tbuckley/cabot-search huggingface dataset:
Effect of NF-kB2 mutation on pathway activitation in the pathogenesis of B-cell lymphomas.
Authors: B. A. McCarthy, L. Yang, D. Liu, J. Ding, H. Ding
Journal: Journal of Clinical Oncology (2011)

8085 Background: Altered NF-kB2 activation is found in many human cancers although the exact mechanisms and affected pathways are not clear. We investigated these questions in a unique transgenic mouse model with lymphocyte targeted expression of p80HT, a lymphoma associated NF-kB2 mutant (Zhang et al.). This model shares features with multiple myeloma (MM) including elevated bone marrow plasma cells and an M spike in some mice. Methods: Microarray analysis was performed on the B cells of p80HT mice, which produced serum monoclonal immunoglobulin (M-protein), and the B cells from wild type littermates, then verified at the RNA and protein levels to identify new downstream targets and investigate regulatory networks. Results: 212 gene probes were significantly changed, 134 up and 78 down. Pathway analysis uncovered known and unknown interactions to factors important in human B cell lymphomas, including cyclins D1 and D2, TRAF1, CD27, SURVIVIN, IL-15 and IL-10. Novel pathways for NF-kB2 are proposed involving IL-10 and other genes in the differentiation of plasma cells, evasion of apoptosis and proliferation. IL-10 is a MM growth factor increased in up to 50% of patient samples. CD27 and IL-10 interact in plasma cell development. SURVIVIN enhances MM cell survival. IL-15 increased proliferation and inhibited apoptosis in MM cell lines and primary cells. Gene Set Enrichment Analysis identified several genes, including Ryk (3.24 fold). A critical role for TNF receptors and STAT signaling is identified. Constitutively activated STAT3 in the bone marrow of MM patients inhibits apoptosis. Four STAT3 targets were identified: IL-10, SURVIVIN, IL-21 and BLIMP1, the master regulator of B cell differentiation. Blimp1 controls plasma cell differentiation via coordinated Bcl-6 downregulation. Consistent is our Blimp1 increase and Bcl-6 decrease. Critical cell cycle components, Ccnd1 and Ccnd2 were significantly upregulated in p80HT mice. Conclusions: Our investigations utilize a novel mouse model to uncover genomic insights into a subset of lymphoma and MM patients, for which no mouse model completely recapitulates their disease, involving NF-kB alternate pathway activation. Treatment strategies targeting IL-10 and STAT3 are suggested.
Weekly docetaxel as second line treatment after mitoxantrone for androgen-independent prostate cancer (AIPC)
Authors: A. M. Joshua, I. Nordman, R. Venkataswaran, M. Stockler, M. Boyer, S. Clarke
Journal: Journal of Clinical Oncology (2005)

4713 Background: Two recent phase III trials have shown an improvement in survival with the use of Docetaxel in metastatic androgen-independent prostate cancer (AIPC) compared to mitoxantrone. However no phase II trials have clearly defined the level of activity of docetaxel after mitoxantrone. We sought to define the activity and toxicity of weekly docetaxel as second line chemotherapy after mitoxantrone in men with AIPC. Patients and Methods: 20 men were treated with docetaxel 40mg/m2 weekly for 3 of every 4 weeks until progression or prohibitive toxicity. Endpoints included PSA response, CTC toxicity, time to progression and overall survival. Results: 9 patients (45%) had a 50% or greater reduction in PSA maintained for at least 1 month. Weekly Docetaxel was well tolerated with few major toxicities: 2 patients had Grade 3 diarrhoea (10%), and 6 had grade 2–4 haematologic toxicities (30%). The median time to progression was 5 months (range 0–13) and median survival was 13 months (range 1 to 24) from starting Docetaxel.The median survival from starting mitoxantrone was 19 months Men who had responded to mitoxantrone were no more likely to respond to Docetaxel (p=0.16 Fischer’s exact test) Conclusions: Weekly Docetaxel is a safe and active second line treatment after mitoxantrone for androgen-resistant prostate cancer with similar levels of activity to the first line setting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Eli Lilly Aventis, Eli Lilly
The impact of body mass index on treatment recommendations for patients with intermediate risk prostate cancer.
Authors: Kosj Yamoah, Alice S. Whittemore, S. Bruce Malkowicz, Elaine Spangler, Michael W. Kattan, Adam Dicker, Timothy R. Rebbeck
Journal: Journal of Clinical Oncology (2014)

48 Background: To evaluate the clinical utility of body mass index (BMI) in predicting adverse pathologic outcomes, hence the need for radiation therapy (RT) following radical prostatectomy (RP) for men with organ-confined prostate cancer. Methods: We compared BMI and preoperative risk factors to adverse pathologic risk factors (RP-risk) that dictate the use of RT following RP. Multivariate analysis was used to determine whether BMI provides clinically relevant information in predicting RP-risk for additional RT as well as biochemical outcome. Results: Patients with elevated BMI had higher RP-risk (p=0.002). Specifically, extraprostatic extension, p less than 0.001; positive surgical margins, p=0.005; and a trend towards worse seminal vesicle invasion, p=0.08. Elevated BMI did not correlate with preoperative risk groupings (p=0.38). However, in patients with intermediate-risk disease BMI greater than 29kg/m 2 was strongly associated with higher RP-risk (p=0.03) and higher rate of pathologic upgrading of tumors (p&lt;0.004). Intermediate risk patients with BMI greater than 29kg/m 2 had a two-fold increased risk of requiring RT following RP based on greater than or equal to two adverse pathologic factors (15% vs. 34%). After controlling for known preoperative risk factors, BMI was an independent predictor of RP-risk for additional RT (p=0.006) and biochemical recurrence (p=0.03). Conclusions: BMI of greater than 29kg/m 2 is an independent predictor of adverse RP-risk requiring additional RT, particularly in patients with intermediate risk disease. This select group of patients may be best treated with definitive radiation therapy to prevent the additional toxicity from adjuvant or salvage RT following RP. We propose including BMI in clinical decision-making for appropriate treatment recommendation for patients with intermediate risk prostate cancer.
Elemene injection combined with radiotherapy in treatment for non-small cell lung cancer with brain metastasis.
Authors: W. Hou
Journal: Journal of Clinical Oncology (2011)

e18074 Background: Non-small cell lung cancer with brain metastasis (BM-NSCLC) shows poor prognosis, shorter median survival time and worse quality of life. The standard therapy for BM-NSCLC is radiotherapy. Elemene Injection with anti-cancer effects is extracted from radix curcumae. Previous researches demonstrate that it can go through the blood brain barrier due to its small molecule. This prospective randomized clinical study is to confirm the effects of radiotherapy combined with Elemene Injection. Methods: 96 BM-NSCLC cases were enrolled (2003-2006) from both the oncology department of Guang’an men Hospital and Beijing Cancer Hospital. The patients were randomly divided into two groups, the treatment group (48 cases) and the control group (48 cases). The treatment group was applied with both radiotherapy and Elemene Injection (400-600mg intravenously everyday for two weeks), while the control group was applied with radiotherapy alone. The treatment lasted for 4 weeks. The clinical symptoms, Karnofsky score and quality of life (QOL) were observed before and after treatment. Results: The effective rate (CR+PR) of the treatment group was 12.76%, and that of the control group was 8.69%. But there was no statistical significance (P=0.178). The main clinical symptoms of both two groups were improved after treatment. There was significantly statistical difference (P=0.000). The improvement rate of the Karnofsky score in treatment group was 46.80%, while that in control group was 13.04%. There was significantly statistical difference (P=0.000). There were no significant differences of the blood routine test, the hepatic and renal function between the two groups before and after treatment. Conclusions: Elemene Injection can increase the efficacy of radiotherapy and improve the QOL of BM-NSCLC without toxicity or side effects.
ATG Plus Cyclosporine-a Should Be Used as Immunosuppressive Therapy in Patients with Severe Aplastic Anemia-Systematic Review and Meta-Analysis
Authors: Anat Gafter-Gvili, Ron Ram, Ronit Gurion, Mical Paul, Moshe Yeshurun, Pia Raanani, Ofer Shpilberg
Journal: Blood (2008)
Differential expression and prognostic value of ERCC1 and thymidylate synthase in resected gastric adenocarcinoma.
Authors: Malcolm Hart Squires, Sarah B. Fisher, Kevin E. Fisher, Sameer H. Patel, David A. Kooby, Charles A. Staley, Alton B. Farris, Shishir K. Maithel
Journal: Journal of Clinical Oncology (2013)

38 Background: Excision repair cross complementing gene-1 (ERCC1) and thymidylate synthase (TS) are key regulatory enzymes whose expression patterns are variably associated with overall survival (OS) in several malignancies. For example, in lung cancer, high ERCC1 expression is inversely associated with OS depending on whether or not patients receive perioperative chemotherapy with surgery. The expression pattern and prognostic value of ERCC1 and TS in resected gastric adenocarcinoma (GAC) are not known. Methods: 109 patients who underwent resection of GAC between 1/00-6/11 had tissue available for analysis. Primary objective was to assess for differential expression of ERCC1 and TS using immunohistochemistry. Secondary objective was to assess for association of ERCC1 and TS expression with OS. Results: Median age was 64yrs. Median FU was 21.2mos and median OS was 28.8mos. Resected GAC exhibited differential expression of ERCC1 (23% high, n=25) and TS (43% high, n=47). ERCC1 and TS expression were not associated with OS. In a planned subset analysis, however, of patients who received chemotherapy (n=73), high ERCC1 expression was associated with decreased OS (16.7 vs. 53.8mos; p=0.03). After controlling for tumor size, margin, grade, T-stage, lymph node involvement, and presence of lymphovascular or perineural invasion, the negative prognostic value of high ERCC1 expression persisted on multivariate Cox regression analysis (HR 2.5; 95%CI: 1.03-6.0; p=0.04). By contrast, in patients who underwent resection only (n=35), high ERCC1 expression was associated with improved OS (40.4 vs. 12.7mos; p=0.10). This finding persisted on multivariate analysis (HR 0.20; 95%CI: 0.04-.86; p=0.03). Conclusions: Resected gastric adenocarcinoma exhibits differential expression of TS and ERCC1. TS expression is not associated with OS. However, similar to what is reported in lung cancer, high ERCC1 tumor expression is associated with decreased OS in patients receiving chemotherapy, but is associated with increased OS in those treated with surgery alone. ERCC1 expression has prognostic value in resected gastric cancer and further investigation is warranted.
A multi-institutional clinical trial of rectal dose reduction via injected polyethylene-glycol hydrogel during IMRT for prostate cancer: Analysis of dosimetric outcomes.
Authors: Danny Y. Song, Klaus Herfarth, Matthias Uhl, Michael J. Eble, Michael Pinkawa, Baukelien Van Triest, Robin Kalisvaart, Damien C. Weber, Raymond Miralbell, Theodore L. DeWeese, Eric Ford
Journal: Journal of Clinical Oncology (2013)

35 Background: To characterize the effect of a prostate-rectum spacer on dose to rectum during external beam radiotherapy for prostate cancer, and to assess for factors correlated with rectal dose reduction. Methods: Fifty-two patients at 4 institutions were enrolled onto a prospective pilot clinical trial. Patients underwent baseline scans, then were injected with perirectal spacing hydrogel and re-scanned. IMRT plans were created on both scans for comparison. Objectives were to establish rates of creation of ≥7.5mm of prostate-rectal separation, and decrease in rectal V70 of ≥25%. Multiple regression analysis was performed to evaluate associations between pre- vs. post-injection changes in rectal V70 and changes in plan conformity, rectal volume, bladder volume, bladder V70, PTV volume, as well as post-injection mid-gland separation, gel volume, gel thickness, length of PTV/gel contact, or gel left-to-right symmetry. Results: Hydrogel resulted in &gt; 7.5mm prostate-rectal separation in 95.8% of patients; 95.7% had decreased rectal V70 of &gt; 25%, with mean reduction of 8.0 Gy. There were no significant differences in pre- and post-injection prostate, PTV, rectal, and bladder volumes. Plan conformities were significantly different pre- vs. post-injection (P = 0.02). In multiple regression analysis, change in plan conformity was negatively associated with reduction in V70 (P=0.01); plans with worse conformity indexes post-injection compared to pre-injection (n=13) still had improvements in rectal V70. Reductions in V70 did not significantly vary by institution, despite significant inter-institutional variations in plan conformity. There were no significant relationships between reduction in V70 and the other characteristics analyzed. Conclusions: Injection of hydrogel into prostate-rectal interface resulted in dose reductions to rectum for &gt; 90% of patients treated. Rectal sparing was statistically significant across a range of 10-75 Gy, and was demonstrated within the presence of significant inter-institutional variability in plan conformity, target definitions, and injection results.
Long-term survival of subjects in the prostate cancer prevention trial.
Authors: Phyllis J. Goodman, Ian Murchie Thompson, Catherine M. Tangen, Howard L. Parnes, Paul Alphonso Godley, Leslie G. Ford
Journal: Journal of Clinical Oncology (2013)

10 Background: As finasteride could reduce by 25% the number of prostate cancers (PCa) diagnosed in the U.S. annually, the public health benefit of prostate cancer prevention could be enormous. We performed a survival analysis to assess for any evidence of increased risk of death in men randomized to finasteride, a potential indicator of a ‘true’ increased risk of high grade (HG) disease in the PCPT. Methods: A Social Security Death Index search was conducted on all randomized men to ascertain date of death. Cox proportional hazards models adjusting for known risk factors for overall survival and survival from time of diagnosis of PCa overall, low grade (LG) and HG were used to estimate hazard ratios (HR) and construct 95% confidence intervals to determine if survival on finasteride and placebo were equivalent. Results: A total of 5,128 deaths have been reported; 2,584 men on finasteride and 2544 on placebo. 15-year survival rates for all randomized men in each arm is 78%. The HR for overall survival on finasteride compared to placebo is 1.04 (95% CI 0.96, 1.10, p=.19). 10-year survival from diagnosis for men with PCa was slightly higher for men randomized to finasteride (10-year survival 83% vs. 81%) but not statistically significant (HR= 0.87, 95% CI 0.73 - 1.04, p=.14). For the men with HG PCa, there was no evidence of worse survival on finasteride (HR= 1.01; 95% CI 0.73, 1.14, p=.97) while those diagnosed with LG disease finasteride had superior survival (HR= 0.73; 95% CI 0.57, 0.94, p=.01). Conclusions: For men in PCPT with PCa there was no difference in survival from diagnosis date, a slightly-superior 10-year survival with finasteride and a statistically-superior survival among men with LG tumors in the finasteride group. A potential explanation for this phenomenon could be a lead-time bias. Arguing against this bias is the identical survival of HG PCa in both groups. Another potential explanation is that the men with LG PCa on placebo include a greater number with undetected HG disease; HG tumors in men on finasteride were more likely detected due to the improved performance of prostate biopsy. With follow-up of 18 years, finasteride administration for 7-years does not appear to affect mortality but significantly reduces the risk of a PCa diagnosis. Clinical trial information: NCT00288106.
Bevacizumab effectiveness and primary tumor location in metastatic colorectal cancer patients.
Authors: Wen-zhuo He, Qiong Yang, Chang Jiang, Fang-xin Liao, Shou-sheng Liu, Liang-ping Xia
Journal: Journal of Clinical Oncology (2016)

683 Background: There is currently no consensus about whether bevacizumab effectiveness is associated with the primary tumor location of metastatic colorectal cancer (mCRC). The aim of this study was to assess whether the primary tumor location was a predictor for bevacizumab treatment. Methods: From 2004 to 2013, 740 patients with mCRC treated with oxaliplatin / 5-FU / leucovorin (mFOLFOX6) or irinotecan / 5-FU / leucovorin (FOLFIRI) (CT group) and 244 patients treated with bevacizumab plus mFOLFOX6 or FOLFIRI (CT + B group) as first-line setting were included from Sun yat-sen university cancer center. Right-side colon cancers included those occurring in the cecum, ascending colon or transverse colon. Left-side colon cancers included those from descending or sigmoid colon. The primary outcome was overall survival (OS). Kaplan-Meier curves with log-rank tests were used to detect difference. All statistical tests were two sided. Results: 222 right-side colon, 259 left-side colon and 259 rectal cancer patients were included in CT group while 78 right-side colon, 86 left-side colon and 80 rectal cancer patients were included in CT + B group. Patients in CT + B group had similar OS compare with CT group only when the primary tumor located at right-side colon (median OS was 19.6 months for CT + B group versus 19.5 months for CT group, P = 0.269). For left-side colon cancer, significantly longer OS were observed in CT + B than CT group (22.3 months versus 21.9 months, P = 0.014). For rectal cancer patients, those in CT + B group also had longer OS than CT group (25.9 months versus 21.1 months, P = 0.005). Conclusions: Our data suggested that patients with right-side colon cancer could not get survival benefit from the addition of bevacizumab to first-line chemotherapy. Further data from randomized trials are needed to test our hypothesis. [Table: see text]
Characterization of mutational load in patients with advanced urothelial cancer.
Authors: Sumanta K. Pal, Siraj Mahamed Ali, Riley Ennis, Julia Andrea Elvin, JoAnn Vergilio, James Suh, Roman Yelensky, Jeffrey S. Ross, Vincent A. Miller, Monika Joshi, Toni K. Choueiri, Philip J. Stephens, Garrett Michael Frampton
Journal: Journal of Clinical Oncology (2016)

460 Background: The efficacy of novel immunotherapeutic agents (e.g., PD-1/PD-L1 and CTLA4 inhibitors) in advanced cancer is linked to tumor mutational load. We assessed mutational load via comprehensive genomic profiling (CGP) performed in the course of clinical care for patients with advanced urothelial cancer (UC). Methods: DNA was extracted from 40 microns of FFPE sections from 760 consecutive patients with relapsed/metastatic UC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 646X for at least 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Mutational load was characterized as the number of such SUBs or INDELs per megabase (Mb) after filtering to remove known somatic and deleterious mutations, given that these are selected for with hybrid capture. Results: The median age of the patients was 66 years old with a 3:1 male:female ratio. Mean mutations per megabase were assessed as a range of 0 to 79, and the 25th, median, and 75th quartile thresholds were 3.2, 5.5, and 8.8. MSH6 alterations in 0.8% cases had a median of 15.2 mutations per megabase. However, the ten most frequently altered genes in this series- TERT (64%), TP53 (54%), CDKN2A (35%), CDKN2B (28%), KDM6A (24%), ARID1A (23%), MLL2 (22%), PIK3CA (21%), RB1 (21%) and FGFR3 (19%) - were not associated with differences in mutational load. Conclusions: A highly variable mutational load was seen in patients with advanced UC. A subpopulation of MSH6-altered UC had very high mutational loads relative to other UCs. Further correlation to clinical outcomes will be investigated to assess the correlation between mutational load and response to immunotherapy.
Response of brain metastases from non-small cell lung cancer to first-line pemetrexed-based chemotherapy: A single-center experience.
Authors: C. Milandri, M. Ricci, M. Burgio, L. Ridolfi, G. Genestreti, M. Monti, V. Di Iorio, N. Riva
Journal: Journal of Clinical Oncology (2011)

e18052 Background: Non Small Cell Lung Cancer (NSCLC) accounts for almost 80% of all lung malignancies, and 40% of these patients go on to develop brain metastases (BM). Furthermore, there are no grade 1 recommendations for the management of multiple BM. The most widely used treatment is whole-brain radiation therapy (WBRT). Current data on pemetrexed suggest that it is active against BM. This drug was recently made available in Italy for front-line treatment of non-squamous NSCLC. Methods: In 2010 we observed 8 patients with central nervous system metastases from non-squamous NSCLC at diagnosis. Patients were treated with first-line cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for a minimum of 3 cycles up to a maximum of 6 cycles in the absence of progressive disease (PD). Results: With regard to brain lesions, 5 patients had partial response (62.5%), 1 had complete response (12.5%), 1 showed stable disease (12.5%) and 1 had PD (12.5%). Only two patients were treated with concomitant WBRT, showing a partial response that continued during treatment and up to the final evaluation. Conclusions: Our data, although based on a relatively small case series, seem to confirm the activity of pemetrexed-based therapy against BM. If confirmed in a larger sample of patients, these results could modify the management of multiple BM by delaying radiotherapy in asymptomatic patients until PD occurs.