FOXP3, whole−exome sequencing and quantitative RNA expression profiling was performed and correlated with clinical outcomes. Results: Exceptional responders had trends toward greater CD8+ lymphocyte infiltrate (126.7 vs 28.8 lymphocytes/hpf), higher number of somatic mutations (67 vs 35 somatic mutations/genome), and higher number of predicted mutation associated neoantigens than primary refractory patients (44 vs 8). Expression analysis demonstrated acute phase and immune tolerance signatures in primary refractory patients, while exceptional responders had higher expression of T cell and innate immune signatures. Conclusions: Exceptional responders and primary refectory patients have distinct pathologic, genomic and RNA expression profiles. Larger studies are needed to fully elucidate the basis of response to PD−1 blockade in patients with renal cell carcinoma.