tbuckley/cabot-search huggingface dataset:
Proteomic analysis of drug metabolizing networks in renal cell carcinomas with differential drug sensitivity and VHL expression.
Authors: L. Dalasanur Nagaprashantha, J. Singhal, R. Vatsyayan, P. Lelsani, S. S. Singhal, L. Prokai, S. Awasthi
Journal: Journal of Clinical Oncology (2010)

e13137 Background: Kidney tumors with mutated VHL constitute 75% of renal cancers. The VHL activity dependent therapeutic outcome is the current focus of translational research in renal oncology. We observed that CAKI-2 kidney cancer cells with wt VHL are more sensitive to sorafenib than 786-O cells with mt VHL, which are more sensitive to temsirolimus (Singhal SS et al 2009). Hence, we performed proteomic analysis to investigate the molecular basis of differential drug sensitivity. Methods: The cell cultures were performed in RPMI medium at 37°C in 5% CO2. The cells were lysed in buffer containing 20mM Tris, 50mM Nacl, 6M urea, 10mM NaPP, 1mM NaF, and 1mM Na3VO4. The lysate (200μg of protein) was subjected to reduction and alkylation of cysteins using 2.5mM DTT and 7mM idoacetamide followed by trypsin digestion and solid phase extraction using a C-18 cartridge (Waters, USA). Liquid chromatography–tandem mass spectrometry (LC-MS/MS) was performed on a linear ion trap–Fourier transform ion cyclotron resonance tandem mass spectrometer (LTQ-FT, Thermo) coupled to an Eksigent nano-LC system. MS/MS spectra were searched against a human protein database by the Mascot software (Matrix Science) and Label-free quantification was done by using spectral counts from the Scaffold program (Proteome Software) with previously validated method (Prokai et al 2009). Results: We detected significant differences in the levels of phase I and II drug metabolizing enzymes in two cell types (Table). Carbonyl reduction catalyzed by AKR1C1 and UGDH involved glucorunidation are vital both in the activation and inactivation of drugs. NQO1 mediates the anticancer effects of beta lapachone (Bey et al. 2006). Conclusions: Our proteomic identification of vital differences in the principal enzymes of drug metabolizing networks identify key molecular determinants of drug sensitivity, which may be further investigated and developed as drug sensitivity biomarkers for clinical use. Proteins identified by LC-MS/MS Fold increase in spectra in CAKI-2 cells comparedto 786-O cells Aldo-keto reductase (family 1 member C1, AKRC1) 6.1 NAD(P)H quinone dehydrogenase 1 (NQO1) 2.8 UDP-glucose 6- dehydrogenase (UGHD) 5.2 No significant financial relationships to disclose.
Survival advantage associated with metformin usage in patients with colorectal cancer (CRC) and type II noninsulin-dependent diabetes (NIDDM).
Authors: H. M. Hassabo, M. Hassan, B. George, S. Wen, V. Baladandayuthapani, S. Kopetz, D. R. Fogelman, B. K. Kee, C. Eng, C. R. Garrett
Journal: Journal of Clinical Oncology (2011)

3618 Background: Patients with NIDDM have an increased risk of colorectal adenomas and CRC possibly mediated through the insulin growth factor receptor pathway. Metformin is associated with anticancer efficacy in preclinical models and a lower risk of cancer mortality in patients with NIDDM. We undertook to evaluate the difference in outcome in NIDDM patients with CRC based upon their medications taken for glycemic control. Methods: We conducted an IRB-approved (DR09-0719) retrospective analysis of 4,758 patients seen at a single institution (MD Anderson) with CRC between the years of 2005-2008, to determine the prevalence of NIDDM in this patient population, in addition to determining whether patient survival differs based upon their diabetic therapy. Results: 424 out of 4,758 CRC patients (8.9%) identified as having NIDDM. Gender, male:female 282:142 (67%, 33%), age, mean 62 years (range 31-91), stage I/II/III/IV 37:55:175:158 (8.7%, 12.9%, 41.2%, 37.2%). Overall survival (OS) for the 397 patients with follow-up data available, by univariable Kaplan Meier analysis, was 63.7 months (95% CI, 52.3-75.5). Patients with NIDDM and CRC treated with metformin as one of their diabetic medications had a survival of 76.9 months (95% CI, 61.4-102.4) as compared to 56.9 months in those patients not treated with metformin (95% CI, 44.8-68.8), p = 0.048. By using a Cox regression model adjusted for age, sex, race, body mass index, and initial stage of disease we demonstrated that NIDDM patients treated with metformin had a 30% improvement in OS when compared to NIDDM patients treated with other diabetic agents. There was a non-statistically significant trend toward higher complete and minor pathologic response rate (≤ 10% residual tumor) in NIDDM patients with rectal cancer receiving chemoradiation who were treated with metformin when compared to those who were not (14/19, 74% vs. 9/19, 47%, p=0.09). Conclusions: In this analysis the use of metformin in NIDDM patients with CRC was associated with an improved overall survival. While these results are consistent with the findings in other solid tumors they will need to be validated in other colorectal cancer data sets.
A phase II trial to assess the activity of MVA5T4 plus interleukin-2 in patients (Pts) with metastatic renal cell carcinoma (MRCC)
Authors: A. Gary, L. Marsh, M. McDonald, S. Naylor, R. Harrop, D. Bernard, R. J. Amato
Journal: Journal of Clinical Oncology (2006)

14642 Background: MVA 5T4 consists of a highly attenuated vaccinia virus (modified Vaccinia Ankara, MVA) containing the human tumor associated antigen (TAA) 5T4. Greater than 90% of renal cell cancers are overexpressed by the 5T4 antigen. The primary purpose of this trial is to validate the hypothesis that, in this group of pts, it is possible to induce immune responses either humoral and/or cellular to 5T4 and to break tolerance to the antigen. The immune response will be correlated to clinical outcome. Methods: Eligibility included: pathologic diagnosis of confirmed clear cell or papillary cancer, progressive measurable MRCC, adequate organ/marrow function, Karnofsky Performance Status (KPS) ≥ 80%, any prior therapy, and no active CNS involvement. The dosage schedule of subcutaneous low dose IL-2 will be an initial dose 250,000 U/kg/dose for 5 days in week 1 followed by 125,000 U/kg/dose for 5 days each of weeks 2–6 inclusive. There will then be a 2 week recovery period before the next cycle commences. The dosage regimen of MVA 5T4 will be intramuscular injections given 14 days prior to the first cycle, day 0 and 1 injection given at the beginning of week 4 of the first cycle. In subsequent cycles, booster injections of MVA 5T4 will be given at week 1 only, prior to the commencement of subcutaneous IL-2 therapy. Results: 10 pts have been treated with MVA 5T4 and the LD IL2 regimen. The combination has been extremely well tolerated with no MVA 5T4 related events thus far. Although the study is still continuing to accrue, there are early signs of clinical responses in a number of patients receiving the combination. The immunological analysis is in progress. Conclusion: MVA 5T4 is well tolerated in this group of patients. The immune response will be presented along with clinical outcome. [Table: see text]
Management of cutaneous metastases by electrochemotherapy.
Authors: J. Gehl, L. W. Matthiessen, A. Humphreys, G. Kessell, T. Muir
Journal: Journal of Clinical Oncology (2010)

8579 Background: Electrochemotherapy is an emerging modality in the treatment of cutaneous metastases. By applying short electric pulses to tumour cells, cell membranes can be permeabilised (electroporation). This can be used to augment the effect of chemotherapy, by providing direct access to the cell cytosol (electrochemotherapy). For the drug bleomycin, the enhancement of effect is several hundred folds, enabling once-only treatment and offering palliative relief to the patient. As part of a non-randomized study, we present the joint results from sites in UK and Denmark. Methods: Patients were enrolled prospectively from oncology/plastic surgery pathways for palliative management of non-respectable/treatable cutaneous tumours. Treatments and outcomes were recorded in the International Network for Sharing Practice in ElectroChemoTherapy (INSPECT) database. Patients were treated in local or general anaesthesia and bleomycin was given either intra tumorally or intravenously, depending on number and size of tumour nodules. Electric pulses were administered using a square wave electroporator (Cliniporator, IGEA), using short trains of high voltage pulses applied through needle electrodes. Re-treatment was administered in case there were areas which had not been sufficiently dealt with in the first treatment round. Results: Between 2007-2009, 47 patients had a total of 54 ECT treatments on 221 lesions, from malignant melanoma (35%), breast cancer (31%), other adenocarc. (11%), squamous cell carc. (6%) or other cancer (17%). The average number of treatments was 1.15, median follow up (FUP) of 55 days. FUP for > 60 days (77 nodules) showed overall response rate of 80%, with complete resolution in 49 (64%), partial response in 12 (16%), no change in 10 (13%) and progressive disease in 5 (6)%. Treatment was well tolerated with 96% of patients indicating they would potentially accept further ECT should the need arise. Conclusions: The cancer patient with treatment resistant cutaneous metastases presents a challenge. ECT is effective in reducing the size and symptoms of cutaneous metastases. Its role as a palliative adjunct is appealing as the treatment is well tolerated and is performed as a routine day-case procedure under local or general anaesthesia. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Iclin, IGEA, Imagingequipment
Prognostic significance of age in curatively resected gastric cancer
Authors: H.-S. Song, Y. R. Do, I. H. Kim, S. S. Sohn, W. S. Lee
Journal: Journal of Clinical Oncology (2004)

4129 Background: Gastric cancer is the most common cancer and the second leading cause of cancer death in Korea. The aim of this study was to investigate the clinical significance of age in curatively resected gastric adenocarcinoma. Methods: Retrospective analysis was performed for 1,158 gastric cancer patients who underwent curative resection from Jan. 1996 to Dec. 2001. Results: Seven hundred sixy-seven (66.2%) of the patients were male and 391 (33.8%) were females. Median age was 56.9 ± 11.5 (range: 19–84). Total gastrectomy was performed in 13.6% and subtotal gastrectomy in 86.4%. Stage was as follows: I 59.4%, II 14.7%, IIIA 16.3%, IIIB 9.6%. Age less than 65 was 838 (72.4%) and ≥ 65 was 320 (27.6%). More than 65 years of age was associated with more tubular type (p=.001), intestinal Lauren type (p=.003), vascular invasion (p=.037), and higher T and total stage (p=.002). Operative complications were more common in age ≥ 65 group (p=.003), and also more frequent in early death rate in age ≥ 65 group (p=.020). Tumor recurrence was more common in age ≥ 65 group (p=.016). 2-, 4-, and 6-year total survival (TS) rates, and 2-, 4-, and 6-year relapse free survival (RFS) rates were 92.7%, 89.1%, 86.3% and 93.3%, 84.4%, 78.7% in age < 65 group and 89.4%, 84.8%, 71.1% (p=.012) and 90.3%, 81.5%, 75.1% (p=.122) in age ≥ 65 group respectively. By multivariate Cox regression analysis, tumor stage was the most important prognostic factor for TS and RFS. Age was an independent prognostic factor for predicting TS (RR 1.025, 95% CI 1.001–1.049), but, not a significant prognostic factor of RFS. But, after excludinga early death cases (within < 2 months of operation), prognostic significance of age was disappeared, and age was not independent prognostic factor for TS and RFS in curatively resected gastric cancer. Conclusions: So, we conclude that increased early death after curative resection causes poor prognosis in elderly gastric cancer patients. No significant financial relationships to disclose.
Benefit of neoadjuvant capecitabine + epirubicin + cyclophosphamide (CEX) versus 5-FU + epirubicin + cyclophosphamide (FEC) for operable breast cancer (BC) followed by adjuvant docetaxel (T)
Authors: D. Berton-Rigaud, H. Roché, F. Penault-Llorca, N. Tubiana-Mathieu, J. Ferrero, B. Coudert, G. A. Milano, M. Mousseau, H. Homokos, P. Fumoleau
Journal: Journal of Clinical Oncology (2008)

598 Background: A phase II trial was conducted to show noninferiority of neoadjuvant CEX vs FEC. Methods: 182 patients (pts) with operable BC (T2–3, N0–1) were randomized (1:1) to four 3-weekly cycles of CEX (X 900 mg/m² bid d1–14, E 100 mg/m² d1, C 500 mg/m² d1; n=94) or FEC (5-FU 500 mg/m², E and C as above; n=88). Pts underwent surgery 4–6 weeks after the 4th cycle, followed by 4 adjuvant cycles of 3-weekly T 100 mg/m2. Primary endpoint was pCR rate (Sataloff criteria). Results: Baseline characteristics were well balanced. All 4 neoadjuvant cycles were given in 95% of CEX and 97% of FEC pts. Median dose intensity was 95% for X and 99% for 5-FU. The primary objective was met: CEX was non-inferior to FEC (Table). Clinical overall response rate was 58% with CEX vs 54% with FEC. Clinical CR occurred in 12% vs 5%, respectively. During neoadjuvant therapy, treatment- related G3/4 AEs occurred in 59% and 65% of pts, respectively. CEX was associated with more treatment-related G3/4 mucositis (6% vs 1%) and less G3/4 nausea/vomiting (11% vs 28%). Median adjuvant T dose intensity was 99% and 100%, respectively. Adjuvant T was well tolerated: treatment-related G3/4 AEs occurred in 5% and 6% of pts receiving CEX and FEC, respectively, and 7% vs 6%, discontinued T prematurely. Pharmacokinetic (PK) analysis revealed no interactions between X, E, and C. Conclusions: CEX was highly active despite the short (4-cycle) regimen, with a meaningful clinical benefit over FEC and no relevant PK interactions. Adjuvant T was very well tolerated after neoadjuvant CEX. CEX should be considered in pts eligible for neoadjuvant FEC. Efficacy (per-protocol population, n=169) CEX (n=86) FEC (n=83) pCR rate * 17 (20%) 11 (13%) Difference (95% 1-sided CI) -6.5% ]-∞; 2.8%] TA/NA 9 (11%) 2 (2%) TA/NB 8 (9%) 9 (11%) * Missing data counted as non-responders Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Hoffmann-La Roche Hoffmann-La Roche Hoffmann-La Roche
CD27-Mediated Apoptosis Is Dependent on Siva-Induced Caspase Activation in Human Multiple Myeloma.
Authors: Yu-Tzu Tai, Xian-Feng Li, Rory Coffey, Iris Breitkreutz, Laurence Catley, Robert L. Schlossman, Paul G. Richardson, Nikhil C. Munshi, Steven P. Treon, Kenneth C. Anderson
Journal: Blood (2005)
Evaluating compliance (com) with hematology (H) -oncology (O) quality (Q) standards in a community-based managed care population
Authors: L. Bosserman, C. Presant, A. Der, A. Estrella, A. Greenburg, G. Upadhyaya, M. Vakil
Journal: Journal of Clinical Oncology (2007)

17050 Background: Better Q and outcomes in HO practice are associated with com with national treatment guidelines (TG). Institution of an O specific electronic medical record (EMR) within a community HO specialty practice allowed analysis of com with TG as well use of high cost treatments (HCT) data from an HMO population in a multi site HO practice are presented. Methods: HO physicians agreed to treat patients (pts) using common EMR, TG and regular treatment (tx) reviews. EMR data over 18 months for the HMO population was reviewed for diagnosis, stage, and tx. This was compared to TG of NCCN. A panel of high cost therapies (HCT) was identified by the HMO medical director, and pt treatment com with TG was tabulated. Non-com was further evaluated as acceptable alternative practice (acc) by NCCN description, recommended (rec) by academic specialist consultation or not appropriate by TG (non-app). Results: Between 1/1/04 and 6/31/05, the HMO had ∼75,000 covered lives at risk. 1210 evaluable HO pts were treated by 5 oncologists. 163 pts had benign H diagnoses (dx), 155 had malignant H dx, and 892 had solid tumor dx (breast 373, colorectal 76, lung 63, prostate 28, ovary 15). Of pt with cancer (ca), 49 had active ca but no rx, 639 had ca in complete remission and had no tx, and 256 had active ca and received tx. 102 had clinical diagnosis but incomplete evaluations, none received tx. Of HMO chosen HCT, Rituximab was given to 25 pt, and all rx was com to TG. Bevacizumab was given to 14 pt and was com in 11, acc in 1, and non-com/acc in 2. Trastuzumab was given to 8 pt, and was com in 4, acc in 3, and rec in 1 pt. IVIG was com in 1 and rec in 1 pt. Of a total 49 HCT, 8 were non-com with TG (16%), but only 2 were non-com, non-acc, and non-rec (4%). Both were associated with 1 new physician whose performance improved after pre tx review of HCT by a senior physician prior to pt tx. Conclusions: Ongoing review and feedback to physicians using EMR and national TG allows objective monitoring and improvement of Q in HO practice. Issues of concern, such as HCT, can also be detailed. Payors and practices can consider using such methods and data to negotiate fair payment for Q care. . No significant financial relationships to disclose.
Use of BIBW 2992, a novel irreversible EGFR/HER2 tyrosine kinase inhibitor (TKI), to treat patients with HER2-positive metastatic breast cancer after failure of treatment with trastuzumab
Authors: T. Hickish, D. Wheatley, N. Lin, L. Carey, S. Houston, D. Mendelson, F. Solca, M. Uttenreuther-Fischer, H. Jones, E. Winer
Journal: Journal of Clinical Oncology (2009)

1023 Background: BIBW 2992 (Tovok) is an oral, novel, and potent, irreversible dual epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) inhibitor, with preclinical activity in trastuzumab-resistant cell lines overexpressing HER2 and phase I clinical activity. A phase II study of BIBW 2992 in patients with HER2-positive breast cancer who have failed treatment with trastuzumab is currently being conducted in the US and the UK. Methods: This is a multi-institutional open label single arm phase II study, planning to recruit 40 patients. Eligibility criteria include stage IIIB or IV HER2-positive metastatic breast cancer, progression following receipt of trastuzumab or intolerance of trastuzumab, measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function. Patients receive 50 mg BIBW 2992 once daily until disease progression. Tumor assessments are performed every two courses (one course = 28 days). The primary endpoint is objective response rate (RECIST criteria). Safety data are also collected. Results: To date, 40 patients have started treatment on the trial. Patients had received a median of three lines of prior therapy. Nine patients discontinued treatment prior to the first assessment at 8 weeks; four due to disease progression, four due to adverse events and one due to withdrawal of consent. Twenty-one patients have had tumor assessment after 8 weeks of treatment. Of these, four patients had a partial response (PR) and 10 patients had stable disease (SD). The PR has been confirmed at 16 weeks in one patient. The most frequently observed side effects to date are rash (Common Toxicity Criteria for Adverse Events [CTCAE] grade 3 in 4 patients) and diarrhea (CTCAE grade 3 in 8 patients). There were 20 dose reductions in 17 patients. Conclusions: BIBW 2992 at 50 mg/day induced responses and seems promising in HER2-positive breast cancer patients who have failed treatment with trastuzumab. Manageable cutaneous adverse events and diarrhea were the main side effects. [Table: see text]
Phase I/II feasibility trial of adjuvant dose-dense (DD) docetaxel/epirubicin/cyclophosphamide (TEC) in stage II/III breast cancer
Authors: S. Burdette-Radoux, M. E. Wood, J. J. Olin, R. Broom, A. Crocker, T. Ashikaga, H. B. Muss
Journal: Journal of Clinical Oncology (2005)

813 Background: Strategies for improving outcome of adjuvant therapy for early stage breast cancer (BC) include escalating anthracycline dose, adding a taxane, and DD scheduling. In this phase I/II trial, we investigate the safety and feasibility of combining these strategies using a DD regimen, TEC. Methods: Eligibility: patients (pts) with stage II/III BC who were candidates for adjuvant or neoadjuvant chemotherapy. Treatment: Cohort 1 (3 pts): docetaxel (T) 75 mg/m2, epirubicin (E) 75 mg/m2, cyclophosphamide (C) 500 mg/m2 IV d1, q 2 wks x 6 cycles, + pegfilgrastim 6 mg SC d2. Cohort 2 (12 pts): same regimen except for E 100 mg/m2. Toxicity assessment by clinical evaluation, CBC and biochemistry q 2 wks. Cardiac function and neoadjuvant response assessment after 6 cycles. Results: 3 pts completed 6 cycles in cohort 1 (18 total). In cohort 2, 11 pts completed 6 cycles; 1 pt withdrew after 3 (69 total). All pts in cohort 1 received 100% planned dose intensity; in cohort 2, 6/12 pts received 100%, 4/12 received 80–96% and 2/12 received <80%. There were no dose reductions/delays for d1 myelotoxicity. Febrile neutropenia (FN) occurred in cohort 2 but not cohort 1 (Table). 2/6 FN episodes had associated thrombophlebitis. 6 pts had anemia ≥ grade 3, 5 received RBC Tx and 7 received an erythropoietin. 3 pts had dose reductions for non-hematologic toxicity (1 neurotoxicity; 1 mucositis; 1 diarrhea + cellulitis). 2/14 pts had asymptomatic decreases in LVEF >10%, all in normal range. All 4 pts receiving neoadjuvant TEC had clinical responses (1 CR, 3 PR). 3/3 pts had pathologic responses at mastectomy, but none were pCRs. Conclusions: DD TEC chemotherapy is feasible, has minimal toxicity at doses equivalent to TAC (Proc ASCO 21:36a, 2002) and moderate but manageable toxicity at an epirubicin dose equivalent to FEC-100 (J Clin Oncol 19:602, 2001), with FN occurring in 5/12 pts at the higher dose. Supported by Aventis Pharmaceuticals, Bridgewater, NJ. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Amgen Amgen, Aventis Ortho-Biotech