tbuckley/cabot-search huggingface dataset:
Targeting occult metastatic disease: A hematogenously derived xenograft model of human pancreatic tumor growth in the murine liver.
Authors: James M. Lindberg, Sara J Adair, Timothy E. Newhook, Robert Tilghman, J Thomas Parsons, Todd W. Bauer
Journal: Journal of Clinical Oncology (2013)

198 Background: Most pancreatic cancer patients will die following surgery due to recurrent metastatic disease. Thus, better systemic therapies are needed to treat occult metastases to improve survival. We have developed a model of occult liver metastasis from pancreatic cancer in order to evaluate novel treatment strategies. Methods: Pancreatic cancer cells (MAD 09-366, 08-608, MPanc96) transduced with green fluorescent protein (GFP) and luciferase were injected into the spleens of athymic, nude mice to generate hepatic metastases. Ninety-six hours after injection, tumor-bearing mice were treated with MEK1/2 inhibitor (trametinib, 0.3mg/kg, daily), gemcitabine (100mg/kg, twice weekly), or vehicle control. Sequential bioluminescence imaging, flow cytometry, and histologic evaluation were used to assess hepatic tumor growth and behavior. Results: All injected cell lines generated hepatic metastases. Different cell lines exhibited different growth kinetics. MPanc96 injected mice demonstrated a 64% decrease in average luminescence from 6 to 72 hrs after injection followed by a 146-fold increase from 72hrs until sacrifice at 21 days. Extensive liver metastases were noted at necropsy. Flow cytometry analysis of digested mouse livers following MPanc96 injection revealed rapid clearance followed by sharp outgrowth of tumor cells that mirror the bioluminescent imaging data. MPanc96 injected mice treated with trametinib exhibited significant hepatic tumor growth inhibition relative to gemcitabine and control treated mice. At 21 days, trametinib treated mice demonstrated a 14.9-fold increase in average luminescence while on treatment compared to an 82.5-fold increased for gemcitabine treated mice (p = 0.028) and a 195.5-fold increase for control mice (p = 0.027). Conclusions: This in vivo model of pancreatic liver metastases has proven effective in assessing treatment effects on pancreatic metastatic growth. Trametinib appears to be a superior agent to gemcitabine at inhibiting metastatic pancreatic tumor growth and its effectiveness will be evaluated using this model with additional patient-derived tumor cell lines.
The relationship between the number of aberrantly methylated regions and the methylation status of p73 and RARB genes and prognosis in patients with breast cancer.
Authors: D. M. Marzese, F. Gago, J. I. Orozco, O. M. Tello, L. M. Vargas-Roig, M. Roqué
Journal: Journal of Clinical Oncology (2011)

10542 Background: Invasive ductal carcinoma (IDC) is the most frequent type of human breast cancer. Despite sharing a common origin, a great variation is observed among patients' outcome, which can be explained by their genetic and epigenetic differences. The most commonly reported epigenetic alteration is the aberrant methylation of CpG islands. In previous reports we have shown that the tumor methylation profile (TMP) is specific for each breast cancer patient. Here we evaluate the epigenetic differences between IDCs from patients with good and poor prognosis. Methods: The methylation status of 49 cancer-related regions was studied in seventy patients bearing IDC using the Methyl Specific-MLPA assay. Statistical associations were determined by chi square test and the strength of associations was assessed by Phi and Cramer's V coefficients. Statistical correlations were established by Pearson's r and Spearman's rho coefficients. Results: Tumors with increased number of methylated cancer-related regions correlate with high histological grade (p=0.002) and high proliferation rate (p<0.001). The methylation of p73 is strongly associated with high histological grade (p<0.001). The methylation of RARB is associated with high histological grade (p=0.003), positive lymph nodes (p<0.001) and high tumor size (p=0.021). Finally, the concurrent methylation of p73 and RARB is associated with high histological grade (p<0.001), high proliferation rate (p=0.002), positive lymph node (p=0.006) and elevated Nottingham Prognostic Index (p<0.001). Conclusions: We demonstrate that the aggressiveness of IDCs can be epigenetically distinguished by quantitative and qualitative DNA methylation analyzes. The number of aberrantly methylated genes and the methylation status of p73 and RARB could contribute to predict the prognosis of breast cancer patients.
Visceral varicella zoster virus (VZV) after allogeneic hematopoietic stem cell transplant (HSCT) in pediatric patients with chronic GVHD
Authors: D. C. Peritz, L. E. Lehmann, C. Duncan
Journal: Journal of Clinical Oncology (2008)

18027 Reactivation of latent VZV, a common infection caused by the extensive immunosuppression associated with HSCT, can lead to significant morbidity and mortality. The reported incidence of reactivation ranges from 23–67%. Most patients reactivate with cutaneous disease; mortality in pediatric patients is low in this setting. Isolated visceral zoster is rare and can be difficult to diagnose, presenting with ileus/abdominal pain, hepatitis and/or hyponatremia. We present 2 cases of visceral VZV in adolescents with cGVHD following unrelated donor HSCT. A 20 y.o, 11 months post-HSCT for Ph+ ALL was diagnosed with skin and hepatic cGVHD and began on prednisone 4 weeks before developing severe abdominal pain and constipation. A CT scan raised the possibility of intestinal obstruction. Concurrently, her Na+ dropped and transaminases markedly increased. Exploratory laporotomy revealed no obstruction but hepatic nodules were noted and biopsied. Acyclovir was begun before pathology returned positive for VZV. The patient developed fulminant hepatitis and died 3 days later, 9 days after first symptoms. The 2nd patient was a 19 y.o, 7 months post-HSCT for induction failure AML. Off immunosuppression, she developed hepatic cGVHD and was placed on prednisone with clinical improvement. The following week she developed abdominal pain and constipation. 2 days later she presented with a generalized seizure, hyponatremia, and elevated liver enzymes. She was begun on acyclovir and initially improved. Subsequent blood and CSF PCRs were positive for VZV. She died of hepatic failure 53 days after her initial symptoms. Given VZV in the spinal fluid, we postulate that the previously unexplained associated hyponatremia represents direct CNS viral toxicity. The diagnosis of visceral zoster can be difficult. A high level of suspicion for VZV is necessary in patients with cGVHD who have abdominal pain and/or hepatitis and antiviral therapy should be started promptly. Patient Summary Time post HSCT at VZV diagnosis: Day +386 Day +255 Conditioning: Cyclophosphamide Cyclophosphamide Total Body Irradiation Total Body Irradiation GVHD Prophylaxis: Tacrolimus Cyclosporine Rapamycin Methotrexate Steroids GVHD Involvement: Skin, liver, oral Liver Immunosuppression: Prednisone (1mg/kg) Prednisone (1.5mg/kg) Cyclosporine Lowest Na+: 117 (mmol/L) 112 (mmol/L) Highest LFT: AST:14920 AST:2506 ALT:7060 ALT:3631 Time from symptoms to acyclovir Initiation: 7 days 5 days Outcome: Death from hepatic failure 9 days after first presenting Death from hepatic failure 53 days after first presenting No significant financial relationships to disclose.
Phase I study of mFOLFOX-6, bevacizumab, and mTOR inhibitor RAD001 as first-line treatment of metastatic colorectal cancer.
Authors: Glynn Weldon Gilcrease, John R. Weis, Kimberly Jones, Thaylon Davis, Marlene Mitchell, Cynthia Davidson, Sunil Sharma
Journal: Journal of Clinical Oncology (2012)

600 Background: This study was designed to determine the dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and efficacy of the mTOR inhibitor RAD001 in combination with mFOLFOX-6 and bevacizumab in metastatic colorectal cancer. Methods: Twenty patients with previously untreated metastatic colorectal cancer received mFOLFOX-6, bevacizumab and RAD001 using a standard three patient cohort dose escalation schema. Seventeen of the twenty patients were evaluable with a median age of 52 (ten females and seven males). RAD001 was administered orally at escalating doses of 2.5 mg, 5 mg and 10 mg daily. mFOLFOX-6 and bevacizumab were administered in standard fashion. Results: The most common grade 3/4 hematological adverse events (AEs) were neutropenia (59%), leucopenia (29%) and thrombocytopenia (12%). The most common grade 3 non-hematological AEs were diarrhea (24%) and hypokalemia (18%). One dose-limiting toxicity was noted at 10 mg/day due to grade 3 anorexia, grade 3 diarrhea, and grade 3 hypokalemia. Grade 1 mucositis was noted in 12% of patients and grade 2 mucositis was noted in 47% of patients. There was no grade 3/4 mucositis. Fourteen patients are evaluable for efficacy. The RR is 86% including 2 CRs, 7 PRs, and 3 SDs. Conclusions: RAD001 in combination with mFOLFOX6 and bevacizumab is well-tolerated at a dose of 10 mg/day. The regimen appears to be effective. Evidence of anti-tumor activity correlated with mutation status (k-ras, BRAF, PIK3CA) and PTEN deletion status will be presented.
Development and implementation of a clinical pathway for radiation of bone metastases on a palliative radiation oncology service.
Authors: Lisa Rotenstein, Joseph Killoran, Tracy A. Balboni, Monica Shalini Krishnan, Allison Taylor, Neil E. Martin
Journal: Journal of Clinical Oncology (2016)

170 Background: Clinical pathways increase compliance with treatment guidelines and reduce in-hospital complications. Evidence around treatment of complicated bone metastases is increasingly nuanced and although ASTRO/ACR recommend single fraction radiation therapy for uncomplicated bone metastases, implementation is variable. We sought to determine the effects of a bone metastases-focused clinical pathway on the practice patterns of our institution’s palliative radiation oncology service (SPRO), which sees 600 patients yearly and on a rotating basis, involves 23 physicians, 28 residents, 2 nurse practitioners, and 1 fellow. We hypothesized that pathway implementation would augment data-driven use of palliative radiation for bone metastases, including use of 8 Gy x 1 for uncomplicated metastases. It would also enhance physician efficiency and confidence. Methods: Using published literature, clinical guidelines, and expert input, we designed a comprehensive clinical pathway for bone metastases radiation. This was translated to a secure electronic interface as a decision support tool and integrated into daily SPRO workflows. Providers were surveyed pre and post implementation to assess expectations and elicit feedback. Rates of pathway compliance and reasons for non-compliance were assessed. Rates of 8 Gy x 1 use for uncomplicated metastases were compared pre and post implementation. Our aim was for approximately 70-80% on-pathway rates. Results: The final pathway, which includes twenty endpoints, integrates several validated scoring systems, including assessments of life expectancy, spinal stability, and appropriateness of surgical management. The pathway has been well received on the SPRO service, with addition of extra steps to workflows being the main cause of resistance to use. Data on rates of pathway adherence will be reported, and rates of 8 Gy x 1 use will be compared to the baseline of 22%. Conclusions: Our experience suggests the utility of pathways-based decision support for bone metastases radiation on a palliation consult service. Next steps include assessing the pathway’s effects on guideline-concordant care and calculating associated cost savings.
Safety and feasibility of S-1 adjuvant chemotherapy for pancreatic cancer in elderly patients.
Authors: Masaaki Murakawa, Toru Aoyama, Yusuke Katayama, Masahiro Asari, Sho Sawazaki, Koichiro Yamaoku, Amane Kanazawa, Akio Higuchi, Satoshi Kobayashi, Manabu Shiozawa, Naoto Yamamoto, Norio Yukawa, Takaki Yoshikawa, Shinichi Ohkawa, Yasushi Rino, Munetaka Masuda, Makoto Akaike, Soichiro Morinaga
Journal: Journal of Clinical Oncology (2015)

486 Background: The safety and feasibility of starting S-1 adjuvant chemotherapy for pancreatic cancer has not been evaluated in elderly patients. Methods: The patients who underwent curative D2 surgery for pancreatic cancer were selected to this retrospective study. The patients were diagnosed within stage I to III disease, and received adjuvant S-1 at our hospital. Patients were categorized into two groups; non-elderly patients (age&lt;70 years: group A) and elderly patients (age≥70 years: group B). The toxicity and drug continuation rates in the two groups were compared. Results: Total 40 patients were evaluated in this study. There were no grade 3 and 4 toxicities. The incidences of grade 2 hematological toxicities were 0% in group A and 11% in group B. The incidences of grade 2 non-hematological toxicities were 50% in group A and 27.8% in group B. The differences in both groups were not significant. The continuation rate at 6 months was 55.7% in group A and 72.7% in group B, and there was also no significant difference in the groups. Conclusions: These results suggest that S-1 adjuvant chemotherapy for pancreatic cancer is safe and feasible, regardless of the age of the patient; especially in elderly patients.
Correlation of pharmacogenetic markers with docetaxel-based chemotherapy resistance in patients with advanced/metastatic non-small cell lung cancer.
Authors: C. Papadaki, E. Tsaroucha, L. Kaklamanis, D. Mavroudis, E. Lagoudaki, M. Trypaki, E. Tsakalaki, V. Georgoulias, I. Sougklakos
Journal: Journal of Clinical Oncology (2010)

7615 Background: Taxane-based doublets are among the most active and commonly used regimens for the treatment of Non-Small Cell Lung Cancer (NSCLC). However, an increasing number of patients being treated with docetaxel-based doublets develop resistance that finally limits chemotherapeutic efficacy. Prior studies have reported the predictive value of tumoral expression of BRCA1, TXR1 and TSP1 in patients with NSCLC treated with first-line docetaxel-gemcitabine (DG). In the present study we explored the predictive significance of this gene profile in patients with any NSCLC histology treated ether with docetaxel-cisplatin (DC) or (DG). Methods: qRT-PCR was used to analyze the tumoral expression of BRCA1, TXR1 and TSP1 from microdissected primary tumors of 131 patients with stage IIIB (wet) and IV NSCLC. Results: The mRNA levels of TXR1-TSP1 were inversely correlated (Spearman's test: -0.37; p = 0.001). Low TXR1 mRNA levels were associated with higher response rate (RR; p = 0.018), longer median progression free survival (PFS; p = 0.029) and median overall survival (mOS p = 0.003), while high TSP1 expression was also, correlated with higher RR (p = 0.035), longer PFS (p < 0.0001) and mOS (p < 0.0001). In addition, patients whose primary tumors presented higher BRCA1 mRNA expression experienced higher RR (p = 0.028) and increased PFS (p = 0.021), but not mOS (p = 0.4) in comparison with those with low BRCA1 tumoral expression. Multivariate analysis demonstrated that low TXR1/high TSP1 expression was an independent prognostic factor for increased PFS (HR 0.5; 95% CI: 0.3-0.7; p < 0.0001) and mOS (HR 0.3; 95% CI: 0.2-0.5; p < 0.0001). Conclusions: These data indicate the TXR1-TSP1 mRNA expression could be used for the prediction of taxanes' resistance in the treatment of NSCLC and are more strong predictors than BRCA1 mRNA expression. No significant financial relationships to disclose.
Phase I/II study of S-1/LV plus oxaliplatin (SOL) for untreated metastatic colorectal cancer: Preliminary report of the phase I part
Authors: K. Yamazaki, T. Yoshino, N. Boku, T. Kojima, Y. Onozawa, S. Hironaka, A. Fukutomi, H. Yasui, K. Taku
Journal: Journal of Clinical Oncology (2008)

15101 Background: S-1, an oral fluoropyrimidine, showed response rates of 35% in monotherapy and 54% in combination with oxaliplatin (SOX) for untreated colorectal cancer. S-1 plus oral leucovorin (S-1/LV) demonstrated that LV might enhance efficacy of S-1 with a higher response rate (56%) than S-1 alone. It was expected that SOL would be more effective than SOX and S-1/LV. Objective: In the phase I part, the recommended dose (RD) for the phase II part of SOL was investigated. Methods: The inclusion criteria were; 1) histologically proven unresectable colorectal cancer, 2) at least one target lesions according to RECIST, 3) age 20 to 74 years, 4) ECOG Performance Status (PS) of 0–2, 5) adequate organ functions, 6) no prior history of chemotherapy. The treatment schedule comprised S-1 and LV (25mg/body, bid) for one week and 2 hour drip infusion of oxaliplatin (OHP) on day 1, repeated every 2 weeks. The starting dose of S-1 was 40mg/m2/bid and that of OHP was 85mg/m2, and the dose should be decreased to 33mg/m2/bid and 70mg/m2 respectively if dose limiting toxicities (DLT) were observed until initiation of the 3rd cycle in more than 2 patients of the six patients. DLT were defined; 1) grade 4 neutropenia persisting longer than 4 days, 2) grade 4 thrombocytopenia, 3) grade 4 anemia, 4) grade 3 or 4 non-hematological toxicities except nausea, vomiting, anorexia, fatigue, and electrolyte imbalance, 5) administration of S-1 less than 5 days per cycle, 6) completion of ten times administration of S-1 later than 10 days per cycle, 7) delay of initiation of 3rd cycle longer than 8 days. Results: Six patients (pts) were enrolled in the phase I part between September and November 2007. The median age was 65 (range, 55- 69) years. All pts showed PS 0. During the first two cycles, grade 3 diarrhea and hypertension were observed in one pt (17%). Presently, the median treatment courses were 4 (range, 3–9) in 6 pts. During the all treatment courses, major toxicities of grade 3 or 4 were neutropenia in one pt (17%), diarrhea in two pts (33%), and nausea in one pts (17%). Partial response were achieved in five pts. Conclusions: The recommended dose of SOL was determined S-1 40mg/m2, OHP 85mg/m2, and the phase II part is underway at RD with an expected response rate of 70%. No significant financial relationships to disclose.
Incidence and predictors of prostate cancer death in men with other prior malignancies: An analysis from SEER Database.
Authors: Kathryn Tindell Dinh, Brandon Arvin Virgil Mahal, David R. Ziehr, Vinayak Muralidhar, Yu-Wei Chen, Vidya Bhavani Viswanathan, Michelle Daniel Nezolosky, Clair Beard, Toni K. Choueiri, Peter F. Orio, Neil E. Martin, Christopher Sweeney, Quoc-Dien Trinh, Paul Linh Nguyen
Journal: Journal of Clinical Oncology (2015)

34 Background: Men with cancer are screened 22% more for prostate cancer (PCa) than men without cancer, yet very little has been published on their prostate cancer outcomes. We aim to describe PCa death and clinical factors associated with dying from PCa in this population. Methods: We studied 22,769 men in the Surveillance, Epidemiology, and End Results database diagnosed with PCa as a second cancer from 1973 to 2006. Proportions of PCa death versus primary-cancer death were calculated, stratified by the nine primary cancers with highest incidence among US men and then further stratified by PCa grade and interval between primary and PCa diagnoses. Results: Urinary-bladder (30.4%), colorectal (27.9%) and lung cancer (10.5%) were the most common primary cancers. Overall, 12.4% of men died from PCa. A greater proportion of patients died from PCa than their first cancer with primary melanoma (11.7 vs 6.97%) and oral cavity/pharynx cancer (15.3 vs 6.98%), a similar proportion for colorectal (14.8% vs 13.7%) and kidney/renal pelvis cancer (11.1 vs 12.7%), but a lower proportion for lung (11.3 vs 42.1%) and bladder cancer (10.8 vs 17.4%). When the interval between cancer diagnoses was more than 5 years, PCa was the leading cause of death for five of the nine cancers. Patients who died from PCa compared to those who died from their primary had higher baseline PSA (39.5 vs 16.9 ng/mL, p&lt;0.001), more Gleason 8-10 (36.7 vs 18.2%, p&lt;0.001), more N1/M1 PCa (2.35 vs 0.30%, p&lt;0.001), were older at PCa diagnosis (74.7 vs 71.9 years, p=0.015), and had a longer interval between diagnoses (63.9 vs 28.8 months, p&lt;0.001). Conclusions: PCa remains a significant cause of mortality when diagnosed as a second cancer, especially if the interval from prior cancer is greater than 5 years, suggesting that treatment of aggressive prostate cancer may be reasonable for many patients with prior cancers.
Retrospective analysis of coagulation abnormalities in patients receiving capecitabine (CAP) and warfarin (WAR)
Authors: H. Shah, M. W. Saif
Journal: Journal of Clinical Oncology (2005)

8130 Background: CAP is commonly used in GI tumors. Pts with these tumors are often on WAR for atrial fibrillation (AF), DVT, etc. There have been reports of altered coagulation parameters and bleeding occurring in pts on both CAP and WAR. Methods: 77 pts at our clinic received CAP. Their charts were reviewed for dates of CAP and WAR administration, demographic data, medical history, concomitant medications, dosage, schedules of CAP and WAR, toxicity defined as hemorrhage, and any transfusion. Laboratory values (PT, INR, CBC, and LFTs) were obtained from laboratory computers. Results: Of 77 eligible pts (age 35–82; M/F: 40/37), 22 received WAR with CAP. 13 were on WAR on avg dose of 19.4mg/wk (r: 7–35mg) prior to CAP with stable INR (r: 0.9–3.3). Indications for WAR were DVT (61%) and AF (38%). Dose of CAP ranged from 1.6 - 2 gm/m2 /day (single agent 22%; with XRT, oxaliplatin, CPT-11: 58%). 13 pts (11 on WAR) had an INR > 3.0 (r: 3.23–11.5) resulting in a probability of an INR >3 of 32% in WAR group vs. 4% in pts not on WAR (p= 5.1 x10–14) at 130 days. 6 pts required a WAR dosage reduction (1–2.5mg decrease). There were 7 episodes of bleeding (all GI) (5 on WAR, only 1 on ASA also). 7 bleeders had INRs ranging from 1.06–8.0 (avg 3.31) at time of bleed. Of 7 bleeding episodes, 5 pts required transfusions averaging 4 units of RBCs and 7 units of FFP. Bleeding at 130 days of treatment with CAP was 18% with WAR vs. 2% without (p=4x10–13). Bleeding episodes were not different (4/40 episodes vs. 3/37 episodes) in pts with and without liver involvement by CT imaging respectively (p=0.12). Pts with INR > 3.0 were evenly distributed (6/40 with vs. 7/37 without liver involvement). No INR elevations persisted after discontinuation of CAP. Conclusions: Exact mechanism of this interaction is unknown, but is likely related to a decrease in WAR metabolism due to inhibition of CYP P450 enzyme system by either 5-DFCR or 5-DFUR. Possible role of high levels of TP in increased formation of 5-FU in liver in such pts is not known and warrants investigation. Wkly monitoring of coagulation parameters is recommended for all pts receiving concomitant WAR and CAP, with appropriate adjustment of WAR dosage. The nature and extent of this interaction requires further investigation. No significant financial relationships to disclose.