tbuckley/cabot-search huggingface dataset:
Clinical significance of dihydropyrimidine dehydrogenase (DPD), epidermal growth factor receptor (EGFR), and excision repair cross-complementing gene 1 (ERCC1) gene expression of tumor tissue in patients with advanced gastric cancer
Authors: T. Nishina, J. Matsubara, M. Toshikazu, Y. Yamada, T. Kajiwara, T. Shimoda, Y. Okayama, Y. Sugimoto, T. Oka, K. Shirao
Journal: Journal of Clinical Oncology (2007)

4629 Background: Many methods for predicting the susceptibility of a gastric cancer(GC) to chemotherapy have been investigated. However, the clinical significance of biomarkers in GC cells remains unclear. There is a need for exploratory evaluations to understand the clinical implications of biomarkers. Methods: This study consisted of 151 patients (pts) who received chemotherapy for advanced GC. cDNA was derived from the laser-captured tumor cells of cancer specimens obtained by surgical resection or endoscopic biopsy and analyzed to determine mRNA expression relative to an internal reference gene (β-actin) using real-time RT-PCR method. Gene expression levels of thymidylate synthase (TS), DPD, orotate phosphoribosyl transferase, dihydrofolate reductase (DHFR), ERCC-1, EGFR and 22 other biomarkers related to anticancer drug sensitivity were measured. Results: DPD, EGFR, and ERCC1 gene expressions were significantly correlated with survival ( Table ). Multivariate analysis revealed that high DPD (p=0.0002, RR=2.67 [95% CI, 1.62–4.25]), low EGFR (p=0.0005, RR=0.29 [0.18–0.50]), and high ERCC1 (p&lt;0.0001, RR=2.27 [1.45–3.47]) gene expressions were independently related to poor survival. As for first-line chemotherapy, an analysis of 60 pts treated with S-1 showed that low DHFR gene expression significantly correlated with a longer time to progression (TTP) (p=0.0017). An analysis of 54 pts who received cisplatin containing regimens ( + irinotecan or + S-1) as first-line therapy showed that low ERCC1 gene expression was slightly related to a better response (p=0.053). Conclusions: These results indicate that expression of DPD, ERCC1, and EGFR gene expressions in cancer specimens have predictive value for the outcome of advanced GC pts treated with chemotherapy. Low DHFR gene expression could be a predictor of a long TTP in patients receiving S-1 therapy. [Table: see text] No significant financial relationships to disclose.
Patupilone combined with carboplatin in patients (pts) with advanced solid tumors: Preliminary safety and activity results
Authors: M. Q. Baggstrom, A. Ravaud, P. M. Fracasso
Journal: Journal of Clinical Oncology (2008)

13538 Background: Patupilone is a novel microtubule targeting agent with demonstrated clinical activity in taxane-sensitive/resistant tumors and synergistic tumor activity when combined with carboplatin in preclinical models. This Phase I study aimed to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of patupilone combined with carboplatin. Secondary endpoints included safety, pharmacokinetics (PK) and assessment of anti-tumor activity. Methods: Pts with solid advanced tumors who progressed after standard therapies received escalating doses of patupilone followed by carboplatin (AUC=6) once every 3 wks. A Bayesian logistic model with overdose control and a starting dose of 4.8 mg/m2 determined the MTD of patupilone. Results: To date, 18 pts have been enrolled into the study receiving a total of 57 cycles. Median age: 60 years (range: 37–79). Tumor types included prostate (5), colon (3), renal (1), bladder (1), endometrial (1), NSCLC (1), breast (1), thymus (1), head and neck (1), melanoma (1) and unknown primary (2). Six pts are ongoing and 12 discontinued: 1 due to toxicity (G3: diarrhea). To date the MTD has not been reached. Dose escalation levels of patupilone 4.8 mg/m2 (6 pts), 6.4 mg/m2 (3 pts), 7.0 mg/m2 (6 pts) and 7.5 mg/m2 each followed by carboplatin (AUC=6) have been administered. One DLT of G2 neutropenia lasting >14 days was reported in the patupilone 7.5 mg/m2 group, in a pt with unknown primary previously treated with paclitaxel/carboplatin/VP-16. Most frequent G3/4 adverse events (AEs) were diarrhea 28%, thrombopenia 21%, neutropenia 14% and asthenia 14%. So far 14 pts are evaluable for tumor response: 1 confirmed and 2 unconfirmed PR, 4 SD and 7 PD were reported. Updated results and PK data will be presented. Conclusion: Preliminary results suggest that patupilone doses up to 7.5 mg/m2 combined with carboplatin have an acceptable toxicity profile with evidence of anti- tumor activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Novartis Novartis Novartis
Clinical utility of a 21-gene breast cancer assay: Experience of women enrolled in a large U.S. insurance program.
Authors: L. I. Hochheiser, K. Krebs, R. Chien, J. C. Hornberger
Journal: Journal of Clinical Oncology (2010)

e16529 Background: Both NCCN and ASCO guidelines recommend a 21-gene RT-PCR assay to help determine the recurrence risk and adjuvant chemotherapy responsiveness of estrogen-receptor-positive, node-negative early-stage breast cancer (ER+, LN- ESBC). We assessed, the effect of the assay on treatment decision, chemotherapy related outcomes in the first 6 months after the test, and direct medical costs. Methods: Observational study of 589 women enrolled with Humana, Inc. (Louisville, KY) tested with the 21-gene RT-PCR assay between June, 2006 and June, 2008. The proportion of women classified by the assay at low, intermediate, and high risk of recurrence, use of adjuvant chemotherapy by risk class, the use and costs of chemotherapy regimens and supportive care, and incidence and costs of adverse events were measured. Results: 161 patients within the tested population received adjuvant chemotherapy. Adjuvant chemotherapy was administered to 10% of women at low risk, 37% of women at intermediate risk, and 71% of women at high risk of recurrence. Doxcetaxel-based regimens were preferred in 65% of the treated women. Average cost of chemotherapy to Humana was $7,032 for this cohort. Chemotherapy-supportive care included anti-emetics and growth factor, with cost an average of $8,375 dollars per treated patient. Three frequently observed adverse-events were anemia, neutropenia and asthenia. Anemia and neutropenia were among the most expensive complications, costing $10,236 and $7,014 per event, respectively. Based on propensity model for treatment in 2004, approximately 65% of patients would have received adjuvant chemotherapy without the risk-stratification provided by the 21-gene RT-PCR assay.The introduction of the assay reduced the use of adjuvant chemotherapy in more than 200 patients. Conclusions: Adjuvant chemotherapy and related-care for ER+, LN- ESBC are significant cost contributors to the health care system. Complications from adjuvant chemotherapy are also common and costly. The adoption of the 21-gene RT-PCR recurrence score lead to more appropriate and targeted management of these 589 women with ER+, LN- ESBC, and consequently save direct medical cost. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genomic Health Genomic Health
A phase IB study of AMG 479, a type 1 insulin-like growth factor receptor (IGF1R) antibody, in combination with panitumumab (P) or gemcitabine (G)
Authors: J. Sarantopoulos, A. C. Mita, M. Mulay, O. Romero, J. Lu, F. Capilla, L. Chen, Y. Hwang, G. Friberg, L. S. Rosen
Journal: Journal of Clinical Oncology (2008)

3583 Background: IGF1R signaling plays a key role in oncogenesis and protects some tumors from anti-cancer agents. AMG 479 is a fully human monoclonal antibody (IgG1) against IGF1R. It has exhibited single-agent activity in early clinical studies and additive effects with other therapies in preclinical models. Methods: This phase 1b, open-label study of AMG 479 in combination with either P or G evaluates safety, pharmacokinetics, and the maximum tolerated dose of AMG 479 for each regimen. Patients (pts) with advanced solid tumors, ECOG 0–2, and without prior G (in G arm only) received P (6 mg/kg IV day 1 Q2 weeks) or G (1000 mg/m2 IV day 1, 8, and 15, Q4 weeks) in combination with AMG 479 in sequential dose escalating cohorts (6 or 12 mg/kg IV Q2 weeks) using a 3+3+3 design. Assessments included dose-limiting toxicities (DLT) during the first 21 days and WHO tumor response (Q8 wks). Results: As of 11/13/07, 18 pts were enrolled (arm P/G, n = 10/8); median age 57; 94% had prior chemo. In arm P (6 or 12 mg/kg AMG 479, n = 6/4) there was 1 DLT in the 6 mg/kg cohort (Grade 3 hyperglycemia). In arm G (6 mg/kg AMG 479, n = 8) there was 1 DLT (Grade 4 neutropenia). Treatment-emergent adverse events (AE) of any grade with n >2 Additional treatment-related Grade 3/4 AEs (P,G): AST/ALT (0,13%); hyperglycemia (10,0%). Clearance of AMG 479 in arm P and G was 12.0 ± 4.2 and 11.4 ± 4.9 mL/day/kg, respectively, similar to the Ph 1 monotherapy study (10.5 ± 4.1, n = 23). A partial response was observed on arm P (AMG 479 12 mg/kg) in a colon cancer patient (KRAS wild-type) who previously progressed on cetuximab. Stable disease as best response was noted in an additional 5 of 6 evaluable pts on arm P, and in 4 of 5 on arm G. Conclusions: AMG 479 (12 mg/kg) appeared tolerable when combined with P and showed activity in refractory disease. AMG 479 (6 mg/kg) appeared tolerable when combined with G; accrual to the 12 mg/kg cohort is complete. Serum biomarker (IGF-1 and IGF binding protein 3) and tumor analyses (PIK3CA & RAS mutation) will be presented. Panitumumab (all grades) n = 10 Panitumumab (grade 3/4) n = 10 Gemcitabine (all grades) n = 8 Gemcitabine (grade 3/4) n = 8 Neutropenia, n (%) 0 (0) 0 (0) 4 (50) 4 (50) Anemia, n (%) 4 (40) 0 (0) 3 (38) 0 (0) Thrombocytopenia, n(%) 1 (10) 0 (0) 5 (63) 0 (0) Rash/Stomatitis, n (%) 10 (100) 2 (20) 3 (38) 0 (0) Hypomagnesemia, n (%) 8 (80) 3 (30) 1 (13) 0 (0) Fatigue, n (%) 3 (30) 0 (0) 3 (38) 0 (0) Nausea/vomiting/anorexia, n (%) 4 (40) 0 (0) 3 (38) 0 (0) Diarrhea, n (%) 3 (30) 0 (0) 0 (0) 0 (0) Dizziness, n (%) 3 (30) 0 (0) 0 (0) 0 (0) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Amgen
Intercellular adhesion molecules and vascular cell adhesion molecule-1 and the kidney.
Authors: R P Wuthrich
Journal: Journal of the American Society of Nephrology (1992)

Adhesion molecules such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 are expressed in the kidney and are regulated by proinflammatory cytokines. These adhesion molecules play an important role in the binding and activation process of leukocytes and are of importance in inflammatory kidney diseases. This review article describes current knowledge regarding the structure, expression, and functional role of adhesion molecules and their significance in immune-mediated renal diseases.
A phase II study of GW786034 (pazopanib) in Asian patients with recurrent/metastatic undifferentiated nasopharyngeal carcinoma.
Authors: W. T. Lim, C. Thng, C. K. Toh, B. Chowbay, B. C. Goh, S. Leong, S. P. Ivy, Q. Ng, D. S. Tan, E. Tan
Journal: Journal of Clinical Oncology (2010)

5556 Background: Pazopanib is a small molecule tyrosine kinase inhibitor of VEGFR1-3, c-kit, and PDGFR. Nasopharyngeal carcinoma (NPC) is endemic in Asia and angiogenesis is important for growth and progression. We hypothesized that anti-angiogenesis with pazopanib would be effective in NPC. Methods: An open-label monotherapy study of pazopanib in patients with WHO type II/III NPC and metastatic/recurrent disease who failed at least one line of chemotherapy was done. A Simon's optimal 2-stage design was employed. Patients with ECOG 0-2 and adequate organ function were treated with pazopanib 800 mg daily on a 21-day cycle. The primary endpoint was the best overall response (CR/PR/SD) achieved after 12 weeks of treatment. Secondary endpoints included toxicity and progression-free survival. Dynamic-contrast enhanced computed tomography (DCE-CT) of target lesions and pharmacokinetics (PK) of pazopanib was also done. Results: Thirty-three patients were accrued (August 2007-August 2009). All patients were ECOG 0-1 with median age of 50 years (range 36-68). Patients had received median of 3 (range 1-7) prior chemotherapy. There were 2 (6.1 %) partial responses, 16 (48.5%) stable disease, 14 (42.4%) progressive disease, 4 (12.1%) not evaluable for response (2 deaths, 2 declined further evaluation), giving a clinical benefit rate of 54.5% (95% CI 38.0-70.2). Fifteen patients (45%) received more than 5 cycles of treatment, 6 (18.2%) had PR/SD that lasted at least 6 months and one patient remains on treatment. One patient each died from epistaxis and myocardial infarction before response evaluation. Grade 3/4 toxicities included fatigue (15.2%), hand-foot syndrome (15.2%), anorexia (9.1%), diarrhea (6.1%), vomiting (6.1%), dehydration (3%), hypertension (3%), hyponatremia (6%), neutropenic fever (3%), proteinuria (3%), pericardial effusion (3%). Serial DCE-CT scans demonstrate significant reductions in tumor blood flow, permeability surface area product, and fractional intravascular blood volume. Conclusions: Pazopanib appears to be active in nasopharyngeal carcinoma with an acceptable toxicity profile. Further PK/PD analyzes are ongoing. No significant financial relationships to disclose.
Novel and existing mutations in the EGF receptor tyrosine kinase domain are predictors of optimal resectability (OR) in malignant peritoneal mesothelioma (MPM)
Authors: J. M. Foster, Z. Gatalica, S. Lilleberg, G. Haynatzki, B. W. Loggie
Journal: Journal of Clinical Oncology (2007)

10503 Background: MPMs represent 20% of all malignant mesothelioma (MM) cases. The median survival for these tumors is less than a year, and like other peritoneal tumors this is due to intra-abdominal recurrence/progression. Currently there is a paucity of information about the biology of these tumors and molecular perturbations that are involved in tumor formation. Elucidation of mutations and biological pathways active in these tumors may identify valuable prognostic markers, as well as facilitate the development of novel therapies. Methods: Twenty-nine MPM patients were evaluated at a single tertiary center and their tumors were probed for mutations in the catalytic TK domain of EGF receptor (mut+). All specimens were examined for somatic mutations by PCR amplification. Twenty-five patients were treated with cytoreductive surgery (CRS) ± IPHC and complete clinical data including age, sex, cytoreductive score, histology, mutation, and survival was available for comparison of the mut+ and mut- groups. Results: The median age was 56, and 71% of the patients were male with a median follow-up time (MFT) of 14.5 months. Mutations were found in 31% (9/29) of the tumors, 7 of these mutations were novel, and the 8th one was the L858R mutation described in NSCLC. Of the 25 patients managed surgically there were 7 mut+ and 18 mut- ( Table ). OR (=R2a) was achieved in 7/7 (100%) of mut+ group and 9/18 (50%) mut- (p=.03). All mut+ are alive with a MFT of 24 months, while 5/18 (28%) of the mut- group are DOD with a MFT of 7 months (p=.27). In an ANCOVA model OR (p=0.04) was found to be predictive of survival. Conclusions: The EGFR-TK appears to be a common site for mutation in MPM, with the identification of novel and known activation mutation in 31% of tumors. Mut+ was predictive of OR. OR was predictive of survival in short term follow-up, and with longer follow-up, mut+ may be predictive of survival as well as represent a subset of patients who may be responsive to TK-inhibitors therapy. [Table: see text] No significant financial relationships to disclose.
Randomized controlled trial to evaluate splenectomy in total gastrectomy for proximal gastric carcinoma (JCOG0110): Analyzes of operative morbidity, operation time, and blood loss.
Authors: T. Sano, M. Sasako, T. Shibata, S. Yamamoto, A. Tsuburaya, A. Nashimoto, S. Ito, M. Kaji, H. Furukawa, N. Fukushima
Journal: Journal of Clinical Oncology (2010)

4020 Background: In European gastrectomy trials, splenectomy was an important risk factor for operative morbidity/mortality associated with poor long-term survival. In Japan where splenectomy seldom causes mortality, 20-30% of proximal gastric carcinomas have nodal metastasis in the splenic hilum and its complete removal with splenectomy produces a cure in about 20% of them. Methods: We conducted a randomized controlled trial to compare splenectomy and spleen preservation in total gastrectomy. Proximal gastric adenocarcinoma of T2-4/N0-2/M0 not involving the greater curvature was eligible. During operation surgeons confirmed that R0 resection was possible with negative lavage cytology, and randomized the patient into splenectomy (pancreas-preserving total gastrectomy, D2) or spleen-preserving group (total gastrectomy, D2, no pancreatic mobilization). The primary endpoint is overall survival, and the secondary endpoints are operative morbidity, operation time and blood loss. The trial was designed to evaluate noninferiority of spleen preservation to splenectomy in overall survival. Sample size was determined to be 500 with one-sided alpha of 0.05 and a noninferiority margin of the hazard ratio as 1.21. The final survival analysis is scheduled for 2014. Results: Between June 2002 and March 2009, 505 patients (splenectomy 254, spleen-preservation 251) were enrolled from 36 institutions. Operative mortality was seen in 3 patients (0.6%: splenectomy 1; spleen-preservation 2). Operative morbidity was significantly higher in splenectomy group (30.3%) than in spleen-preserving group (16.7%) (p < 0.001). Blood loss was significantly larger in splenectomy group (median 390.5 mL vs. 315 mL, p = 0.02), but there was no difference in operation time (median 231 vs. 224 min). Five more lymph nodes (median 64 vs. 59) were dissected in splenectomy group. Conclusions: Splenectomy in total gastrectomy was associated with higher morbidity and larger blood loss but not longer operation time than spleen preservation, and was safely performed by specialized surgeons with low mortality. The impact on long term survival should be awaited. No significant financial relationships to disclose.
The impact of stage migration on survival after resection in the UICC 7 TNM classification of lung cancer.
Authors: J. P. Van Meerbeeck, K. Chansky, P. Goldstraw
Journal: Journal of Clinical Oncology (2010)

7022 Background: A change of staging classification has been associated with improvements in stage-specific survival without improvement of overall survival (Feinstein, 1985). We aim to estimate in patients with resected non-small cell lung cancer (NSCLC), included in the IASLC staging database (Goldstraw, 2006) 1) the magnitude and direction of stage migration between the 6th and 7th editions of the UICC-TNM classification, and 2) its impact on stage-specific outcome. Methods: Resected NSCLC cases were extracted from the IASLC database and classified according to the 6th and 7th editions of UICC-pTNM. Cases having received preoperative chemotherapy and/or radiotherapy were excluded from the set; postoperative deaths were included, as were substages A and B for stage III only. Migration was estimated by calculating the rate of patients classified in any higher or lower UICC-7 p-stage over the corresponding UICC 6 p-stage. Outcome was estimated by the Kaplan-Meier method and expressed as 5-year survival rate (5y SR) with lower and upper 95% confidence intervals (95%CI). Results: Stage distribution of 15,952 cases with full pathological data, classified according to UICC 6 and 7, with corresponding overall and stage specific 5-y SR are in the Table. Overall, 2,480 cases (16%) migrate, of whom 1,747 (11%) to a higher and 733 (5%) to a lower stage. Substantial changes in 5y SR occur for pI (+3%) and pIIIB (-10%). Conclusions: The change of TNM staging classification of resected NSCLC from UICC6 to 7 results in the net migration of 1 out of 6 cases, to a higher stage in 70% of them, with substantial changes in 5y SR for p-stages I and IIIB. This stage migration should be accounted for when comparing outcome across series using different TNM classifications. UICC 6 UICC 7 Net migration Total 15,952 (100%) 2,480 (16%) 5y SR 47% (46-48) 0% pI 8,092 (51%) 6,766 (42%) - 5y SR 63% (62-64) 66% (65-67) +3% pII 3,544 (22%) 4,831 (30%) 1,476 (9%) 5y SR 39% (37-41) 41% (40-43) +2% pIIIA 3,091 (19%) 3,792 (24%) 701 (4%) 5y SR 25% (23-26) 24% (23-26) −1% pIIIB 1,042 (7%) 297 (2%) 71 (<1%) 5y SR 19% (17-22) 9% (6-13) −10% pIV 183 (1%) 266 (2%) 232 (2%) 5y SR 21% (15-27) 13% (9-17) −8% No significant financial relationships to disclose.
Sexual activity and functioning in women who underwent salpingo-oophorectomy to prevent hereditary breast ovarian cancer.
Authors: T. M. Michelsen, A. A. Dahl, C. Trope, A. Dørum
Journal: Journal of Clinical Oncology (2010)

5097 Background: Risk-reducing salpingo-oophorectomy effectively prevents ovarian cancer in women at risk for hereditary breast/ovarian cancer. Surgically induced menopause may affect sexual functioning. We aimed to explore sexual activity and functioning in women with risk-reducing salpingo-oophorectomy compared to age-adjusted controls from the general population (NORM). Methods: Through surgical records 361 women with risk-reducing salpingo-oophorectomy were identified, and 327 (67%) agreed to participate and delivered written informed consent (cases). Cases filled in the Sexual Activity Questionnaire and were compared to 654 controls from the general Norwegian population (controls). Results: Mean age at survey was 54.4 years and 54.5 years for cases and controls, respectively. 265/327 (81%) of the cases were sexually active compared to 465/654 (71%) of the controls (p = 0.001). The sexually active cases reported higher levels of sexual pleasure (mean scores 15.5 vs. 12.8 [p < 0.001]) and higher levels of discomfort (mean scores 4.0 vs. 3.0 [p < 0.001]) compared to sexually active controls. Conclusions: Women who had undergone risk-reducing salpingo-oophorectomy reported higher levels of sexual activity, higher levels of sexual pleasure but also higher levels of sexual discomfort compared to controls from the general Norwegian population. Sexual discomfort could represent an area for medical intervention in women who have undergone risk- reducing salpingo-oophorectomy to prevent hereditary breast/ovarian cancer. No significant financial relationships to disclose.