tbuckley/cabot-search huggingface dataset:
Role of aurora kinase A on regulating inflammation and inducing NF-κB pathway activation in gastric cancer.
Authors: Ahmed M. Katsha, Vikas Sehdev, Mohammed Soutto, DunFa Peng, Abbes Belkhiri, Wael El-Rifai
Journal: Journal of Clinical Oncology (2014)

78 Background: Aurora kinase A gene (AURKA) is frequently amplified and/or overexpressed in several malignancies. Inflammation contributes to the pathogenesis of gastric tumorigenesis. We explored the roles of AURKA in inflammation and tumorigenesis. Methods: Immunofluorescence, immunohistochemistry, Quantitative real-time PCR, immunoblot, co-immunoprecipitation, luciferase reporter, and in vitro kinase assays were used to analyze AGS and MKN28 gastric cancer cells. We also analyzed Tff1–/– mice, growth of tumor xenografts, and human tissues. Results: We showed an elevated level of AURKA in the Tff1–/– gastric tissues as compared to wild-type. We also found a positive correlation between AURKA and inflammation (coefficient r = 0.25; P = 0.0056) as well as TNF-α (coefficient r = 0.25; P = 0.0057). AURKA inhibition by MLN8237, a specific AURKA inhibitor, reduced nuclear staining of NFκB in human gastric cancer samples and mouse epithelial cells, suppressed NFκB reporter activity, and reduced the expression of NFκB target genes that regulate inflammation and cell survival. Additionally, AURKA inhibition reduced xenograft tumor size in mice and reversed the development of gastric tumors in Tff1–/– mice. Further, we found that AURKA regulate NFκB activity by directly binding and phosphorylating IκBα in vitro. Premalignant and malignant lesions from the gastric mucuosa of patients had increased levels of AURKA protein and nuclear NFκB, compared with healthy gastric tissue. Conclusions: In analyses of gastric cancer cell lines, human tissue samples, and mouse models, we found AURKA to be upregulated during chronic inflammation to promote IκBα-mediated activation of NFκB and tumorigenesis. This provides a novel role of AURKA in cancer and shows the importance of targeting it as a therapeutic approach in cancer treatment.
New aromatase inhibitors (Ais) as 1st-line endocrine therapy (ET) in metastatic breast cancer (MBC): A pooled analysis of 3238 women from 8 phase III trials
Authors: P. Carlini, E. Bria, G. Ferretti, A. Felici, P. Papaldo, A. Fabi, E. M. Ruggeri, F. Cognetti, E. Terzoli, D. Giannarelli
Journal: Journal of Clinical Oncology (2005)

602 Background: Some of the new non-steroidal AIs (anastrozole and letrozole) have been registred for the treatment of first line ET for MBC. We previously presented the results of a pooled analysis of AIs in 2nd line ET for MBC (Carlini P, ASCO 2004). In order to assess the benefit in TTP and ORR of all AIs when compared to tamoxifen, we performed a pooled analysis including all phase-III trials with new AIs (letrozole, anastrozole, fadrazole, formestane, exemestane) as 1st-line ET for MBC. Methods: Entry criteria: published/presented phase-III studies evaluating AIs as 1st-line ET in MBC. Randomized phase-II trials were ruled out. Time to progression (TTP) and overall response rate (ORR) were our end-points. Event-based relative risk ratio (RR) and 95% confidence intervals (CI) were derived. Combined effect estimation was computed with a fixed-effect model. An heterogeneity test was applied as well. Results: Eight trials were eligible (3238 pts). Significant benefit in favour of AIs versus tamoxifen were seen in TTP (RR 0.83, 95% CI 0.76–0.90, p<0.001), although significant heterogeneity (p<0.00001). When considering only trials with non-steroidal AIs (6 studies, 2458 pts), a significant benefit in favour of AIs versus tamoxifen were seen in TTP (RR 0.80, 95% CI 0.73–0.89, p<0.001), although significant heterogeneity (p<0.0001). Significant benefit in favour of AIs versus tamoxifen were seen in ORR (RR 1.18, 95% CI 1.06–1.31, p=0.002), although significant heterogeneity (p<0.011). When considering only trials with non-steroidal AIs (6 studies, 2458 pts), a significant benefit in favour of AIs versus tamoxifen were seen in ORR (RR 1.19, 95% CI 1.06–1.36, p=0.005), although significant heterogeneity (p=0.04). Conclusions: When all subgroups were analyzed for TTP and ORR, significant differences were found. AIs in 1st-line ET for MBC seem to add a significant benefit versus tamoxifen. The significant heterogeneity of all outcomes requires a careful evaluation of these results No significant financial relationships to disclose.
Treatment of colorectal liver metastasis: Comparison of radiofrequency ablation and hepatic resection.
Authors: Min Yong Yoon, Hyung Ook Kim
Journal: Journal of Clinical Oncology (2012)

637 Background: Hepatic resection is the mainstay of management for colorectal liver metastases. But, the treatment for colorectal liver metastases requires a multidisciplinary therapeutic strategy. The aim of this study was to compare recurrence and survival rates for patients treated with hepatic resection or radiofrequency ablation (RFA) for colorectal liver metastases. Methods: Between July 2002 and September 2010, 52 patients underwent hepatic resection and 58 underwent RFA for synchronous or metachronous colorectal liver metastases. A retrospective analysis was performed. Patients with extrahepatic metastases were excluded. Results: The two groups had similar mean age, comorbid medical conditions, primary disease stage, and number of tumors. Preoperative median serum carcinoembryonic antigen (CEA) level was significantly higher in the resection group (13.8 ng/mL vs. 3.1 ng/mL; p = 0.001). Median diameter of main tumors was significantly greater in resection group (4.1 cm vs. 2.0 cm; p = 0.002). Recurrence rate after treatment was 46.2% (24/52) in the resection group and 70.7% (41/58) in the RFA group. Marginal recurrence after resection or RFA was observed in 7.6% (4/52) and 46.6% (27/58), respectively (p = 0.003). Median recurrence free survival (28.0 vs. 12.0 months; p = 0.007) and median overall survival (43.0 vs. 26.0 months; p = 0.023) were significantly longer in the resection group. Conclusions: Hepatic resection is the treatment of choice for colorectal liver metastases. RFA for colorectal liver metastases was associated with higher marginal recurrence rate and shorter recurrence free and overall survival.
Causes of death in intermediate- and high-risk prostate cancer treated with radiotherapy with or without androgen deprivation therapy: Analysis from two phase III trials.
Authors: Abdenour Nabid, Nathalie Carrier, Eric Vigneault, André-Guy Martin, Luis Souhami, Marie Duclos, Jean-Paul Bahary, Thu-Van Nguyen-Huynh, Céline Lemaire, Marc-André Brassard, Sylvie Vass, Boris Bahoric, Robert Archambault, François Vincent
Journal: Journal of Clinical Oncology (2016)

34 Background: The purpose of this analysis was to establish causes of death in a population of intermediate-risk (IR) and high-risk (HR) prostate cancer treated on two phase III trials. Methods: From October 2000 to September 2010, 1,230 patients were randomized: 630 with HR (ClinicalTrials.gov, #NCT00223171) and 600 with IR (#NCT00223145). HR was defined as T3-4, PSA &gt;20 g/ml, Gleason &gt;7 (with at least one of these 3 factors). IR was defined as T1-T2, Gleason &lt; 6 and PSA 10-20 ng/ml or T1-T2, Gleason 7 and PSA &lt; 20 ng/ml. Causes of death were compiled until July 2015 and were established from data sent by the different investigators and centrally reviewed. Causes of death were mainly based on data from clinical records, then by family members, obituaries, death certificates and family physicians. Results: The median follow-up for the 1,230 patients was 7.5 years (HR 8 vs. IR 6.8 years, p&lt;0.001). 30.2% (372/1,230) patients had died: (HR 37% vs. IR 23.2%, p&lt;0.001). A total of 8% (99/1,230) patients developed local, regional, and metastatic prostate cancer recurrences: (HR 11.6% vs. IR 4.3%, p&lt;0.001) and 4.4% (54/1,230) died from prostate cancer: (HR 7.3% vs. IR 1.3%, p&lt;0.001). The most frequent cause of death was a second cancer (120/1,230, 9.8%): (HR 10.6% vs. IR 8.8%, p=NS). Cardiovascular deaths occurred in 6.3% (78/1,230) (HR 7.1% vs. IR 5.5%, p=NS) with no statistical difference between the different durations of androgen deprivation therapy (ADT) 0, 6, 18, or 36 months. Other causes of death were pulmonary (3.7%), digestive (1.1%), others (3.3%), and unknown (1.7%). Majority of deaths occurred between 3 and 9 years after randomization (HR 70% and IR 73%). Prostate cancer deaths were distributed over all the follow-up period. The 5/10 year overall survival between HR and IR were 88.6%, 91.8%, and 61.6%, 69.8%, respectively with significant differences (p=0.045 and p=0.016). Conclusions: In patients with localized HR and IR prostate cancer, the first cause of death was a second cancer and prostate cancer came as the third one after cardiovascular disease. There was no statistical difference in the incidence of cardiovascular deaths in patients treated with different durations of ADT. Clinical trial information: Clinical Trials, gov. #NCT00223145 - Clinical Trials, gov. #NCT00223171.
Li-Fraumeni syndrome: Retesting archival DNA samples to identify previously unrecognized germ-line <i>p53</i> mutations.
Authors: A. Novokmet, B. Baskin, D. Malkin
Journal: Journal of Clinical Oncology (2011)

1520 Background: Li-Fraumeni syndrome (LFS) is a familial cancer predisposition syndrome that results from germline alterations in the p53 gene. Unlike other cancer predisposition syndromes, LFS predisposes to a wide range of cancers including premenopausal breast cancer, sarcomas, brain tumors, adrenocortical carcinomas, and others. Over the years, the criteria for LFS have expanded beyond the classical definition, resulting in an increased number of individuals being tested. Additionally, technological advances have facilitated discovery of previously occult alterations. Upon review of samples received by our laboratory for p53 analysis between 1991 and 2004, we identified 67 samples for retesting. Methods: We searched our Cancer Genetics database for banked blood-derived DNA samples that had undergone p53 mutation analysis prior to April, 2004 and were found not to have an alteration. Diagnosis and/or family history were confirmed to meet the classical, Birch, or Chompret criteria for LFS. Seventy-three patient samples were retrieved and of those, 67 were of sufficient quality and quantity for analysis. The samples were submitted to the hospital’s Molecular Genetics Laboratory for analysis. Results: Of the 67 samples submitted for p53 analysis, 4/67 were found to harbor a heterozygous p53 germline deleterious mutation (Cys229Arg, Val157Ile, and Tyr236X (n=2)), 1/67 was found to be wildtype, and the remaining 62/67 were found to harbor a presumed non-disease-causing codon 72 polymorphism (Arg72Arg, Pro72Arg). Although these mutations have previously been identified in somatic tissues (www-p53.iarc.fr), this is the first published report of their occurrence in the germline. Conclusions: Technological advances in genetic testing facilitated the identification of a p53 mutation in four individuals who were previously found to be wildtype. Positive findings are important for affected individuals with respect to risk of development of second malignancies and for other at-risk family members, given an overall lifetime cancer risk of 85% in individuals with LFS. These findings stress the importance of banking DNA in anticipation of future advances in technology.
Predictors for readmission after pancreatic resection for malignancy.
Authors: Naeem A Newman, John T Lucas, Diandra A Peacock, Paul A Trottman, Shira M Winters, Sean S Wentworth, Edward A. Levine, Perry Shen
Journal: Journal of Clinical Oncology (2013)

301 Background: Readmission after pancreatic resection has been reported as high as 50%. This study was undertaken to determine factors predicting readmission after pancreatic resection for malignancy. Methods: We reviewed the medical records of 202 patients to identify patients that had a pancreatic resection for malignancy between 2003 and 2010. Outcome measures included patient characteristics, medical comorbidities, and perioperative factors. Results: A total of 202 patients underwent pancreatic resection for malignancy. AJCC T stage was T1, T2, T3, and T4 in 10.9%, 26.3%, 52% and 9.2% respectively. Pancreatic head malignancies made up 84.8% of the patients, 2.3% were pancreatic neck, 8.4% were pancreatic body, and 4.5% were pancreatic tail primaries. Preoperative biliary stents were placed in 58% of patients. Adjuvant radiation and chemotherapy were given in 47.8 and 61.39% respectively. The readmission rate following resection was 20% at 60 days. The most common reasons for readmission within 60 days were delayed wound healing and renal insufficiency. On univariate analysis, factors predicting higher readmission rates included positive retroperitoneal margin (p=0.048), delayed gastric emptying (p=0.015), and presence of wound infection (p=0.0020). Conclusions: Factors related to tumor burden and GI/infectious complications were the most common predictors of readmission after pancreatic resection for malignancy. Though tumor size is a relatively immutable variable, improved management of postoperative complications remains an important factor in decreasing readmission rates after pancreatic resection for malignancy.
A randomized phase II study comparing mFOLFOX-6 combined with axitinib or bevacizumab or both in patients with metastatic colorectal cancer (mCRC).
Authors: J. R. Infante, A. L. Cohn, T. R. Reid, W. J. Edenfield, T. Cescon, J. T. Hamm, J. C. Tarazi, S. Kim, B. Rosbrook, T. H. Cartwright
Journal: Journal of Clinical Oncology (2011)

485 Background: Vascular endothelial growth factor receptor inhibitors, including axitinib (AG-013736), may be useful in treating patients with mCRC. The goals of this study were to estimate the objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety in patients with mCRC treated with mFOLFOX-6 combined with axitinib or bevacizumab or both. Methods: Patients with mCRC untreated with any systemic chemotherapy &gt;12 months prior to enrollment, ECOG PS 0/1, adequate organ function, and controlled hypertension were eligible for this randomized, open-label, phase II study. Patients receiving prior treatment with antiangiogenic agents or those who were pregnant were ineligible. All patients received standard mFOLFOX-6 treatment and were randomized to receive either axitinib 5 mg (Arm A), or bevacizumab 5 mg/kg (Arm B), or axitinib 5 mg + bevacizumab 2 mg/kg (Arm C). Axitinib was administered orally twice daily. Efficacy was determined by RECIST criteria. Results: A total of 42, 43, and 41 patients were enrolled in Arms A, B, and C, respectively. The ORR was 29%, 49%, and 39% for Arms A, B, and C, respectively. Median PFS was 315 days, 350 days, and 377 days, with 1-year survival of 72%, 79%, and 80% for Arms A, B, and C, respectively. Discontinuations due to adverse events (AEs) were more common in Arm A (36%), than in Arms B (19%) or C (32%). More patients withdrew from Arm A (18%) than from Arms B (5%) or C 12%). The rates of grade 3 AEs were similar across arms, except for hypertension and fatigue which were more common in Arms A (15% and 12%) and C (21% and 29%) compared with Arm B (2% and 12%). Serious AEs were reported by 41%, 40%, and 56% of patients in Arms A, B, and C, respectively; the most common were gastrointestinal disorders (21%, 16%, 15%, respectively). Conclusions: In combination with mFOLFOX-6 chemotherapy, treatment with axitinib resulted in a lower ORR but comparable survival to bevacizumab and this did not appear to improve significantly in the presence of both agents. This result may have been affected by the higher numbers of discontinuations and withdrawals in Arm A compared with the other 2 arms. [Table: see text]
Phase I and II trial of neoadjuvant conformal radiotherapy plus sorafenib for patients with soft tissue sarcoma of the extremity.
Authors: A. Olusanya, R. M. Tamurian, S. Christensen, D. Borys, A. M. Chen, W. Mak, M. Buonocore, P. Mack, W. Monsky, R. J. Canter
Journal: Journal of Clinical Oncology (2010)

TPS333 Background: Despite effective local therapy, patients with locally advanced extremity soft tissue sarcoma (ESTS) are at high risk for distant failure and demise. Novel therapies for this group of patients are needed. Sorafenib is a pleiotropic tyrosine kinase inhibitor with effects on tumor proliferation and angiogenesis. Data demonstrate activity for sorafenib against soft tissue sarcoma in the metastatic setting, and experience with other malignancies suggests a synergistic effect when antiangiogenic targeted therapies are combined with radiotherapy (RT). Methods: We have initiated a phase I/II, single-institution trial evaluating sorafenib in combination with 3D-conformal RT prior to resection with curative intent for patients with ESTS ≥ age 18. Patients with nonmetastatic, biopsy-proven high-grade tumors > 5 cm (AJCC 7th edition stage III) or low-grade tumors > 8 cm are eligible. Patients who have received prior systemic for sarcoma or who have a histologic diagnosis of rhabdomyosarcoma or Ewing's sarcoma are not. Treatment consists of oral sorafenib administered concurrently with neoadjuvant RT (50 Gy in 25 fractions). Surgical resection occurs 4 to 6 weeks following cessation of treatment. The phase I study entails sorafenib dose-escalation in a traditional 3+3 cohort design. The phase II study is single-arm with pathologic complete/near-complete response (≥ 95% tumor necrosis) as the primary endpoint. Imaging and molecular correlative studies include dynamic contrast-enhanced magnetic resonance imaging, serial plasma assays for angiogenic markers including VEGF, OPN, PDGF, bFGF, IL-8, and IL-6, and serial tumor tissue assays of pERK, pAKT, and pmTOR activation status using immunohistochemistry. Enrollment for the phase I/II is anticipated at approximately 30 patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer
Inhibition of Kupffer Cell Autophagy Abrogates Nanoparticle‐Induced Liver Injury
Authors: Shasha Zhu, Jiqian Zhang, Li Zhang, Wentao Ma, Na Man, Yiming Liu, Wei Zhou, Jun Lin, Pengfei Wei, Peipei Jin, Yunjiao Zhang, Yi Hu, Erwei Gu, Xianfu Lu, Zhilai Yang, Xuesheng Liu, Li Bai, Longping Wen
Journal: Advanced Healthcare Materials (2017)

The possible adverse effects of engineered nanomaterials on human health raise increasing concern as our research on nanosafety intensifies. Upon entry into a human body, whether intended for a theranostic purpose or through unintended exposure, nanomaterials tend to accumulate in the liver, leading to hepatic damage. A variety of nanoparticles, including rare earth upconversion nanoparticles (UCNs), have been reported to elicit hepatotoxicity, in most cases through inducing immune response or activating reactive oxygen species. Many of these nanoparticles also induce autophagy, and autophagy inhibition has been shown to decrease UCN‐induced liver damage. Herein, using UCNs as a model engineered nanomaterial, this study uncovers a critical role for Kupffer cells in nanomaterial‐induced liver toxicity, as depletion of Kupffer cells significantly exacerbates UCN‐induced liver injury. Furthermore, UCN‐induced prodeath autophagy in Kupffer cells, and inhibition of autophagy with 3‐MA, a well‐established chemical inhibitor of autophagy, enhances Kupffer cell survival and further abrogates UCN‐induced liver toxicity. The results reveal the critical importance of Kupffer cell autophagy for nanoparticle‐induced liver damage, and inhibition of autophagy may constitute a novel strategy for abrogating nanomaterial‐elicited liver toxicity.
A national survey on the management of liver metastases from colorectal cancer (CRC): Comparison of perspectives and expectations among medical oncologists and hepatobiliary surgeons across Canada.
Authors: Maria Yi Ho, Sean P. Cleary, Matthew Mazurek, Sunita Ghosh, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2016)

690 Background: To compare the perspectives of medical oncologists versus hepatobiliary surgeons in the management of liver metastases from CRC. Methods: Medical oncologists and hepatobiliary surgeons across Canada were surveyed to evaluate for criteria used to determine resectability of liver metastases from CRC and availability of multidisciplinary clinics. Results: Of 220 experts surveyed, 145 (66%) responded. 137 (95%) had received specialized training in oncology. Only 37 (26%) respondents reported access to both multi-disciplinary tumor boards and clinics. 109 (75%) reported lack of institutional criteria. Oncologists and surgeons disagreed with regard to absolute contraindications for resection of hepatic metastases. More oncologists reported a higher percentage of liver parenchyma involvement (70% vs. 45%), proximity to major vessels and poor performance status as contraindications compared to surgeons (p &lt; 0.05). All physicians deemed CT as the preferred first-line imaging study for evaluating CRC liver metastases with significantly more surgeons indicating the need for MRI of the liver (p &lt; 0.05). Oncologists and surgeons also showed high discordances with respect to both clinical and radiographic findings in terms of their influence on surgical decision regarding resection of liver metastases (Table). Conclusions: Medical Oncologists and surgeons have discordant criteria with respect to resection of hepatic metastases and the roles they play in the management of these complex patients. Uncertainties and discordances can lead to deficiencies in care, supporting the need for a standardized clinical preoperative risk scoring system for resection of liver metastases from CRC. [Table: see text]
Safety and Clinical Activity of Temsirolimus in Combination with Rituximab and DHAP in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma - Report of the Prospective, Multicenter Phase II STORM Trial
Authors: Mathias Witzens-Harig, Andreas Viardot, Ulrich Keller, Christian Buske, Anne Crombé, Elisabeth Hoenig, Johannes Atta, Johann Schmier, Julia Meissner, Anthony D. Ho, Paul LaRosee, Reinhard Marks, Martin Dreyling, Georg Hess
Journal: Blood (2016)