tbuckley/cabot-search huggingface dataset:
Trastuzumab (T), paclitaxel (P), carboplatin (C), and gemcitabine (G) in advanced HER2-positive urothelial carcinoma: Results of a multi-center phase II NCI trial
Authors: M. Hussain, D. Petrylak, R. Dunn, U. Vaishampayan, P. N. Lara, G. Chatta, D. Nanus, L. M. Glode, D. Trump, H. Chen, D. C. Smith
Journal: Journal of Clinical Oncology (2005)

4507 Background: We have previously reported a > 50% HER2 overexpression in patients (pts) with metastatic urothelial cancer (UC). Methods: Metastatic UC pts were screened for HER2 overexpression. Pts eligible for therapy had: HER2 overexpression by immunohisto-chemistry (IHC) (2+ or 3+) and/or gene amplification by FISH (> 2 by Vysis) and/or elevated serum HER2 >16 ng/ml by OSDI; no prior chemotherapy for metastasis (mets); normal cardiac function, performance status (PS) 0–2; and adequate organ function. HER2 assays were performed centrally. Pts received T 4mg/kg loading dose followed by 2mg/kg on days (D) 1, 8, & 15; P 200 mg/m2 D1; C (AUC 5) on D1; G 800 mg/m2 on D 1& 8. Response and MUGA were assessed Q 3 cycles. Primary end point: toxicity of TPCG. Secondary endpoints: efficacy, survival, time to progression (TTP) and prospective evaluation of HER2 status. Results: 59/109 registered pts (54%) were HER2 positive (+ve) (IHC 51%, FISH 13%, serology 12%). Based on the higher of the IHC score from primary or mets tissue, 27 pts were 2+ and 29 were 3+. HER2 +ve pts had more liver/bone mets (39% vs 22%, p=0.06), more lung mets (32% vs 24%, p=0.40) and more mets sites (47% with ≥ 2 sites vs 28%, p=0.03) than HER2 negative pts. 44/59 HER2 +ve pts (median age 65.5 years, median PS 1, 55% had visceral mets and 32% had prior chemotherapy) were treated with TPCG. The median number of cycles was 6 (range 1–12). The most common grade (G) 3/4 adverse events were neutropenia (77%), thrombocytopenia (64%), anemia (38%), PRBC (25%), fatigue (16%), diarrhea (16%), platelet transfusion (14%), sensory neuropathy (11%), cardiac (all G3, 4.5%) and 3 possibly or definitely therapy-related deaths. There were 32 responses (5 complete and 27 partial, response rate 72.7%), 4 pts had stable disease, 5 not assessable, and 3 with progressive disease. TTP and median survival were 8.5 and 15.2 months, respectively. Conclusions: This is the first trial to prospectively characterize HER2 status in pts with metastatic UC. The combination of TPCG is feasible and is associated with high level of activity. These results warrant validation in a phase III trial. Support: CTEP, 5 P30 CA46592, NO1 CM17101 & Genentech. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech
Prognostic relevance of increased detection of lymphovascular invasion in primary melanoma using D2-40 and CD34 compared to routine histology.
Authors: F. Darvishian, A. E. Rose, P. J. Christos, T. Tu, R. L. Shapiro, R. S. Berman, A. C. Pavlick, H. Kamino, M. Mazumdar, I. Osman
Journal: Journal of Clinical Oncology (2010)

8596 Background: Use of immunohistochemistry (IHC) can increase the detection of lymphovascular invasion (LVI) in primary melanoma, but the prognostic relevance of this enhanced detection is unknown. We evaluated LVI using lymphatic endothelial marker D2-40, panvascular endothelial marker CD34, and routine histology to determine if detection of LVI using D2-40 and/or CD34 improves the prognostic relevance of LVI detected by routine histology alone. Methods: Primary melanoma tissues from patients (pts) prospectively enrolled in the NYU IMCG were assessed for LVI using D2-40, CD34, and routine histology. We then tested the association between LVI and clinicopathologic variables (e.g., thickness, ulceration, mitotic index, histotype, stage, SLN status), disease-free survival (DFS), and overall survival (OS) using univariate and multivariate analyses. Results: 246 melanoma pts were studied (median age 59, median thickness 1.2 mm, stage I=146, II=58, III=40, IV=2). 104 pts recurred, and 82 pts died (70 of melanoma). Median f/u was 6.0 years (range 2.3-17.3). LVI positivity by D2-40 and/or CD34 was significantly higher than by routine histology (18% vs. 3%, p<0.0001). On univariate analysis, only LVI detected by D2-40 and/or CD34 (not histology) was significantly associated with higher stage (p=0.05), presence of mitotic figures (p=0.003), and histotype other than superficial spreading melanoma (p=0.002). Because of strong collinearity between LVI, ulceration, and mitosis, it was not feasible to test the association between LVI and recurrence controlling for ulceration and or mitosis simultaneously. However, a reduced multivariate model comparing D2-40 and/or CD34 LVI positivity to routine histology showed the combination of IHC markers to be a stronger predictor of both DFS and OS than LVI by histology alone. Conclusions: LVI detection in primary melanoma using IHC expression of lymphatic and vascular markers is a better predictor of outcome than LVI detected by histology alone. HR 95% CI p value DFS: LVI+, D2-40 and/or CD34 2.1 1.26-3.4 0.004 LVI+, routine histology 1.89 0.76-4.7 0.17 OS: LVI+, D2-40 and/or CD34 2.3 1.35-3.92 0.002 LVI+, routine histology 0.98 0.29-3.3 0.97 No significant financial relationships to disclose.
Bevacizumab (BEV) continued beyond first progression in patients (pts) with metastatic colorectal cancer (mCRC) previously treated with BEV + chemotherapy (CT): Biomarker findings from ML18147.
Authors: Stefan Kubicka, Roger Von Moos, Richard Greil, Javier Sastre, Pia J. Osterlund, Dirk Arnold, Thierry André, Eric Van Cutsem, Thomas Mueller, Irmarie Reyes-Rivera, Jaafar Bennouna
Journal: Journal of Clinical Oncology (2013)

452 Background: In ML18147, BEV + standard CT was continued as 2nd-line treatment for pts with mCRC progressing after 1st-line BEV + CT. ML18147 met its primary and secondary endpoints and had a comprehensive biomarker programme, including exploratory analyses of immunohistochemistry (IHC) and single nucleotide polymorphisms (SNPs). Methods: Tumour samples were analysed by IHC for VEGFA, VEGFR1, VEGFR2 and neuropilin-1; H-scores were generated. Tumor angiogenesis was determined by stereological analysis of CD31-stained microvessels; 183 SNPs of 30 mainly angiogenesis-related genes were genotyped. We assessed consistency of treatment effect point estimates, i.e. hazard ratios (HRs) on the same side of 1. Analyses were not adjusted for multiple testing or powered to detect statistically significant treatment by biomarker interactions. Results: IHC data were available for 213 pts (26% of ITT population) and SNP data for 274 pts (33% of ITT). There was no significant evidence of biomarker expression levels or their cellular localisation correlating with BEV treatment effect. Point estimates for a CD31 derivative (i.e. vessel or tumour area) suggested a trend for being predictive for overall survival (OS; HR 1.39 and 0.70 for CD31 derivative &lt;median and ≥median, respectively), similar to data from previous studies. Other previously reported correlations (progression-free survival [PFS] with VEGFA and NRP1 in NO16966; OS with NRP1 in AVAGAST) were not seen. SNP analyses confirmed previous correlations for OS (VEGFA, VEGFR2) and suggested additional biomarker candidates (PFS: VEGFA, VEGFR1, VEGFR2, EGLN3; OS: VEGFR2, EGLN1). Five EPAS1 (HIF2α) SNPs were associated with BEV treatment effect, thus confirming previous findings of HIF2α SNPs as a predictive biomarker for BEV treatment effects. Conclusions: Exploratory IHC and SNP analyses in ML18147 revealed potential biomarker candidates for BEV in pts with mCRC. SNP analyses of angiogenesis-relevant genes were consistent with previous findings for a subset of SNPs, consolidating their role as potential predictive biomarkers of BEV treatment across indications. Clinical trial information: NCT00700102.
Different gene sets correlated to overal and chemotherapy survival in human malignant melanoma
Authors: B. Gyorffy, H. Lage, M. Dietel, J. Timar, U. Trefzer
Journal: Journal of Clinical Oncology (2008)

20034 Background: Resistance to chemotherapy regimes is a critical problem in the clinical management of metastatic melanoma malignum resulting in a very short survival in the majority of patients. The biological mechanisms behind the therapy resistance are still unclear. The identification of survival and thereapy-specific dysregulated genes could identify new molecular markers. Patients and Methods: Twelve patients treated with malignant melanoma with known complete survival and chemotherapy data were enrolled in the study. All patients received cisplatin/carboplatin combination therapy. After surgery, the tissue samples were frozen, and RNA was isolated using the Qiagen RNeasy kit. Microarray analysis was performed using Affymetrix HGU133A chips. Before statistical analysis the genes exhibiting less than 50% present calls and genes with less than 10% having at least 1.5 fold intensity variations were excluded. Feature selection was performed using the Wald statistic, Cox proportional hazard model of the survival analysis in the BRB ArrayTools software package. Significance was set at p<0.05. For an in silico validation we used the key word “melanoma” and found one microarray study containing 83 microarrays and available raw data in GEO (GSE8401). The downloaded dataset was MAS5 normalized and SAM was performed setting the false discovery rate below 0.01. Results: Seven patients passed the quality criteria and were included in the study. All together 8207 genes passed the filtering criteria. 33 genes were associated with aggressiveness and 42 genes with survival after chemotherapy. Only PICALM (phosphatidylinositol binding clathrin assembly protein) was associated with both therapy response and survival. In GSE8401 3006 genes were significant to discriminate metastasis and primary melanomas. The overlap of the significant GSE8401 and the top 33 survival- associated genes contains 5 genes. The overlap of the significant GSE8401 and the top 42 chemoresponse-associated genes contains 11 genes. Conclusions: Our results demonstrate a high diversity of gene expression profiles associated with melanoma overall- and therapy survival. We provide new data that can be used to obtain further insight into the mechanisms of therapy response. No significant financial relationships to disclose.
Protective effect of a brisk tumor infiltrating lymphocyte infiltrate in melanoma: An EORTC melanoma group study
Authors: A. Spatz, P. A. Gimotty, M. G. Cook, J. J. van den Oord, N. Desai, A. M. Eggermont, U. Keilholz, D. J. Ruiter, M. C. Mihm
Journal: Journal of Clinical Oncology (2007)

8519 Background: Tumor-infiltrating lymphocytes (TILs) in melanoma are responsible for tumor killing and may induce spontaneous regression. Brisk TILs in the melanoma vertical growth phase (VGP) is a strong, albeit not independent, prognostic factor associated with superior survival. This study investigated whether more detailed classes of TIL patterns, based on topography and intensity, are independent prognostic factors and identify patients with good prognosis. Methods: The study included 1,171 patients with cutaneous VGP melanoma with at least 3 years of follow up for whom slides were available for review. TIL infiltrate was assessed for pattern (absent, non brisk, brisk), intensity (scanty, moderate, dense), and topography (peripheral, central, both). Pattern was assessed qualitatively: brisk TIL infiltrate was defined as a continuous band of lymphocytes at the base of the melanoma, or throughout the tumor. Other studied variables were: thickness, mitotic count (MC), ulceration, gender, age, anatomic site, melanoma-related death (MRD). Subsequently, Chi-square tests, Kaplan-Meier curves (KM), logrank tests, and Cox models were applied to examine the relation between MRD, TIL categories and interaction with other variables. Results: A brisk infiltrate was observed in 21.2% of the cases. Adjusted hazard ratio for MRD as compared to the absent category was 0.82 (95% CI=0.64–1.06) in the non-brisk category, and 0.43 (95% CI=0.28–0.68) in the brisk category. Based on the Cox model, brisk TIL was an independent prognostic factor for MRD (p&lt;0.001) controlling for thickness, MC, ulceration, gender, age and site. Intensity was significantly associated with MRD for melanomas with peripheral and central brisk TILs (p=0.027) but not for other melanomas. Remarkably, no death was observed in the 5.5% of melanomas with dense, brisk TIL infiltrate at ten years. Conclusions: A brisk TIL pattern was shown to have prognostic value for MRD underscoring the importance of TILs in the outcome of VGP melanoma patients. Furthermore, we identified a small population of “super-responder” patients whose tumor was characterised by a continuous and dense TIL infiltrate and who did not display signs of tumor progression. No significant financial relationships to disclose.
R-CHOEP-14 X 6 Followed by Systemic CNS Prophylaxis for Diffuse Large B-Cell Lymphoma (DLBCL)/Follicular Lymphoma (FL) Grade 3 with Age Adjusted IPI Score 2–3: Preliminary Results of a Nordic Lymphoma Group (NLG) Phase 2 Study Including 160 Patients Aged 18- 64 Years
Authors: Harald Holte, Sirpa M. Leppa, Magnus Bjorkholm, Oystein Fluge, Sirkku Jyrkkio, Jan Delabie, Christer Sundstrom, Marja-Liisa Karjalainen-Lindsberg, Martin Erlanson, Arne Kolstad, Alexander Fossa, Björn Östenstad, Eva Lofvenberg, Marie Nordström, Lars Möller-Pedersen, Harald Anderson, Mats Jerkeman, Mikael Eriksson
Journal: Blood (2008)
The real-life variability of CA 125 in ovarian cancer patients
Authors: M. Markman, E. Tso, F. Van Lente, P. Elson, D. Odar, G. Peterson, B. Kulp, M. Sessana
Journal: Journal of Clinical Oncology (2004)

5014 Background: CA 125 has proven to be useful in predicting changes that affect prognosis and management of ovarian cancer; however, interpreting variations in the tumor marker is still not well-defined. Our goal was to further understand the analytical variability of CA 125 in a conventional hospital laboratory. Methods: Patients with ovarian or primary peritoneal cancer, who received active therapy at the Cleveland Clinic Foundation from July 2003 to December 2003, were included in this IRB-approved study. A blood sample was obtained prospectively from each consenting patient during a routine clinic visit. This blood sample was separated into three aliquots, then submitted on three different weekdays for CA 125 analysis. Laboratory personnel performing the CA 125 assays had no knowledge that these samples were part of a research study. The CA 125 assay used was a microparticle enzyme immunoassay from Abbott AxSYM system. Results: Fifty-one blood samples were obtained from 46 patients. Age range is 45–89 years old. Blood samples from patients were stratified into 3 groups: <100 U/ml (24 samples), 100–600 U/ml (15 samples) and >600 U/ml (12 samples). Analysis of CA 125 consisted of calculating the standard deviations and coefficients of variations for each patient's samples. Conclusions: CA 125 assay imprecision contributes considerably to result variations in a conventional laboratory setting, with the degree of variation being directly related to the CA 125 level. However, the relative variability is fairly constant with a median of 1.5–2.5% of the CA 125 level. No significant financial relationships to disclose.
CXCR4/SDF-1 expression in early breast cancer (BC) is not influenced by circulating estrogens serum levels
Authors: G. Marini, S. Grisanti, G. Ruggeri, L. Ardighieri, E. Simoncini, V. Amoroso, G. Rangoni, F. Valcamonico, L. Lucini, F. Facchetti
Journal: Journal of Clinical Oncology (2007)

21159 Background: The chemokine SDF-1 and its receptor CXCR4 have been found to enhance the metastatic potential of BC cells and correlate with a poorer prognosis of BC patients. Estradiol is a known mitogenic factor for BC cells. SDF-1 has been reported to be an estradiol (E2)-inducible autocrine growth factor that supports the growth of breast cancer cell lines in vitro. The aim of this study was to verify whether estrogens serum levels may influence SDF-1 and CXCR4 expression in vivo, in a series of patients with early stage BC. Methods: 68 patients sequentially observed at the Spedali Civili di Brescia from 2001 to 2002, with a diagnosis of T1a,b,c, N0 breast cancer were retrospectively analysed. CXCR4 and SDF-1 expression was determined by immunohistochemistry with anti-human CXCR4 (Clone 44716) and anti-human SDF-1 (Clone 79018) monoclonal antibodies (R&amp;D Systems, Minneapolis, USA) followed by incubation with the EnVision peroxidase kit (Dakocytomation, Glostrup, Denmark). A serum sample was obtained from all patients at baseline before surgery. Serum estrone (E1) and estradiol (E2) were measured by radioimmunoassay by using commercial kits (Alifax, Padua, IT and Ortho-Clinical Diagnostics, Amersham, UK, respectively). Results: Estrogens serum levels analysis revealed elevated levels of E1 in 9/54 (16%) post-menopausal patients, while E2 levels were in the normal ranges. SDF-1 was expressed in 68/68 (100%) patients with a diffuse and intense cytoplasmatic pattern of staining and CXCR4 was coexpressed in 15/68 (22%) patients with a predominant faint nuclear distibution (p 0,06). No significant correlations were found between CXCR4, SDF-1 and E1 or E2, respectively, as well as with other clinico-pathological characteristics. After a median follow-up of 48 months, 3/68 (4%) patients which all resulted CXC4/SDF1-positive, relapsed and are dead for metastatic disease. Conclusions: This study demonstrates that in T1N0 BC patients: 1) SDF-1 is high levels in the majority of cases; 2) CXCR4 is expressed in approximately 20% of cases with restriction to the nucleus and 3) serum levels of circulating E2 and E1 in pre- or post-menopausal patients, respectively, do not influence CXCR4/SDF-1 expression on breast cancer cells. No significant financial relationships to disclose.
Randomized 3-arm, phase 2 study of temsirolimus (CCI-779) in combination with letrozole in postmenopausal women with locally advanced or metastatic breast cancer
Authors: J. T. Carpenter, H. Roché, M. Campone, R. Colomer, A. Jagiello-Gruszfeld, L. Moore, M. D’Amore, S. Kong, J. Boni, J. Baselga
Journal: Journal of Clinical Oncology (2005)

564 Background: Temsirolimus (tem, CCI-779), a novel mTOR inhibitor, is well tolerated and has antitumor activity in heavily pretreated patients (pts) with metastatic breast cancer (MBC, Proc ASCO 22:193,2003). In this trial, we evaluate safety and activity of oral tem in combination with letrozole. Methods: Patients with measurable MBC were randomized in a 1:1:1 ratio (∼30 evaluable pts/arm): 1) letrozole alone or letrozole with 2) tem daily (tem daily arm) or 3) tem daily for 5 days every 2 weeks (tem intermittent arm). All pts received 2.5 mg letrozole daily. Results: Initially, tem doses were 25 mg daily and 75 mg intermittent but were amended to 10 mg daily and 30 mg intermittent because 10 of 12 pts had dose delays, reductions, or discontinuations. Data collected by 15 Nov 2004 are presented for the 92 pts enrolled after the amendment (tem daily: 33; tem intermittent: 30; letrozole alone: 29). Grade 1–4 toxicities, regardless of causality, that occurred in >30% of pts included 10 mg daily: asthenia (45%), mucositis (42%), peripheral edema (36%); 30 mg intermittent: asthenia (63%), mucositis (57%), arthralgia (37%), anorexia (37%), diarrhea (33%), epistaxis (33%); letrozole alone: asthenia (52%), nausea (31%). Grade 3–4 toxicities, regardless of causality, that occurred in >5% of pts included 10 mg daily: hyperglycemia (9%); 30 mg intermittent: hyperglycemia (17%), asthenia (7%), hypertension (7%), hypokalemia (7%); letrozole alone: none. Objective responses (RECIST) occurred, 10 mg daily: 9 PR; 30 mg intermittent: 1 CR, 8 PR; letrozole alone: 2 CR, 10 PR. Clinical benefit (CR + PR + SD ≥8 wks) was 82%, 83%, and 79%, respectively. Progressive disease occurred at ≤8 wks in 12%, 10%, and 14% of pts, respectively. Progression-free survival (PFS) at 1 yr was estimated to be 69%, 62%, and 48%, respectively. Median PFS has been reached for the letrozole alone arm (9.2 mo) but not for the combination arms. Conclusions: Letrozole with 10 mg daily or 30 mg intermittent temsirolimus showed tolerability and clinical activity. Early data suggest that PFS may be longer for the combination arms than for the letrozole alone arm. An actively recruiting phase 3 study is being conducted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wyeth Wyeth Wyeth
EPOCH-FR: A novel salvage regimen for patients with lymphoid malignancies being considered for reduced-intensity allogeneic hematopoietic stem cell transplantation.
Authors: R. B. Salit, D. H. Fowler, W. H. Wilson, S. Z. Pavletic, K. Dunleavy, F. Hakim, S. M. Steinberg, J. Odom, K. Bryant, M. R. Bishop
Journal: Journal of Clinical Oncology (2010)

6536 Background: There is no standard chemotherapy regimen for patients (pts) with lymphoid malignancies being considered for reduced intensity allogeneic hematopoietic stem cell transplantation (RI-alloHSCT). The ideal regimen would result in disease control and recipient lymphocyte depletion and have limited toxicity. We developed a novel regimen consisting of continuous infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus fludarabine ± rituximab, depending on CD20+ expression (EPOCH-FR). Methods: 147 pts, median age 50 yrs (range 21-71), with high-risk lymphoid malignancies (47% with chemo-resistant disease to last regimen, median 3 prior regimens [range 1-13]) were given EPOCH-FR (74% dose-adjusted) prior to RI-alloHSCT. Pts received 1 (48%), 2 (21%), or 3 (31%) cycles of EPOCH- FR until they were lymphodepleted (CD4+ count < 100/μl) or had progressive disease. Results: Overall response rate (RR) was 41% (16% CR, 25% PR); 39% had SD. RR of FCC/CLL>DLBCL/HL>TCL (p = 0.047). More EPOCH-FR cycles were associated with higher RR (17% vs. 33% vs. 84%) (p < 0.0001). 17% of pts with chemo-resistant disease had CR/PR. EPOCH- FR resulted in significant lymphodepletion (pretreatment median CD3+ = 574/μl, CD4+ = 244/μl, and CD8+ = 249/μl vs. posttreatment CD3+ = 184/μl, CD4+ = 97/μl and CD8+ = 68/μl (p < 0.0001). Pts with greater lymphodepletion of CD3+ (p=0.038) and CD4+ (p=0.017) were more likely to achieve CR/PR. Toxicity in 263 cycles included Grade 4 thrombocytopenia in 25%, neutropenia in 65%, and non-heme toxicity in 6%. Of 147 pts, 143 proceeded to RI-alloHSCT. Pts with greater lymphodepletion of CD3+ (p = 0.0007), CD4+ (p = 0.0004), and CD8+ (p = 0.0019) were more likely to achieve full donor lymphoid chimerism by Day +14 post-transplant. Following transplant, pts with CR/PR vs SD/PD to EPOCH-FR had median EFS = 77.4 vs. 4.8 mos (p < 0.0001) and OS = 98.5 vs. 16.2 mos (p = 0.0006) respectively. Conclusions: EPOCH-FR safely provides disease response and lymphodepletion in pts with lymphoid malignancies being considered for RI-alloHSCT. No significant financial relationships to disclose.