tbuckley/cabot-search huggingface dataset:
Examination of genomic copy number alterations in renal cell carcinoma with sarcomatoid features.
Authors: Timothy Ito, Jianming Pei, Essel Dulaimi, Craig Menges, Philip Abbosh, David Y. T. Chen, Richard E. Greenberg, Rosalia Viterbo, Alexander Kutikov, Marc C. Smaldone, Robert G. Uzzo, Joseph R. Testa
Journal: Journal of Clinical Oncology (2015)

478 Background: Sarcomatoid differentiation is an uncommon histological finding in renal cell carcinoma (RCC) that may develop from any RCC subtype and is associated with a very poor prognosis. The identification of genetic alterations that drive this aggressive phenotype could aid in the development of more effective targeted therapies. In this study, we aimed to identify unique copy number alterations (CNAs) in patients with sarcomatoid RCC when compared to those with other RCC subtypes. Methods: Genomic copy number analysis was performed using single nucleotide polymorphism (SNP)-based microarrays on tissue extracted from the tumors of 80 patients (9 with sarcomatoid features (sRCC), 39 clear cell (ccRCC), 26 papillary (pRCC) and 6 chromophobe RCC (chRCC)) who underwent renal mass excision between 2010 - 2014. Statistical analysis was performed using Kaplan Meier (KM) survival analysis, t-tests and Fisher exact tests where appropriate. Results: sRCC tumors exhibited significantly higher numbers of CNAs when compared to ccRCC, pRCC and chRCC (mean 20.1 vs. 6.6 vs. 7.0 vs. 6.3, respectively; p &lt;0.0001). The most common copy number losses occurred in chromosome arms 1p, 3p, 9q, 15q, 18q, 21q, and 22q, with losses of 9q (88%), 15q (77%), 18q (66%), and 22 (77%) being unique among sRCC tumors when compared to the other 3 histologies. The most common copy number gains were in chromosome arms 1q, 8q, 17q, and 20p/q, with 1q (55%) and 8q (66%) gains unique when compared to the other 3 histologies. Of the sRCC tumors, 3 arose from ccRCC, 2 from pRCC and 4 from unclassified RCC. sRCC was associated with worse survival compared to ccRCC, pRCC and chRCC on KM analysis (p=0.0006), and higher rates of lymph node positivity (77% vs. 3% vs. 12% vs. 0%, respectively; p&lt;0.0001) and metastases (100% vs. 13% vs. 4% vs. 0%, respectively; p&lt;0.0001) on presentation were observed with sRCC. Conclusions: Sarcomatoid differentiation in RCC is associated with a high rate of chromosomal changes with unique copy number alterations including losses of 9q, 15q, 18q and 22q and gains of 1q and 8q. Identification and validation of candidate driver genes or tumor suppressor loci within these chromosomal regions may help identify targets for future therapies.
ENGAGE-501: Phase II study investigating the role of epigenetic therapy with entinostat (SNDX-275) in relapsed and refractory Hodgkin's lymphoma (HL).
Authors: A. Younes, P. J. Rosen, F. J. Hernandez-Ilizaliturri, G. Bociek, Y. L. Kasamon, A. Copeland, G. T. Lee
Journal: Journal of Clinical Oncology (2010)

TPS298 Background: Entinostat is an oral, class 1 isoform selective histone deacetylase inhibitor (HDACi) with a half-life of 80- 100 hours in humans and has been well tolerated as a single agent and in combination with other agents tested to date. In preclinical studies entinostat demonstrated a dual effect on apoptotic and immunomodulatory pathways that resulted in significant antitumor activity in HL cell lines and primary patient samples. A phase II study was initiated in HL patients to investigate the hypothesis that entinostat will exhibit antitumor activity through the induction of p21 and TRAIL death receptors, downregulation of STAT-6 expression, modulation of cytokines and chemokines, and upregulation of expression of B cell and other antigens. Methods: ENGAGE-501 is an open-label, multicenter two-stage design. Entry criteria mandates that patients must have failed a primary therapy and if eligible, stem cell transplantation. A dose of entinostat of 10 mg on day 1 and day 15 in 28-day cycles was selected. If 1/9 pts responded in the first stage, an additional 15 patients were to be enrolled for a total of 24 evaluable. The primary endpoint is objective response rate over 6 cycles. Duration of response, progression free survival and overall survival will also be measured. Biomarker evaluations on peripheral blood samples (pre-dose: cycle 1 d1, day 15; d8 at anytime; predose Cycle 3) will include: HDAC activity measured by protein lysine acetylation, RNA expression of genes related to mechanism (e.g., p21, TRAIL death receptors, STAT), cytokines/chemokine array analysis (e.g., TARC, IL-12, IL-5), and flow cytometric analysis of antigens on circulating lymphocyte subsets. Pharmacokinetic evaluation will measure entinostat levels in cycle 1 at pre-dose, 15, 30, 60 and 120 minutes, day 8 and day 15 post entinostat. The study is currently enrolling for the second stage. Based on the initial tolerability, the protocol was amended to allow a dose escalation to 15 mg on day 1 and day 15. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Syndax Abbott Laboratories, Amgen, Biogen Idec, Genentech, MethylGene, Novartis, Pharmion, Sandoz, sanofi-aventis, Seattle Genetics, Trubion, Xencor Syndax Abbott Laboratories, Amgen, Biogen Idec, Genentech, MethylGene, Novartis, Pharmion, Sandoz, sanofi-aventis, Seattle Genetics, Trubion, Xencor
Comprehensive analysis of predictive biomarkers for patients with curative colorectal cancer patients and high risk of recurrence.
Authors: Koichiro Mori, Yuji Toiyama, Susumu Saigusa, Tomofumi Noguchi, Shozo Ide, Hiroki Imaoka, Ryo Uratani, Satoshi Oki, Hiroyuki Fujikawa, Junichiro Hiro, Minako Kobayashi, Masaki Ohi, Toshimitsu Araki, Yasuhiro Inoue, Koji Tanaka, Yasuhiko Mohri, Masato Kusunoki
Journal: Journal of Clinical Oncology (2015)

607 Background: Preoperative serum systemic inflammatory response (SIR) has been reported in patients with various cancers including colorectal cancer (CRC) as predictive biomarker of early recurrence. Molecular phenotypes of CRC including microsatellite instability (MSI) status and tumor infiltrating lymphocytes (TILs) have also known to be associated with recurrence in curative CRC patients. We comprehensively evaluated SIR status, MSI status and TILs in curative CRC patients and investigated which can be promising as high risk markers of recurrence in these patients. Methods: This retrospective study enrolled 157 CRC patients with stage I-III undergoing curative operation for whom preoperative neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and CRP were available as indicators of SIR status. For analysis of molecular phenotypes, we evaluated TILs by counting the number of intra-tumor Foxp3 and CD8 positive T cells by IHC analysis. Next, MSI status was determined in using 5 mononucleotide repeat microsatellite markers. Finally, we investigated the impact of SIR status, TILs and MSI status on the recurrence of these patients. Results: This study included a total of 90 males and 67 females, with an average age of 66.9 years. Twenty-nine patients (18.4%) developed recurrence. Kaplan-Meier analysis using SIR indicators revealed that patients with high CRP, NLR and PLR levels were significantly poorer disease free survival (DFS) than those with low levels. Low infiltrating CD8-positive T cells were significantly predictive factors for poor DFS, but there was no correlation between MSI status and recurrence, In univariate analysis, low infiltrating CD8-positive T cells, high CEA, CRP, NLR and PLR levels in serum were significantly predictive factors for poor DFS, respectively. Multivariate analysis showed that low infiltrating CD8-positive T cells and high serum CRP levels were independent predictive markers for recurrence in curative CRC patients. Conclusions: We demonstrated that evaluation of both CRP levels in preoperative serum and tumor infiltrating CD8 lymphocytes in CRC tissues are useful to predict the curative CRC patients with early relapse.
Octreotide LAR dosage and survival among elderly patients with distant-stage neuroendocrine tumors.
Authors: Chan Shen, Ya-Chen T. Shih, Ying Xu, James C. Yao
Journal: Journal of Clinical Oncology (2015)

392 Background: Octreotide long-acting repeatable (LAR) is approved for the management of symptoms due to carcinoid syndrome and may delay tumor progression among patients with neuroendocrine tumors (NETs). It is unknown whether dosage of octreotide LAR has an impact on survival. The current analysis evaluates the impact of initial octreotide LAR dosage on survival of elderly patients with NETs. Methods: Distant stage NET patients diagnosed between 1/1999 and 12/2009 who had received octreotide LAR treatment within 12 months of diagnosis were identified from the SEER-Medicare database. Those under age 65, enrolled in HMOs, or without continuous enrollment in Medicare Parts A and B were excluded. We compared the five-year survival of NET patients based on dose per 28 days averaged over the initial 3 months: Group A, &lt;= 20 mg; B, 21 to 30 mg; C, &gt; 30 mg. Kaplan-Meier estimations and Cox proportional hazard modeling were used to examine the association between octreotide LAR dose and survival. Results: Among 214 distant stage patients (mean and median age at 74 years old) with octreotide LAR treatment, 73 (34%) received &lt;= 20 mg, 82 (38%) received 21 – 30 mg, while 59 (28%) received &gt;30 mg. Median survival for patients who received low, medium and high dosage levels were 20.8 (95% CI: 13.2 – 31.5), 32.6 (95% CI: 20.5 – 51.1), and 36.3 (95% CI: 24.8 – N/A) months respectively. The log rank test had a p-value of 0.006. Multivariate analyses showed that higher octreotide LAR dosage levels were associated with significant survival improvement for distant stage patients. Compared to patients with the low dosage level, patients with medium dosage (HR=0.52, P=0.002) and patients with high dosage (HR=0.48, P=0.004) had better five-year survival. The difference in survival between Groups B and C was not statistically significant. Conclusions: This population-based study suggests potential survival benefits for octreotide LAR 30 mg dosage level among elderly distant stage NET patients.
Outcome in carcinoma of the uterus with papillary serous and clear cell histology: A Turkish Oncology Group Study
Authors: P. F. Yumuk, S. Kucucuk, B. M. Atasoy, A. Aydin, I. Cicin, F. Yildiz, G. Atkovar, I. Aslay, S. Okkan, E. Topuz
Journal: Journal of Clinical Oncology (2008)

16516 Background: To determine the outcomes of patients with uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CCC) of the endometrium treated in Turkey. Methods: 191 patients with UPSC and CCC, treated in 9 university oncology centers around Turkey between 1991–2007 were analysed retrospectively. Results: Median age was 65 years (29–85yrs). FIGO Stage was IA in 10, IB in 38, IC in 30, IIA in 13, IIB in 26, IIIA in 27, IIIB in 4, IIIC in 41, and IV in 2 patients. 93 patients had UPSC, 91 had CCC, and 7 had UPSC and CCC. 77% of patients had complete surgery, while surgery was incomplete in 41. 2 patients (1%) were medically inoperable. Treatment included radiotherapy (RT) alone (120), chemotherapy (CT) alone (14), CT and RT (46), and none (11). RT was administered as external alone (ERT) in 27%, intravaginal brachitherapy (IBT) alone in 12%, ERT and IBT in 48% of patients, and 13 patients didn’t receive any RT. 14% of stage I, 26% of II, 53% of III patients had CT. Median follow-up was 27 months (3–189). Five-year overall (OS) and disease-free survival (DFS) rates were 61% and 55%. OS was significantly better in younger patients, with early stages and patients receiving RT. There were no survival difference for receiving CT or completeness of surgery when adjusted for stage. Surgery was incomplete in patients with early stage disease, while advanced disease was completely resected in our patient group (p=0.028). A significant difference in recurrence site was seen in patients treated in adjuvant setting between the types of tretment (p<0.001) and types of RT (p=0.001). Conclusions: Administration of ERT with IBT appears to decrease the rate of locoregional recurrences significantly. Positive impact of CT or complete surgical debulking on survival were not shown in this study. These factors need to be further evaluated with prospective studies in this rare but aggressive types of endometrial carcinoma. No significant financial relationships to disclose.
Comprehensive analysis of melanoma antigen specific T cell repertoire: EPIMAX (EPItope MAXimum)
Authors: A. Palucka, J. Banchereau, L. Vence, J. Connolly, J. Fay, H. Ueno
Journal: Journal of Clinical Oncology (2007)

3016 Background: We have demonstrated in phase I clinical trial treating 20 patients with metastatic melanoma that dendritic cells (DCs) loaded with killed allogeneic tumor cells can elicit immune and clinical responses. Loading DC vaccines with killed allogeneic tumor cells allows: i) presentation of antigens via both MHC class I and class II, ii) strong help, iii) applicability to any cancer, and iv) loading tumor antigen independent of HLA haplotype of the patient. However, this renders the immunomonitoring step complex as the antigens and their restriction elements are unknown. To address this issue, we developed EPIMAX. Methods: EPIMAX measures simultaneously cell proliferation and secretion of multiple cytokines that distinguish Type 1, Type 2 cytokines and IL-10 secretion using Luminex. Briefly, 5x10 5 CFSE-labeled PBMCs are plated with peptide pools of overlapping peptide libraries from appropriate antigens. After 48hrs, supernatants are transferred for cytokine determination. After an additional 6 days of culture, cell proliferation is analyzed by flow cytometry after staining for surface markers CD4 and CD8. Results: We demonstrated that EPIMAX permits us to assess: i) Specificity and breadth of induced immune responses, ii) Type of induced immunity (Type I, Type II, IL-10), and iii) Function of specific T cells as measured by cytokine secretion and proliferation. To date 8 patients with stage IV melanoma were analyzed at baseline and after vaccination with DCs loaded with killed allogeneic melanoma cells. We assessed epitopes derived from MART-1, NY-ESO1, TRP-1 and gp100. Analysis of CD8+T cells: We have identified 15 melanoma antigen CD8+T cell epitopes in 8 patients. These include: three Tc0 epitopes (IL2), and twelve Tc1 epitopes triggering IP-10 secretion. Analysis of CD4+T cells: We have identified 15 melanoma antigen CD4+T cell epitopes in 5 patients. These include: nine Th0 epitopes (IL2), four Th1 epitopes (IFNγ) and two Th2 epitopes (IL13). Finally, we analyzed secretion of IL-10 and found thus far IL-10 secreting CD4+T cells in seven patients. Further studies demonstrated that these T cells have regulatory function. Conclusions: EPIMAX permits comprehensive assessment of melanoma antigen specific T cell repertoire. No significant financial relationships to disclose.
Randomised phase III trial of vinflunine (V) plus best supportive care (B) vs B alone as 2<sup>nd</sup> line therapy after a platinum-containing regimen in advanced transitional cell carcinoma of the urothelium (TCCU)
Authors: J. Bellmunt Molins, H. von der Maase, C. Theodore, T. Demkov, B. Komyakow, L. Sengelov, G. Daugaard, A. Caty, J. Carles, N. Morsli, F. Dubois
Journal: Journal of Clinical Oncology (2008)

5028
M-Protein Is Associated With Aggressive Disease In Patients With MALT Lymphoma
Authors: Nobuhiko Yamauchi, Yosuke Nagahata, Yasuhiro Kazuma, June Takeda, Yuki Funayama, Yuichiro Ono, Nobuhiro Hiramoto, Sumie Tabata, Noboru Yonetani, Akiko Matsushita, Hisako Hashimoto, Takayuki Ishikawa
Journal: Blood (2013)
Multicenter, randomized, double-blind, ondansetron (ond)-controlled, dose-ranging, parallel group trial of the neurokinin-1 receptor antagonist (NK-1 RA) casopitant mesylate for chemotherapy-induced nausea/vomiting (CINV) in patients (pts) receiving moderately emetogenic chemotherapy (MEC)
Authors: W. Arpornwirat, I. Albert, V. L. Hansen, M. A. Russo, G. A. Ross, C. D. Pence, R. R. Bandekar, S. M. Grunberg
Journal: Journal of Clinical Oncology (2006)

8512 Background: Casopitant mesylate is a potent, selective, oral NK-1 RA, which has shown activity in preventing CINV in preclinical studies. Based on phase I positron emission tomography (PET) studies, casopitant doses from 50–150 mg result in 70–95% saturation of NK-1 receptors. This phase II trial evaluated the addition of casopitant to standard prophylaxis (ond + dexamethasone [dex]) in pts receiving MEC. Methods: MEC regimens included ≥ 1 of the following (in mg/m 2 ): cyclophosphamide (ctx) 500–1,500 with other MEC; ctx alone 750–1,500; oxaliplatin ≥ 85; doxorubicin ≥ 60; epirubicin ≥ 90; or carboplatin AUC ≥ 5. Pts were stratified by gender and taxane use. Pts in the first 5 arms received ond 8 mg BID days (D) 1–3 + dex 8 mg IV D1 with either placebo, casopitant 50 mg QD D1–3, casopitant 100 mg QD D1–3, casopitant 150 mg QD D1–3, or casopitant 150 mg D1. Arm 6 received a different ond regimen (16 mg QD D1–3) + dex 8 mg IV D1 + casopitant 150 mg QD D1–3. Primary endpoints were rates of complete response (CR [no vomiting, retching, rescue meds or premature withdrawal]) and no significant nausea (SN, assessed by visual analogue scale) during the first 120 h after initiation of MEC. Arms 5/6 were exploratory and not included in primary analysis. Planned enrollment was 118 pts/arm for intent-to-treat (ITT) analysis. Results: ITT group includes 719 pts (60% male, 40% female). CR rate (120h) was 70% with ond control; 81% for casopitant 50mg; 79% for 100mg; and 85% for 150mg (p=.012, Cochran-Armitage trend test). CR rates (24h) and no SN (120h) were similar among all groups. CR and no SN rates in the exploratory arms were 80% and 66%, respectively, in arm 5 and 84% and 70% in arm 6. Adverse events were similar across all arms, with nausea, fatigue, and neutropenia (≤ 24%) as most common. All casopitant doses were generally well tolerated. Conclusions: Casopitant demonstrated activity in control of CINV at all doses, with the 1-day dose of particular interest, when added to a standard ond + dex regimen in both male and female pts receiving a variety of MEC regimens. [Table: see text]
Stanford V regimen in 59 patients (pts) with HD and HIV Infection (HD-HIV): A very effective approach in the long-term analysis
Authors: M. Spina, J. Gabarre, M. Fasan, A. Re, C. Schiantarelli, R. Talamini, R. Talamini, E. Vaccher, U. Tirelli
Journal: Journal of Clinical Oncology (2006)

7583 Background: The introduction of HAART has significantly improved the outcome of pts with HD-HIV. However there are no data on the long-term follow-up of HD-HIV pts treated with conventional chemotherapy (CT) regimens and concomitant HAART. In 2002, we reported the results of a prospective phase II study with the intensive 12-week CT with adjuvant radiotherapy (Stanford V) and concomitant HAART in 59 pts with HD-HIV, a well-known unfavorable subgroup of HD (Spina et al. Blood 2002; 100:1984–1988). Methods: To analyze the long-term outcome of patients included in the Stanford V and HAART protocol. Results: The median follow-up is 53 months (range 3–104 months The overall survival (OS) is 59%, the freedom from progression (FFP) is 62% and the disease free survival (DFS) is 72%. The 5-year probability of OS was significantly different in pts with an international prognostic score (IPS) &lt;3 in comparison to that of pts with an IPS &gt;2 (84% vs 36%, p = 0.001). Similarly, the percentages of FFP at 5 years in these groups were 72% and 45% (p = 0.03). No significant side effects have been observed so far. Conclusions: After a median follow-up of 4.5 years, 72% of pts with this unfavorable subgroup and IPS &lt;3 is free from progression, superimposable to that observed in the general population with comparable adverse prognostic factors. Therefore, Stanford V is a very effective regimen in pts with HD-HIV in the long-term analysis. Supported by AIRC and ISS grants. No significant financial relationships to disclose.
Exceptional responses in patients with metastatic colorectal cancer enrolled in first-in-man studies from 2002 through 2012.
Authors: Shiven B. Patel, Danielle Tometich, Zachary L Reese, Sunil Sharma, Ignacio Garrido-Laguna
Journal: Journal of Clinical Oncology (2015)

687 Background: Understanding exceptional responses to therapy at the molecular level may open new venues for the treatment of patients with metastatic colorectal cancer (mCRC). Responses in first-in-man (FIM) studies with targeted therapies are rare and may indicate that actionable genetic aberrations are present in these patients. Methods: We utilized Scopus using the search term “phase 1 and solid tumors” to collect all FIM studies published between 2002 and 2012. We identified patients with mCRC who attained an exceptional response to therapy defined as a complete response (CR) or a partial response (PR) lasting &gt; 6 months (m). Results: We identified 118 FIM studies enrolling 5,369 patients with advanced malignancies. mCRC was the most common tumor type, totaling 1,055 (19.6%) patients. Of these, two patients enrolled in protocols with MDX-1106 (anti PD-1) and RG7180 (mAb EGFR) attained a complete response (CR). Five patients had PR lasting &gt; 6 m. These patients were treated with RG7180 (time on study 7.8 m), Apatinib, a VEGFR tyrosine kinase inhibitor (8.5 and 7.1 m), PV701, a replication-competent oncolytic virus (10 m) and RO4929097, a gamma-secretase inhibitor (7 m). In addition two patients had PR lasting &lt; 6 m with regorafenib (5.3 m) and RG7180 (5.6 m). This database of exceptional responders to therapy will be publicly available at Huntsman Cancer Institute website. Currently, regorafenib and EGFR mAbs (cetuximab and panitumumab) are approved for use in mCRC. EGFR mAbs have shown improvement in survival in RAS wild-type mCRC. Clinical trials are underway evaluating apatinib. Anti-PD1s have shown limited activity as single agents in mCRC and are currently undergoing testing in combination with chemotherapy. Conclusions: We identified exceptional responses among patients with mCRC enrolled in FIM in the last decade. Ongoing efforts are directed to conduct next generation sequencing (NGS) in archived tissue from these patients. Ultimately, this initiative may facilitate the identification of biomarkers of response to be tested in clinical trials with these or novel drugs sharing similar mechanisms of action.