tbuckley/cabot-search huggingface dataset:
Effect of alvimopan on gastrointestinal recovery and length of hospitalization after retroperitoneal lymph node dissection for testicular cancer.
Authors: Kushan Dilip Radadia, Nicholas Farber, Alexandra Tabakin, Lee Milas, Thomas Jang
Journal: Journal of Clinical Oncology (2017)

424 Background: Alvimopan use in enhanced recovery programs has reduced the hospital LOS in patients undergoing major abdominal surgeries. Retroperitoneal lymph node dissection (RPLND) for testicular cancer may be associated with delayed GI recovery prolonging hospital LOS. In this study, we evaluate whether alvimopan is associated with enhanced GI recovery and shorter hospital LOS in men undergoing RPLND for testicular cancer. Methods: From 2010 to 2016, 29 patients underwent RPLND by a single surgeon (23 post-chemotherapy). All patients underwent bilateral template dissection. Data for patients who received alvimopan was prospectively collected and compared to a historical cohort of patients who did not receive alvimopan. Primary outcomes measured were hospital LOS and recovery of GI function. Mann-Whitney Wilcoxon and Chi square tests were used to determine statistical significance between the two groups. Results: Of 29 men who underwent RPLND, 8 received alvimopan and 21 did not. There were no differences in preoperative or operative variables between the groups (Table). Median hospital LOS for men receiving alvimopan was 4 days compared to 6 days for those who did not (p=0.074). The median time to return of flatus in men receiving alvimopan was 2 days compared to 4 days for those who did not (p=0.0023). The median time to first bowel movement (BM) in men receiving alvimopan was 2.5 days compared to 4 days for those who did not (p=0.0028). Conclusions: Alvimopan significantly reduced the median time to return of flatus and to first BM after RPLND. Furthermore, there was a trend towards shorter hospital LOS in those receiving alvimopan. [Table: see text]
Expression and methylation profiles associated with recurrent mutations in stage II colorectal cancer.
Authors: Laia Pare-Brunet, Rebeca Sanz-Pamplona, Adriana Lopez-Doriga, Antoni Berenguer-Llergo, Susanna Ausso, David Cordero, Adria Closa, Victor Moreno
Journal: Journal of Clinical Oncology (2013)

e14613 Background: Aberration of normal genetic and epigenetic patterns occurs at early stages of colorectal cancer (CRC) and accumulates throughout cancer progression. To characterize pre-metastatic tumors, a series of stage II, microsatellite stable, colon tumors and their paired mucosa were profiled on RNA expression and DNA methylation microarrays ( www.colonomics.org ). Our aim is to define molecular subtypes based on recurrent gene mutations, methylation and expression profiles, and explore if these molecular subtypes are associated to patients’ prognosis. Methods: We have sequenced exomes (Illumina Genome Analyzer) of a subset of 42 COLONOMICS normal-tumor paired samples (21 good and 21 bad prognosis). Variants identified in normal tissue were used to filter SNPs. DNA methylation (Infinium Human Methylation 450k) and RNA expression (Affymetrix U219) data from those samples were used in this analysis. Correlation was used to assess the association between tumor mutations and differentially expressed/methylated genes. Significant genes were subsequently used to perform tumor clustering. Results: Exome analysis revealed a mean of 150 somatic mutations per sample. From these, 12 variants were recurrently mutated (KRAS, TP53, etc) in more than 3 tumors that were used to define tumor subtypes based on gene methylation/expression patterns. We obtained 12 profiles that clearly identified the cluster of mutated samples. For some profiles, the cluster only includes those tumors with the mutation. Interestingly, some clusters included the mutated samples and additional tumors showing the same phenotype despite not having the mutation. For each mutation, the overlapping between the differently methylated/expressed genes ranged from 14 to 200 common genes. When combining data from the three platforms two main CRC molecular subtypes emerge; each of which shows molecular heterogeneity but no association with prognosis. Conclusions: Mutational status is associated with gene methylation and expression patterns in CRC patients. Although none of these clusters was associated with prognosis, different groups of tumors could be related to distinctive pathways, which may reveal useful as therapeutic targets.
Treatment patterns and outcomes with HER2-directed therapy for the treatment of HER2-positive metastatic breast cancer.
Authors: Rakesh Luthra, Maxine Fisher, Melissa Brammer, Deepa Lalla
Journal: Journal of Clinical Oncology (2012)

e11063 Background: The goal of this study was to compare treatment patterns and outcomes in patients receiving a HER2 directed therapy for the treatment of HER2+ metastatic breast cancer (mBC). Methods: Female mBC patients (with ≥2 claims with ICD9 diagnosis codes for mBC), age ≥18 years receiving treatment with trastuzumab (T) or lapatinib (L) between 1/1/06 and 8/31/11 were identified in the HealthCore Integrated Research Database (HIRD SM ). The earliest mBC claim was defined as index date. Patients with &lt;12 months preindex and ≥6 months postindex continuous eligibility were excluded. Two cohorts were identified: T group received T only; TL group received both L and T (sequentially or together). Treatment duration, metastasis site (mets) at mBC diagnosis, no. of chemotherapy agents, no. of hospitalizations, and total cost of care were assessed in the two groups. Results: Of 1449 patients who received a HER2 directed agent, 1165 were in the T group (mean age 56 yrs) and 284 in the TL group (mean age 54 yrs). T group mets included bone (n=553, 48%), liver (n=336, 29%) and brain (n=283, 24%) mets; TL group had bone mets (n=225, 79%), brain mets (n=167, 59%) and liver mets (n=153, 54%). Mean no. of chemotherapy agents received was lower in T group 3.3 (SD 1.7) compared to TL group 5.8 (SD 2.1) (p=0.0002). The time from 1st mBC diagnosis to treatment with T or L was 117 (SD 217) days in T group and 107 (SD 208) days in TL group. For TL group, time between index date and treatment was 114 (SD 214) days for T and 690 (SD 400) days for L. The mean treatment duration was shorter in T group 417 (SD 366) days compared to TL group 724 (SD 433) days (p&lt;0.0001). TL patients received 579 (SD 402) days of T and 205 (SD 234) days with L. Number of hospitalizations and total cost of care (mean monthly) were 0.1 (SD 0.2) and $12561 (SD $10,975), respectively for T group and 0.1 (SD 0.1) and $13,532 (SD $7,220), respectively for TL group. Conclusions: Mean treatment duration and mean number of chemotherapy agents suggest that the TL group may have received more lines of treatment than the T group. There was no difference in mean monthly costs between the two groups. Medical chart data will be used to confirm treatment patterns and evaluate treatment outcomes in both groups.
Long non-coding RNA-mediated PTEN regulation in prostate cancer.
Authors: Tong Sun, Zhou Du, Teng Fei, Myles Brown, Gwo-Shu Mary Lee, Yiwen Chen, Xiaole Shirley Liu, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2015)

e16081 Background: Loss of expression of PTEN is a common event in prostate cancer and is associated with a poor prognosis. Multiple mechanisms may be associated with its loss of expression. Mounting evidence suggests that lncRNA could function as microRNA sponges and compete for microRNA binding to protein-coding transcripts. However, the prevalence, functional significance and targets of lncRNA-mediated sponge regulation in cancer are largely unknown. Methods: We developed a computational pipeline to repurpose exon-array data to interrogate the lncRNA expression across a large number of human prostate tumor samples. We utilized an integrative analysis of sequence features and gene expression profiles of both lncRNAs and protein-coding genes in tumors. We also experimentally validated our analyses by confirming the tumor-suppressive function of two lncRNAs and their regulation of PTEN expression in prostate cancer. Results: We have uncovered a pervasive lncRNA-mediated sponge regulatory mechanism that impacts the expression of many protein-coding driver genes in prostate cancer. Surprisingly, one of the two lncRNAs, TUG1, has an established function in polycomb repressive complex 2 (PRC2)-mediated transcriptional regulation, but was previously not recognized as having an alternative function in cytoplasm. Conclusions: Our study suggests a significant role of the sponge mechanism of lncRNA in PTEN regulation in prostate cancer.
Tissue transglutaminase induction in the pressure-overloaded myocardium regulates matrix remodelling
Authors: Arti V. Shinde, Marcin Dobaczewski, Judith J. de Haan, Amit Saxena, Kang-Kon Lee, Ying Xia, Wei Chen, Ya Su, Waqas Hanif, Inderpreet Kaur Madahar, Victor M. Paulino, Gerry Melino, Nikolaos G. Frangogiannis
Journal: Cardiovascular Research (2017)

Tissue transglutaminase (tTG) is induced in injured and remodelling tissues, and modulates cellular phenotype, while contributing to matrix cross-linking. Our study tested the hypothesis that tTG may be expressed in the pressure-overloaded myocardium, and may regulate cardiac function, myocardial fibrosis and chamber remodelling.In order to test the hypothesis, wild-type and tTG null mice were subjected to pressure overload induced through transverse aortic constriction. Moreover, we used isolated cardiac fibroblasts and macrophages to dissect the mechanisms of tTG-mediated actions. tTG expression was upregulated in the pressure-overloaded mouse heart and was localized in cardiomyocytes, interstitial cells, and in the extracellular matrix. In contrast, expression of transglutaminases 1, 3, 4, 5, 6, 7 and FXIII was not induced in the remodelling myocardium. In vitro, transforming growth factor (TGF)-β1 stimulated tTG synthesis in cardiac fibroblasts and in macrophages through distinct signalling pathways. tTG null mice had increased mortality and enhanced ventricular dilation following pressure overload, but were protected from diastolic dysfunction. tTG loss was associated with a hypercellular cardiac interstitium, reduced collagen cross-linking, and with accentuated matrix metalloproteinase (MMP)2 activity in the pressure-overloaded myocardium. In vitro, tTG did not modulate TGF-β-mediated responses in cardiac fibroblasts; however, tTG loss was associated with accentuated proliferative activity. Moreover, when bound to the matrix, recombinant tTG induced synthesis of tissue inhibitor of metalloproteinases (TIMP)-1 through transamidase-independent actions.Following pressure overload, endogenous tTG mediates matrix cross-linking, while protecting the remodelling myocardium from dilation by exerting matrix-preserving actions.
CEA response and depth of response (DpR) to predict clinical outcomes in patients (pts) with metastatic colorectal cancer (mCRC) treated with first-line cetuximab plus oxaliplatin-based chemotherapy: A sub-analysis of the JACCRO CC-05/06 trials.
Authors: Yu Sunakawa, Wataru Ichikawa, Akihito Tsuji, Tadamichi Denda, Yoshihiko Segawa, Yuji Negoro, Ken Shimada, Mitsugu Kochi, Masato Nakamura, Masahito Kotaka, Hiroaki Tanioka, Akinori Takagane, Satoshi Tani, Tatsuro Yamaguchi, Masahiro Takeuchi, Masashi Fujii, Toshifusa Nakajima
Journal: Journal of Clinical Oncology (2017)

648 Background: Carcinoembryonic antigen (CEA) decrease was faster and greater in cetuximab (cet) treatment than bevacizumab treatment and correlated with prolonged survival in mCRC pts receiving FOLFIRI plus cet (Michl M, et al. Ann Oncol 2016). We investigated if the CEA decrease is a surrogate for DpR reported to be associated with clinical outcomes. Methods: This study evaluated the association between the percentage of CEA decrease or DpR and clinical outcomes in pts with KRAS exon 2 wild-type from 2 phase II trials of 1st-line therapy; JACCRO CC-05 of cet plus FOLFOX ( n= 57, UMIN000004197) and CC-06 of cet plus SOX ( n= 61, UMIN000007022). The association was analyzed using Spearman’s rank correlation coefficient. The cut-off value of 75% CEA decrease was used for CEA response to discriminate CEA responders according to the previous report. The DpR was defined as the percentage of tumor shrinkage at the nadir as compared with the baseline values. Results: In total of 113 pts of the 2 trials in the full analysis set, 92 were eligible for analyses of both CEA and DpR. In the population consists of 92 evaluable pts, median progression-free survival (PFS) was 9.1 months, and median overall survival (OS) was 36.2 months. Median CEA decrease was 67.4% and median time to CEA nadir was 2.8 months similar to median time to DpR of 3.0 months. The DpR was associated with PFS and OS (r s = 0.56; P&lt; 0.0001, r s = 0.39; P= 0.0090, respectively); moreover, CEA decrease correlated with PFS (r s = 0.56, P&lt; 0.0001) as well as OS (r s = 0.35, P= 0.019). CEA responders showed significantly longer PFS [11.8 vs. 5.5 months; hazard ratio (HR) 0.46; 95% Cl, 0.28–0.73; P= 0.0009] and numerically longer OS (36.2 vs. 23.5 months; HR 0.57; 95% CI, 0.30-1.05; P= 0.072) than CEA non-responders. The CEA decrease was statistically significantly associated with DpR (r s = 0.44, P&lt; 0.0001). Conclusions: Our study demonstrates that DpR and CEA response both correlated with clinical outcomes of 1st-line treatment with cet plus oxaliplatin-based chemotherapy. The CEA decrease may serve as a surrogate for DpR in 1st-line cet treatment.
Clinical significance of PCR-detected metastases in sentinel nodes of breast cancer patients: An interim report
Authors: K. M. Verbanac, J. Min, A. E. Mannie, L. Tafra
Journal: Journal of Clinical Oncology (2004)

9516 Background: The presence of metastases in axillary lymph nodes (LN) is an important prognostic indicator in breast cancer and provides important staging information for treatment selection. Standard pathology fails to identify many patients with LN metastases; ∼30% “node-negative” patients die of recurrent disease. Retrospective analyses show that many of these LN contained missed metastases. In 1996 we initiated a prospective multicenter trial to test the hypothesis that RT-PCR analysis of sentinel lymph nodes (SLN) would improve the prediction of disease-free survival. Methods: In this translational study, we first identified mammaglobin (MAM) as a superior molecular marker, then proceeded to analyze blinded consecutive patient specimens. Alternate sections of SLN were analyzed by standard pathology (H&E, IHC) or frozen for end point RT-PCR for MAM. This is an interim report of the first cohort of 300 consecutive patients at 5 yrs follow-up. Results: MAM is expressed in 99% primary tumors (153/155) and in 93% (78/84) patients with path+ SLN. Patients with path–SLN (30%; 64/216) were upstaged based on high MAM expression. High MAM expression correlated with ER status, tumor size, and number of path+ LN (Χ2, p<0.02 each). MAM PCR detection of SLN metastases correlated with distant recurrence, with 5 yr survivals of 96% PCR–vs. 84% PCR+ (estimated by Kaplan-Meier; log rank p=0.02). Most importantly, MAM PCR detected nodal disease in the majority (5 of 9) of recurrent patients with path- LN. The addition of MAM PCR to histological LN staging improved correlation with distant metastases (p=0.02) independently of tumor size (p=0.01) by Cox regression. These are the first follow-up data to compare RT-PCR detection of LN metastasis with distant recurrence in breast cancer patients. Conclusions: MAM RT-PCR detection of metastatic disease is associated with a significant reduction in recurrence-free survival. This interim analysis indicates that PCR detection of metastatic disease appears to be a valuable prognostic indicator in breast cancer patients, complements staging by nodal pathology and may ultimately lead to more individualized therapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Veridex, LLC, a Johnson & Johnson Co. Veridex, LLC, a Johnson & Johnson Co. DOD Clinical Translational Research Award
Immune profile and survival outcomes in stage 2 colon cancer.
Authors: Peter Gibbs, Ryan Hutchinson, Ben Tran, Jeanne Tie, Andrea Muranyi, Irma Gresshoff, Michael Christie, Belinda Lee, Emma Schwerkolt, Shalini Singh, Kandavel Shanmugam, Paul Michael Waring
Journal: Journal of Clinical Oncology (2016)

3576 Background: Tumor associated immune response impacts outcomes in cancer. In colon cancer (CC), a good immune response, as represented by a dense lymphocytic infiltrate, is known to be associated with improved overall survival (OS). To date studies have used a subjective scoring system and improved OS has been presumed to solely be the consequence of reduced cancer recurrence. The relationship with deficient mismatch repair (dMMR) status, a good prognostic marker that is typically associated with an immune infiltrate, remains unexplored. We examined an objectively determined Immune Profile (IP) and survival outcomes in stage 2 CC. Methods: Stage 2 CC cases were identified from a hospital registry that prospectively records comprehensive point of care data, including recurrence free survival (RFS) and OS. MMR status was determined by immunohistochemistry. The density of CD3 and CD8 T-cells within each tumor was assessed by immunostaining and automated image analysis. A pattern recognition algorithm scored CD3 and CD8 density at the tumor core (TC) and invasive margin (IM). Raw scores for each region (CD3TC , CD3IM , CD8TC and CD8IM ) were added and categorised as IP High or IP Low. Survival analyses used the Kaplan–Meier method and log-rank test. Results: We included 463 subjects with stage II CC, median age 70.4 years, with median follow-up 57.7 months. 93 (16.5%) tumors were dMMR. 220 (47.5%) tumors were categorised as IP High. IP High was associated with improved survival outcomes compared to IP Low, including RFS (HR 0.25, p < 0.001), post-recurrence survival (HR 0.20, p < 0.001), cancer-specific survival (HR 0.08, p < 0.001) and OS (HR 0.10, p < 0.001). The improved RFS for IP high cases was independent of MMR status (dMMR: HR 0.10, p = 0.03; pMMR: HR 0.27, p< 0.001). In patients without recurrence IP High was associated with reduced non-cancer mortality (HR 0.10, p < 0.001). Conclusions: Using an automated and objective measure, we have confirmed that immune infiltration is strongly associated with improved RFS and OS outcomes in stage II CC, independent of MMR status. We have also shown that a good immune response (IP High) is associated with post recurrence survival (where cancer recurs), and with reduced non-cancer mortality in patients that remain recurrence free.
Phase I/II study on stereotactic hypofractionated once-weekly radiation therapy (SHORT) for localized prostate cancer.
Authors: Indranil Mallick, Moses Arunsingh, Sriram Prasath, B Arun, Paromita Roy, Deepak Dabkara, Sujoy Gupta
Journal: Journal of Clinical Oncology (2017)

130 Background: The low α/β ratio of prostate cancer (PrCa) is well established. However, stereotactic hypofractionated radiotherapy (SRT) has been investigated primarily in highly selected patient populations with low-intermediate risk disease. We performed a clinical trial of SRT delivered in once-weekly fractions on an unselected cohort of patients with non-metastatic PrCa. Methods: In this Phase I/II study 30 patients with non-metastatic PrCa (multiparametric MRI cT1-4N0, M0, Gleason 6-10, PSA &lt; = 60 ng/ml) were treated with SRT to a prescription dose of 35Gy in 5 fractions delivered once a week (overall treatment time 29 days). Elective nodal RT at 25Gy/5Fr was delivered in patients high-risk by NCCN criteria, and androgen deprivation therapy given to intermediate and high-risk patients. SRT was planned using volumetric intensity modulated arc therapy (VMAT) or Helical Tomotherapy (HT) with pre-defined dose-criteria. The primary endpoint was acute toxicity NCI CTC v4, and secondary endpoints were biochemical control and late toxicity. Results: Thirty patients completed treatment per-protocol. Stage T3, Gleason 8-10, and PSA &gt; 10 was seen in 18 (60%), 7 (23%) and 24 (80%) respectively. Overall 20 (66.7%) were high-risk. Median of Mean PTV dose was 36Gy, and normal tissue constraints could be met in all patients (Table). Acute urinary toxicities (Gr 0: 1; Gr 1: 27; Gr 2: 1; Gr 3-4: 0) and acute rectal toxicities (Gr 0: 20; Gr 1: 10; Gr 2: 0; Gr 3-4: 0) were very modest. The mean IPSS scores at baseline, end of treatment and 3 months after treatment were 8.8, 14.7, and 9.9. With a median follow up of 23.7 months, the 2 year biochemical control was 96%. Late grade 2 rectal bleeding developed in 1 patient. Conclusions: Carefully planned stereotactic VMAT/HT based once-weekly SRT to a predominantly high-risk non-metastatic PrCa cohort was very well tolerated and found to be safe for clinical use. Preliminary biochemical control and late toxicity profiles are encouraging. Clinical trial information: CTRI/2016/02/006671. [Table: see text]
Impact of bevacizumab dose reduction on clinical outcomes for patients treated on the Eastern Cooperative Oncology Group’s Study E3200
Authors: B. J. Giantonio, P. J. Catalano, P. J. O’Dwyer, N. J. Meropol, A. B. Benson
Journal: Journal of Clinical Oncology (2006)

3538 Background: E3200 demonstrated improved survival (OS) for previously treated metastatic colorectal cancer patients who received second-line therapy with bevacizumab (10 mg/kg) in combination with FOLFOX4. Dose reductions of bevacizumab to 5 mg/kg were allowed for: hypertension, bleeding and thrombosis of ≤ grade 2; proteinuria of &gt; 2 grams/24 that resolved to &lt;0.5 grams/24hrs; liver function abnormalities ≥ grade 3 that resolved to ≤ grade 1. Methods: Data on dose modifications of bevacizumab were obtained from a post-study survey of participating institutions for all participants. Median OS and progression-free survival (PFS) were determined based upon a dose reduction any time during treatment. Hazard ratios (HR) for OS and PFS were stratified by number of cycles (1–5, 6–10, 11+) to adjust for the time-varying nature of dose reductions. Results: Surveys were received on 84% of E3200 patients treated with bevacizumab. Dose reductions of bevacizumab were performed in 134 of 240 (55.8%) patients treated with FOLFOX + bevacizumab (Arm A) and 77 of 205 (37.6%) patients treated with bevacizumab alone (Arm C). The average number of cycles of bevacizumab administered at a dose reduction for Arm A is 42% and for Arm C is 52%. Conclusions: OS and PFS on E3200 were not compromised for patients who underwent dose reductions of bevacizumab. [Table: see text] [Table: see text]