bluuebunny/crossref_metadata_2025 huggingface dataset:
Pleotrophic action of renal cell carcinoma: Dysregulated microRNAs on hypoxia-related signaling pathways.
Authors: Bjarnason Georg A. , Lichner Zsuzsanna , Mejia-Guerrero Salvador , Ignacak Monika , Krizova Adriana , Bao Tian Tian , Girgis Andrew , Youssef Youssef M. , Yousef George M.
Published: February 2017

428

Background: The von Hippel-Lindau (VHL) gene is lost in 70% of clear cell Renal Cell Carcinomas (ccRCC); however, additional mechanisms are proposed to regulate VHL expression, including suppression by microRNAs (miRNAs). miRNAs are a class of naturally occurring, small non-coding RNA molecules that downregulate gene expression of target mRNAs. We demonstrate that ccRCC-dysregulated miRNAs can target multiple members of the ccRCC-related signaling pathways.

Methods: miR-17 and miR-224 mimics and inhibitors were transfected into ccRCC cell lines using siPORT (Ambion). PicTar and TargetScan were used for target prediction. Target expression and miRNA expression was analyzed by qRT-PCR (Ambion). Western blot antibodies were purchased from Millipore or Cell Signaling. Cell lines were purchased from ATCC. All methods followed the manufacturer’s protocol.

Results: According to our preliminary results, the miRNAs that are dysregulated in ccRCC specimens are predicted to target multiple members of the hypoxia-related pathways. To confirm the in silico analysis, miR-17 and miR-224 were selected for experimental target validation, as they were among the most up-regulated miRNAs in ccRCC. We experimentally validated VHL and HIF1α as likely direct targets of miR-17 and miR-224. Luciferase reporter assay confirmed that miR-17 directly downregulates VHL. Moreover, VHL protein level decreased upon miR-17 and miR-224 transfection. We also established a negative correlation between the expression of miR-17 and two predicted targets VEGF-A, EGLN3 in RCC specimens, and miR-224 and its predicted targets SMAD4 and SMAD5. This suggests that downstream signaling pathways are also modulated by miR-17 and miR-224. These results confirm the most important findings of the bioinformatics analysis: miR-17 targets different molecules along the same signaling pathway and that multiple ccRCC-dysregulated miRNAs can synergistically suppress a single target, which functions in the pathogenesis.

Conclusions: Our results indicate that miRNAs possibly regulate hypoxia-related pathways at multiple points. This is of special interest as miRNAs may serve as potential therapeutic targets.
Risk of treatment failure after first-line sunitinib therapy in patients with metastatic renal cell carcinoma.
Authors: Chen Chi-Chang , Hess Gregory P. , Liu Zhimei , Gesme Dean H. , Agarwala Sanjiv S. , Hill Jerrold W. , Guo Min Amy
Published: February 2017

438

Background: Treatment options for metastatic renal cell carcinoma (mRCC) are rapidly evolving. Current treatment options include surgery, immunotherapy, and several targeted therapies including kinase inhibitors, mTOR inhibitors and anti-VEGF agents. The aim of this study was to inform choices and outcomes on the sequential use of targeted therapies for mRCC through the evaluation of the comparative effectiveness of common second-line targeted therapies following 1st line sunitinib treatment.

Methods: A retrospective observational study using claims data was conducted. Final study subjects were mRCC patients who received everolimus, sorafenib or temsirolimus from 4/1/2008 to 2/29/2011 following 1st line sunitinib treatment. Patients were followed from the start of second-line treatment until treatment failure or last observation in the database. Treatment failure was defined as advancement to a third-line of mRCC therapy, or mortality. Results were analyzed using Cox proportional hazards model controlling for baseline clinical and demographic factors.

Results: The study sample consisted of 257 mRCC patients who received everolimus (n=117), temsirolimus (n=75) and sorafenib (n=65) following 1st line sunitinib treatment. Patients had a mean age of 63 years, and 72% were male. The mean observation period from the start of second-line treatment was ∼6.4 months. Treatment failure was observed in 38.5% (20.2% advanced from 2nd to 3rd line and 18.3% died) of the study sample and 61.5% of patients were censored at last observation without any treatment failure event. Results from the Cox proportional hazards model indicated that, compared to everolimus, both sorafenib and temsirolimus patients experienced a statistically significant higher adjusted risk of treatment failure (sorafenib: HR=1.77, p=0.043; temsirolimus: HR=2.05, p=0.004).

Conclusions: Following systemic treatment for mRCC with first-line sunitinib, patients on second-line targeted therapies were observed with differential risks of treatment failure, as defined by line advancement or death. The risk of treatment failure was significantly higher with sorafenib and temsirolimus as compared to everolimus.
Comparison of the 2002 and 2010 version of the TNM classification system regarding the prediction of metastasis-free survival in patients with renal cell carcinoma.
Authors: Hutterer Georg C. , Pichler Martin , Chromecki Thomas F. , Jesche Johanna , Kampel-Kettner Karin , Pummer Karl , Zigeuner Richard
Published: February 2017

448

Background: A new version of the TNM classification system for renal cell carcinoma (RCC) has been introduced in 2010 by the American Joint Committee on Cancer (AJCC). However, data for it’s ability to predict metastasis-free survival in RCC patients from validation studies of independent cohorts are sparse. Therefore, we decided to compare the predictive ability of the 2010 vs. the 2002 version of the TNM classification system.

Methods: Pathological reports of 2595 patients with uni- or bilateral synchronous non-metastatic (pT1-4N0M0) RCCs, treated with radical nephrectomy or nephron sparing surgery between 1984 and 2010 at a single tertiary academic center, were re-evaluated. Metastasis-free survival (MFS) was assessed using the Kaplan-Meier method and pairwise log-rank tests.

Results: Mean follow up was 95 (0-322) months and 430 (16.6%) patients were found to develop metastatic disease from RCC. Pairwise comparisons revealed statistically significant differences in MFS between adjacent 2002 primary tumor classifications, including pT1a vs. pT1b (p<0.001), pT1b vs. pT2 (p=0.029), pT3a vs. pT3b (p<0.001), and pT3c vs. pT4 (p=0.007) but excluding, pT2 vs. pT3a (p=0.963) and pT3b vs. pT3c (p=0.968). With the changes to the 2010 primary tumor classification different trends in statistical significance were observed in pairwise comparisons, including pT1a vs. pT1b (p<0.001), pT3a vs. pT3b (p=0.001) but excluding pT1b vs. pT2a (p=0.062), pT2a vs. pT2b (p=0.856), pT2b vs. pT3a (p=0.395), pT3b vs. pT3c (p=0.891) and pT3c vs. pT4 (p=0.933).

Conclusions: The 2010 version of the TNM classification system remains a robust predictor of MFS compared to the 2002 version. However, the 2010 version showed less discriminative power in higher pT-stages compared to the 2002 version of the TNM classification system.
Virtual HDR SBRT for localized prostate carcinoma: Efficacy and quality-of-life assessment.
Authors: Fuller Donald B. , Shirazi Reza , Naitoh John , Mardirossian George
Published: February 2017

45

Background: We designed a CyberKnife (CK) prostate Stereotactic Body Radiotherapy (SBRT) method to recapitulate HDR fractionation and target volume coverage (“Virtual HDR”). We report 4 year efficacy, toxicity and quality of life (QoL) outcomes.

Methods: Eligible patients had low- (Gleason < 6, PSA < 10 ng/mL, < T2bN0) or intermediate-risk (Gleason < 6 with PSA 10.01 – 20 ng/mL or Gleason 7 with PSA < 10 ng/mL, < T2bN0) prostate cancer. A dose of 38 Gy/4 fractions was given to > 95% of the PTV; with “HDR-like” bladder, urethral and rectal dose constraints, and “HDR-like” dose escalation in the PTV. Toxicities were assessed using CTCAE3.0 criteria. QoL was assessed using the Expanded Prostate Cancer Index Composite (EPIC).

Results: Since July 2006, 59 patients were treated. Two were lost to follow-up and 6 have been followed < 6 months, leaving 51 (32 low- and 19 intermediate-risk) patients for analysis. Median f/u is 42 months (range, 6-60). 4-year actuarial biochemical-disease free survival is 98% (ASTRO, Phoenix). Freedom from local and distant relapse is 100% and 98%. Median baseline PSA of 6.3 ng/mL (range 1.0 – 14.1) decreased to 0.1 ng/mL by 48 months. Acute grade 2 GU and GI toxicity rates were 22% and 4%, respectively (0% Grade 3+). Three (6%) late Grade 3 GU toxicities occurred at 18, 48 and 48 months. No grade 3+ GI toxicity occurred. Late grade 2 GU and GI toxicity rates were 18% and 2%, respectively. Only 2 patients (4%) had ongoing late > grade 2 GU toxicity at last follow-up (0% GI). Mean EPIC urinary and bowel scores decreased at 2 months, with subsequent improvement and stability to 48 months. Mean EPIC sexual scores gradually declined to 48 months. Of patients potent at baseline, 63% were potent at 3 years, including 100% < age 60, 64% age 61-70 and 60% > age 70.

Conclusions: To 4 years, HDR-like CK SBRT for low- and intermediate-risk prostate cancer results in a very low PSA nadir and relapse rate, minimal toxicity and a favorable QoL outcome, with an age-dependent potency preservation rate. The occasional occurrence of late grade 3 urethral stricture can likely be reduced by better patient selection (caution re: patients with significant pre-existing uropathy). Acute and late grade 2 GU toxicity usually resolves with conservative management.
Tissue array analysis in patients with renal cancer.
Authors: Areses Manrique Maria C , Anido Urbano , Abdulkader Ihab , Leon Luis
Published: February 2017

450

Background: Development and progression of kidney cancer is the result of an imbalance in signals promoting and inhibiting cellular proliferation and apoptosis. The aim of this study is to analize the expression of some molecular regulators and correlate them with clinical outcome in renal carcinoma, in order to establish common prognostic biomarkers.

Methods: Tissue sample was obtained from nephrectomized patients in our center between 1998 and 2003. Biopsies were taken from 150 patients; a tissue array was done to analyze immunoexpression of proteins related to proliferation, cell cycle control and angiongenesis: p53, Ki 67, VEGF, VEGFR1, VEGFR2, HIF1, HIF2, cyclin D1, cyclin D3, cyclin B1, cyclin A, bcl2, p63, COX2, p16, p27, p21, EGFR, PDGF, PTEN, CAIX, BRAF, Akt and P13K. Subsequently the results were correlated with clinical variables (age, hypertension, smoking), pathological (tumor size, stage, Fuhrman grade) and time to progression and overall survival.

Results: 92.3% of patients underwent nephrectomy, 11% associated with lymphadenectomy. Histology: 66.6% clear cell his, 14.1% papillary, chromophobe 6.4% and 15% miscellaneous. Stage I 49.4%; II 17.9%; 14.7% III; IV 14.1%; 3.8% unknown. Of the 150 patients analyzed, 23% had a second tumor. Median time to progression was 90.5 months (95% CI 81.7 to 114.3). The median survival has not yet been reached. Results of tissue array analysis wil be presented in the meeting.

Conclusions: Patients in this serie have a good prognosis, since most tumors are stage I and II. We will present data on the expression of factors related to proliferation, cell cycle control and angiogenesis.
Medicines use review in renal cancer: How are we doing? What could we do better?
Authors: MacLeod Nicholas James
Published: February 2017

458

Background: Following guidance from the National Institute for Clinical Excellence (NICE), sunitinib became available for use in the West of Scotland (WOS) in March 2009 as first line treatment for patients with advanced renal cell carcinoma (RCC) who were suitable for immunotherapy and had a performance status (PS) of 0 or 1. We performed a Medicines Use Review of sunitinib in patients who commenced treatment between March 2009 and February 2010. Data were analysed in April 2011.

Methods: Patients were identified from an electronic prescribing database. A mixture of prospective and retrospective data were collected using case notes and electronic patient records.

Results: 89 patients commenced treatment during this time. 16 patients were excluded as they were enrolled in clinical trials. 73 patients were included in the study. 54 (74%) were male. At the time of analysis, 31 patients were alive. Mean age at first cycle was 62 years. 22 (30%) patients had non clear cell pathology (NCC). 59 (81%) patients had prior nephrectomy and 31 (42%) had prior drug therapy. Median duration of therapy was 6.9 months. Median survival (MS) was 14.4 months (15.1 months for clear cell patients and 8.1 months for non clear cell patients). The most common toxicities (grade 2 or above) were cutaneous, diarrhoea and fatigue. PS was not documented for 43 patients. Where PS was documented, 13 were PS 0, 13 were PS 1 and 4 were PS 2. 32 patients required at least one dose reduction. Three patients later had their dose re-escalated.

Conclusions: Our survival figures are lower than those reported in the pivotal trial 1, but comparable to the expanded access programme 2. This may reflect the high proportion of our patients with NCC and with prior treatment. 1. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cancer. J Clin Oncol 27 (22): 3584-90, 2009. 2. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded access trial. Lan Oncol 10: 757-63, 2009.
Association of hypothyroidism with improved outcomes in first-line treatment of renal cell carcinoma with sunitinib.
Authors: Pinto Flavio Augusto Ismael , Pereira Augusto Akikubo Rodrigues , Formiga Maria Nirvana , Fanelli Marcello Ferretti , Chinen Ludmilla T. D. , Lima Vladmir C. , De Melo Gagliato Debora , Santos Elzabeth Santana , Dettino Aldo A. , Sousa Carlos Eduardo Pires , Rodrigues Newton Augusto Ferreira , Padua Fernando Vidigal , Freitas Paulo Henrique Aires , Alves Marclesson S. , Nicolau Ulisses Ribaldo , Lisboa Joyce , Ribeiro Adriana G. , Jesus Victor Hugo Fonseca , Rinck JosÃƒÂ© A.
Published: February 2017

466

Background: Sunitinib, a multitarget tyrosine-kinase inhibitor, has become a standard of care for first-line low and intermediate risk metastatic renal cell carcinoma (mRCC). Sunitinib-induced hypothyroidism and hypertension have been correlated with better outcomes in those patients.

Methods: Fifty patients with mRCC, treated in the first-line with sunitinib, were retrospective analyzed at one brazilian institution, for overall survival (OS), progression free survival (PFS), overall response rate (ORR) and toxicity. We evaluated clinical and laboratory parameters, such as hypothyroidism (TSH level > 5,5 mIU/L) and hypertension, to identify prognostic factors.

Results: The median age of patients was 58 years (range: 37-73 years), 82% were male, 54% were ECOG 0 or 1, and 76% were classified in low or intermediate risk. Nefrectomy was performed in 96% of cases. Lung and bone were the most common sites of metastases. The incidence of hypothyroidism and hypertension during treatment were 40% and 34%, respectively. ORR for the entire population was 40% and it was statistically superior in patients that developed hypothyroidism during treatment (90% vs. 20%; p<0,0001). Median survival and PFS were 21.7 months (10.65-17.70 months, 95% CI) and 14.2 months (15.77-27.58 months, 95% CI), respectively. In univariate analysis, ECOG (p<0,0001), MSKCC criteria (p<0,0001), hypothyroidism (p<00001) and hypertension (p=0,001) were associated with OS. In multivariate analysis, ECOG (p<0,0001), MSKCC criteria (p<0,0001) and hypothyroidism (p<00001) were independent prognostic factors for OS. The most common severe adverse events (G3-4) were asthenia (14%), diarrhoea (6%), neutropenia (14%), thrombocytopenia (10%), hand-foot syndrome (6%) and hypertension (8%).

Conclusions: Efficacy in survival and toxicity profile of sunitinib in first-line treatment of mRCC in patients out of clinical trials were comparable to prior studies. Hypothyroidism, MSKCC criteria and ECOG were independent prognostic factors for survival.
MARC-2: An open-label trial to characterize patients with metastatic renal cell carcinoma (mRCC) treated with everolimus after failure of the first VEGFR-TKI therapy.
Authors: Staehler Michael D. , Bergmann Lothar , Grünwald Viktor , Huschke Torsten , Keilholz Ulrich , Ohlmann Carsten Henning , Stöckle Michael , Weigang-Koehler Karin , Hauswald Kirsten , Schaller Felix , Strassl Luise , Junker Kerstin
Published: February 2017

467

Background: Clinical research in mRCC is leading to increased treatment options. Most patients (pts) are treated with sequenced systemic medications based on the clinical course of the disease. Characterization of pts most likely to benefit from a specific targeted agent has not yet been sufficiently addressed in this area. So far, no reliable biomarkers exist to predict therapy response or resistance in the individual patient. Further investigation is needed to understand drug effects in vivo. In the MARC-2-study, pts treated with everolimus will be characterized by serum and tissue biomarkers in order to identify a pattern possibly suggestive of treatment outcome.

Methods: 80 pts are to be enrolled at about 15 study centers in Germany over 2 years. Major inclusion criteria are confirmed predominantly clear cell mRCC, failure of exactly 1 prior VEGFR-TKI therapy, no pretreatment with mTOR inhibitors or bevacizumab. Tumor response is assessed according to RECIST 1.1. Safety assessments include monitoring of adverse events and laboratory parameters. Primary objective is the rate of pts free of disease progression after 6 months of treatment. Secondary objectives are relation of biomarkers to the clinical benefit, progression free survival, overall survival, objective response rate and safety profile. For explorative assessments, blood samples are taken pre-treatment and at prespecified time points during the treatment. Central histopathological classification of tumor samples will be performed. Biomarker projects include: Serum protein profiling by using SELDI-TOF-MS; quantification of Treg cells in blood samples; identification of serum metabolic biomarkers; polymorphisms in genes related to the VEGFR signaling pathway; expression analysis of the mTOR-pathway in tumor samples. Pharmacokinetic consists of everolimus trough levels. Tumor assessments by functional MRI will be performed within a substudy at selected sites.

Results: The 1st patient was enrolled in 03/2011. Until 08/2011, 10 sites have been initiated and 9 pts were recruited.

Conclusions: The new project MARC-2 was introduced and started successfully in 2011.
Prognostic significance of degree of anemia in renal cell carcinoma.
Authors: Mozayen Mohammad , Tesfaye Anteneh , Katato Khalil
Published: February 2017

469

Background: Anemia can precede the diagnosis of renal cell carcinoma (RCC). It has been well studied that it has a negative effect on the outcome of RCC. The impact of the severity of anemia on the overall all survival of patients with RCC is not well known. Our study examined the impact of severity of anemia on the overall survival of patients with RCC.

Methods: We retrospectively reviewed 204 patients diagnosed with RCC between 1995 and 2008 in a community hospital setting. Patients with additional malignancies, lymphoma of the kidneys, with no follow up data or no preoperative Hemoglobin levels (Hg) measurement were excluded from the study. Demographics, preoperative complete blood count (CBC), pathology, disease stage, operative note, and subsequent follow up data were reviewed. Patients were grouped based on their preoperative Hg. Anemia was defined as Hg <12g/dl for females and <13g/dl for males. Patients were divided based on Hg to Group A (females with Hg<10 g/dl, males with Hg<11g/dl), group B (females with Hg 10-12 g/dl, males with Hg 11-13 g/dl), group C (females with Hg >12 g/dl, males with Hg >13g/dl). Last follow up date was used to calculate the 3 year overall survival for patients. The primary outcome was 3 year overall survival.

Results: A total of 204 patients were reviewed, 127 (62.3%) were males, 176 (85.9%) were Caucasians. The median age of the study population was 65 (22-91). Clear Cell was the commonest histology (79%). Anemia was found in 90 (44.1%) patients. The median Hg was 12.8 g/dl (Range: 7.2-18.2). Anemia was present in 41.8% of females and 46.2% of males. The median Hg level for stages I, II, III, IV were (13.05, 12.45, 12.45, 11.45) respectively. The 3 year overall survival for the study population was 67.3% (95% CI: 60.4-73.7). The 3-year overall survival for anemic patients was 51.2% (95% CI: 40-61) compared to 81.6% (95% CI: 72-87) in non anemic (p<0.0001). The 3-year overall survival significantly decreased with Hg levels, as shown by the Groups A (33.3%), B (60.7%), and C (81.6%) (p<0.0001).

Conclusions: Our finding was consistent with other studies in portraying anemia as a negative prognostic factor in patients with renal cell carcinoma. Our study also showed that the severity of anemia corresponds to poorer overall patients survival.
Radical salvage prostatectomy for locally recurrent prostate cancer after radiation therapy.
Authors: Heidenreich Axel , Porres-Knoblauch Daniel , Epplen Robin , Piper Charlotte , Pfister David J. K. P. ,   EURO Prostate Center Aachen
Published: February 2017

47

Background: Radical salvage prostatectomy (SRP) is one local treatment option with curative intent in patients failing radiation therapy (RT) for localized prostate cancer (PCA). We compared the surgical, histological and functional outcome of a large cohort of patients who underwent SRP for locally recurrent PCA following LDR – brachytherapy (BRT).

Methods: 66 consecutive patients with locally recurrent PCA after BRT underwent retropubic SRP and pelvic lymphadenectomy. Preoperative PSA, PSA doubling time, PSA prior to initial RT, biopsy Gleason score, number of positive biopsies, cT stage, neoadjuvant androgen deprivation were correlated with pathohistological stage, complications and functional outcome by uni- and multivariate analysis.

Results: Mean preop. PSA was 5.6 (2-13.5) ng/ml; mean preoperative biopsy Gleason score was y5.6 (4-9). 1 patient (1.5%) experienced a rectal lesion, mean blood loss was 430 (200-900) ml, none of the patients received blood transfusions. Pathohistology demonstrated organ confined prostate cancer pT2a-2c in 38 (57.5%) patients, stage pT3a and stage pT3b was identified in 14 (21.1%) patients and in 14 (21.1%) patients, respectively. Positive surgical margins were diagnosed in 9 (13.6%) patients and 12 (15.1%) patients harboured lymph node metastases. Functional outcome was good with a continence rate of 82%; the mean time until recovery of continence was 8.4 (6-14) months. After a mean follow-up of 22.5 (1-72) months, 28% of the patients experienced a PSA relapse defined as any PSA increase > 0.2 ng/ml validated by 2 consecutive measures.

Conclusions: SRP can be performed safely and with a low morbidity in biopsy proven locally recurrent PCA following BRT. However, our data demonstrate an unfavourable histology with locally advanced disease in about 40% of the patients who all were diagnosed with low risk prostate cancer. These data question the quality of the selection process for patients being counselled for BRT and the data raise the possibility of both intrinsic radioresistance of prostate cancer or poorly performed BRT.
Prostate-specific antigen and long-term prediction of prostate cancer incidence and mortality in the general population.
Authors: Orsted David D , Nordestgaard Borge G. , Bojesen Stig E.
Published: February 2017

5

Background: It is largely unknown whether prostate-specific antigen at first date of testing predicts long-term risk of prostate cancer incidence and mortality in the general population. We tested the hypothesis that baseline prostate-specific antigen levels predict long-term risk of prostate cancer incidence and mortality.

Methods: Using a prospective study, we examined 4383 20-94 year old men from the Danish general population followed in the Copenhagen City Heart Study from 1981 through 2009. Prostate-specific antigen was measured in plasma samples obtained in 1981-83.

Results: During 28 years of follow-up, 170 men developed prostate cancer and 94 died from prostate cancer. Median follow-up was 18 years (range 0.5-28 years). For prostate cancer incidence, the subhazard ratio was 3.0 (95% confidence interval (CI) 1.9-4.6) for a prostate-specific antigen level of 1.01-2.00 ng/ml, 6.8 (4.2-11) for 2.01-3.00 ng/ml, 6.6 (3.4-13) for 3.01-4.00 ng/ml, 16 (10.4-25) for 4.01-10.00 ng/ml, and 57 (32-104) for >10.00 ng/ml versus 0.01-1.00 ng/ml.. For prostate cancer mortality, corresponding subhazard ratios were 2.2 (1.3-3.9), 5.1 (2.8-9.0), 4.2 (1.8-10), 7.0 (3.8-14), and 14 (6.0-32). For men with prostate-specific antigen levels of 0.01-1.00 ng/ml, absolute 10-year risk of prostate cancer was 0.6% for age <45 years, 0.7% for 45-49 years, 1.1% for 50-54 years, 1.2% for 55-59 years, 1.3% for 60-64 years, 1.1% for 65-69 years, 1.3% for 70-74 years, and 1.5% for age≥75 years; corresponding values for prostate-specific antigen levels >10.00 ng/ml were 35%, 41%, 63%, 71%, 77%, 69%, 75%, and 88%, respectively.

Conclusions: Stepwise increases in prostate-specific antigen at first date of testing predicted a 3-57 fold increased risk of prostate cancer, a 2-16 fold increased risk of prostate cancer mortality, and a 35-88% absolute 10-year risk of prostate cancer in those with prostate-specific antigen levels >10.00 ng/ml. Equally important, absolute 10-year risk of prostate cancer in those with levels 0.01-1.00 ng/ml was only 0.6-1.5%.
Multiparametric magnetic resonance imaging in the diagnosis and characterisation of prostate cancer: The PROMIS study.
Authors: Parker Chris , Kaplan Richard S. , Gabe Rhian , Ahmed Hashim Uddin , Rantell Khadija , Emberton Mark ,   on behalf of the PROMIS Trial Management Group
Published: February 2017

62

Background: Over 1 million US men undergo prostate biopsy each year. About two thirds will test negative. This negative status is uncertain as up to a quarter will have prostate cancer on repeat biopsy. Further, a positive result often fails to discriminate clinically significant from insignificant disease. PROMIS will investigate whether multi-parametric MRI (mpMRI) can discriminate between men with no cancer or clinically insignificant cancer versus those with clinically significant cancer, using template prostate mapping (TPM) biopsies as the most accurate and appropriate reference test in men referred for biopsy.

Methods: PROMIS is a multicenter, validating paired cohort study designed to include up to 714 men who will have an mpMRI (index test) and, under general anaesthetic, undergo 10-12 core TRUS biopsy (standard test) and TPM with sampling every 5mm throughout the prostate (reference test). All tests will be assessed independently. Clinically significant cancer on TPM is defined as dominant Gleason pattern ≥4 and/or cancer core length of ≥6mm. PROMIS is powered to measure an absolute increase in sensitivity from 48%, on TRUS biopsy, to at least 70%, by mpMRI.

Results: The study will report the proportion of men (i) who could safely avoid biopsy and (ii) correctly identified by mpMRI to have clinically significant prostate cancer. mpMRI will be assessed using an ordinal score of 1 to 5 (highly likely benign - highly likely malignant), with a score ≥3 indicating a positive mpMRI for presence of clinically significant cancer. Secondary objectives will include outcomes based on another definition of clinically significant cancer (non-dominant Gleason pattern ≥4 and/or cancer core length ≥4mm), and cost-effectiveness of using mpMRI prior to biopsy.

Conclusions: PROMIS will provide level 1 evidence by comparing mpMRI with the current standard, TRUS biopsy, using an accurate reference test that can be applied to all men advised to have a biopsy. If successful, mpMRI could in the future allow between a quarter and a half of US men referred to safely avoid a biopsy and/or improve the detection of clinically significant cancer by 20%.
Phase IB trial redesign to test role of IL2 with anti-PSMA designer T cells to yield responses in advanced prostate cancer.
Authors: Junghans Richard P.
Published: February 2017

70

Background: We created a chimeric antigen receptor (CAR) for prostate specific membrane antigen (PSMA). When expressed in patient T cells, these “designer T cells” specifically kill prostate cancer cells in vitro and in vivo in animal models (Ma et al. Prostate 2004:61:12-25). FDA approved a Phase I clinical trial.

Methods: Patient T cells are retrovirally transduced and expanded. Patients undergo non-myeloablative (NMA) conditioning to create “hematologic space” into which designer T cells are infused for engraftment and improved in vivo efficacy. Patients are co-administered continuous infusion IL2. Patients are monitored for safety and response.

Results: Five patients were treated, three at 10^9 and two at 10^10 cell dose levels with safety. Partial responses (PR) were seen in 2/5 patients (40%), with PSA suppressions of 50 and 70% over 1-2 months and PSA progression delay of 70 and 150 days. Yet these responses were observed only at the lowest T cell dose (10^9 cells) and not the higher tested dose (10^10 cells). Response correlated with plasma IL2 that was as much as 10-fold lower in non-responders vs responders. This low IL2 correlated in turn with high engrafted fractions of infused activated T cells. This prompted a hypothesis that infused activated T cells at high engrafted cell numbers absorbed out IL2 to a level too low to sustain dTc activation for effective tumor killing. A study redesign will test high dose IL2 (HDI) versus moderate dose IL2 (MDI) in Phase Ib/Pilot at 10^10 cell dose, then advancing to the maximum practical dose (MPD, 10^11 cells) of dTc under the optimal IL2 plan.

Conclusions: A new approach to adoptive immune therapy in metastatic prostate cancer has been devised with encouraging early results. We postulate that adequate higher IL2 in vivo will allow the greater potency of higher dTc doses to be revealed, thereby potentially inducing PSA reductions of 100%, with durable remissions of metastatic prostate cancer that is refractory to all other treatments. Patients are being recruited. This clinical trial received funding from US Army/DOD and from Prostate Cancer Foundation for preclinical work.
Rye bread consumption in early life and reduced risk of advanced prostate cancer.
Authors: Torfadottir Johanna Eyrun , Valdimarsdottir Unnur Anna , Mucci Lorelei , Stampfer Meir J. , Kasperzyk Julie , Fall Katja , Tryggvadottir Laufey , Aspelund Thor , Olafsson Orn , Harris Tamara B. , Jonsson Eirikur , Tulinus Hrafn , Adami Hans-Olov , Gudnason Vilmundur , Steingrimsdottir Laufey
Published: February 2017

79

Background: Prior evidence suggests that rye consumption may reduce risk of prostate cancer (PCa). Our aim is to study whether consumption of rye bread and oatmeal (sources of lignans and fiber), both in early- and midlife, is associated with risk of PCa.

Methods: In 2002 to 2006, 2,268 men, aged 67-96 years, reported their dietary habits in the AGES-Reykjavik cohort study. Dietary habits were assessed retrospectively, for early and midlife using a validated food frequency questionnaire (FFQ). Through linkage to cancer- and mortality registers, we retrieved information on PCa diagnosis and mortality through 2009. We used logistic regression to estimate odds ratios (ORs) for PCa according to rye- and oatmeal consumption, adjusted for possible confounding factors including fish-, fish liver oil-, meat-, and milk intake.

Results: Of the 2268 men, 347 had or were diagnosed with PCa during follow-up, 63 with advanced disease (stage 3+ or died of PCa). Daily rye bread consumption in adolescence (vs. less than daily) was associated with a decreased risk of PCa diagnosis (OR 0.78; 95% CI: 0.60, 1.00), and of advanced PCa (OR 0.53; 95% CI: 0.32, 0.93). High intake of oatmeal in adolescence (≥5 vs. ≤4 times/ week) was not significantly associated with risk of PCa diagnosis (OR 1.00; 95% CI: 0.78, 1.29) nor advanced PCa (OR 0.73; 95% CI: 0.41, 1.31). Midlife consumption of rye or oatmeal was not associated with PCa risk.

Conclusions: Our data suggest that frequent rye bread consumption in adolescence may be associated with reduced risk of PCa, particularly advanced disease.
Significance of a case-management-led, multidisciplinary team approach in the treatment of prostate cancer.
Authors: Helbert Matthew , Brand Timothy
Published: February 2017

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Background: Prostate cancer is the most commonly diagnosed non-skin malignancy within the Madigan Health System. Madigan recognized the burden of prostate cancer and began a process improvement initiative on June 1, 2009 to provide patient-focused multi-disciplinary counseling and consultative service to patients newly and previously diagnosed with prostate cancer.

Methods: The multi-disciplinary team and Prostate Cancer Pathway are led by a RN Case Manager in collaboration with the Departments of Urology, Radiation Oncology and Hematology Oncology. Patients enrolled in the pathway are case managed in accordance with NCCN evidenced based guidelines and have access to all specialty services contained within Madigan, the U.S. Army Western Region Medical Command, and the Tricare referral network. Major program goals of the Prostate Cancer Pathway are to bolster patient surveillance to levels congruent with national evidenced based guidelines, and to promote efficient use of clinic time by selectively scheduling patients based on acuity. The aims of the pathway are primarily accomplished through case management.

Results: Prior to the implementation of case management, prostate cancer patients averaged 3.3 appointments per annum. Per NCCN guidelines, the average number of annual visits is 2.8 during the initial 5 year post treatment phase. Upon completion of 18 consecutive months of case management, program metrics indicate that the average number prostate cancer visits decreased to 2.9 appointments per year. Concurrently, case management screening impacted scheduled visits; resulting in 485 avoided appointments for reasons of clinical stability and favorable patient reported quality of life indicators. As a result of enhanced access, the total number of post program deployment prostate cancer patients increased by approximately 15%.

Conclusions: Initial identified metrics indicate that prostate cancer case management can considerably impact surveillance rates and clinic efficiency and may be disseminated to additional populations. The case management led model has recently been utilized to create a similar pathway to address testicular cancer within the Madigan Health System.
Single or two instillations of pirarubicin as prophylaxis for recurrence after transurethral resection of Ta and T1 transitional cell bladder cancer: A prospective, randomized controlled study.
Authors: Saika Takashi , Tsushima Tomoyasu , Nasu Yasutomo , Kumon Hiromi ,   Okayama Urological Research Group
Published: February 2017

LBA266

Background: Although single intravesical instillation chemotherapy immediately after transurethral resection (TUR) is the standard treatment for non-muscle-invasive bladder tumors, 40% to 80% of tumors show intravesical recurrence. In this prospective randomized controlled study, we try to evaluate the prophylactic efficacy and safety of twice intravesical instillation using pirarubicin (THP) administered immediately after TUR and on the next day following TUR by comparison with single instillation immediately after TUR.

Methods: Between 2005 and 2009, 250 patients with Ta and T1 solitary bladder carcinoma were enrolled in this study. Patients were randomized into two groups. Group A patients were treated with two intravesical instillations of THP 30 mg/50 ml saline immediately after TUR and within 24 hours. Group B patients were treated with single instillation of the same dose immediately after TUR as a control group. The primary endpoint was duration to the first recurrence, and the secondary endpoint was safety.

Results: The enrollment was closed on 2009, and the follow-up phase is in process. Of the 250 patients, 125 in Group A and 125 in Group B could be evaluated as full analysis set. One hundred eight male and 17 female were in Group A, on the other hands, one hundred five male and 20 female were in Group B. Eighty-six cases (69%) in group A, and 88 cases (70%) in group B were primary tumor. Fifty-seven cases (46%) in group A, and 56 cases (45%) in group B were small tumor (less than 10mm). There was no difference between backgrounds of both groups. The randomization worked well. In this ad interim report, median follow up was 48 months. Two-year recurrence-free rates were 76.8% in group A and 67.5% in group B. Adverse reactions related to instillation were observed in about 20% of the patients. These toxicities were mild and transient. Only the incidence of frequency in group A was higher than that in group B (20% vs. 8%, p=0.0106).

Conclusions: Intravesical instillation of THP 30 mg twice within 24 hours after TUR was effective as prophylactic therapy for non-muscle-invasive cancer with tolerable toxicity problems.
Obesity and Energy Balance in GI Cancer
Authors: Brown Justin C. , Meyerhardt Jeffrey A.
Published: February 2017

The prevalence of overweight (body mass index [BMI], 25 to 29.9 kg/m2) and obesity (BMI ≥ 30 kg/m2) have increased dramatically in the United States. Because increasing BMI is associated with the development of multiple different cancer types, including most GI cancers, providers will frequently encounter patients with GI cancer who are overweight or obese. Mounting evidence associates overweight and/or obesity with worsened prognosis in multiple GI cancers, including esophageal, gastric, hepatocellular, pancreatic, and colorectal. However, these data are observational and may be subject to bias and/or confounding. Furthermore, in some cancer types, the associations between BMI and outcomes is not linear, where overweight and class I obese patients may have an improvement in outcome. This report provides a brief highlight of existing studies that have linked overweight and/or obesity to prognosis in GI cancer; provides recommendations on best management practices; and discusses limitations, controversies, and future directions in this rapidly evolving area. There are multiple areas of promise that warrant continued investigation: What are the comparative contributions of energy balance, including weight, dietary patterns, and physical activity on cancer prognosis? What are the specific physiologic pathways that mediate the relationship between energy balance and prognosis? What is the relationship between low muscle mass (sarcopenia) or sarcopenic obesity and cancer prognosis? Are there subsets of patients for whom purposefully altering energy balance would be deleterious to prognosis? This area is rich with opportunities to understand how states of energy (im)balance can be favorably altered to promote healthy survivorship.
Inflammatory Cytokines and Comorbidity Development in Breast Cancer Survivors Versus Noncancer Controls: Evidence for Accelerated Aging?
Authors: Alfano Catherine M. , Peng Juan , Andridge Rebecca R. , Lindgren Monica E. , Povoski Stephen P. , Lipari Adele M. , Agnese Doreen M. , Farrar William B. , Yee Lisa D. , Carson William E. , Kiecolt-Glaser Janice K.
Published: February 2017

Purpose

The sequelae of cancer treatment may increase systemic inflammation and create a phenotype at increased risk of functional decline and comorbidities, leading to premature mortality. Little is known about how this trajectory compares with natural aging among peers of the same age without cancer. This longitudinal study investigated proinflammatory cytokines and comorbidity development over time among breast cancer survivors and a noncancer control group.

Methods

Women (N = 315; 209 with breast cancer and 106 in the control group) were recruited at the time of their work-up for breast cancer; they completed the baseline questionnaire, interview, and blood draw (lipopolysaccharide-stimulated production of interleukin [IL] -6, tumor necrosis factor-α, and IL-1β). Measures were repeated 6 and 18 months after primary cancer treatment (cancer survivors) or within a comparable time frame (control group).

Results

There were no baseline differences in comorbidities or cytokines between survivors and the control group. Over time, breast cancer survivors had significantly higher tumor necrosis factor-α and IL-6 compared with the control group. Survivors treated with surgery, radiation, and chemotherapy accumulated a significantly greater burden of comorbid conditions and suffered greater pain associated with inflammation over time after cancer treatment than did the control group.

Conclusion

Survivors who had multimodal treatment had higher cytokines and comorbidities, suggestive of accelerated aging. Comorbidities were related to inflammation in this sample, which could increase the likelihood of premature mortality. Given that many comorbidities take years to develop, future research with extended follow-up beyond 18 months is necessary to examine the evidence of accelerated aging in cancer survivors and to determine the responsible mechanisms.
Randomized Phase II Trial of Seribantumab in Combination With Paclitaxel in Patients With Advanced Platinum-Resistant or -Refractory Ovarian Cancer
Authors: Liu Joyce F. , Ray-Coquard Isabelle , Selle Frederic , Poveda Andrés M. , Cibula David , Hirte Hal , Hilpert Felix , Raspagliesi Francesco , Gladieff Laurence , Harter Philipp , Siena Salvatore , del Campo Josep Maria , Tabah-Fisch Isabelle , Pearlberg Joseph , Moyo Victor , Riahi Kaveh , Nering Rachel , Kubasek William , Adiwijaya Bambang , Czibere Akos , Naumann R. Wendel , Coleman Robert L. , Vergote Ignace , MacBeath Gavin , Pujade-Lauraine Eric
Published: February 2017

Purpose

Seribantumab is a fully human immunoglobulin G2 monoclonal antibody that binds to human epidermal growth factor receptor (HER) 3 (ErbB3), blocking heregulin (HRG) –mediated ErbB3 signaling and inducing ErbB3 receptor downregulation. This open-label randomized phase II study evaluated progression-free survival (PFS) with seribantumab in combination with once-per-week paclitaxel compared with paclitaxel alone in patients with platinum-resistant or -refractory ovarian cancer. A key secondary objective was to determine if any of five prespecified biomarkers predicted benefit from seribantumab.

Patients and Methods

Patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned at a ratio of two to one to receive seribantumab plus paclitaxel or paclitaxel alone. Patients underwent pretreatment core needle biopsy; archival tumor samples were also obtained to support biomarker analyses.

Results

A total of 223 patients were randomly assigned (seribantumab plus paclitaxel, n = 140; paclitaxel alone, n = 83). Median PFS in the unselected intent-to-treat population was 3.75 months with seribantumab plus paclitaxel compared with 3.68 months with paclitaxel alone (hazard ratio [HR], 1.027; 95% CI, 0.741 to 1.425; P = .864). Among patients whose tumors had detectable HRG mRNA and low HER2 (n = 57 [38%] of 151 with available biomarker data), increased treatment benefit was observed in those receiving seribantumab plus paclitaxel compared with paclitaxel alone (PFS HR, 0.37; 95% CI, 0.18 to 0.76; P = .007). The HR in patients not meeting these criteria was 1.80 (95% CI, 1.08 to 2.98; P = .023).

Conclusion

The addition of seribantumab to paclitaxel did not result in improved PFS in unselected patients. Exploratory analyses suggest that detectable HRG and low HER2, biomarkers that link directly to the mechanism of action of seribantumab, identified patients who might benefit from this combination. Future clinical trials are needed to validate this finding and should preselect for HRG expression and focus on cancers with low HER2 levels.
Cetuximab Plus Chemoradiotherapy for HIV-Associated Anal Carcinoma: A Phase II AIDS Malignancy Consortium Trial
Authors: Sparano Joseph A. , Lee Jeannette Y. , Palefsky Joel , Henry David H. , Wachsman William , Rajdev Lakshmi , Aboulafia David , Ratner Lee , Fitzgerald Thomas J. , Kachnic Lisa , Mitsuyasu Ronald
Published: February 2017

Purpose

Squamous cell carcinoma of the anal canal (SCCAC) is characterized by high locoregional failure (LRF) rates after definitive chemoradiation (CRT), associated with anogenital human papilloma virus, and often appears in HIV infection. Because cetuximab enhances the effect of radiation therapy in human papilloma virus–associated oropharyngeal SCC, we hypothesized that adding cetuximab to CRT would reduce LRF in SCCAC.

Methods

Forty-five patients with stage I to III SCCAC and HIV infection received CRT: 45 to 54 Gy radiation therapy to the primary tumor and regional lymph nodes plus eight once-weekly doses of concurrent cetuximab and two cycles of cisplatin and fluorouracil. The study was designed to detect at least a 50% reduction in 3-year LRF rate (one-sided α, 0.10; power, 90%), assuming a 35% LRF rate from historical data.

Results

The 3-year LRF rate was 42% (95% CI, 28% to 56%; one-sided P = .9) by binomial proportional estimate using the prespecified end point (LRF or alive without LRF and followed < 3 years), and 20% (95% CI, 10% to 37%) by Kaplan-Meier estimate in post hoc analysis using definitions and methods consistent with historical data. Three-year rates by Kaplan-Meier estimate were 72% (95% CI, 56% to 84%) for progression-free survival and 79% (95% CI, 63% to 89%) for overall survival. Grade 4 toxicity occurred in 26%, and 4% had treatment-associated deaths.

Conclusion

HIV-associated SCCAC is potentially curable with definitive CRT. Although addition of cetuximab may result in less LRF, the 20% recurrence and 26% grade 4 toxicity rates indicate the continued need for more-effective and less-toxic therapies.
How to Manage the Obese Patient With Cancer
Authors: Renehan Andrew G. , Harvie Michelle , Cutress Ramsey I. , Leitzmann Michael , Pischon Tobias , Howell Sacha , Howell Anthony
Published: February 2017

Purpose

Obesity (body mass index [BMI] ≥ 30 kg/m2) is common among patients with cancer. We reviewed management issues in the obese patient with cancer, focusing on how obesity influences treatment selection (including chemotherapy dosing), affects chemotherapy toxicity and surgical complications, and might be a treatment effect modifier.

Methods

The majority of evidence is drawn from observational studies and secondary analyses of trial data, typically analyzed in N × 3 BMI categories (normal weight, overweight, and obese) matrix structures. We propose a methodological framework for interpretation focusing on sample size and composition, nonlinearity, and unmeasured confounding.

Results

There is a common perception that obesity is associated with increased treatment-related toxicity. Accordingly, cytotoxic chemotherapy dose reduction is common in patients with elevated BMI. Contrary to this, there is some evidence that full dosing in obese patients does not result in increased toxicity. However, these data are from a limited number of regimens, and fail to fully capture cytotoxic drug pharmacodynamics and pharmacokinetic variability in obese patients. Among patients undergoing surgery, there is evidence that elevated BMI is associated with increased perioperative mortality and increased rates of infectious complications. A novel finding is that these relationships hold after surgery for malignancy, but not for benign indications. There are biologic plausibilities that obesity might be an effect modifier of treatment, but supporting evidence from clinical studies is inconsistent.

Conclusion

In line with the ASCO 2012 guidelines, chemotherapy dosing is probably best performed using actual body weight in obese patients. However, specific regimens known to be associated with increased toxicity in this group should be used with caution. There is no guidance on dose for obese patients treated with biologic agents. Currently, there are no specific recommendations for the surgical management of the obese patient with cancer.