tbuckley/cabot-search huggingface dataset:
Quantitative comparison of mRNA level of corticotropin- releasing factor peptide family in normal kidney and corresponding clear cell renal cell carcinoma specimens.
Authors: Hossein Tezval, Axel S. Merseburger, Markus A. Kuczyk, Christoph von Klot, Juergen Serth
Journal: Journal of Clinical Oncology (2015)

466 Background: Urocortin (Ucn), a 40 amino acid peptide, belongs to the corticotropin releasing factor (CRF) family and exerts its actions mainly in the periphery through activation of two CRF receptors (CRFRs), CRFR1 and CRFR2 and a binding protein (CRFBP/CRHBP). Both receptors are G-protein coupled and binding of Ucn leads to activation of cAMP-dependent protein kinases via elevation of cAMP levels. Ucn and Urocortin III (UcnIII) are involved in conditions such as regulation of local inflammation, angiogenesis, and inhibition of proliferation. Suppression of neovascularization and inhibition of tumor cell cycling by Urocortins is modulated through CRFRs. Activation of CRFRs by e.g. Ucn inhibits angiogenesis via reduction of vascular endothelial growth factor (VEGF) and suppresses the cell proliferation. Here we characterized the whole CRF family on mRNA levels quantitatively comparing the normal and clear cell carcinoma of the kidney (ccRCC). Methods: In this study we measured the mRNA level of Ucn, UcnIII, CRFR1, CRFR2 and CRHBP in 78 RCC samples and paired histologically normal appearing tissues using quantitative PCR. Statistical analyses were carried out using univariate logistic regression analysis. Results: We found tumour specific down regulation of mRNA expression of UcnIII, CRFR1, CRFR2 and CRHBP in samples of RCCs with clear cell histology compared to paired normal tissues (P&lt;0.01 for all targets). Only Ucn did not show any expression difference between two groups (p=0.17). Conclusions: For the first time we showed the expression profile of the whole CRF peptide family in ccRCC compared to normal kidney on mRNA level. Our data underlines the malfunction of this actually strong protective and anticancer system in renal malignancy and shows the involvement of CRF system in carcinogenesis in kidney. More studies are necessary to find out the detailed roles of the CRF system in renal carcinoma.
Plasma levels of TIMP-1 in chemo-naive patients with metastatic colorectal cancer treated with first-line FLOX with or without cetuximab: Results from the Nordic VII Study.
Authors: Line Schmidt Tarpgaard, Tormod Kyrre Guren, Bengt Glimelius, Halfdan Sorbye, Tone Ikdahl, Ib Jarle Christensen, Camilla Qvortrup, Elin Kure, Per Pfeiffer, Kjell Magne Tveit, Hans J. Nielsen, Nils Brünner
Journal: Journal of Clinical Oncology (2013)

392 Background: KRAS status is presently the best known biomarker to select patients with metastatic colorectal cancer (mCRC) for therapy with EGFR inhibition. However, in NORDIC VII a survival benefit of adding cetuximab to the Nordic FLOX regimen could not be confirmed. Plasma Tissue Inhibitor of MetalloProteinases-1 (TIMP-1) is a promising biomarker in patients with mCRC, and has multiple actions including regulation of apoptosis, angiogenesis, cell growth and differentiation. High levels of TIMP-1 associate with reduced sensitivity to irinotecan-based treatment in patients with mCRC. We investigated whether high plasma TIMP-1 also correlates with response rate, progression-free survival (PFS) and overall survival (OS) in patients with mCRC treated in NORDIC VII. Methods: In NORCIC VII 571 patients with mCRC were randomized to: (A) Nordic FLOX; (B) Nordic FLOX + cetuximab or (C) Nordic FLOX intermittently + cetuximab continuously. Baseline plasma samples for TIMP-1 analysis were available from 426 patients (79%). Plasma TIMP-1 was determined using the MAC15 antibody in-house validated kinetic Enzyme Linked Immunosorbent Assay. Results: Median plasma TIMP-1 was 296 ng/mL. The tumor was KRAS mutated in 149 patients (35%). Best response did not correlate to TIMP-1 values (OR=1.16, 0.91-1.49, p=0.22). High plasma TIMP-1 was associated with short PFS (HR=1.22, 1.07-1.39, p=0.003) and OS (HR=1.55, 1.36-1.80, p&lt;0.0001). Multivariate analysis (TIMP-1, age, gender, KRAS, ALP, WBC, platelets, CRP, CEA, WHO PS, no. of metastatic sites) demonstrated that high plasma TIMP-1 was not an independent biomarker of PFS (HR=0.95, 0.76-1.18, p=0.65) or OS (HR=1.17, 0.91-1.50, p=0.22). Multivariate analysis retained CRP, PS and no. of metastatic sites in the final model for PFS and alkaline phosphates, PS and no. of metastatic sites for OS. Conclusions: Plasma TIMP-1 is a new prognostic biomarker in patients with mCRC treated with 1st line Nordic FLOX +/- cetuximab. Due to the design of NORDIC VII, a predictive effect of plasma TIMP-1 could only be estimated for cetuximab treatment and no significant treatment by marker intervention was observed.
Effect of the addition of algenpantucel-L immunotherapy to standard adjuvant therapy on survival in patients with resected pancreas cancer.
Authors: J. M. Hardacre, M. F. Mulcahy, W. Small, M. Talamonti, J. C. Obel, C. S. Rocha Lima, H. Safran, H. Lenz, E. G. Chiorean, C. J. Link
Journal: Journal of Clinical Oncology (2011)

236 Background: Pancreatic cancer portends a poor prognosis with ∼4% long-term survival. Among the estimated 20% of patients who have resectable disease, the 1-/3-/5-year survival rates approximate only 70%/30%/18%, even with adjuvant therapy. Better treatment options are needed and addition of algenpantucel-L (HyperAcute-Pancreas) to standard adjuvant therapy is proposed to improve prospects for survival. Algenpantucel-L is composed of irradiated, live, allogeneic human pancreatic cancer cells expressing the enzyme α-1,3 galactosyl transferase (α-GT), which is the major barrier to xenotransplantation from lower mammals to humans (e.g., hyperacute rejection). Up to 2% of circulating human antibodies are directed against the α-GT epitope of algenpantucel-L and are the proposed mechanism of initiating the anti-tumor immune response. Methods: Open-label, single arm, multi-institutional phase II study (NLG0205) to evaluate algenpantucel-L + standard adjuvant therapy (RTOG-9704, JAMA, 2008: gemcitabine + 5-FU-XRT) for pancreatic cancer patients undergoing R0/R1 resection. Disease-free (DFS) and overall survival (OS) are the primary and secondary endpoints, respectively. Results: 73 patients (70 evaluable, 15 month median follow up) received gemcitabine + 5-FU-XRT + algenpantucel-L (mean 12 doses, range 1-14). Demographics and prognostic factors: median age 62 years, 47% female, 81.4% lymph node positive, median tumor size 3.2 cm (range 2-15 cm; 26% &gt; 4cm) and 24% post-operative CA 19-9 &gt; 90. Kaplan-Meier estimated survival rates at 12 and 24 months are 91% and 54%, respectively, comparing favorably to 63% and 32% expected based on the nomogram described by Brennan et al (Ann Surg, 2004). Likewise, the current median DFS of 16 months compares favorably to the 11 months observed in RTOG 9704. OS data continues to mature, with 74% still censored. Algenpantucel-L was well tolerated with no likely/directly attributable grade 3 SAEs. The most common adverse events were injection site pain and induration. Conclusions: Addition of algenpantucel-L to standard adjuvant therapy for resected pancreatic cancer may improve survival. A phase III study began patient enrollment in May 2010. [Table: see text]
Does a change from IHC to FISH enhance patient selection for HER2 therapy?
Authors: A. Barochia, A. G. Ayoola, L. Cream, H. A. Harvey
Journal: Journal of Clinical Oncology (2011)

e11015 Background: Breast cancer is the most commonly diagnosed malignancy among women in the United States. Among various subtypes of breast cancer, tumors that overexpress the human epidermal growth factor receptor 2 (HER2) have an aggressive biology. The frequency of HER2 gene amplification is about 20% among breast cancer patients. The diagnostic tests to determine HER2 status in breast cancer include Immunohistochemisty (IHC), and Fluorescence In-Situ Hybridization (FISH). The interpretation of IHC is subjective and may depend on the pathologist. It is unknown whether the use of FISH has led to higher detection of HER2 overexpression. Methods: We conducted a retrospective review of patients diagnosed with breast cancer from 2000 to 2008. A total of 865 breast cancer patients were reviewed. One hundred and sixty five (19%) were diagnosed with HER2+ subtype. Our institution utilized IHC (HER2-pY 1248 antibody, Dako Corporation) from 2000 to 2003 and FISH (Path Vysion, HER-2 DNA Probe Kit) from 2004 to 2008. Results: The frequency of HER2 detection in breast cancer by IHC from 2000-2003 was 17%. The detection by FISH from 2004-2008 was 20%, an increase of 3%. Conclusions: We observed an increase in the diagnosis of HER2+ breast cancer with the introduction of FISH. This modest difference when applied to a large group of patients could translate into more patients being eligible for anti-HER2 therapy and may enhance accrual to clinical trials.
Overall survival (OS) in renal cell carcinoma (RCC) before and after the introduction of targeted therapies (TTs): A Norwegian population-based study (2000–2011).
Authors: Olbjorn Harald Klepp, Tom Børge Johannesen, Jan Oldenburg, Knut Martin Torgersen, Jan Kowalski, Oddvar Solli, Rickard Sandin, Christian Beisland
Journal: Journal of Clinical Oncology (2015)

443 Background: The Renal Comparison study in Norway (RECON) is a retrospective non-interventional study of OS in all patients diagnosed with RCC and metastatic (m)RCC before and after the introduction of TTs. Methods: Using data from two national health registries, Cancer Registry of Norway (diagnosis and cause of death) and Norwegian Prescription Database (all dispensed drugs), we assessed OS in RCC and mRCC patients diagnosed during two periods after (2009–2011 and 2006–2008) and one period before (2000–2005 [RCC]; 2002–2005 [mRCC]) the introduction of TTs and factors influencing OS in mRCC. Multivariate analysis was performed using a Cox proportional hazards model, including estimation of adjusted HR. The regression model included the covariates age, gender, geographic region, nephrectomy status, diagnostic period and TT prescription. Results: In total, 2,176, 1,887, and 3,233 RCC patients were identified in 2009–2011, 2006–2008 and 2000–2005, respectively, of whom 2,160 (30%) had mRCC. From 2006 to 2011, TT use in mRCC patients significantly increased from 21% to 56% (p&lt;0.01); sunitinib was the most frequent first-line treatment (93%). RCC patients diagnosed in 2009–2011 and 2006–2008 had a significant improvement in OS compared with patients diagnosed in 2000–2005 (median OS: not reached and 76 vs. 49 months, respectively; both p&lt;0.001 [log-rank]). Similarly, a significant OS improvement was shown in mRCC patients diagnosed in 2009–2011 and 2006–2008 compared with 2002–2005 (median OS: 11.0 and 8.0 vs. 6.0 months, respectively; both p&lt;0.001 [log-rank]; with adjusted HR [95% CI] of 0.77 [0.68–0.87] and 0.87 [0.78–0.98], respectively). Factors significantly associated with longer OS in mRCC were (HR, 95% CI): younger age (0.98, 0.98–0.99), female gender (0.88, 0.79–0.97), prior nephrectomy (0.49, 0.43–0.55) and TT prescription (0.58, 0.51–0.65). Significant regional variation was also shown. Conclusions: A significant OS improvement was shown in RCC and mRCC patients following the introduction of TTs. This advance has continued into the later TT era and, although multifactorial in origin, the contribution of TTs in mRCC is highly likely.
Safety, tolerability, and pharmacokinetics (PK) of rilotumumab in Japanese patients (pts) with advanced solid tumors.
Authors: Toshihiko Doi, Rui Tang, Yilong Zhang, Elwyn Loh, Richard Lizambri, Hirofumi Yasui
Journal: Journal of Clinical Oncology (2014)

130 Background: Rilotumumab (R) is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor, the only known MET receptor ligand. The MET pathway has been identified as a potentially useful target for therapeutic blockade in oncology. R has been studied in multiple phase 2 trials either as monotherapy or combination therapy, including a phase 2 trial in gastric cancer combining R with epirubicin, cisplatin, and capecitabine. A phase 1 study was done to evaluate the safety, tolerability, and PK of R in Japanese pts. Methods: An open-label, dose-escalation study was performed with R at 10 mg/kg (Cohort 1A), escalating to 20 mg/kg (Cohort 1B) if no dose-limiting toxicities (DLTs) were observed. Key eligibility criteria were Japanese pts with unresectable locally advanced or metastatic carcinoma, age ≥ 20 yr, ECOG ≤ 1, and refractory to standard treatment (tx). Pts received R as an intravenous infusion on days 1 and 15 of each 28-day cycle, except for cycle 1 in which the day 15 dose was skipped to facilitate PK analysis. DLTs were evaluated in cycle 1. Results: A total of 9 pts were enrolled (1A, n = 3; 1B, n = 6). No DLTs were noted. As of 17 April 13, tx-emergent AEs were reported in 89% of pts. Tx-emergent AEs occurring in &gt; 1 pt overall were vomiting (33%), diarrhea (22%), decreased hemoglobin (22%), hypoalbuminemia (22%), and nausea (22%). One grade 3 tx-emergent AE was observed (decreased hemoglobin; 10 mg/kg). Tx-related AEs were reported in 56% of pts. One grade ≥ 2 tx-related AE was observed (hypoalbuminemia; 20 mg/kg). 8 pts discontinued R due to disease progression; 1 pt remained on the investigational product. Mean exposure of R (C max and AUC) appeared to be doubled as dose increased from 10 to 20 mg/kg. The estimated mean CL was approximately 0.2 mL/hr/kg in both cohorts, suggesting a linear PK from 10 to 20 mg/kg. The terminal half-life of R was about 15 days. Conclusions: R monotherapy had an acceptable safety profile in Japanese pts with advanced solid tumors. These phase 1 safety and PK data support the further evaluation of R combined with chemotherapy in Japanese pts with MET-positive metastatic gastric cancer. Clinical trial information: NCT01791374.
Regional trends of renal mass management in the Southeast.
Authors: J. Hammett, P. L. Crispen, J. Ko, N. Byrd, J. R. Bylund, N. S. Schenkman, T. L. Krupski
Journal: Journal of Clinical Oncology (2011)

e16562 Background: Current management of renal masses emphasizes nephron sparing procedures due to similar oncologic outcomes while potentially decreasing renal and cardiovascular morbidity compared to radical nephrectomy. According to the AUA guidelines radical nephrectomy is overly utilized leading to increased morbidity from chronic renal insufficiency. Partial nephrectomy is now considered the treatment of choice in T1 renal masses. Here, we analyzed epidemiologic data from the southern states of Virginia, VA, and Kentucky, KY, to assess compliance with a changing standard of care. Methods: Using the Department of Health Patient Level Database System reported via the Thomson Reuters Polaris Suite, we identified all patients hospitalized for a primary International Classification of Disease (9th revision; ICD-9) code suggestive of malignant renal mass and compared the prevalence of nephrectomy, partial nephrectomy, and ablative procedures in VA and KY. Data analysis was performed using Microsoft Excel 2007 for both academic and community hospitals. Results: We identified patients treated in VA and KY from 2004-2009. The proportion of radical nephrectomies has been steadily decreasing from 2004 with peak prevalence in 2004 for both KY and VA. The proportion of nephron sparing procedures has been increasing from 2004 to 2007 with peak prevalence in 2007 in VA and 2009 in KY. By 2009 nephron sparing procedures accounted for 32% and 31% of all renal mass surgery in KY and VA, respectively. The proportion of all renal procedures performed that were radical nephrectomies has decreased in both academic and community hospitals. Academic institutions experienced an earlier and more rapid rise in nephron sparing procedures in both VA and KY. Conclusions: VA and KY inpatient data indicate practice patterns for management of renal masses has been changing with increased use of nephron sparing therapies relative to radical nephrectomy. Furthermore, academic hospitals appear to have adopted nephron sparing therapies earlier than community hospitals. However, given that partial nephrectomies are the recommended standard of care for T1 renal masses by the AUA, the percentage of these procedures being performed are still surprisingly low.
Chemotherapy use in the treatment of glioblastoma multiforme: Comparing patient characteristics using the National Cancer Data Base (NCDB).
Authors: Christopher J. Inserra, Nabin Khanal, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2014)

305 Background: Glioblastoma Multiforme (GBM) is the most common and most deadly type of human glioma. Nearly half of all gliomas are diagnosed as GBM at which point the median survival of patients is approximately one year and the two-year survival rates are approximately 10%. Current treatment options for GBM include surgical resection, external beam radiation, and oral temozolomide chemotherapy. However, the patterns of chemotherapy use in GBM as well as the patient characteristics that determine its use have yet to be investigated. Methods: This is a retrospective study of glioblastoma patients (n = 96,966, making this the largest trial ever on glioblastoma) diagnosed between 2000 and 2011 in the NCDB. The NCDB contains nearly 70% of new cancer cases diagnosed in the United States and consists of data from over 1,500 cancer programs across the country. A chi-squared test was used to determine any differences in the characteristics of patients who did or did not receive chemotherapy. Results: Patients who were younger than 70 years of age, male, white, had private/managed insurance, no comorbidities, household income greater than $49,000, were receiving radiation therapy, and diagnosed between 2004 and 2011 were significantly more likely to have received chemotherapy to treat glioblastoma (see Table). Conclusions: Understanding any potential barriers in the use of chemotherapy to treat glioblastoma can help improve its utilization among people of diverse socioeconomic backgrounds. [Table: see text]
First-line chemotherapy with gemcitabine, etoposide, and cisplatin in combined-multimodality treatment for patients with advanced urothelial carcinoma.
Authors: Shinji Urakami, Junji Yonese, Yasuhisa Fujii, Shinya Yamamoto, Takeshi Yuasa, Shinichi Kitsukawa, Mizuaki Sakura, Akihiro Yano, Kazutaka Saito, Hitoshi Masuda, Iwao Fukui
Journal: Journal of Clinical Oncology (2013)

262 Background: We had previously reported the phase I/II study of a combination regimen of gemcitabine, etoposide, and cisplatin (GEP) in second-line treatment for patients with advanced UC. This study sought to examine the combination chemotherapy of GEP as first-line treatment for advanced urothelial carcinoma (UC) to assess efficacy, feasibility, prognostic factors, and the impact of postchemotherapy surgery on outcomes. Methods: Forty-two patients were treated with GEP as first-line treatment for metastatic or unresectable locally advanced UC. GEP was recycled every 4 weeks. Etoposide and cisplatin were given on days 1 through 3 at doses of 60 mg/m 2 and 20 mg/m 2 , respectively, and gemcitabine was given on days 1, 8, and 15 at a dose of 800 mg/m 2 . Results: The median patient age was 64 years. Twenty-three male patients and 19 female patients were included. The primary cancer site is urinary bladder in 21 patients, and upper urinary tract in 21 patients. Nineteen had visceral/bone metastases, 16 had disease restricted to lymph nodes, and the remaining 7 had unresectable disease at primary site. The median number of GEP courses was 4. Thirty of 42 assessable patients (71.4%) demonstrated objective responses. At a median follow-up of 14.6 months, the median overall survival time (OS) was 16.2 months. Twenty-four of 30 responders underwent postchemotherapy surgeries. Median OS in the patients with postchemotherapy surgery was 25.4 months. In the multivariable analysis, anemia and visceral/bone metastasis were significant pretreatment prognostic factors for OS. In addition, being male and anemic were independent poor prognostic factors in patients with postchemotherapy surgery. Grade 3-4 neutropenia, anemia and thrombocytopenia occurred in 84%, 73% and 57%. There were no treatment-related deaths. Conclusions: GEP as first-line chemotherapy in combined-multimodality treatment is active and moderately tolerable for advanced UC. Postchemotherapy surgery may yield favorable outcomes in patients who achieved objective responses. Anemia and visceral/bone metastasis were independent pretreatment predictors for OS.
Telomerase activity in normal human breast and cancer, association with Bcl-2, estrogen receptors (α-, β-) and clinical parameters
Authors: B. Murillo, J. M. Malacara, M. Perez, M. A. Pluma, C. Ramirez, J. A. Silva, L. Benitez, H. Astudillo-de la Vega
Journal: Journal of Clinical Oncology (2005)

9675 Background: Telomerase has been shown to be specifically expressed in immortal cells. Bcl-2 overexpression has been found to be associated with estrogen receptor (ER) positivity. There is controversy with respect to use telomerase activity (TA) as prognostic marker or even more if TA could be associated with other breast molecular markers. Methods: Using a fluorometric detection for detect TA by the use of FRET primers was determined in 44 core central biopsies of infiltrating breast carcinoma and by immunohistochemistry were determined Bcl-2 and estrogen receptors (α-, β-). A semiquantitative method was use to analyze the protein expression. Clinical data were available for statistical analysis. Results: 52% of all patients were post-menopausal, the average age was 49.3+ SD 11.6 years, 70% of cases were stage III and IV, and 72.7% were moderately and high differentiated. TA was scored since 0 to 49.9 units of total generated product. ERα were detected in 39/44(88.6%); ERβ in 16/44(36.44%). Bcl-2 immunoreactivity was observed in 36/44 (82%). We found a strong association between TA and moderately and high differentiated tumors (p=0.033). Bcl-2 protein expression was associated with clinical stage I and II (p=0.02). Bcl-2 protein expression correlated directly with the expression of ERα (p=0.024). Conclusions: It was clear that TA was positive and correlated with high grade malignancy. It seems that TA is not regulated by the anti-apoptotic protein bcl-2 because we did not find an association between them. The expression of the protein bcl-2 shows a significant increase in breast tumors within early stage and also with the absence or early relapse. We were not able to find the expected relation between the expression of the estrogen receptors and the TA. The ERα is associated with the expression of Bcl-2 in 82% but it was not found a positive correlation with ERβ. Our results suggest a possible role of ERα in the regulation of Bcl-2 protein expression in Breast cancer. No significant financial relationships to disclose.