tbuckley/cabot-search huggingface dataset:
Clinicopathological correlation of beclin-1 expression in human colon cancer.
Authors: S. Choi, S. J. Lim, B. s. Kim, J. J. Lee, W. Kang
Journal: Journal of Clinical Oncology (2011)

464 Background: We investigated the expression of beclin-1 and bcl-2 in human colon cancer tissue by immunohistochemical analysis using a tissue microarray in relation to other prognostic factors. Methods: Tissue samples from 78 cases of invasive colon cancer were used for the present study. A positive control for bcl-2 expression was small lymphocytes in the mantle zone. Immunohistochemical staining for beclin-1 and bcl-2 was evaluated according to intensity and proportion. The intensity score was determined as 0 (no staining), 1 (weak), 2 (moderate) and 3 (strong). The proportion score was determined as 1 (&lt; 30% of tumor cells) and 2 (≥ 30% of tumor cells). The intensity score and proportion score were multiplied together for a total score. Total scores were as follows: 0-1 (negative) and 2-6 (positive). Results: The normal colonic epithelium showed weak to no beclin-1 expression. Positive beclin-1 expression and positive bcl-2 expression of colon cancer cells was observed in 48 cases (61.5%) and 10 cases (12.8%), respectively. beclin-1 expression was significantly correlated with lymph node metastasis (p = 0.035) Bcl-2 expression in colon cancer cells showed no significant correlation with clinocopathologic factors studied. Beclin-1 expression was not correlated with bcl-2 expression in colon cancer cells (p = 0.348). Conclusions: In conclusion, we have characterized the expression of beclin-1 in human colon cancer and the relationship with bcl-2 protein. Our results suggest that it seems reasonable to assume that beclin-1 might play a role in the development of colorectal cancer. No significant financial relationships to disclose.
Persistence of CD30 expression by embryonal carcinoma (EC) in the treatment time course: A retrospective series of multirelapsing germ cell tumors (GCT).
Authors: Patrizia Giannatempo, Andrea Necchi, Maurizio Colecchia, Biagio Paolini, Nicola Nicolai, Daniele Raggi, Mario Catanzaro, Davide Biasoni, Tullio Torelli, Silvia Stagni, Luigi Piva, Roberto Salvioni, Alessandro M. Gianni
Journal: Journal of Clinical Oncology (2013)

329 Background: CD30 is invariably expressed by untreated EC thus lending support to a rationale for a targeted approach. However, preliminary reports claimed an effect of chemotherapy (CT)-induced downmodulation of CD30 that might affect the potential use in relapsing disease. We aimed at evaluating the persistence of CD30-positivity in post-CT residuals. Methods: We retrieved paraffin-embedded post-CT samples yielding non-teratoma viable cells after ≥ 1 CDDP-based CT from the institutional surgical series. EC component was required and assessed by morphology and Oct-3/4 staining. The entire set was re-stained for CD30 and assessed by 2 pathologists blinded to study purpose. CD30-positivity was defined as a &gt;80% membranous staining with a diffuse moderate-to-strong intensity. Clinical data included site of tumor primary, histology, CT regimen, and type of surgery. Results: From 12/1990 to 09/2012, a total of 246 cases with pure EC or mixed GCT residuals were treated. 49 (EC: 16; mixed GCT: 33) had both complete data and suitable tissue for study purposes. 40 pts had retroperitoneal or mediastinal nodes, 12 pts had lung metastases, 4 had either liver, bone or brain mets. 35/49 cases (70%) preserved CD30 positivity. 20/35 (57%) pts had residual disease after 1 st line CT, 15/35 (43%) after multiple CTs (median 3.5, range 2-5). 2 pts (6%) had undergone high-dose CT and 4/35 (11%) were late relapses. 32/35 pts (91%) had gonadal primary, 1 had a retroperitoneal and another a mediastinal primary. The median survival of 35 CD30-positive patients was 16 mos (IQR 3.3-22.9) while it was 48.5 mos (IQR 21.7-72.6) for the 14 CD30-negative patients (p=0.0297 at Gehan-Breslow-Wilcoxon test). 5-year overall survival of CD30-positive and negative patients was 35.7% (95% CI: 18.2-53.6) and 49.7% (95% CI: 19.7-74.0), respectively. Conclusions: Our results on selected relapsing pts suggest that EC retained CD30 even in the far salvage setting, thus confirming to be a reliable target for treatment. A trend towards a poorer prognosis and shorter survival characterized CD30+ cases. A phase 2 study with the antibody-drug conjugate Brentuximab vedotin is currently in plan for GCT.
A phase II study of pegylated liposomal doxorubicin, bortezomib, dexamethasone, and lenalidomide (DVD-R) for patients with relapsed/refractory (R/R) multiple myeloma (MM).
Authors: O. Yellin, J. R. Berenson, T. Kazamel, C. Chen, A. Cartmel, T. B. S. Woliver, M. S. Flam, E. N. Bravin, Y. Nassir, R. A. Vescio, R. Swift
Journal: Journal of Clinical Oncology (2011)

8082 Background: The combination of either pegylated liposomal doxorubicin (PLD) and bortezomib (BORT) or lenalidomide (LEN) and dexamethasone (DEX) have shown significant anti-MM activity. However, both regimens are associated with significant toxicity and produce response rates in only 40-60% of patients. We modified the doses of BORT (1 mg/m2) and PLD (5 mg/m2) and added intravenous (IV) DEX 40 mg with all 3 drugs administered on days 1, 4, 8, and 11 of a 28-day schedule for the treatment of MM patients in both the frontline and R/R setting, and have found this to be a highly effective regimen with reduced toxicities including peripheral neuropathy (PN), cytopenias, and hand-foot syndrome. Methods: This trial is an ongoing, single-arm, multi‐center, phase II study for R/R MM patients. Its objective is to evaluate the combination of IV 40 mg DEX, 1 mg/m2 BORT, 4 mg/m2 PLD on days 1, 4, 8, and 11, and a modified dose of LEN at 10 mg daily on days 1-14 of each 28-day cycle. Patients were treated to maximum response plus 2 additional cycles or to a maximum of 8 cycles of therapy without disease progression. Results: Thirty (of 40 planned) patients have been enrolled to date with data evaluable on 27 patients. Patients were heavily pretreated with a median of 3 (1-17) prior regimens. Nineteen patients (70%) have shown objective responses to the DVD‐R regimen, including 5 complete responses (19%), 4 very good partial responses (15%), 4 partial responses (15%), and 6 minimal responses (22%). An additional 6 patients showed stable disease and 2 progressed while on study. Fifteen patients experienced grade 3 or 4 adverse events, including: reversible neutropenia (n=3), pneumonia (n=4), reversible anemia (n=6), and thrombocytopenia (n=3) with only one patient experiencing a grade 4 reversible thrombocytopenia. Eight (27%) have developed PN with no cases of stomatitis or hand-foot syndrome. Conclusions: Thus, these results suggest that the DVD-R regimen is a well tolerated treatment that produces high response rates for heavily pretreated MM patients with R/R disease.
Phase I study of lapatinib (L) in combination with whole-brain radiation therapy (WBRT) in patients (pts) with brain metastases from HER2-positive breast cancer.
Authors: N. U. Lin, N. Ramakrishna, W. J. Younger, A. M. Storniolo, S. E. Come, R. S. Gelman, E. Eisenberg, E. P. Winer
Journal: Journal of Clinical Oncology (2010)

1154 Background: In preclinical models, lapatinib sensitizes breast cancer cell lines to radiation. This study was designed to determine the maximum tolerated dose (MTD) and feasibility of L + WBRT in pts with brain metastases from HER2+ breast cancer. Methods: Eligible pts had HER2+ breast cancer and at least one brain metastasis. Measurable disease (dz) was not required. Pts received L 750 mg BID on day 1, followed by 1,000 mg, 1,250 mg, or 1,500 mg QD, beginning 1-8 days(d) prior to WBRT (37.5 Gy in 15 fractions) and continuing through RT. Following WBRT, pts received trastuzumab 2 mg/kg weekly and L 1,000 mg QD. The primary endpoint was determination of the MTD, defined as the dose at which DLTs occurred in 7 d during WBRT. Planned accrual at the MTD was 27 pts to fully assess feasibility. The regimen would be considered feasible if ≤ 3/27 patients experienced a DLT. Secondary endpoints included objective response, QOL, and survival. Results: 35/35 planned pts have enrolled. 0/3 pts receiving L 1,000 mg and 0/5 pts receiving L 1,250 mg experienced a DLT. At L 1,500 mg, DLTs were observed in 2 pts: G3 diarrhea and G3 rash, each associated with L dose hold of 16 d during cycle 1. An additional 22 pts were enrolled at the MTD (1,250 mg); DLT have been observed in 5/24 pts with >/=8 wks data (21%, 95% CI 7-42%): 2 cases of pulmonary embolus (PE), 1 pt with G3 herpes simplex rash, 1 pt with G3 hypoxia, 1 pt with G3 hyponatremia/hypokalemia. No G3/4 neurological toxicity has been reported. Of 24 pts with measurable dz and who have at least 8 wks follow-up, 20 (83%, 95% CI 63-95%) achieved an objective CNS response by 1 month after completion of WBRT. Conclusions: The study did not meet the predefined criteria for feasibility. However, the relationship between study treatment and some of the DLTs (e.g. PE) seems uncertain. L + WBRT using this dose or a lower dose of L could still be considered in future trials, though careful safety monitoring would be required. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline BrainLAB Genentech, GlaxoSmithKline
Standardizing quality breast cancer care throughout all New York university facilities.
Authors: Anna C. Pavlick, Freya Ruth Schnabel, Amy Tiersten, Matthew Volm, Jennifer J. Wu, Cindy Boester, William L. Carroll
Journal: Journal of Clinical Oncology (2012)

160 Background: NYU physicians provide breast cancer care (BCC) at several locations throughout New York. The NYU Clinical Cancer Center (NYUCCC) is a private, university-based facility while Bellevue and Woodhull Hospitals are city hospitals. The diversity of BCC provided to patients (pts) in city hospitals can vary greatly from that of private centers and intra-center physician variability also diversifies care. This variability can impact on pt satisfaction and outcomes. Breast cancer (Br Ca) pts make up the greatest number of pts seen and treated at all NYU affiliated sites, therefore, a "Br Ca Quality of Care Program" will be incorporated into the electronic medical record (EMR) at all facilities. A treatment algorithm based on the pt’s stage and a simple "drop-down menus" will simplify use. It will encompass diagnostic imaging, pathology, biopsy procedures, surgery, radiation, chemo, and hormonal therapy as well as survivorship guidelines for maintaining wellness. Methods: Leaders of each Br Ca program have identified potential barriers to care and rectifiable issues. Algorithms and “drop down menus” in the EMR will be presented to the NYUCCC Br Ca physicians for feedback. This tool will then be refined and launched at NYUCCC. After evaluating this program at NYUCCC, the data will be presented to the all NYUCCC faculty. Achieving the city hospitals to adopt this EMR program will be the ultimate success and standardized quality care will be the result. Results: An assessment of the endpoints of physician adherence to guidelines, cost effectiveness and pt/provider satisfaction will be conducted 6 months later. Random audits of breast cancer pt charts will evaluate provider compliance. A cost analysis of this care will be done and compared to a random sampling of previously treated pt charts. Review and analysis of this data would be presented to the NYUCCC faculty, then programs launched at both city-hospitals. Conclusions: If the endpoints of quality standardized care, cost effectiveness and pt/provider satisfaction are met, incorporation of similar programs into other high volume oncologic disease entities seen at all NYU facilities would be developed.
Treatment-related hypertension (HTN) as a predictive biomarker for clinical outcomes in patients (pts) with advanced pancreas cancer (APCA) treated with bevacizumab (B): A pooled analysis of four prospective clinical trials.
Authors: Ludmila Katherine Martin, Lai Wei, Katherine Van Loon, Renuka V. Iyer, Shubham Pant, David R. Fogelman, Andrew H. Ko, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2013)

239 Background: Phase III studies of B in unselected APCA pts have been negative. Recent data suggest subsets of pts may benefit from B, but no validated predictive biomarkers exist for B efficacy in APCA. The pathogenesis of B-related HTN (B-HTN) is not well understood, but studies suggest association between B-HTN and improved clinical outcome in various advanced solid tumors. We conducted a pooled analysis of raw data from 4 prospective clinical trials to evaluate that predictive role of B-HTN in APCA. Methods: Relevant raw data were collected from 4 multi-institution single-arm phase II trials of GEM-based doublet chemotherapy + B as 1st line treatment of APCA. Pts were grouped according to B-HTN of any grade (Group 1) and no B-HTN (Group 2). Clinical outcomes including OS, TTP, ORR, and DCR (disease control rate = ORR + SD &gt;16 weeks) were compared between Group 1 and 2. For pts in Group 1, outcomes were also compared according to CTCAE HTN grade (1-2 vs 3-4). Results: 166 pts (85 M, 81 F) with median age 55 (31-85) were included. Group 1= 37 pts (Grade 1-2 HTN, N=18; Grade 3-4 HTN, N=19), Group 2 = 129 pts. Demographics were similar except % stage 4 (92% group 1, 100% group 2, p=0.01). Results are summarized in the Table. Group 1 had significantly prolonged mOS and mTTPand improved ORR and DCR vs Group 2. There was no difference in outcome according to HTN grade. Conclusions: B-HTN of any grade may be an important pharmacodynamic biomarker for B in APCA. This subset of pts could benefit from B and identification of characteristics that predict development of B-HTN may aid in future pt selection for B therapy in APCA. Future prospective studies may consider pharmacodynamic titration of B to grade &gt; 1 HTN to potentially maximize B efficacy. [Table: see text]
Nomograms for overall survival (OS) and progression-free survival (PFS) in metastatic colorectal cancer (mCRC): Construction from 19,678 ARCAD patients.
Authors: Katrin Marie Sjoquist, Lindsay A. Renfro, John Simes, Niall C. Tebbutt, Stephen John Clarke, Jeffrey P. Meyers, Wilson I. Gonsalves, Richard Adams, Matthew T. Seymour, Leonard Saltz, Hans Schmoll, Daniel J. Sargent, Aimery De Gramont, John Raymond Zalcberg
Journal: Journal of Clinical Oncology (2015)

659 Background: Prospective survival prediction of patients with metastatic colorectal cancer is difficult. Prognosis estimation based on readily available clinicopathologic factors has the potential to inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic nomograms for OS and PFS in mCRC using the multi-trial ARCAD database. Methods: Data from 19,678 mCRC pts accrued to 24 first line randomized phase III clinical trials since 1997 were used to construct and validate Cox models for PFS and OS, stratified by treatment arm within each study. Candidate variables included age, gender, BMI, performance status, colon vs. rectal cancer, prior chemotherapy, number of metastatic sites, sites of metastases (liver, lung, lymph nodes), and baseline bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil:lymphocyte ratio (dNLR). Missing data (&lt;11%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions considered if p&lt;0.001. Final models were internally validated via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices, and externally validated using a 10% holdout sample from each trial. Results: Nomograms for OS and PFS including remaining variables were well calibrated with C-indices of 0.66 and 0.60, respectively. Evaluation of external validity revealed good concordance; 71% and 67% respectively between predicted (&gt; vs. &lt;50% probability) and actual (yes/no) 1-year OS and 6-month PFS, and median 1-year OS and 6-month PFS predictions fell within the actual 95% Kaplan-Meier intervals. Gender, liver and lung metastases, and dNLR were not prognostic for OS; prior chemo, colon vs. rectum, dNLR, liver and lymph node metastases, and gender did not predict for PFS. No clinically relevant pairwise interactions were identified. Conclusions: The proposed nomograms are well calibrated and internally and externally valid. These tools have the potential to aid prognostication and patient/physician communication, and balance risk in randomized trials in mCRC.
A multicenter, open-label phase II trial of dovitinib (TKI258) in advanced urothelial carcinoma patients with either mutated or wild-type FGFR3.
Authors: M. I. Milowsky, G. L. Carlson, M. M. Shi, G. Urbanowitz, Y. Zhang, C. N. Sternberg
Journal: Journal of Clinical Oncology (2011)

TPS186 Background: Dovitinib (TKI258) is an oral investigational drug that inhibits angiogenic factors, including the fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor with IC50 values of ≈ 10 nM. Increased signaling through FGFR3 characterizes many urothelial carcinoma (UC) tumors, which may contribute to both tumor development and vascularization. The increase in FGFR3 signaling may arise from mutations, though many UC tumors without mutations also overexpress FGFR3. Dovitinib has demonstrated inhibition of tumor growth and proliferation in UC models selected for the presence of FGFR3 activating mutations or protein overexpression. These data support testing in advanced UC patients (pts) relapsed or refractory to standard first-line chemotherapy, for whom no standard therapy exists. Methods: This multicenter, 2-stage, open-label phase II trial will determine the safety and efficacy of dovitinib administered at a dose of 500 mg/day on a 5 days on/2 days off dosing schedule in advanced UC pts. In stage 1, 40 pts will be stratified into 2 groups of 20, based on the presence or absence of mutation in the FGFR3 gene. The 2 groups will be recruited and analyzed independently. An additional 20 pts per group will be enrolled in stage 2 if the predetermined response criteria of at least 2 responding pts is met in that group in stage 1. Treatment will continue until disease progression or the occurrence of unacceptable toxicity. Pts must have received at least 1 but no more than 3 prior treatment regimens for UC. Archival tissue for analysis of FGFR3 mutational status is required. The primary objective is overall response rate. Secondary objectives include safety, progression-free survival, overall survival, and disease control rate. Biomarkers related to dovitinib’s mechanism of action will be measured and their correlation with clinical response will be explored. Currently, 29 FGFR3 wild-type and 11 FGFR3-mutant patients have been enrolled in stage 1. A decision to open stage 2 for wild-type FGFR3 patients is pending.
The old antibiotic acriflavine inhibits epithelial-to-mesenchymal transition and the unfolded protein response thereby resensitizing resistant hepatoma cells to sorafenib
Authors: Jeroen Dekervel, Ashenafi Shiferaw Bulle, Petra Windmolders, Diether Lambrechts, Eric Van Cutsem, Chris Verslype, Jos van Pelt
Journal: Hepatology (2016)
miR-34a as a prognostic marker of relapse in non-small-cell lung cancer (NSCLC) patients (p)after curative surgery
Authors: E. Gallardo, A. Navarro, E. Carcereny, S. Jansa, N. Viñolas, R. Marrades, J. Ramirez, M. Monzo
Journal: Journal of Clinical Oncology (2008)

11029 Background: MicroRNAs(miRNAs) are small non coding RNAs that inhibit the translation of mRNA to protein by binding to the 3´UTR region. Several miRNAs have emerged as components of oncogene and tumour suppressor networks. We analyzed the following miRNAs: hsa-let 7a, hsa-let 7c, hsa-let 7f, hsa-miR-17–5p, hsa-miR-17–3p, hsa-miR-21, hsa-miR-155, hsa-miR-145 and hsa-miR-34a, in surgical samples from primary surgery of NSCLC p. Methods: Between January 1997 and December 2001, 54 NSCLC p from a single institution (median age 65; range 35–85; males 98%) underwent curative surgery as first and only treatment. 25 adenocarcinoma (46.3%), 26 squamous (48.1%), 2 large cell (3.7%) and 1 bronchioalveolar (1.9%). Disease Stage: I (57%), II (26.3%) and III (15%). Follow-up after surgery of five years( unless in 4 p) or until relapse or death. 30 p (55.6%) relapsed. Total RNA was extracted from formalin-fixed paraffin embedded surgical tumour samples using Recover All Total Nucleic Acid Isolation (Ambion). Mature miRNA expression was analyzed by stem loop RT-PCR and Real Time PCR( TaqMan) in a 7500 Sequence Detection system (AB). Statistical analysis was performed with SPSS 14.0. The characteristics considered were age (65), WHO histological classification, Stage and the expression of above-mentioned miRNAs. Clinical outcomes analyzed were relapse rate. Results: In the Kaplan Meier analysis patients with low expression of miR-34a had higher probability of relapse than patients with high expression (Log Rank p=0.014). In the multivariate analysis the miR-34a (RR 2.40 p=0.030) and disease stage (RR 3.32 p=0.011) were the only prognostic factor for relapse. Conclusion: The results of this retrospective analysis suggest that miR-34a could be a prognostic marker for relapse in NSCLC p after curative surgery. miR-34a has recently been recognized as a target of p53, which could help to explain these results. No significant financial relationships to disclose.
Targeted therapies in early-phase trials for the treatment of advanced fibrolamellar hepatocellular carcinoma.
Authors: Ishwaria Mohan Subbiah, Vivek Subbiah, Aung Naing, Siqing Fu, Ahmed Omar Kaseb, Gerald Steven Falchook, Dongfeng Tan, Cynthia E. Herzog, Filip Janku, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2013)

232 Background: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare primary liver malignancy, affecting young adults w/o chronic liver disease. Limited data exists on the novel therapeutics for this disease. Methods: Given its rarity, we evaluated the characteristics, outcomes and performed molecular analysis for targetable pathways in patients with FLHCC enrolled on phase I trials with an emphasis on targeted therapies. Results: Ten FLHCC patients (8 female, 2 male; median age 23yrs) were evaluated in the Phase I Clinic. Eight had recurrence from prior resections. Eight patients enrolled on a phase I trial. Pt #7 (58F w recurrence post-resection), received sunitinib (inhibitor of PDGFR, VEGFR, FLT3, RET) with valproic acid (HDAC inhibitor) and had a 41% decrease per RECIST for 16.5 months without any high-grade toxicities. Pt #5 (24F) had a 22% decrease for 5.4 months pazopanib (inhibitor of VEGFR, PDGFR, FGFR, cKIT) and vorinostat (HDAC inhibitor). Pt #8 remains on study with bevacizumab+sorafenib now for 5 months with 9% decrease. Pt #1 received a novel proteosome inhibitor with stable disease &gt;9 months while pts #3, #5, and #7 received HDAC inhibitors vorinostat and valproic acid. Analysis for molecular aberrations and next generation sequencing are in progress with preliminary data showing the activation of the PI3K/AKT/mTOR signaling pathway. Conclusions: This work is the first such to report on the use of targeted therapies in advanced FLHCC. Overall pts tolerate targeted therapy with early data showing clinical efficacy and biologic activity of multikinase inhibitors, specifically sunitinib and pazopanib, in combination with HDAC inhibitors, valproic acid and vorinostat. Li et al report morphoproteomic analysis showing high expression of phosphorylated (p)-NF-κBp65 (at serine 536, a putative site of activation) in FLHCC in comparison to normal liver (p &lt; 0.001) in 7 of 8 (88%) tested FL-HCC samples, signifying the constitutive activation of the NF-κB pathway and the therapeutic potential of proteosome inhibitors and HDAC inhibitors. Given the lack of consensus on treatment of unresectable FLHCC, this analysis presents seminal data on targeted agents for these patients.