tbuckley/cabot-search huggingface dataset:
Genotype-guided neoadjuvant therapy for rectal cancer
Authors: H. L. McLeod, B. Tan, R. Malyapa, E. Abbey, J. Picus, R. Myerson, B. Zehnbauer, M. Mutch, D. Dietz, J. Fleshman
Journal: Journal of Clinical Oncology (2005)

3024 Background: Neoadjuvant therapy with 5-fluorouracil (5FU) and radiation has become standard therapy for bulky rectal cancer and achieves a downstaging (DS) rate of 45%. The presence of two 28 bp repeats (*2) in thymidylate synthase was recently associated with superior DS (60%) compared with homozygous triple repeat (*3/*3; 22% DS) (J Clin Oncol 2001;19:1779–86). Multiple studies have linked TYMS *3/*3 with risk of 5FU failure. Pharmacogenomics has provided the promise of better therapy, based on retrospective evaluation of patient treatment. Therefore a study was conducted to provide initial experience with the conduct of genotype-guided therapy and to generate data for the design of future randomized pharmacogenomics trials. Methods: A two-stage design was used to construct 2 distinct phase II studies, directed by TYMS genotype. After informed consent, patients with stage T3/T4 rectal cancer were genotyped for the TYMS repeat sequence. ’Good risk’ patients (TYMS *2/*2 or *2/*3) received 5 weeks of 5FU 225 mg/m2/day and 45 Gy radiation. ’Bad risk’ patients (TYMS *3/*3) received 5FU/radiation plus irinotecan 50 mg/m2 weekly x 5 doses. Surgical resection was performed 6–10 weeks post therapy. The primary endpoint of both phase II studies was DS. Toxicity was measured by CTC criteria. Results: Successful accrual occured for 60/61 patients treated during the study period for T3/T4 rectal cancer. The 32 evaluable ’good risk’ patients achieved 56% DS, with 28% pCR. Grade 3 leukopenia (85%) and diarrhea (15%) was observed, with 9% hospitalization. The 13 evaluable ’bad risk’ patients recieved triple therapy and achieved 85% DS, with 62% pCR. Grade 3 leukopenia (93%) and diarrhea (29%) was observed, with 33% hospitalization. One patient died of cardiac arrest. Conclusions: Genotype-guided neoadjuvant therapy was successfully conducted for treatment of rectal cancer. The use of 5FU/radiation in patients with a TYMS ’good risk’ genotype enriched for a higher rate of DS and pCR than previously observed. Intervention with additional chemotherapy in patients anticipated to have lower DS (TYMS *3/*3) led to high DS and pCR, but a higher incidence of toxicity-associated hospitalization. Accrual continues to enroll 77 TYMS *2/*2 or *2/*3 and 31 TYMS *3/*3 patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Neopharm, Orion Genomics, Sanofi- Synthelabo, Veridex Merck
Clinical outcomes of patients (pts) age 60 or younger treated with docetaxel (DOC) for castration-resistant prostate cancer (CRPC): Results of an Italian multicenter retrospective study (CYCLOP study).
Authors: Antonello Veccia, Cinzia Ortega, Giuseppe di Lorenzo, Francesca La Russa, Salvatore Luca Burgio, Gaetano Facchini, Caterina Messina, Cosimo Sacco, Gilbert Spizzo, Michele Aieta, Michele Lodde, Giovanni Mansueto, Paolo A. Zucali, Alessandro D'Angelo, Roberto Iacovelli, Francesco Massari, Franco Morelli, Giuseppe Procopio, Fiorella Ruatta, Orazio Caffo
Journal: Journal of Clinical Oncology (2014)

214 Background: Since prostate cancer is usually diagnosed in patients (pts) over age 60, castration-resistant prostate cancer (CRPC) is rarely observed in pts age 60 or younger. Despite the clinical outcomes of these pts are not clearly defined, there is a common feeling of a worse prognosis for pts with CRPC age 60 or younger. The present study is aimed to assess the clinical outcomes of this specific population. Methods: In this multicentric retrospective study, after Ethical Committee approval, we have reviewed the clinical records of all pts younger than 60 with CRPC from participating institutions, treated with docetaxel (DOC), both in clinical trials and in clinical practice. We recorded the pre- and post-DOC clinical history, the DOC treatment details and outcomes. Results: To date we have collected a consecutive series of 128 pts from 24 Italian hospitals. The median age was 57 (range 41 to 60). The median baseline prostate-specific antigen (PSA) was 85 ng/ml (range 1 to 3,020); 87% of the pts had bone metastases while 47%, 10%, and 13% showed nodal, liver and lung metastases, respectively. All but 12 pts received DOC with a 3 week standard schedule, the remaining being treated with a weekly schedule. A PSA reduction greater than 50% was observed in 61% of the pts; among the 86 pts with measurable disease who underwent a radiological re-evaluation at the treatment end, four and 13 pts achieved complete and partial response, respectively (response rate 20%). The main grade 3-4 toxicities were anemia (five pts), neutropenia (18 pts), febrile neutropenia (one pt), fatigue (five pts), peripheral neuropathy (three pts). The median progression-free survival (PFS) and overall survival (OS) were 7 months and 21 months, while the 1 year PFS and OS rates were 17.6% and 74.9%, respectively. Conclusions: Our data seems to not confirm that younger pts with CRPC have a worse prognosis compared to the older pts since their survival outcomes and response rate are similar to those observed in general population of pts wiht CRPC.
Phospho-Flow Cytometry Quantitation of STAT Signalling Checkpoints in Malignant and Non-Malignant Cells Identifies Patients Suitable for pSTAT3 and 5 Targeted Inhibitors
Authors: Ross D Brown, P Joy Ho, Douglas E Joshua, Shihong Yang, Christian Bryant, Hayley Suen, Claire Weatherburn, Stephen Larsen, Derek NJ Hart, John Gibson
Journal: Blood (2015)
Circulating tumor cells (CTC) as a prognostic and predictive factor in Lung Cancer Patients–a pilot study in PUMCH
Authors: X. Zhou, L. Li, M. Wang, L. Zhang, X. Zhang, W. Zhong, H. Hao, S. Wang, P. Lin, J. Xu
Journal: Journal of Clinical Oncology (2008)

22201 Background: We explored the clinical value of circulating tumor cells (CTCs) in prognosis and the assessment of treatment effects for patients with lung cancer. Methods: In a prospective, single center and small sampling study, we tested the levels of CTC at baseline in 100 patients with emerging or recurring lung cancer and followed up 60 with CTC numbers after each cycle of chemotherapy. We then did correlation analysis between CTC variation and treatment-response evaluation based on RECIST criteria. We used AVIVABio Cancer Cell Isolating Technology, an immunomagnetic beads-based rare cell enrichment system using leucocyte depletion mechanism, to count the identified CK+/EGFR+/CD45- CTCs in 7.5ml venous blood of the lung cancer patients under fluroscence microscopy. Results: 100 blood samples were collected from newly diagnosed or recurrent lung cancer patients who had been treatment-naive for at least 2 months before hospitalization. Benign respiratory diseases and tuberculosis and healthy control samples were collected, 20 for each group, during the same study period. The AVIVABio Technology is easy to manage and repeatable with a sentivity of 92.5%and specificity of 68.4% in lung cancer patients. The patients with TNM stage IIIA or below had a CTC positive rate of 31.8%(7/22), and those of IIIB or above had a statistically high rate of 87.2%(68/78) (P<0.001). 60 patients were followed up with CTC after each cycle of chemotherapy. After one chemo cycle, 93.3%(56/60) patients' CTC were negative with the remaining persistent or turning positive. Correlation analysis showed the variation of CTC was coincident with RECIST criteria by CT scan after two chemo cycles. Conclusions: The above-mentioned method is highly sensitive and specific in detecting CTC of the patients with advanced lung cancer. The initial level of CTC identified using this method has prognostic value. The variation of CTC in the course of chemotherapy might be a useful predictor of the chemo-response or disease-progression. Correlation between CTC levels and Clinical Factors Factors Sub-Group Number of Sampled Patients Number of CTC Positive Patients CTC Positive Rate (%) P value TNM staging Operatable 22 7 31.8 < 0.001 Unoperatable 78 68 87.2 Pathology Adenocarcinoma 69 57 82.6 < 0.05 Squamous Carcimona 16 10 62.5 not Small Cell 15 8 53.3 not Due to AJCC TNM Staging System: below IIIA-operatable; above IIIB-unoperatable No significant financial relationships to disclose.
Are practice patterns of high-volume pancreatic surgeons distinct from low-volume pancreatic surgeons? A IHPBA/AHPBA web-based survey study.
Authors: Fransisco Igor Macedo, Sandeep Anantha, Alice J Race, Awinderpreet Singh, Michael J Jacobs, Janak A Parikh
Journal: Journal of Clinical Oncology (2016)

449 Background: Pancreatoduodenectomy (PD) is still one of the most complex operations with varied intraoperative techniques and postoperative management. The surgeon volume performing this complex surgery can determine patient outcomes and they might have distinct practice patterns. We aim to compare the practice patterns in perioperative management between high- (HV) and low-volume (LV) hepatobiliary surgeons. Methods: A 25-item survey questionnaire was electronically distributed using Survey Monkey to IHPBA and AHPBA members between May and August 2015 regarding their practice patterns for PD. HV surgeons were defined as those performing greater than 10 PD per year. Results: A total of 285 responses were included (HV, n=229; LV, n=57). The majority of participants were from United States (34.7%), Asia (14.3%) and Europe (28.1%). A significant higher proportion of LV surgeons were observed in Europe (p=0.04) and Asia (p=0.003). LV surgeons are more likely to continue perioperative antibiotics beyond 24 hours postoperatively (57.1% vs. 36.2%, p=0.009) and use more drains (p=0.04), however less likely to routinely measure postoperative drain amylase (73.6% vs. 85.6%, p=0.003). No significant difference was observed regarding management of infection, bile culture, or wound care. Conclusions: Practice patterns are variable between LV and HV pancreatic surgeons. LV surgeons are more likely to prolong prophylactic antibiotics, and use more suction drains, however HV surgeons have closer monitoring for signs of pancreatic leak. Further studies are warranted to elucidate the impact of these variations on surgical outcomes of patients undergoing pancreatoduodenectomy.
Examining the relationship between multiple primary cancers and psychological distress: A systematic literature review.
Authors: Sarah M. Belcher, Emilie A. Hausmann, Mary Lou Klem, Susan M. Cohen, Heidi AS Donovan, Elizabeth A. Schlenk
Journal: Journal of Clinical Oncology (2016)

214 Background: The incidence of multiple primary cancers (MPC) in cancer survivors is increasing. However, little is known about the psychological effects of MPCs on cancer survivors. The purpose of this systematic review was to synthesize the evidence regarding the impact of MPC on psychological distress in cancer survivors. Methods: Relevant studies were identified in PubMed database (up to June 2015). Non-English articles were excluded. Two independent evaluators reviewed articles for relevancy and data extraction. Data was organized and recorded using a coding log with exclusionary rationale, a PRISMA flow diagram, and a standardized table of evidence. Effect sizes (ES) were calculated using Cohen’s d to measure relationship magnitude and direction. Results: Of the 543 potentially relevant articles identified, four articles met criteria and were retained for analysis. Different quality of life (QOL) measures were used to assess psychological distress across studies, so ES were calculated for individual studies. There were consistently small but significant ES found for the impact of MPC on distress. When compared to survivors of a single cancer: one study found lower global QOL and higher total stress (ES, 0.1430 and 0.3653); one study reported that those with MPC were more likely to experience frequent mental distress and sleep problems (ES, 0.1404 and 0.2235); and one study found that those with MPC had lower global QOL and emotional function and greater anxiety and depressive symptoms (ES range, 0.1026 - 0.3215). Finally, the one study that evaluated suicidal ideation in survivors of childhood cancers did not find a higher incidence among those with MPC. Conclusions: The ES noted in the four studies suggest a small but significant increase in psychological distress in survivors of MPC compared to survivors of a single cancer. Clinicians should be aware of this at-risk population when screening for distress in cancer survivors. Additional studies that control for care transition points known to increase distress are warranted to explore the impact of MPC on psychological distress over time. Additionally, as the science in this area grows, it will be necessary to reevaluate the literature.
A phase II study of prolonged daily temozolomide for low-grade glioma
Authors: P. Y. Wen, D. Schiff, L. Doherty, D. Gigas, A. Musikansky, J. Bradshaw, B. Levy, S. Kesari, N. Ramakrishna, E. Maher, P. Black
Journal: Journal of Clinical Oncology (2005)

1522 Background: There is increasing evidence that chemotherapeutic agents, including PCV and temozolomide (TMZ), are active in low-grade gliomas. We evaluated a prolonged daily regimen of TMZ in patients with either histologically confirmed newly-diagnosed oligodendroglioma with a MIB-1 index of >5%, or recurrent low-grade gliomas (oligodendrogliomas, astrocytomas and oligoastrocytomas). Method: Eligibility criteria included age ≥ 18 years, KPS ≥ 70%, adequate organ function, measurable disease, and informed consent. Patients were treated with TMZ at a dose of 75mg/m2/day in 11 week cycles, consisting of 7 weeks on treatment followed by a 4 week break. MRI was performed every 11 weeks. Patients were treated until tumor progression, development of unacceptable toxicity, or for a total of 6 cycles. Results: To date 29 patients have been enrolled (8 female, 21 male). Median age is 44 (range 22–69). Median KPS 90 (range 70–100). One patient withdrew consent after registration and was never treated, another was discontinued because of non-compliance. The regimen was generally very well-tolerated. Toxicities included neutropenia (5 grade 3), thrombocytopenia (1 grade 3), leukopenia (2 grade 3), lymphopenia (6 grade 3) and elevated SGPT (1 grade 3). Three patients came off treatment during the first cycle for toxicities: 1 persistent grade 3 thrombocytopenia, 1 grade 2 nausea, and 1 for worsening depression and agitation felt to be unrelated to TMZ. There were no grade 4 toxicities or treatment-related deaths. Patients have been followed for a median of 21 months (range 2–36 months). Of the 24 patients evaluable for response, there were 7 PR (29%), 9 MR (38%), 6 SD (25%) and 2 PD (8%). Two patients progressed rapidly on therapy; one in retrospect had gliomatosis cerebri. To date, a total of 6 patients have progressed at a median time of 13 months (2–26 months). Median progression-free survival was excess of 16 months. Conclusion: This is a very well-tolerated regimen that produces effective tumor control, comparable to those obtained with the standard 5-day every 28 day regimen of TMZ. Accrual to this study continues and updated results will be presented. This study is supported in part by Schering Plough Corporation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering
Prognostic and predictive potential of omics studies from blood in pancreatic cancer patients treated with concurrent radiotherapy, gemcitabine, and cetuximab.
Authors: Peter E Huber, Carmen Timke, Nils H Nicolay, Ramon Lopez
Journal: Journal of Clinical Oncology (2015)

326 Background: Pancreatic cancer is a cancer with dismal prognosis. Multimodal therapy approaches integrating targeted drugs into radiochemotherapy regimens may be promising concepts for patients with locally advanced disease. It would be desirable to better understand patterns of therapy response, clinical outcome and side effect spectra by performing gene expression and protein analyses from blood samples before, during and after actual treatments. Methods: At defined time points before, during and after neoadjuvant triple therapy consisting of IMRT +/-gemcitabine chemotherapy +/-cetuximab EGFR antibodies, blood samples were collected from 21 patients with advanced pancreatic cancer. Whole blood transcriptomics was performed using Agilent’s human genome wide microarray platform. Quantitative serum protein analysis was performed using the ‘FastQuant’ (sandwich antibody) system on 20 selected proteins with a focus on cytokines and angiogenesis related proteins. Cluster analyses were performed and array data were correlated to local control, survival, CA19-9 response, and side effects e.g. acne grading and hematotoxicity. Results: Whole blood transcriptomics was feasible and showed statistically significant prognostic and predictive value for therapy specific and patient specific expression signatures. RNA expression signatures obtained before and during treatment course appeared to have significant statistical power to predict CA19-9 response, clinical outcome and side effect parameters. Similarly, the serum proteomic time course correlated with clinical outcome. Moreover, cetuximab increased e.g. PDGF, MCP-1, Rantes, Il-6, Angiopoietin, serum and downregulated TIMP-1, Il-8, and Angiogenin levels while radiochemotherapy had primarily the respective opposite effects. Conclusions: Whole blood analyses provides a promising tool to monitor pancreatic cancer patients undergoing radiotherapy+gemcitabine+cetuximab, and the protein and gene expression “signatures” from blood may be prognostic and predictive for clinical endpoints.
Overexpression of HMGA2 promotes metastasis and impacts survival of advanced colorectal cancers.
Authors: X. Wang
Journal: Journal of Clinical Oncology (2011)

e14116 Background: The high mobility group A2 (HMGA2) protein regulates the expression of a cohort of genes by either enhancing or suppressing their transcription. The change of HMGA2 mRNA or protein levels has been reported to correlate with malignant tumor phenotypes. Therefore, we hypothesized that the expression level of HMGA2 is related to cancer survival and serves as prognostic biomarkers for clinical outcome of colorectal cancers (CRCs). Methods: 191 consecutive CRCs who received surgical treatment in second affiliated hospital of Zhejiang University from 1999 to 2004 were entered into this outcome study. In addition, 89 CRCs from City of Hope were collected as validation set. Patients were periodically followed up for survival. The IHC study was conducted on tissue arrays to determine the expression of HMGA2 proteins. The Kaplan-Meier analysis and COX proportional hazard model were employed to conduct uni- and multi- variant survival analysis. Results: The IHC results displayed that the expression of HMGA2 could be seen significant higher in malignant tumor section in comparing corresponding normal colon epithelial cells. Univariate and multivariate logistic analysis indicated that the nuclear expression of HMGA2 is significantly related to distant metastasis among 191 CRCs (p < 0.05). Survival analysis revealed that the higher nuclear staining of HMGA2 is significantly related to poor survival of CRCs (p < 0.05). The adjusted hazard proportional ratios (HRs) are 1.81 (95% CI 1.04-3.12) and 1.86 (95% CI 1.08-3.22) for overall and progress-free survival respectively. Further analysis indicated that HMAG2 impacts the survival on CRCs at III-IV stage, rather than I-II stage. The HRs of HMGA2 at stage III-IV is 1.92 (95% CI 1.02-3.58) for overall survival, and 2.03 (95% CI 1.07-3.80) for progress-free survival. It was validated on stage III-IV CRCs from City of Hope (HRs=1.80 for overall survival, HRs=2.05 for progress-free survival). Conclusions: HMGA2 might play a critical role in promoting the invasion and metastasis phenotype of colorectal cancer. Overexpression of HMGA2 significantly impacts the survival on advanced CRCs. Therefore, HMGA2 may serve as a potential prognostic marker for predicting outcome of CRCs.
Synergy of water soluble prodrug triptolide (minnelide) with gemcitabine and nab-paclitaxel in pancreatic cancer.
Authors: Vikas Dudeja, Shrey Modi, Bhuwan Giri, Kaustav Majumder, Sulagna Banerjee, Ashok Saluja
Journal: Journal of Clinical Oncology (2016)

259 Background: Gemcitabine with nab-paclitaxel is the standard of care for metastatic Pancreatic Ductal Adenocarcinoma (PDAC). Addition of nab-paclitaxel to gemcitabine improves the survival of patients with metastatic pancreatic cancer by only 6 weeks while increasing toxicity. Meaningful combinations that reduce the doses while improving efficacy are required. Water soluble prodrug of triptolide (Minnelide) is effective against PDAC in preclinical studies and has demonstrated activity in the ongoing phase I trial. We have evaluated the combination of low dose triptolide prodrug with lowered doses of Abraxane and gemcitabine in PDAC. Methods: Pancreatic cancer cell lines S2-013 and S2-VP10 were xenografted both subcutaneously as well as orthotopically in athymic nude mice. Efficacy of a combination of triptolide prodrug (Minnelide: 0.21mg/kg) with reduced dose of gemcitabine 100mg/kg + Abraxane 10mg/kg (~40% of the clinically effective dose) was evaluated and compared with both standard of care gemcitabine 250mg/kg + Abraxane 25mg/kg as well as reduced dose of gemcitabine + Abraxane in animal models. We also used the immunocompetent model where murine PDAC cell line KPC001 implanted subcutaneously in C57/bl6 mice. Results: In subcutaneous syngeneic model, combination of triptolide prodrug and paclitaxel significantly inhibited tumor growth (tumor volumes expressed as % of Control, Mean±SEM: triptolide prodrug : 75.4±25, paclitaxel: 50.0 ±3, triptolide prodrug + paclitaxel: 11.0 ±1). In metastasis model combination therapy markedly improved survival (median survival in days: Vehicle-13, triptolide prodrug -20, standard of care -45, reduced dose standard of care-30, and Minnelide + reduced dose standard of care (all mice alive at 90 days). Combination of triptolide prodrug and low dose gemcitabine + nab-paclitaxel decreased tumor size, increased survival, reduced metastases and malignant ascites in orthotopic model of PDAC. Conclusions: Triptolide prodrug synergizes with reduced dose standard of care (gemcitabine and nab-paclitaxel) and helps in reducing the doses of these toxic drugs all the while achieving same or better efficacy in animal models of PDAC.