tbuckley/cabot-search huggingface dataset:
New DNA methylation markers associated with oral cancer (OC) development (dvlpt).
Authors: Pierre Saintigny, Wenhua Lang, Jaroslav Jelinek, Curtis R. Pickering, Lei Feng, Mitchell J. Frederick, Li Zhang, Henning Ren, J. Jack Lee, Edward S. Kim, You Hong Fan, Adel K. El-Naggar, Waun Ki Hong, Jeffrey Myers, Vassiliki Papadimitrakopoulou, Jean-Pierre Issa, Scott Michael Lippman, Li Mao
Journal: Journal of Clinical Oncology (2012)

5524 Background: We have reported that DNA methyltransferase-3B (DNMT3B) gene expression is a strong predictor of OC dvlpt. Using high-throughput DNA methylation profiles of oral preneoplastic lesions (OPL), we identified 86 candidate genes that were hypermethylated in patients (pts) developing OC and suggested that a CpG island methylation phenotype may occur early during OC dvlpt. Our aim was to validate some of the candidate genes and to study the value of LINE1 repetitive element methylation, a surrogate of global DNA methylation, as biomarkers of risk to develop OC. Methods: Validation cohort included 40 pts with a median follow-up of 4.2 years, including 14 pts who developed OC. None of them were used in the discovery phase. Frozen OPL were collected prospectively and subject to DNA extraction. We performed a quantitative analysis of the degree of methylation of LINE1, and AGTR1, FOXI2, PENK, and HOXA9 promoters CpG sites using pyrosequencing. Results: The degree of methylation of AGTR1 (Mann-Whitney P&lt;0.0001), FOXI2 (P=0.0002), PENK (P&lt;0.0001), but not HOXA9 (P=0.0714) was significantly higher in pts who developed OC. On the contrary, LINE1 methylation was significantly lower in pts who developed OC (P&lt;0.0001). The median percent of methylation was used to dichotomize the pts into high versus low methylation levels. Oral cancer-free survival (OCFS) was significantly worse in pts with high levels of AGTR1 (Log-rank P=0.0229), FOXI2 (P=0.0170), and PENK (P=0.0142) promoter methylation. No significant difference was found with HOXA9. A Methylation Index (MI) was developed by averaging the percent of methylation of AGTR1, FOXI2, and PENK promoters; pts with a high MI had a worse OCFS (P=0.0031). On the other hand, pts with low levels of LINE1 methylation had a significantly worse OCFS (P=0.0118). Finally, in 26 pts, a positive correlation was observed between DNMT3B gene expression levels and the MI (rho=0.65, P=0.0003); surprisingly, there was a negative correlation with LINE1 methylation (rho=-0.74, P&lt;0.0001). Conclusions: AGTR1, FOXI2 and PENK promoter methylation may be associated with increased OC risk in pts with OPL and correlate with DNMT3B expression. Global DNA hypomethylation is an early event in OC dvlpt.
Phase I trial of sorafenib, bevacizumab, and temsirolimus in advanced solid tumors.
Authors: Shannon Neville Westin, Melody L. Smart, Navdeep Pal, Diana L Urbauer, Filip Janku, Jennifer J. Wheler, Sarina Anne Piha-Paul, Aung Naing, Apostolia Maria Tsimberidou, Siqing Fu, Gerald Steven Falchook, David S. Hong, Ralph Zinner, Vivek Subbiah, Kirk Salvatore Culotta, Karen H. Lu, Robert L. Coleman, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2013)

2611 Background: Pathway crosstalk and emergence of drug resistance have limited the activity of targeted therapies, including anti-angiogenic agents and mTORC1 inhibitors. However, this vulnerability may be addressed by rationally combining targeted therapies to improve outcomes. We sought to determine the MTD/recommended phase II dose and define the pharmacokinetics (PK) of the combination of sorafenib (S), bevacizumab (B), and temsirolimus (T) in patients with advanced solid tumors. Methods: S was given once or twice daily, B was given intravenously every three weeks, and T was given intravenously weekly. Doses were escalated in a stair-step dose escalation with 6 planned dose levels (DL) in a standard 3+3 design. Responses were defined using RECIST 1.1. Results: To date, 51 patients have been enrolled. Three patients withdrew consent after only one dose. One dose-limiting toxicity (DLT) occurred at DL 5 (grade 4 fatigue, pain) and one DLT occurred at DL 6 (G3 headache). However, 5/6 patients required dose reduction on DL6 (G2 nausea, fatigue, hand/foot syndrome, rash). Thus, DL5 (B 10mg/kg, T 20mg, S 200mg twice daily) is being explored in dose expansion (N=10) and tumor expansion cohorts as the recommended phase II dose. The most common adverse events (&gt;10%) were fatigue (69%; G3/4 6%), nausea (38%, G3/4 2%), pain (35%, G3/4 10%), thrombocytopenia (33%, G3/4 8%), mucositis (33%, 0%), constipation (29%, G3/4 0%), hand/foot syndrome (23%, G3/4 0%), rash (19%, G3/4 0%), hypertension (17%, 0%), neuropathy (17%, G3/4 0%), diarrhea (15%, G3/4 6%), vomiting (15%, G3/4 2%), headache (12%, G3/4 2%), and hypertriglyceridemia (10%, G3/4 2%). Of 34 patients evaluable for response, 4 had PR including ovarian (-57%, +6m), gastric (-46%, +5m), colorectal (-32%, +5 m), and thyroid (-31%, +6m) cancer. Eight patients had SD for greater than 4 months including ovarian (0%, +7m), colorectal (-5%, +8m), endometrial (-26%, +5m; -16%, +4m; -15%, +6m), leiomyosarcoma (-5%, +6m), squamous lung cancer (-6%, +6m), and triple negative breast (-15%, +4m) cancer. Conclusions: The combination of S, B, and T is well tolerated and demonstrates preliminary evidence of tumor activity in a variety of solid tumors. PK studies at the recommended phase II dose are ongoing. Clinical trial information: NCT01187199.
Mixed Hematopoietic Chimerism for Sickle Cell Disease Prevents Intravascular Hemolysis and Corrects Biomarkers of Endothelial Function.
Authors: Catherine J. Wu, Lakshmanan Krishnamurti, Mark T. Gladwin, Melinda Biernacki, Shelby A. Rogers, Xunde Wang, David Zahrieh, Joseph H. Antin, Jerome Ritz
Journal: Blood (2005)
Association between c-Met expression and tumor recurrence in colorectal cancer patients after liver resection.
Authors: Hirokazu Shoji, Yasuhide Yamada, Hirokazu Taniguchi, Natsuko Okita, Atsuo Takashima, Yoshitaka Honma, Satoru Iwasa, Ken Kato, Tetsuya Hamaguchi, Yasuhiro Shimada
Journal: Journal of Clinical Oncology (2013)

3559 Background: c-Met is a receptor for hepatocyte growth factor that has been implicated in the pathogenesis and growth of a wide variety of human malignancies, including colorectal cancer (CRC). The aim of the present study was to clarify the correlation between c-Met protein expression in the primary lesion and relapse-free survival (RFS) in patients who had undergone curative hepatectomy for colorectal metastases. Methods: Between January 2004 and December 2009, formalin-fixed paraffin-embedded sections of surgical specimens from 108 CRC patients who had undergone hepatectomy were obtained at a single center. We performed immunohistochemical staining to detect c-Met expression. c-Met expression levels were scored dependent on staining intensity; 0, negative; 1, weak; 2, moderate; 3, strong. We defined scores 0 and 1 as c-Met-low, and scores 2 and 3 as c-Met-high. The Kaplan-Meier method and Cox proportional hazards model were used to investigate relationships between c-Met expression, patient characteristics, and RFS. Results: We identified 65 males and 43 females with a median age of 62 years. A total of 53% of patients underwent simultaneous resection of primary and metastatic liver lesions, and the others underwent metachronous resection. High levels of c-Met expression (c-Met-high) in the primary tumor were observed in 52% of patients. There were no differences in terms of size or number of metastatic liver lesions between the c-Met-low patients and the c-Met-high patients. RFS was significantly shorter in the c-Met-high patients (9.7 months) than that in the c-Met-low patients (21.1 months) in primary tumors (p=0.013). Multivariate analyses demonstrated that c-Met-high (hazards ratio [HR], 1.73; 95% confidence interval [95% CI], 1.08-2.79 for c-Met-high vs. c-Met-low) and hepatic resection for synchronous disease (HR, 2.17; 95% CI, 1.36-3.46 for synchronous vs. metachronous resection) were associated with worse RFS. Conclusions: High levels of c-Met expression in the primary tumor were associated with shorter RFS after hepatic metastasectomy.
A qPCR gene expression module test to predict resistance to cetuximab in colorectal cancers independent of KRAS mutation status.
Authors: Dan Rhodes, Sean Eddy, Paul Williams, Mark Tomilo, Seth Sadis, Peter Wyngaard, Lien Vo, Kahuku Oades, Hyunsoo Kim, Yipeng Wang, Byung-In Lee, Joseph Monforte
Journal: Journal of Clinical Oncology (2012)

e14164 Background: While KRAS mutation predicts resistance to anti-EGFR therapy in colorectal cancer, not all KRAS wild-type patients benefit from such therapy, suggesting that complementary biomarkers capable of identifying additional non-responsive patients would have clinical utility. Methods: To search for such a biomarker, we studied the relationship of cetuximab response with twelve gene expression modules, derived from an unsupervised analysis of 20 independent microarray datasets comprising more than 2,000 colorectal cancer patients. Each module represents a set of highly co-expressed genes related to an important aspect of colorectal cancer variability. Two cetuximab-treated cohorts were studied. The first was a Phase II clinical trial (Khambata-Ford et al, J Clin Oncol, 2007) with accompanying microarray data from pre-treatment biopsies. The second was a single-institution study of cetuximab response from which formalin-fixed paraffin-embedded primary tumor specimens were available. Results: In the first study, module scores were computed by averaging co-expressed module genes in the microarray data. In the second study, module scores were generated from a qPCR gene expression module test, OncoScore Colon, which quantifies modules by averaging three representative module genes relative to housekeeping controls. Notably, in both studies, the mesenchymal module was significantly associated with cetuximab resistance, with module positive patients tending to progress on cetuximab within 10 weeks. Additionally, the status of this module was independent of KRAS mutation status—KRAS mutations occurred in both module-positive and -negative patients. Future clinical studies will continue to test the predictive capacity of the module in regards to cetuximab resistance and other mechanisms. Conclusions: In summary, this study demonstrates the value of a gene expression module-based qPCR panel for stratifying colorectal cancer patients for treatment response, and suggests that our approach may have immediate utility for cetuximab treatment response prediction.
Allogeneic hematopoietic cell transplantation (alloHCT) in diffuse large B-cell lymphoma (DLBCL) after nonmyeloablative (NMA) or reduced-intensity (RIC) conditioning: Long-term outcome in 116 patients.
Authors: L. M. Poon, Rima Saliba, Gabriela Rondon, Grace-Julia Okoroji, Yasuhiro Oki, Richard E. Champlin, Chitra Hosing, Ken H Young, Francesco Turturro, Issa F. Khouri
Journal: Journal of Clinical Oncology (2013)

8561 Background: The role of alloHCT and conditioning intensity in DLBCL remains unclear. In this retrospective study, we determined their effectiveness in 116 patients (pts) with DLBCL (de novo, n=59, transformed, n=57) receiving alloHCT at our institution, between 1998-2011. Methods: Median age was 51years (range, 19-70); median prior therapies was 4 (range 2-12). Disease status at alloHCT was complete response (CR) (n=22), partial response (PR) (n=58), stable (SD) (n=25) or progressive disease (PD) (n=11). 41 (35%) pts had previous autografts. 74 (64%) pts received RIC of melphalan/fludarabine (Flu) or BEAM, and 42 (36%) received a NMA conditioning of Flu/cyclophosphamide or cisplatin/cytarabine/ Flu. Donor source was HLA-identical sibling (MRD) (65%), HLA-matched unrelated (MUD) (31%) or a 1-Ag mismatched donor (4%). Results: With median follow-up among survivors of 63 months (range 5-157), estimated 5-yr OS and PFS for the whole cohort was 41% and 34% respectively. On multivariate (MV) analysis, disease status was most significant predictor for OS, with chemo refractory disease (SD/PD) being associated with higher mortality rate (HR 3.7, 95% CI 1.6-8.6, p=0.002). Combined use of NMA conditioning and MRD was associated with significantly lower mortality rate (HR 0.4, 95% CI 1.6-8.6, p=0.005). OS was highest [69% (95% CI 49-82)} for pts in CR/PR after NMA with a MRD (n=29), and lowest [(12% (95% CI 3-29)] for SD/PD pts after RIC with a non MRD (n=32). Disease status was strongest predictor of PFS on MV analysis, with CR pts having improved PFS compared to SD/PD (5-year estimates of 58% and 13%, respectively (P&lt;0.001). Pts in PR with early disease stage (&lt; Stage 4) and negative PET at alloHCT had PFS comparable to pts in CR (56% at 5 yr HR=1.3, p=0.6), while all other PR pts had PFS comparable to SD/PD pts (PFS=20%, p 0.1). Conclusions: Our study shows disease status, donor type and conditioning intensity are predictors of outcomes after alloHCT in DLBCL. Pts with chemosensitive disease and receiving NMA, MRD had improved survival rates compared to RIC alloHCT. PR pts with low volume PR had similar outcomes to CR pts.
Abstract 333: AAV9 Serca2a Gene Transfer Reverses Some but Not All Electrophysiological Deficits in a Chronic Model of Congestive Heart Failure
Authors: Chaoqin Xie, Jiqiu Chen, Jun Hu, Antoine H Chaanine, Dongtak Jeong, Erik Kohlbrenner, Roger J Hajjar, Fadi G Akar
Journal: Circulation Research (2015)

SERCA2a gene transfer (GT) to the failing heart improves it mechanical function. The electrophysiological (EP) consequences of SERCA2a GT are less clear. We investigated the EP substrate, total (t) and phosphorylated (p) Cx43 expression in a chronic model of heart failure (HF) with &amp; without SERCA2a GT. Methods: After 2 mo of aortic banding rats underwent 30min LAD occlusion &amp; reperfusion for another 2 mo. Rats developed widespread proliferation of reactive fibrosis in ischemic &amp; remote zones and were randomized to receive AAV9 GFP (HF) or AAV9 SERCA2a (HF treatment) at the time of LAD occlusion/reperfusion. Hearts from normal (Sham, N=6), HF (AAV9.GFP, N=7), and HF treatment (AAV9.SERCA2a, N=9) rats were studied using optical mapping. Cx43 levels (t &amp; p) were measured. Results: HF rats exhibited significant APD prolongation (by 50%) &amp; CV slowing (by 30%). More importantly APD heterogeneity was increased 2.5 fold (p=0.006). The ratio of S368 p-to-t Cx43 was reduced in the ischemic zone of HF rats where SERCA2a expression was decreased (Fig). AAV9 SERCA2a GT increased SERCA2a levels in the ischemic and remote zones. Surprisingly, APD &amp; CV were comparable (p=NS each) in HF and HF treatment groups. In contrast SERCA2a GT reduced APD heterogeneity by 30% relative to untreated rats (p=0.03), fully restored pCx43 expression to sham levels in the ischemic zone and abolished regional differences in p-to-t Cx43 (Fig). Conclusions: AAV9 SERCA2a GT reverses key EP and molecular deficits that are causally related to arrhythmias in HF. This therapy, however, fails to reverse other hallmark features of HF, which are likely dependent on widespread ion channel and structural remodeling, namely fibrosis.
Coordinated follow-up Breast Cancer Survivorship Care Program study.
Authors: Kathryn Jean Ruddy, Hao Guo, Emily Baker, Matthew Goldstein, Erin E. Mullaney, Lawrence N. Shulman, Ann H. Partridge
Journal: Journal of Clinical Oncology (2015)

e17727 Background: Previous research has demonstrated that cancer survivors often fail to receive recommended care, but also often receive redundant or unnecessary care, reducing care quality and increasing costs. Methods: This phase II trial randomized 100 stage 0-IIIa breast cancer pts who had primary care providers within our hospital network (with accessible online records), and seen at Dana-Farber/Faulkner medical oncology, to either Coordinated Follow-Up Care = CC (entailing a patient navigator calling every 3 months, a tailored survivorship care plan, and a follow-up care algorithm aimed to reduce redundant care) or standard care = SC for one year after completion of last active treatment (chemotherapy, surgery, or radiation) to assess whether the CC made subsequent medical care more efficient. The 1° endpoint was frequency of redundant exams ( > 1 breast/chest wall exam per pt within any 30 day period in the absence of a new breast/chest wall complaint over the year of follow-up); a secondary endpoint was total number of visits to a health care provider during the year (not including plastic surgery visits). Results: 2 pts (both in CC) were ineligible, and 2 (1 in SC, 1 in CC) had recurrence or died during follow-up, leaving 96 for analysis (47 in CC and 49 in SC). Clinical characteristics were similar between groups except that trastuzumab tx was more common in CC pts (26% vs. 6%). 22/47 CC (47%, 95% CI 32-62%) and 19/49 SC (39%, 95% CI 25-54%) pts had 1+ redundant breast/chest wall exam during the year of follow-up. The median # of non-plastic surgery visits was 12 in CC (range 4-25) and 8 in SC (range 2-30) pts. When we focused only on pts who did not receive trastuzumab, 13/35 in CC (37%, 95% CI 22-55%) and 19/45 in SC (42%, 95% CI 28-58%) had a redundant exam, though the median # of non-plastic surgery visits was 11 in CC (range 4-22) and 7 (range 2-30) in SC pts. Conclusions: Early stage breast cancer pts are seen frequently in follow-up, and often receive breast/chest wall exams in the absence of a new breast/chest wall complaint. Our CC intervention did not reduce this surrogate for redundant care in entire study population, although greater use of trastuzumab in CC pts (with associated visits) may have obscured an effect. Further analysis of secondary outcomes is planned.
Association of the development of bone metastases with the development of brain metastases in patients with non-small cell lung cancer.
Authors: Mohamed Salem, Paul Elson, Nathan A. Pennell, Ammar Sukari, Sherif El-Refai, Khaled B. Ali, Shirish M. Gadgeel, Nicholas Szerlip, Antoinette J. Wozniak
Journal: Journal of Clinical Oncology (2013)

e13030 Background: In patients (pts) with non-small cell lung cancer (NSCLC), it is unknown whether pts with bone metastases are predisposed to the development of brain metastases. The impact of bevacizumab (Bev) on the development of bone and brain metastases is not fully characterized. Methods: Retrospective review of pts with stage IV NSCLC without brain metastasis at diagnosis was undertaken. The primary endpoint was to determine whether the development of bone metastases is predictive of the development of brain metastases. Secondary endpoints involved the proportion of pts who developed brain and/or bone metastases while being treated with Bev. Data were analyzed using competing risks methods. Results: A total of 175 pts (52% males, median (range) age: 60 y (35-80)) were studied. Of whom 79% received Bev and 21% did not receive Bev as part of their treatment. Overall 34% of pts had bone metastases at the start of therapy. Pts with pre-existing bone metastases tended to develop new bone disease more frequently than pts who did not initially have bone metastases (39% vs. 19%, p =. 01). The incidence of the development of brain metastases among pts who had pre-existing bone metastases was 17% vs.16 % in pts without pre-existing bone metastases. However, the incidence of brain metastases among pts with pre-existing bone disease who developed new bone metastases was 33% vs. 6% in pts who did not develop new bone disease but had pre-existing bone metastases. Adjusting for initial bone disease, development of new bone metastases was associated with a shorter brain metastases-free interval HR 5.06 (2.03-12.65; p = 0.005). In a subgroup analysis based on Bev exposure, the likelihood of developing brain and bone metastases within 2 years of starting Bev was estimated to be 25% and 27%, respectively, while the likelihood of developing brain and bone metastases without Bev treatment was 33% and 43 %, respectively. Conclusions: In pts with NSCLC, the development of new bone metastases may be indicative of the subsequent development of brain metastases. Additionally, Bev therapy may have an effect on the development of both bone and brain metastases. A prospective investigation may be warranted.
Phase I study of interleukin 2 (IL2) maintenance after induction with weekly docetaxel and estramustine in patients with metastatic hormone refractory prostate cancer (HRPC)
Authors: P. Jiang, C. S. Higano
Journal: Journal of Clinical Oncology (2006)

14526 Background: Patients with HRPC commonly respond to docetaxel, but many develop asthenia and other docetaxel related toxicities that impair quality of life and hence, many clinicians prescribe a “chemotherapy vacation”. IL2 exerts its anti-tumor effect through activation of T cells and NK cells and at high dose has been shown to have efficacy (and toxicity) in men with HRPC (Maffezzini, The Prostate 1996). Low dose IL2 and 13-cis-retinoic acid given as maintenance after cytoreduction of advanced solid tumors was associated with increased numbers of circulating NK cells as well as further tumor responses (Recchia, Proc ASCO 2001). A phase I trial of low dose IL2 maintenance after chemo induction was undertaken. Methods: Chemotherapy naive pts with metastatic HRPC were induced with weekly docetaxel 35 mg/m 2 on day 2 and estramustine 280 mg/M2 TID on days 1 and 2 for 3 wks followed by 1 wk off for a total of 12 doses of chemotherapy. Responding pts received maintenance IL2 for 5 days/wk for 3 wks, followed by 1 wk off. During the 3rd wk, a boost dose was administered on days 2 and 3. Level 1 maintenance was 0.5 x106 IU/m 2 SC bid, level 2 was 0.75 × 10 6 IU/m 2 SC bid. Level 1 boost was 3 × 10 6 IU/m 2 , level 2 was 4.5 × 106 IU/m 2 SC bid. Cohorts of 3 patients were treated at a given dose level according to standard dose escalation schemes for toxicity. IL2 was continued until objective progression was documented. Results: 15 pts, median age of 70 (range 46–78), median PSA 32.7 (range 2.28 to 1248) were enrolled. After chemotherapy, 12 pts had &gt; 50% (7 had &gt; 75%) decline in PSA, 3 pts had &lt; 50% decline. 13 pts went on to receive IL2. The MTD for maintenance IL2 was 0.5 × 10 6 IU/m 2 SC bid (4 pts at level 1 had no toxicity but 3 of 4 at level 2 had grade 2 toxicity requiring a drop to level 1). MTD for the boost was 3 × 10 6 IU/m 2 (4 with no toxicity at level 1, 3 of 3 with grade 2 toxicity at level 2 requiring a drop to level 1). The most common toxicities were fatigue, nausea, chills, edema. One pt has received IL2 maintenance for 25 months. Conclusions: IL2 maintenance can be safely administered at the MTD. Immunological studies before/after chemotherapy and during IL2 are pending. No significant financial relationships to disclose.