tbuckley/cabot-search huggingface dataset:
Erythropoietin and erythropoietin receptor coexpression is associated with poor survival in stage I non-small cell lung cancer
Authors: P. Saintigny, B. Besse, P. Callard, A. Vergnaud, S. Czernichow, M. Colombat, P. Girard, P. Validire, J. Breau, J. Bernaudin, J. Soria
Journal: Journal of Clinical Oncology (2007)

7655 Background: The role of erythropoietin (EPO) and its receptor (EPO-R) in tumor biology is under active investigation. This study was designed to evaluate the prognostic impact of EPO and EPO-R expression in stage I non-small cell lung cancer (NSCLC) patients. Methods: EPO and EPO-R expression in 158 tumor samples from resected stage I NSCLC was evaluated using immunohistochemistry and tissue-array technology. Disease specific survival time was calculated from the date of surgery to death from cancer-related causes. Results: EPOR and EPO were highly expressed in 20.9% and 35.4% of the tumors respectively. High EPO-R compared to negative or low level of expression was associated with a poor 5-year disease specific survival (60.6% versus 80.8%, logrank test: p=0.01). High EPO compared to negative and low level of expression was associated with a trend toward a poor 5-year disease specific survival (69.6% versus 80.4%, logrank test: p=0.13). High level of EPO-R and EPO coexpression compared to other groups of patients was associated with a poor 5- year disease specific survival (50.0% versus 80.0% of survival at the end of follow-up, logrank test: p=0.005). In multivariate analysis for disease specific survival, high level of EPO-R and EPO coexpression was an independent prognostic factor for disease specific survival (HR 2.214, 95% CI: 1.012–4.848, p=0.046). Conclusions: These results establish for the first time the pejorative prognostic value of EPO and EPO-R expression in early stage resected NSCLC and suggest a potential paracrine and/or autocrine role of endogenous EPO in NSCLC aggressiveness. No significant financial relationships to disclose.
Abstract LB-050: Patient-derived tumor xenografts in humanized NSG mice: a model to study immune responses in cancer therapy
Authors: Minan Wang, James G. Keck, Mingshan Cheng, Danying Cai, Leonard Shultz, Karolina Palucka, Jacques Banchereau, Carol Bult, Rick Huntress
Journal: Cancer Research (2015)

Abstract Mouse models are frequently used to test the therapeutic efficacy of anti-cancer drugs. However, the translation of murine experimental data to treatments for patients with cancer often fails due to significant differences between the species, including the differences in the immune system. Our goal is to bridge this gap and to establish an in vivo preclinical model of human tumor immunotherapy by engrafting immunodeficient mice expressing a partial human immune system with human tumor implants. Humanized NOD-scid IL2Rγ (null) (hu-NSG) mice were initially generated by transplanting NSG mice with human CD34+ hematopoietic stem and progenitor cells (HSPCs) which support human hematopoietic and immune system development. Hu-NSG mice develop functional human T cells and B cells with high levels of TCR excision circles, complex TCR repertoire diversity and antigen-specific T cell proliferative responses. Several types of patient-derived tumors (non small cell lung cancer, sarcoma, triple negative breast cancer and invasive bladder cancer) were successfully implanted into HLA mismatched hu-NSG mice. Tumor growth curves show a delay in tumor growth in hu-NSG compared to non-humanized NSG mice. In a colon cancer xenograft model, treatment with chemotherapy agent (5-FU) or with a therapeutic antibody directed against VEGF (Avastin) resulted in decreased tumor growth. In addition to PDX tumors we have also tested human cancer cell lines. Tumor growth was observed in all hu-NSG mice implanted with human ovarian tumor cell line SKOV3-Luc-D3 cells at different time points post HSPC engraftment, showing no evidence of tumor rejection. Thus, our model of humanized mice bearing tumor-derived xenografts provides opportunities to study both the safety and efficacy of current cancer therapies. Citation Format: Minan Wang, James G. Keck, Mingshan Cheng, Danying Cai, Leonard Shultz, Karolina Palucka, Jacques Banchereau, Carol Bult, Rick Huntress. Patient-derived tumor xenografts in humanized NSG mice: a model to study immune responses in cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-050. doi:10.1158/1538-7445.AM2015-LB-050
Abstract 5032: Acute phase liver graft injury mobilizes regulating B cells after transplantation for HCC patients through TLR4/CXCL10/CXCR3 signaling
Authors: Kwan Man, Yan Shao, Chang Xian Li, Chung Mau Lo
Journal: Cancer Research (2015)

Abstract We aim to investigate the impact of acute-phase small-for-size graft injury on mobilization of circulating regulating B cells (Bregs) in HCC patients after liver transplantation and to explore the molecular mechanism therein. Methods From May 2000 to November 2009, 115 HCC recipients were included. The intragraft gene expression profile and Bregs infiltration of the grafts greater (Group 1) and less than 60% (Group 2) of standard liver weight (SLW) were detected by RT-PCR and immunostaining. Circulating Bregs (CD19+CD24hiCD38hi) were compared by FACS analysis after transplantation. Clinical-pathological data including the incidence of tumor recurrence and metastasis were compared. The direct roles of TLR4, CXCL10 and CXCR3 on circulating Bregs mobilization were investigated in TLR4-/-, CXCL10-/- and CXCR3-/- mice models, respectively. The association of intragraft Bregs infiltration and tumor invasiveness were also examined in a rat liver transplantation for liver cancer model. The role of Bregs on liver tumor growth and invasiveness were further studied in a series of in vitro and in vivo functional experiments. Results The patients were grouped into Group 1 (&amp;gt; = 60% SLW, n = 37) and Group 2 (&amp;lt;60% SLW, n = 78). Much more patients in Group 2 developed tumor recurrence and lung metastasis [19/78(24.4%) vs 3/37(8%), p = 0.04]. Level of circulating Bregs was significantly higher in Group 2 (Week1: 7.02 vs 1.31/10^5PBMC, p = 0.03; month3: 5.7 vs 1.3/10^5PBMC, p = 0.03). There was more intragraft Bregs infiltration in group 2 indicated by CD20/IL10 staining. Intragraft gene expression of TLR4, CXCL10 and CXCR3 were significantly higher in Group 2 at early phase after transplantation. In rat liver transplantation model, more Bregs infiltration at early phase after transplantation correlated with late phase invasive tumor growth. Levels of circulating Bregs were significantly lower in the mice model with major hepatectomy and hepatic I/R injury using TLR4-/-, CXCL10-/- and CXCR3-/- mice, respectively. Bregs also promoted liver cancer cell proliferation and migration in vitro, and tumor growth in vivo. Conclusion A significantly higher population of circulating Bregs, which are mobilized by small-for-size graft injury, may lead to a higher incidence of tumor recurrence and metastasis after LDLT. TLR4/CXCL10/CXCR3 signaling may play important roles on Bregs mobilization. Citation Format: Kwan Man, Yan Shao, Chang Xian Li, Chung Mau Lo. Acute phase liver graft injury mobilizes regulating B cells after transplantation for HCC patients through TLR4/CXCL10/CXCR3 signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5032. doi:10.1158/1538-7445.AM2015-5032
An autologous Vγ9Vδ2 T lymphocytes cell therapy product generated by BrHPP (INNACELL Gamma Delta [IGD]) in metastatic renal cell carcinoma patients: Phase I clinical trial results
Authors: E. Bompas, E. M. Neidhardt, F. Rolland, I. Philip, C. Galéa, S. Salot, J. Tiollier, S. Saiagh, S. Negrier, J. Bennouna
Journal: Journal of Clinical Oncology (2006)

2550 Background: Vγ9Vδ2 (γδ) T lymphocytes, a peripheral blood lymphocyte subset, have shown to be directly cytotoxic against renal carcinoma cells. Lymphocytes γδ can be selectively expanded ex vivo with BrHPP (Phosphostim) and IL-2. We conducted a phase I trial, to define the dose limiting toxicities (DLT), characterize the safety profile, the pharmacodynamics and potential efficacy. Methods: Patients (pts), with progressive mRCC, PS of 0–1 and no organ dysfunction, were included. A one hour iv infusion of IGD was administered alone at cycle 1, and combined with low dose of sc IL-2 (2 MIU/m 2 d1 to d7) in the 2 subsequent cycles (every 3 weeks). IGD dose was escalated from 1, up to 8 billions cells (bil). Results: 10 mRCC pts were treated in the study at 3 IGD dose levels: 1 patient at 1 bil, 6 pts at 4 bil, 3 pts at 8 bil. One patient experienced a grade (G)3 hypotension (4 bil, cycle 3), and one patient presented reversible signs of biological disseminated intravascular coagulation (8 bil, cycle 2) graded as a serious adverse event and fulfilling a DLT criteria. At all doses the treatment was well tolerated during the product alone infusion (cycle 1). The most frequent type of adverse events presented was mild to moderate flue like symptomes as fever, chills and asthenia reported during the second and third cycles in the IL-2 combined cycles. Patients presented also gastrointestinal symptoms as nausea and vomiting of grade 1 or 2. Preliminary efficacy assessment evaluation shows: 2 pts were not evaluable, 3 pts were withdrawn for disease progression at 3, 8 and 11 weeks, 2 pts maintained a stable disease for 36 and 63 weeks, and 2 pts are still under follow up with a stable disease at &gt;91 and &gt;124 weeks post treatment. Of note, one patient showed a 19% decrease in tumour size and another one presented a significant pain decrease leading to quality of life improvement. One other patient recently treated, is still under follow-up without progression after &gt;16 weeks post treatment. Conclusion: IGD in combination with sc low dose IL-2 is safe, well tolerated, and shows promising antitumor signs of efficacy. These results warrant further product evaluation in phase 2 clinical trials. [Table: see text]
A pilot study of the individualized maximum repeatable dose (iMRD), a new dose-finding system, of weekly paclitaxel for patients with metastatic stomach cancer as second line therapy -including a PK study-
Authors: Y. Takahashi, K. Yamashita, M. Mai
Journal: Journal of Clinical Oncology (2005)

4238 Background: We developed and established a new dose-finding system, the individualized maximum repeatable dose (iMRD), suitable to induce prolonged TTP rather than tumor shrinkage, which is determined by toxicity grade 1 marrow depression (ASCO 2003, and Pancreas, in press). Method: We applied this system in weekly paclitaxel therapy for 21 metastatic gastric cancer patients as second line therapy. We determined the iMRD at the 5th week, after weekly dose adjustments. We started at 60 mg/m2 of paclitaxel and repeated the treatment with an increase or a decrease of 10 mg/m2 each week, if toxicity was 0 or more than grade 1, respectively. Moreover, we studied the correlation between iMRD and AUC at 60 mg/m2 of paclitaxel in 11 patients. Results: The iMRD of weekly gemcitabine was 40 mg/m2 in 1 patient, 50 mg/m2 in 6 patients, 60 mg/m2 in 6 patients, 70 mg/m2 in 4 patients, and 80 mg/m2 in 1 patient, demonstrating the significant differences among individual patients. Grade 3 marrow depression occurred in 2 patients (9.5%). Of these 21 patients studied, 5 (23.8%), 12 (57.2%) and 4 (19.0%) patients showed PR, SD and PD, respectively. The median TTP and survival were 5.0 months and 9.5 months, respectively. AUC at 60 mg/m2 of paclitaxel ranged from 1894 ng/ml*hr to 4352 ng/ml*hr and showed a significant reverse correlation with their iMRD (p<0.05). Conclusion: These results suggest that iMRD can be a simple method to determine an individual`s tailored dose for chemotherapy and could be the optimal dose for patients with non-curable cancers such as metastatic stomach cancer, and could be predicted by the AUC of the starting dose. No significant financial relationships to disclose.
A phase 1 study of MM-111, a bispecific HER2/HER3 antibody fusion protein, combined with multiple treatment regimens in patients with advanced HER2-positive solid tumors.
Authors: Donald A. Richards, Fadi S. Braiteh, A. A. Garcia, Crystal Shereen Denlinger, Paul R. Conkling, William Jeffery Edenfield, Stephen Patrick Anthony, Beth A. Hellerstedt, Robert N. Raju, Carlos Becerra, Wael A. Harb, David A. Smith, Charlotte Fenton McDonagh, Kate-Lyn Kawash, Sasha Frye, Victor M. Moyo
Journal: Journal of Clinical Oncology (2014)

651 Background: MM-111 (111) inhibits ligand activated HER3 signaling in HER2+ tumors. This study evaluated the safety of 111 combined with standard of care (SOC) HER2-targeting regimens (Rx): capecitabine (X) + cisplatin (C) + trastuzumab (T) (Arm 1); lapatinib (L) +/- trastuzumab (Arm 2); paclitaxel (P) + trastuzumab (Arm 3); lapatinib + paclitaxel + trastuzumab (Arm 4); docetaxel (D) + trastuzumab (Arm 5). Methods: This was a multi-arm Phase 1, dose escalation study of 111 in combination with SOC regimens to evaluate safety, pharmacokinetics (PK), and anti-tumor activity. Patients were required to have documented advanced HER2-positive cancer and adequate organ function. Each arm was designed to run as a separate Phase 1 study to address safety and tolerability and utilized a "3 + 3" design with standard dosing of the SOC regimen. 111 was dosed weekly at 10 mg/kg and escalated up to 20 mg/kg where possible. For Arm 5, 111 was dosed q3w starting at 30mg/kg and escalated up to 40mg/kg. Results: A total of 86 patients (11 bladder, 46 breast, 15 gastro-esophageal, 14 other cancers) were enrolled and treated across all five arms. Dose-limiting toxicities (DLTs) included anemia, acute renal failure (assessed as cisplatin-related), chest pain, decreased appetite, diarrhea, febrile neutropenia, hyperuricemia, hypokalemia, hyponatremia, hypophosphatemia, mucosal inflammation, nausea, neutropenia, stomatitis, thrombocytopenia, and vomiting. An MTD was not reached in Arms 2-5; Arm 1 required a capecitabine dose reduction. Conclusions: Treatment with 111 and SOC HER2-directed regimens was feasible. The Recommended 111 Phase 2 doses are 20mg/kg QW and 40mg/Q3W. Additional safety, PK and preliminary activity data will be provided. Clinical trial information: NCT01304784.Patient outcomes summary. Arm Rx (Dose) Units 111 and T (mg/kg) X, D, C and P (mg/m2) Arm 1 X (1000) C (80) T (4/2) 111 (5-10) Arm 2 T (4/2) L (1000) 111 (10-20) Arm 3 P (80) T (4/2) 111 (10-20) Arm 4 P (80) L (750) T (4/2) 111 (10-20) Arm 5 D (75) T (8/6) 111 (30-40) N (safety population) 17 31* 23 9 6 DLT 6 4 1 1 0 SAE 5 12 6 4 1 N (evaluable population) 14 24 21 9 6 CR; PR; SD 1 CR;3 PR;6 SD 4 PR;10 SD 6 PR;7 SD 4 PR; 3 SD 1 PR; 2 SD *10 patients did not receive T.
COM-1 is over-expressed in human colorectal carcinomas
Authors: M. L. Davies, G. Watkins, J. Torkington, O. Fodstad, W. G. Jiang
Journal: Journal of Clinical Oncology (2007)

21001 Background: COM-1, candidate of metastasis-1, is a primarily nuclear protein thought to play a role in the development and maintenance of metastatic tumours and to have some mitogenic activity. However subsequent investigations have demonstrated a much more diverse role in cancer and cell growth. Here we have investigated the expression and sub-cellular distribution patterns of COM-1 in human colorectal carcinomas. Methods: Carcinoma and normal matched tissues were collected following surgery and frozen for future analysis. Sections of tissue underwent immuno-histochemistry (IHC) staining for COM-1 to determine degree of staining and changes in cellular distribution of the proteins within the tissue. Furthermore, quantitative analysis (quantitative polymerase chain reaction - qPCR) of mRNA levels of COM-1 transcripts was performed to compare levels in normal tissue with those in carcinoma tissues. Statistical analysis was by the Mann-Whitney test. Results: IHC -Normal tissue demonstrated strong nuclear staining for COM-1 protein with little or no cytoplasmic staining. In carcinoma tissue the level of overall staining was found to be much greater, with a greater degree of cytoplasmic staining and little evidence of nuclear staining. qPCR- COM-1 mRNA expression within cells was significantly higher within tumour tissue when compared to normal tissue (Mean 36.7 v 26.5, p=0.003). Moreover, there was a trend in increasing levels of expression and significance of difference between normal tissue and carcinoma tissue with increasing Dukes stage (A p=.52, B p=0.03, C p=0.03) , T-Stage (1 p=1.0, 2 p=0.69, 3 p=0.04, 4 p=0.03), Nodal status (−ve p=0.07, +ve p=0.04 and tumour differentiation (well diff p=0.91, Mod. Diff p= 0.06, Poor. Diff. p= 0.026). Conclusions: COM-1 expression is increased in colorectal tumour tissues when compared to normal mucosa. This is reflected at both the protein and mRNA levels within the cells. In addition there is evidence of dislocated expression and redistribution of COM-1 protein with normal protein expression remaining intra-nuclear however, in tumours COM-1 then becomes cytoplasmic. Aberant over-expression of COM-1 has been identified in other human carcinoma types and has been linked with advanced disease, here we have demonstrated a similar pattern in colorectal carcinomas. No significant financial relationships to disclose.
The role of FDG-PET before and 3 weeks after neoadjuant chemoradiotherapy (NACRT) in predicting N2 clearing and survival after surgical resection in patients with biopsy-proven N2 positive non-small cell lung carcinoma (NSCLC)
Authors: G. Jang, S. Kim, J. Ryu, D. Moon, H. Sohn, D. Lee, C. Suh, J. Lee, E. Choi, S. Park
Journal: Journal of Clinical Oncology (2008)

7503 Background: Downstaging via NACRT is a significant prognostic factor for better survival in patients (pts) with NSCLC. Thus, identification of N2 clearing after NACRT is a critical factor for patient selection for thoracotomy. We evaluated the usefulness of FDG- PET in predicting N2 clearing after NACRT and survival after surgical resection in pts with N2 positive NSCLC. Methods: From November 2002 to October 2006, 45 pts with biopsy-proven N2 positive NSCLC were enrolled for NACRT. Thirty-four pts who had FDG-PET data before and after NACRT and underwent surgical resection were analyzed. They received 6 weekly chemotherapy with paclitaxel (50mg/m2)/cisplatin (20mg/m2) and concurrent radiotherapy (1.8Gy/day x 5/week, 45 Gy) during 5 weeks. FDG-PET scan was repeated before and 3 weeks after NACRT. Maximum standardized uptake values (SUVmax) of primary tumor and N2 nodes were measured, and percent changes in SUVmax were calculated. After surgery, the pathology of N2 nodes was assessed. Results: After NACRT, overall mean SUVmax of primary mass and N2 nodes decreased from 7.02±3.68, 6.78±4.18 to 1.80±1.27, 1.52±1.74 (74%, 78% reduction, respectively) and 17/34 pts had metabolic N2 clearing (including 8 false negative) and 17/34 pts had remained positive N2 (including 10 false positive) by FDG-PET. Mean percentage changes of SUVmax of primary mass and N2 nodes in pathologic N2 clearing group (n=19) were 75% and 76% and those with remained N2 group (n=15) were 67% and 78%, with no significant difference between two groups. Median progression-free survival (PFS) and overall survival (OS) of all 34 pts were 38 months and 45 months with median follow-up duration of 34 months (range 9–56). Median PFS in pts who achieved a reduction in SUVmax of N2 nodes of more than 60% and in pts who achieved one of less than 60% were 38 months and 14 months (log-rank test, p=0.044). OS between two groups had no significant difference. Conclusions: FDG-PET before and 3 weeks after NACRT could not predict pathologic N2 clearing. Patients who had a reduction in SUVmax of N2 nodes of more than 60% showed better PFS in patients with NSCLC treated with NACRT followed surgical resection. No significant financial relationships to disclose.
Changing demographics and the contemporary surgical management of renal cortical tumors
Authors: P. Russo, M. E. Snyder, F. Rabbani, M. W. Kattan, R. Motzer, V. Reuter
Journal: Journal of Clinical Oncology (2004)

4637 Background: To study the demographics and clinical outcomes in the surgical management of renal cortical tumors in a large 14-year contemporary single institutional experience. Methods: All patients presenting to our center for the surgical management of renal cortical tumors between 7/89 and 7/03 were prospectively entered and followed in a comprehensive database. Demographic features studied include: clinical presentation, tumor size, stage, histologic sub-type, and operation performed. Differences between groups were analyzed using Kaplan Meier survival distributions and the log rank test. The 2002 UICC staging system was employed (P1a<4cm, P1b<7cm). Results: 1548 patients with renal cortical tumors, including 78 patients (5.0%) with bilateral tumors, were studied. 63.6% of patients were male, 36.4% female, 88.0% white, 5.0% black, and 3.1% Hispanic. The median age is 63 (15–94) and mean follow-up is 46.2 months (0.1–164.9). Significant trends were observed in both modes of incidental presentation (Year 1: 55.2%; Year 14: 72.8%, p<0.01) and median tumor size (Year 1: 6.0 cm; Year 14: 3.5 cm, p<0.001). The percentage of patients with P1a (2002 UICC staging) tumors rose from 20.9% in Year 1 to 53.9% in Year 14 (p<0.01) while patients presenting with M1 or N1 disease declined from 17.9% in Year 1 to 4.4% in Year 14 (p<0.01). Partial nephrectomy increased from 14.9% in Year 1 to 58.3% of nephrectomies in Year 14 (p<0.01). Progression Free Probability is 90.1% at 3 years and 87.5% at 5 years. Histologic subtype was the most critical determinant of prognosis with 5-year Progression Free Probability of 84.7% for conventional clear cell, 92.6% for papillary, 90.0% for chromophobe, and 100% oncocytic (p=0.02). Conclusions: Incidental tumor detection, smaller primary tumors, appreciation of histologic subtype, and increased application of kidney-sparing surgery are the current characteristics of the surgical management of renal cortical tumors at our center. No significant financial relationships to disclose.