bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction between intratumoral ERCC1 expression and adjuvant treatment with S-1 on the survival of patients enrolled in the ACTS-GC study.
Authors: Kitada Koji , Ochiai Atsushi , Ichikawa Wataru , Terashima Masanori , Kurahashi Issei , Sakuramoto Shinichi , Katai Hitoshi , Sano Takeshi , Imamura Hiroshi , Sasako Mitsuru
Published: February 2017

53

Background: Excision repair cross-complementing group 1 (ERCC1) is thought to be involved in resistance to platinum-based therapy. Recently, expression of this gene was shown to be associated with the outcome in patients with gastric cancer. Biomarker analysis was conducted to evaluate the influence of this gene expression on the outcomes of patients enrolled in the ACTS-GC study, a randomized phase III trial, which demonstrated the efficacy of adjuvant treatment with S-1 after D2 dissection for stage II and III gastric cancer (Sakuramoto et al., NEJM 2007).

Methods: Formalin-fixed paraffin-embedded specimens were available for 829 of a total of 1,059 (78.3%) patients. ERCC1 expression was measured by RT-PCR in the macrodissected tumor specimens and normalized to β-actin expression as the reference gene. The expression of ERCC1 was categorized into low and high values at the median.

Results: The ERCC1 expression level was quantifiable in 97% of the 829 specimens and the distribution was balanced across the arms. In the S-1 group, overall survival (OS) tended to be longer in the high ERCC1 expression group than in the low ERCC1 expression group (HR, 0.698; 95% CI, 0.469-1.040; p= 0.076). On the contrary, in the surgery group, the OS was shorter in the high ERCC1 expression group than in the low ERCC1 expression group (HR, 1.216; 95% CI, 0.881-1.679; p= 0.232), although the difference was not statistically significant. The HR for OS of S-1 to surgery alone was smaller in the high-ERCC1 (HR, 0.465; 95% CI, 0.320-0.678) than in the low-ERCC1 group (HR, 0.805; 95% CI, 0.568-1.141). Significant interaction between the S-1 group and ERCC1 expression was observed (p= 0.033).

Conclusions: This large biomarker study showed that intratumoral ERCC1 gene expression may be a predictive marker in gastric cancer patients receiving postoperative adjuvant chemotherapy with S-1.
A novel potential biomarker to monitor treatment response in gastric cancer.
Authors: Maturana Maria J. , Garrido Marcelo , Medina Lidia , Slako Milenko , Funke Ricardo , Acevedo Francisco , Giraldo Claudia , Sanchez Marianela , Munoz Cesar , Corvalan Alejandro
Published: February 2017

55

Background: Gastric cancer (GC) is the second leading cause of death from cancer worldwide. No clinical useful biomarkers that detect early gastric cancer and have prognostic/predictive value are available. DNA methylation of promoter region of Reprimo (RPRM), a p53-dependent G2 arrest mediator candidate gene, has been postulated as a potential biomarker for early diagnosis of GC (Clin Cancer Res. 2008;14:6264-9). Since RPRM has been found methylated in more than >90% of GC cases, we evaluate RPRM as a biomarker for monitoring response to treatment.

Methods: We enrolled 28 patients with GC. Staging classification was carried out by AJCC system and evaluation of clinical response by RECIST criteria. DNA was obtained from plasma/serum by Proteinase K/quiagen and bisulfite converted by EZ DNA Methlyation Direct Kit (Zymo Research). Absolute quantification of DNA Methylation in serum/plasma of RPRM was performed by MethyLight technology. The IRB of PUC approved this study. All patients gave informed consent.

Results: Among 28 patients with histological diagnoses of GC, average age was 64 y.o.(38-81 y.o.), male/female ratio 1.3/1, number of cases stage I 2, stage II 4, stage III 8, stage IV 13 and In situ or with preneoplastic lesions 3 patients. 13 patients underwent total gastrectomy and 19 cases received standard chemotherapy (CHM), 6 of them on a neoadjuvancy basis. At initial diagnoses, RPRM was detected in 67,8% (19/28) of patients (X 1049,7 copies per mL[49-11991]). 79% of patients had an objective response with one patient developing a complete response. In cases with clinical response, and at least two detections of RPRM, agreement was 81% with RPRM levels. At the end of study, one third of the patients finally died of gastric cancer. Interestingly, the average initial level of RPRM was higher on those with a fatal outcome (1822 vs 483 copies per mL). The two highest levels were seen on patients who developed a rapid progressive disease and died within months of diagnosis.

Conclusions: RPRM could be a potential biomarker to monitor treatment-response in GC. Levels of RPRM may anticipate clinical progression. All these findings should be evaluated in a large, prospective clinical trial.
Phase II trial of panobinostat (LBH589) in patients (pts) with refractory metastatic colorectal cancer (MCRC).
Authors: Gold Philip Jordan , Smith David A. , Iriarte Desiree , Boatman Barry , Kaplan Henry G.
Published: February 2017

582

Background: LBH589 is a novel histone deacetylase inhibitor (HDACi) which induces apoptosis of tumor cells. LBH589 has been shown to cause regression of colon cancer in animal models and phase I trials have shown the agent to be well tolerated, providing rationale for studying this agent in pts with MCRC.

Methods: This was a multicenter, open-label phase II study of single agent LBH589 in patients with MCRC who failed at least 2 prior regimens for metastatic disease. Measurable disease, adequate organ function and ECOG performance status of 0-2 were required. Pts received LBH589 30mg po on M/W/F until disease progression. Pts were evaluated for toxicity every 2 weeks and for response every 8 weeks. The primary endpoint was overall survival. Secondary endpoints included response rate, time to progression (TTP), and toxicity.

Results: 29 pts were enrolled (16 male, 13 female). The median age was 59 (range 41-76). The median number of prior treatment regimes was 3 (2-11). The median survival was 5.1 months (range 1-24+). There were no objective responses. 3 pts had SD at 8 weeks. The median TTP was 7.7 weeks (range 1-38.). Six pts had grade 4 thrombocytopenia requiring platelet transfusion. Nine pts required dose reductions for toxicity.

Conclusions: Single-agent LBH589 was not associated with objective tumor responses in this heavily pre-treated pt population. However, the median survival was comparable to that seen in other trials of single agent targeted therapy in the treatment of refractory MCRC. Thrombocytopenia was significant, and may complicate potential trials of combination therapy.
Gender differences in outcomes for early-stage colon cancer.
Authors: Alipour Sina , Kennecke Hagen F. , Lim Howard John , Cheung Winson Y.
Published: February 2017

605

Background: Retrospective analyses of clinical trials suggest that gender may influence the risk of recurrence and survival in patients diagnosed with early stage colon cancer. Whether this association persists in the setting of routine clinical practice is unclear. Our aims were to 1) assess for gender differences in outcomes in early stage colon cancer and 2) evaluate if the effect of gender on outcomes is modified by adjuvant therapy (AT).

Methods: Using a population-based cohort of patients diagnosed with stage II or III colon cancer and referred to any 1 of 5 regional cancer centers in British Columbia, Canada from 2001 to 2005, we compared 5-year outcomes between men and women. Multivariate Cox proportional hazard models were constructed to explore the relationships between gender and prognosis, while controlling for patient and tumor characteristics. Interaction terms between gender and AT were used to examine the predictive value of gender.

Results: We included 1837 patients: 970 men and 867 women. Baseline characteristics were similar: median ages were 68 and 69 years; 39 and 38% had stage II colon cancer; and 46 and 44% received AT, respectively. Outcomes were better in women than in men (5-year cancer-specific survival rate 73 vs. 71% and 5-year overall survival rate 68 vs. 62%). In Cox regression models, women continue to experience better overall prognosis (HR for death = 0.80, 95% CI 0.69-0.92, p=0.003) when compared to men. Advanced age, stage III disease, and lack of AT also correlated with worse outcomes (all p<0.01). The effect of gender on outcomes remained similar regardless of AT (HR 0.86 among women with AT and HR 0.75 among women without AT, interaction p=0.35).

Conclusions: Gender is a prognostic, but not a predictive, factor for this cohort of patients with early stage colon cancer. Studies to investigate the biological mechanisms underlying this gender difference in outcomes are warranted.
Variation in gross tumor volume delineation using CT, MRI, and FDG-PET in planning radiotherapy of anal cancer.
Authors: Serup-Hansen Eva , Hendel Helle Westergren , Johannesen Helle Hjorth , Ottosson Wiviann , Hollensen Christian , Persson Gitte Fredberg , Geertsen Poul F. , Havsteen Hanne
Published: February 2017

652

Background: Radiotherapy (RT) outcome depends on accurate delineation of gross tumor volume (GTV) regarding tumor size and position. CT and MRI are standard image modalities as they provide the necessary structural information. Positron emission tomography with flourodeoxyglucose (FDG-PET) visualizes glucose metabolism in active tumor tissue. The main objective was to explore the intra-observer and inter-modality variation of the GTV delineated on CT, MRI and PET images.

Methods: Between November 2006 and July 2009, 22 patients with biopsy-proven anal carcinoma stage T1-T4/N0-3/M0-1 scheduled for curative RT were included in the study. All patients underwent FDG-PET/contrast enhanced CT and MRI. The delineations of GTV were done twice for each imaging modality with a minimum of 3 months in between. Delineations on the CT and MRI were done by routine methods. For the PET part three different cut-off values were used: SUV 2.5, 40% and 50% of maximum SUV. Non-overlap was calculated by subtracting the intersection from the union of two sets both regarding intra-observer variation and inter-modality variation. The GTV were compared for size, intra-observer variation and non-overlap using Wilcoxon rank sum test, where p < 0.05 was considered significant.

Results: Volume size: the median GTV-CT was 25.6 cm3 which was significantly larger compared to GTV-MRI (7.2 cm3) and the GTV from the different PET cut offs (6.2 cm3, 10.6 cm3 and 7.0 cm3). Intra-observer variation: the median GTV delineated on CT, MRI and PET did not vary significant between delineation number 1 and 2. Non-overlap: the non-overlapping regions in GTV between delineation 1 and 2 using CT and MRI (20.5% and 22.5%) were significantly different from the PET cut offs (5.5% , 6.4% and 5.8%).

Conclusions: Delineation of anal tumors is difficult; CT gives rise to the largest GTV with considerable intra-observer variation. MRI has the same degree of inaccuracy, but smaller GTV. PET-GTVs are the smallest with significant smaller intra-observer uncertainty.
Intensity-modulated radiation therapy (IMRT) with concurrent chemotherapy for anal cancer: A large single-institution experience.
Authors: Mitchell Melissa Pulfer , Abboud Mirna , Crane Christopher H. , Eng Cathy , Chang George J. , Rodriguez-Bigas Miguel A. , Skibber John Michael , You Y. Nancy , Beddar Sam , Krishnan Sunil , Delclos Marc E. , Das Prajnan
Published: February 2017

661

Background: IMRT for squamous cell anal carcinoma enables sparing of normal tissues potentially leading to decreased toxicity. We evaluated toxicity, local control and survival in anal cancer patients treated with IMRT and concurrent chemotherapy.

Methods: Between March 2007 and January 2011, 65 patients were treated at our institution with IMRT and concurrent chemotherapy for newly diagnosed, localized squamous cell carcinoma of the anal canal. Radiotherapy was delivered with a simultaneous integrated boost technique, with dose based on the T stage. The median total dose to the primary tumor was 54 Gy (range 50 – 58.8 Gy) and the median dose to the pelvis was 45 Gy (range 40.5-50.4 Gy) delivered in 25-29 fractions. The concurrent chemotherapy regimens were 5-fluorouracil (5-FU) and cisplatin (75%), capecitabine and oxaliplatin (11%), 5-FU and mitomycin C (MMC) (5%), cisplatin and MMC (2%), capecitabine and cisplatin (2%), capecitabine and MMC (2%), and 5-FU given alone due to other co morbidities (5%).

Results: Median age at diagnosis was 57 years (range 35-80). The patient population was 71% female. The percentage of patients with stage I, II, IIIA, and IIIB disease were 12%, 28%, 14% and 42%, respectively. Stage was Tx in 5%. 8% of patients were HIV positive. Grade 3 gastrointestinal toxicity occurred in 9% and moist desquamation beyond the perianal area occurred in 17%. 91% of patients completed treatment without a break. The median follow-up was 19 months (range 1 to 49 months). The 2-year local control was 93%. Four patients had a local recurrence, of which two underwent salvage APR, one refused surgery, and one patient, who also had metastatic disease, received chemotherapy. Four patients developed metastasis. The 2 year distant control was 93%. There were two deaths due to the development of metastatic disease. The 2-year overall and disease-free survival were 96% and 89%, respectively.

Conclusions: Concurrent IMRT and chemotherapy was well tolerated with low rates of acute toxicity, and excellent local control, disease-free survival and overall survival. Our results compare favorably with other published data despite a higher proportion of patients with advanced disease.
Clinical outcomes with high-dose image guided radiotherapy (IGRT) compared with non-IGRT for the treatment of clinically localized prostate cancer.
Authors: Zelefsky Michael J. , Kollmeier Marisa , Cox Brett Wayne , Pei Xin , Hunt Margie
Published: February 2017

12

Background: To compare toxicity profiles and biochemical tumor control outcomes between patients treated with high-dose image-guided radiotherapy (IGRT) and high-dose intensity-modulated radiotherapy (IMRT) for clinically localized prostate cancer.

Methods: 186 patients with prostate cancer were treated with IGRT to a dose of 86.4 Gy with daily correction of the target position based upon kilovoltage imaging of implanted prostatic fiducial markers. This group of patients was retrospectively compared with a similar cohort of 190 patients who were treated with IMRT to the same prescription dose without, implanted fiducial markers in place (non-IGRT). In both groups the margins used for the prostate were the same. The median follow-up time was 2.8 years (range, 2-4 years).

Results: A significant reduction in late urinary toxicity was observed for IGRT patients compared with the non-IGRT patients. The 3-year likelihood of urinary toxicity for the IGRT and non-IGRT cohorts were 10.4% and 20.0%, respectively (p=0.02).Multivariate analysis identifying predictors for late urinary toxicity demonstrated that, in addition to the baseline IPSS, IGRT was associated with significantly less late urinary toxicity compared with non-IGRT. The incidence of late rectal toxicity was low for both treatment groups (1.0% and 1.6%, respectively; p = 0.81). No differences in prostate-specific antigen relapse–free survival outcomes were observed for low- and intermediate-risk patients when treated with IGRT and non-IGRT. For high-risk patients a significant improvement was observed at 3-years for patients treated with IGRT compared with non-IGRT.

Conclusions: IGRT is associated with a reduction in late urinary toxicity and improvement in biochemical tumor control after definitive high-dose external beam radiotherapy compared with high-dose IMRT. These data suggest that, for definitive radiotherapy, the placement of fiducial markers and daily tracking of target positioning should be the preferred mode of external beam radiotherapy delivery for the treatment of prostate cancer.
A randomized phase II study of OGX-427 plus prednisone versus prednisone alone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer.
Authors: Chi Kim N. , Hotte Sebastien J. , Ellard Susan , Gingerich Joel Roger , Joshua Anthony Michael , Kollmannsberger Christian K. , Yu Evan Y. , Gleave Martin Edwin
Published: February 2017

121

Background: Heat Shock Protein 27 (Hsp27) is a stress-activated, multi-functional chaperone protein highly expressed in cancer that regulates cell signaling and survival pathways implicated in cancer progression. In prostate cancer models, Hsp27 complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes. OGX-427 is a 2nd generation antisense that inhibits Hsp27 expression with in vitro and in vivo efficacy. Phase I studies have demonstrated tolerability and single agent activity.

Methods: Patients (pts) with CRPC, no/minimal symptoms and any prior treatment other than chemotherapy were randomized 1:1 to receive prednisone (P) 5 mg PO BID or P with OGX-427 600 mg IV x 3 loading doses followed by 1000 mg IV weekly. Primary endpoint was the proportion of pts progression free (PSAWG 2 criteria) at 12 weeks. A 2-stage MinMax design (H0 = 5%, HA >20%, α=0.1, β=0.1) will enrol 32 pts total per arm and provide 70% power to detect the difference at a 0.10 1-sided significance. Secondary endpoints include PSA decline, measurable disease response, and circulating tumour cell (CTC) enumeration.

Results: In the first 22 pts randomized (11 to OGX-427+P, 11 to P), baseline median age was 71 years (53-86), ECOG PS 0 or 1 in 64% and 36% of pts, median PSA 89 (6-606), metastases in bone/lymph nodes/liver or lung in 77%/64%/10%, 23% had prior treatment with P, and 91% had ≥5 CTC/7.5 ml (median 18/7.5 ml). Thus far, 82% of pts randomized to OGX-427+P have had a PSA decline (55% with ≥30% decline) and 18% a PSA increase; 40% of pts treated with P have had a PSA decline (20% with ≥30% decline), 10% no change and 50% with PSA increase. CTC conversion from ≥5 to <5/7.5 ml has occurred in 60% of pts randomized to OGX-427+P and 20% of pts treated with P alone. Grade 1-2 infusion reactions (e.g., chills, diarrhea, flushing) have occurred in 45% of pts receiving OGX-427+P and 1 pt developed hemolytic uremic syndrome after week 7 probably related to OGX.

Conclusions: Preliminary data provide clinical support for the role of Hsp27 in AR signalling and as a therapeutic target for prostate cancer. Enrolment on this study continues. Funded by a grant from the Terry Fox Research Institute.
Sick leave in patients with prostate cancer before, during, and after radiotherapy.
Authors: Sveistrup Joen , Meidahl Petersen Peter , Mortensen Ole Steen , Engelholm Svend Aage
Published: February 2017

153

Background: Returning to work following cancer treatment is a sign of recovery. Side-effects might result in sick leave rendering patients unable to work. The purpose of this study was to determine the pattern of sick leave in patients with prostate cancer (PCa) before, during and after definitive radiotherapy.

Methods: The Danish DREAM-database contains information on all social benefits paid out to Danish citizens. Based on the DREAM-database it is possible to assess whether a patient is working, on sick leave, or retired. Data on 427 of 473 Danish citizens, treated with definitive intensity-modulated radiotherapy for PCa at our center between January 1 2005 and May 1 2010, were obtained from the DREAM-database. Of the 427 patients 118 patients were working or available to the job market at the start of radiotherapy. Of the 118 patients 59 patients were on sick leave at some point during the course of radiotherapy and they followed in the DREAM-database from one year prior to radiotherapy until one year after the treatment. The median age was 60 (age, range 49–65). Based on the data from the database the 59 patients were divided into the four categories “Working or unemployed”, “Sick leave”, “Retirement” or “Dead”. Furthermore, the patients’ statuses after sick leave were determined.

Results: The results are shown in the table. Nearly all patients (91.5%) return to work following sick leave. One year after radiotherapy 64.4% of the patients are working, and 13.6% are on sick leave.

Conclusions: The vast majority of patients that are on sick leave during the course of radiotherapy for PCa return to work. However, one year after RT only 64 % are working or available for work indicating that the return to work for a lot of the patients is relatively short-lasting. Further research is needed to clarify why.

[Table: see text]
Urinary exosomes as a stable source of mRNA for prostate cancer analysis.
Authors: Russo Leileata M. , Bate Kendall , Motamedinia Piruz , Salazar Guillermo , Scott Anna , Lipsky Michael , Sadeghi Neda , Lin James , Comper Wayne D. , Petrylak Daniel Peter , McKiernan James M.
Published: February 2017

174

Background: Exosomes are novel lipid bilayer vesicles that are released into biofluids such as urine and carry high integrity RNA from the parent cell which they were derived. Due to their unique stability and the fact that they contain prostate specific mRNA transcripts, we examined their potential as a non-invasive source of mRNA biomarkers for prostate cancer analysis.

Methods: Following a Columbia University approved IRB protocol, random urine samples were collected from 163 men who were stratified into 4 groups: biopsy negative (Bx Neg, n=39), biopsy positive (Bx Pos, n=47), post-radical prostatectomy (RP, n=37) and controls (males <35 yrs, n=40). Urine samples were stored at 4°C and 0.8 μm filtration was used to remove whole cells and debris. Urinary exosomal RNA was isolated using our in-house technique. RT-qPCR was used to analyze PSA, PCA3, androgen receptor (AR), survivin, NCOA2, RAD21, transmembrane protease serine 2 (TMPRSS2), ERG and TMPRSS2:ERG fusion at the mRNA level.

Results: Mean serum PSA protein level and age were similar in the Bx Neg and Bx Pos groups. Relative quantitation (RQ) of genes standardized to the PSA gene revealed that ERG (P<0.005), PCA3 (P<0.005), TMPRSS2:ERG fusion (P<0.05), TMPRSS2 (P<0.05) and survivin (P<0.005) were significantly increased in the Bx Pos vs. Bx Neg group. TMPRSS2:ERG fusion events occurred in 68% of Bx Pos vs. 44% of Bx Neg patients and were present in only 5% of controls. No patient in the RP group had positive TMPRSS2:ERG detection; this finding was further supported by the loss of TMPRSS2:ERG expression for 4 Bx Pos patients following prostatectomy suggesting specificity of the fusion event to the prostate.

Conclusions: This study confirms urinary exosomes as a source of high quality RNA and showed significant differences in the expression of ERG, PCA3, TMPRSS2:ERG genes between the Bx Pos and Bx Neg groups. Our findings are consistent with previous studies based on tissue and post-prostate massage urinary cell analyses. The unique stability and yield of urinary exosomal RNA collected without a prostatic massage will hopefully simplify sample handing, obviate sample variability and patient discomfort inherent to prostate massage, and broaden the role of exosomes in future diagnostic testing.
11C-choline PET scanning is more accurate than biopsy in assessment of localized prostate cancer planned for radical prostatectomy.
Authors: Davis Ian D. , Lee Sze Ting , Shanker Lekshmy , Clouston David , Bolton Damien M , Angus David , Webb David , Lawrentschuk Nathan , Woon Dixon Teck Sing , Esler Stephen , Lim Joon Daryl , Chang Joe , O'Sullivan Richard , Pathmaraj Kunthi , Tochon-Danguy Henri , O'Keefe Graeme Joseph , Scott Andrew Mark
Published: February 2017

182

Background: A decision to treat prostate cancer (PC) with radical prostatectomy (RP) with curative intent requires confidence that the PC is confined to the prostate. PC outcomes will improve with better selection of surgical candidates. Current imaging modalities include CT and MRI but have limited accuracy. We assessed 18F-FDG (FDG) and 11C-choline (CHOL) PET in men planned for RP to determine the accuracy of PET, effects of PET on decision making by surgeons, and correlation with PSA.

Methods: Written informed consent was obtained from eligible participants (pts) planned for RP. All men underwent TRUS-guided prostatic biopsies, CT and MRI scans, PSA and standard tests of organ function. The urologist then documented the treatment plan based on these results. Pts then underwent FDG and CHOL PET and the urologist then determined whether this information altered the treatment plan. After surgery the RP specimen was reconstructed, examined histologically and correlated with TRUS and imaging results on a sextant-based analysis (apex/mid/base on both sides).

Results: 30 pts entered and completed the trial. Outcomes are shown in the table. Neither PET modality significantly affected decisions about surgery. Preoperative PSA did not correlate with degree of involvement. FDG PET was unhelpful.

Conclusions: CHOL PET was the most sensitive and most accurate modality with highest congruity with pathology and had excellent positive predictive value, but was least specific. CHOL PET was superior to both TRUS biopsy and MRI. Supported by grant 487916 through Cancer Australia, Prostate Cancer Foundation Australia, Australian Government Department of Health and Aging.

[Table: see text]
Effect of chronic treatment of combined statins and aspirin on the risk of prostate cancer detection.
Authors: Suarez Cristina , Morales Rafael , Placer Jose , Nunez Isaac , Planas Jacques , Valverde Claudia María , Ropero Jordi , Maldonado Xavier , Morote Juan , Carles Joan
Published: February 2017

185

Background: The role of chronic treatment (ChT) with statins and aspirin on prostate cancer (PC) carcinogenesis is controversial. Both drugs are frequently used in adult men who are at risk of PC, and many of them receive both drugs simultaneously. The impact of the combined treatment (CT) with statins and aspirin on PC risk has never been reported. We proposed to explore the influence of ChT with statins and aspirin in the PC risk detection and their aggressiveness.

Methods: 2408 men were consecutively biopsied for cause: PSA > 4 ng/mL (64.4%), abnormal DRE (9%) or both (26.6%). ChT with statins and aspirin (>1 year) was controlled. Median age was 68 years (46–86) and median PSA 7.0 ng/mL (0.7-1279). At least 10 cores, plus 1 to 8 additional cores, were obtained. The PC detection rate was 35.2% and the Gleason score was < 7 in 20.8%, 7 in 50.9% and > 7 (HGPC) in 28.3%. Multivariate and univariate analysis were done and OR calculated to analyze the strength of the relationships.

Results: 440 men (18.3%) were receiving statins alone (SA), 160 (6.6%) aspirin alone (AA), and 304 (12.6%) both drugs simultaneously. Multivariate analysis showed that CT was the only independent predictor of a reduced risk of PC detection, p=0.025, (OR 0.589, 95%CI 0.370-0-936). PC was detected in 552 of 1502 men (36.7%) not receiving statins or aspirin, 34.5% (152/440) receiving SA, 40% (64/160) receiving AA, and in 26.3% (80/304) receiving statins and aspirin simultaneously. Related to cancer aggressiveness, multivariate analysis showed that combined treatment predicted significantly an increased risk of HGPC, p=0.013, (OR 2.672, 95%CI 1.226-5.825). HGPC was detected in 136 of 552 (24.6%) PCs detected in men not receiving statins or aspirin, in 40 of 152 (26.3%) PCs detected in men receiving SA, in 24 of 64 (37.7%) PCs detected in men receiving AA, and in 40 of 80 (50%) PCs detected in men receiving statins and aspirin simultaneously.

Conclusions: This study suggests that ChT with the combination of statins and aspirin reduce significantly the risk of PC detection in men subjected to prostate biopsy for cause. However, this reduction of PC detection is accompanied by a significant increase of PC aggressiveness.
Neoadjuvant chemotherapy with DD-MVAC and bevacizumab in high-risk urothelial cancer: Results from a phase II trial at the M. D. Anderson Cancer Center.
Authors: Siefker-Radtke Arlene O. , Kamat Ashish M. , Corn Paul G. , Matin Surena F. , Grossman H. Barton , Millikan Randall E. , Dinney Colin P.N.
Published: February 2017

261

Background: DD-MVAC has shown an improved 5-year survival in metastatic urothelial cancer; however, there is no prospective data on its use in the neoadjuvant setting. Previous work suggested that over-expression of VEGF was associated with a high risk of relapse in our neoadjuvant patients, leading to the hypothesis that combining a VEGFR inhibitor with chemotherapy may improve patient outcomes.

Methods: Between 8/07 and 12/10, 60 patients with urothelial carcinoma of the bladder or upper tract tumor were enrolled on a prospective phase II clinical trial. Eligibility requirements included at least one of the following: 3-D mass on EUA (cT3b disease), LVI, hydronephrosis, micropapillary features, tumor in a diverticula, and for upper tract tumors a high grade tumor or radiographically measurable sessile mass. The primary endpoint was pathologic down-staging to <=pT1N0M0.

Results: Forty-four patients with bladder/urethral tumors and 16 patients with upper tract tumors were enrolled. Pathologic down-staging to <= pT1N0M0 occurred in 53% of patients overall (bladder/urethra 45%, upper tract 75%), and to <= pT0N0M0 in 38% overall (bladder/urethra 39%, upper tract 38%). At a median follow-up of 21 months, the 2-year OS and DSS was 78% and 85%, respectively (bladder 2-yr OS and DSS 75%, 82%; upper tract 93%, 93%). The median OS and DSS have not yet been reached. The most common grade 3 or greater toxicity was neutropenia in 27% of patients, followed by fatigue in 10%. The following grade 3 toxicities were observed in < 10% of patients: mucositis, DVT/PE, hypertension, nausea/vomiting, thrombocytopenia. One patient experienced cardiac ischemia.

Conclusions: Neoadjuvant chemotherapy leads to pathologic down-staging in 45% of patients with bladder cancer. DD-MVAC appears an acceptable alternative to traditional M-VAC in the neoadjuvant setting. Although bevacizumab did not impact down-staging based upon historical expectations, determining the effect on recurrence requires longer follow-up.
Influence of preoperatively detected circulating tumor cells on the outcome of patients with urothelial carcinoma of the bladder treated with radical cystectomy.
Authors: Rink Michael , Soave Armin , Chun Felix K. , Dahlem Roland , Minner Sarah , Kluth Luis A. , Ahyai Sascha A. , Heinzer Hans , Heuer Roman , Eichelberg Christian , Engel Oliver , Shariat Shahrokh F. , Pantel Klaus , Fisch Margit , Riethdorf Sabine
Published: February 2017

268

Background: Circulating tumour cells (CTC) are frequently detectable in the peripheral blood of patients with urothelial cancer of the bladder (UCB) prior to radical cystectomy (RC). We hypothesize that CTC can predict advanced stages, nodal status and disease outcome after radical cystectomy and therefore represent an optimal biomarker for treatment decision making and patient counseling.

Methods: Blood samples of 120 consecutive, clinically non-metastatic UCB patients scheduled for RC were prospectively investigated for CTC. Preoperatively collected blood samples (7.5 ml) were analysed for CTC using the CellSearch system (Veridex, USA). Uni- and multivariable models evaluated the association of CTC status and number of CTC with clinical and nodal stage and disease outcome.

Results: CTC were detectable in 30/120 patients (25%) with an average number of 5.7±18.3 CTC (range:1-100; median:1). Eighteen patients (60.0%) had 1 CTC/7.5mL, 8 patients (26.7%) had 2-5 CTC and 4 patients (13.3%) had >5 CTC, respectively. CTC status was not associated with tumour stage, grade, lymph node metastases or lymphovascular invasion. Moreover, increasing numbers of CTC were not associated with higher stages or increasing numbers of lymph node metastases. However, at a median follow-up of 18 months (range:1-48 months) CTC detection prior to RC was an independent risk factor for disease recurrence (p<0.001, HR=4.9, 95%CI 2.1–11.7) and cancer-related death (p=0.002, HR=4.9, 95%CI 1.7-13.6). Disease recurrence and cancer-related death were not associated with the number of detected CTC.

Conclusions: Although CTC can not predict pathological or nodal stage, they are associated with inferior disease outcome. Detection of even 1 CTC/7.5 mL blood in UCB patients prior to RC is an independent predictor for disease recurrence and cancer-related death. These findings are very important for future investigations, as they are in contradiction to theories supporting a cut-off value of 5 or more CTC needed for accurate outcome prediction. Therefore, CTC may represent a feasible biomarker for monitoring response to neoadjuvant and adjuvant chemotherapy.
Phase I trial of sorafenib with concurrent radiotherapy (RT) in patients with invasive bladder cancer treated with bladder-sparing intent: A Spanish Oncology Genitourinary Group study.
Authors: Martin Liberal Juan , Maroto José Pablo , Mellado Begoña , Ferrer Ferran , Sancho Gemma , Rovirosa Angels , Vigues Francesc , Palou Joan , Ribal Maria Jose , Bellmunt Joaquim , Garcia del Muro Xavier
Published: February 2017

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Background: Preclinical studies suggest enhanced radiation-induced cell death when VEGFR inhibitor therapies are combined with RT.

Methods: Patients with localized muscle invasive urothelial carcinoma of the bladder in clinical stage T2-3 N0 M0, who were not eligible or rejected radical cystectomy, ECOG PS 0-2, and adequate hematological, renal and hepatic function, were enrolled in this phase I study to assess safety and identify the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of sorafenib and RT. A 3+3 dose escalation design with cohorts of 3-6 patients was used. Treatment consisted of TUR, followed by normofractionated (2 Gy/day) external-beam RT with high-energy photons, 46 Gy to minor pelvis and 66 Gy to bladder, combined with sorafenib given po continuously. Sorafenib was started two weeks before RT and was administered for 12 weeks, finishing 4 weeks after RT. Dose levels 1, 2 and 3 corresponded to sorafenib 200 mg qd, 200 mg bid and 800 mg bid. Pathological response was assessed by post-treatment TUR.

Results: Ten patients were included: median age 71 years (44-84); gender 7M: 3F. Patients were treated at 3 dose levels, the MTD was reached at level 3 and the RD was: sorafenib 200 mg bid with RT. Two DLTs occurred, both at the third dose level: diarrhea grade 3 and digestive bleeding grade 3 with secondary anemia and hemodynamic angor in a patient with previous small bowel angiodysplasia. The most frequent toxicity was diarrhea. Other grade 1-2 toxicities included rash, fatigue, hand-foot syndrome, hypertension, dysuria and urinary frequency. One patient developed late radiation cystitis. Pathological complete response was achieved in 8 of 9 patients evaluated. Salvage cystectomy has been performed in one patient due to recurrent superficial bladder tumor. After a median follow up of 30 months, 6 patients remain disease-free with intact bladder.

Conclusions: The combination of sorafenib and RT appears to be feasible and safe allowing long-term bladder preservation in selected patients. A phase II study to assess the activity of this promising combination is warranted.
Prospective randomized controlled trial of robotic versus open radical cystectomy for bladder cancer: Median 3-year follow-up.
Authors: Smith Angela , Nix Jeffrey W. , Nielsen Matthew Edward , Wallen Eric , Pruthi Raj
Published: February 2017

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Background: We reported our results on a prospective, randomized trial of open vs. robotic cystectomy in 2008. Three years later, we report our findings with regard to overall (OS) and disease-specific survival (DS), recurrence rates and long-term complications.

Methods: A prospective, randomized study comparing open vs. robotic cystectomy for bladder cancer was initiated at our institution with IRB approval in 2008. A target accrual of 40 patients was established to evaluate for non-inferiority based upon nodal yield. Peri-operative and pathologic results were reported in 2008. We now report our median 36-month follow-up for this patient cohort.

Results: Of the 41 patients, 21 were randomized to robotic and 20 to open. On surgical pathology, in the robotic group 14 patients had <= pT2, 3 pT3/T4, and 4 N+ disease. In the open group, 9 had <= pT2, 5 pT3/T4, and 7 N+ disease. No positive margins were noted. With median follow-up of 35 and 36 months in the robotic and open arms, OS was 65% (13/20) and 81% (17/21) respectively (p=0.3058). DSS was 68% in the open group (13/19) and 85% in the robotic group (17/20) (p=0.2733). There were 7 recurrences (35%) in the open cohort compared to 3 patients (14%) undergoing the robotic procedure (p=0.1589). Examining overall complications, there were no differences between the open and robotic groups when evaluating 30-day complications and >=90 day complications (p=0.8651). The open and robotic cohorts demonstrated 2 strictures in each cohort. Two parastomal hernias were noted in the open group compared to none in the robotic group. On multivariate analysis, controlling for age, BMI and pathologic stage, cystectomy type did not predict OS or DSS, recurrences, or complications.

Conclusions: Median 3-year follow-up evaluating open versus robotic cystectomy demonstrates no differences with regard to OS, DSS, cancer recurrence or long-term complications. Although this study was not powered to assess survival differences, this is the first randomized study to report such data in a non-selected population with 3-year median follow-up.
Effect of lenalidomide on the response of bladder cancer to BCG immunotherapy in an in vivo murine model.
Authors: Lee Eugene K. , Gerald Jinesh , Kamat Ashish M.
Published: February 2017

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Background: Intravesical BCG is the gold standard for non-muscle-invasive bladder cancer (NMIBC). However, many patients do not respond to therapy while others relapse and/or progress. As a result, there remains a need for therapies that can enhance the efficacy of BCG. We explore the efficacy of lenalidomide, an immunomodulatory agent used in multiple myeloma and myelodysplastic syndrome, in combination with BCG in vitro and in an in vivo bladder cancer model.

Methods: We studied the effects of lenalidomide in combination with BCG induced cytokines in MBT-2 cells using PI-FACS. For in vitro studies, we used 10 and 100 nM of lenalidomide in combination with TNF-a and FasL. We then performed Western blotting for cell cycle and apoptosis regulatory proteins. Subsequently, we tested the efficacy of this combination in an immunocompetent murine model of bladder cancer with MBT-2 cells in C3H mice using the flank injection method. Drug dosages were 30 mg/kg for lenalidomide and 105 CFU of BCG. Tumor growth curves were created for the control, lenalidomide, BCG and combination treatment mice groups. Immunohistochemistry (IHC) was then performed using antibodies against proteins related to cell cycle, apoptosis, angiogenesis and immune response.

Results: PI-FACS identified increased DNA fragmentation in the combinations of lenalidomide and TNF-a and FasL compared to control and each agent alone. Using Western blotting, we demonstrated that the combination resulted in apoptosis via caspase-3 activation. In the murine model, combination therapy resulted in a statistically significant decreased tumor size compared to the control group. While the BCG alone and lenalidomide alone groups did show a trend toward smaller tumor, they did not reach statistical significance. Furthermore, the TUNEL assay showed a substantial increase in apoptosis only in the combination group. Immunohistochemistry demonstrated decreased angiogenesis in all treatment groups compared to control, as well as, decreased T-cell infiltration.

Conclusions: Our study demonstrates a potential role for the immunomodulatory agent, lenalidomide, in combination with BCG for NMIBC. This in vivo model serves as a template for future clinical trials.
Use of next-generation deep sequencing to improve FGFR3 mutation detection in the urine of patients with bladder cancer.
Authors: Millholland John M. , Li Shuqiang , Fernandez Cecilia A. , Shuber Anthony P.
Published: February 2017

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Background: FGFR3 mutations have been identified in ∼60-70% of low-stage, non-invasive tumors. Our group and others have developed assays to detect FGFR3 mutations in the urine of bladder cancer patients. However, urine-based assays have been limited by the technical ability to detect rare events in a dilute medium where there is a high background of normal DNA. In these assays, FGFR3 mutations are generally found in ∼30% of the urine samples, which is < 50% concordance with the expected detection in tissue. We have now developed an ultra-deep amplicon sequencing technique that increases FGFR3 mutation detection in urine to ∼67%, near the expected detection if every mutation found in tissue could be detected in urine.

Methods: Amplicons were designed against FGFR3 exons 7, 10, and 15 using PCR primers containing the adapter sequences for unidirectional sequencing. Taqman probes were used to determine if sufficient DNA was present in each sample. Primary amplification was performed from DNA isolated from 4 ml of urine. The resulting PCR products were used as template for emulsion PCR and these were then sequenced using the Roche 454 GS Junior. Samples were analyzed for total DNA reads per sample and number of mutant sequencing reads to determine percent mutation.

Results: Urine samples from 29 patients with stage Ta bladder cancer were analyzed by both our previously described qPCR method and the new ultra-deep sequencing approach. Of the 29 samples, 2 did not have sufficient DNA for analysis by sequencing. Using ultra-deep amplicon sequencing, 18 out of 27 (66.7%) were positive for FGFR3 mutations, while only 3 out of 27 (11.1%) were positive for mutations by qPCR. The urine samples from the 15 newly identified mutations using deep sequencing contained FGFR3 mutations as low as 0.05%. The sensitivity achieved using deep sequencing approximates the FGFR3 mutations observed in tissue.

Conclusions: We have developed a highly sensitive non-invasive urine based assay that can detect FGFR3 mutant DNA when present at < 1% of the sample and suggests > 90% concordance with the expected mutations in Ta tumor tissues. To our knowledge, this is the first practical application of next generation sequencing technology for diagnostic use.
Chronic kidney disease and the risk of incident renal and urothelial cancer in a population-based cohort of 1.2 million adults.
Authors: Lowrance William Thomas , Udaltsova Natalia , Ordoñez Juan , Russo Paul , Go Alan S.
Published: February 2017

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Background: Prior studies have observed an increased risk of cancer in patients with end stage renal disease, but whether less severe chronic kidney disease influences the risk of cancer is uncertain.

Methods: Among 1,190,538 adults at least 40 years of age and no prior dialysis, renal transplant or known cancer who received care within Kaiser Permanente Northern California, we examined the independent association between estimated glomerular filtration rate (eGFR) and the risk of cancer, overall and by type, between 2000 and 2008. Incident cancers were identified from a comprehensive regional cancer registry and potential confounders were ascertained using validated algorithms based on health plan electronic medical records. The impact of time-varying eGFR on incident cancer risk was examined using multivariable extended Cox regression, after excluding any cancers detected during the first two years of follow-up and any eGFR values within 3 months before a cancer diagnosis to reduce potential biases.

Results: During 6,000,420 person-years of follow-up, 76,809 incident cancer diagnoses were identified among 72,875 patients (38,744 M, 34,131 F). After adjustment for possible confounding factors, the risk of renal cancer increased with lower eGFR (ml/min/1.73 m2): the adjusted hazard ratio [HR] for renal cancer was 1.35 (95% CI: 1.18–1.55) for eGFR 45–59, HR 1.65 (1.37 to 1.97) for eGFR 30–44, and HR 2.09 (1.62 to 2.70) for eGFR <30. There was a similar association between eGFR and urothelial cancer. However, there was not a significant multivariable association between eGFR and prostate, colorectal, lung, breast, or any cancer.

Conclusions: We observed a graded, independent increased risk of renal and urothelial cancer risk with lower eGFR in a large, population-based cohort. However, lower eGFR was not significantly associated with other major cancer types. Additional research is needed to understand potential contributing mechanisms between reduced renal function and renal or urothelial malignancies, as well as whether differential cancer screening strategies are effective in patients with chronic kidney disease.
A phase II and biomarker study (MET111644) of the dual Met/VEGFR-2 inhibitor foretinib in patients with sporadic and hereditary papillary renal cell carcinoma: Final efficacy, safety, and PD results.
Authors: Choueiri Toni K. , Vaishampayan Ulka N. , Rosenberg Jonathan E. , Logan Theodore , Harzstark Andrea Lynne , Rini Brian I. , Srinivas Sandy , Adams Laurel M. , Sherman Laurie Jill , Ottesen Lone Harild , McDermott David F. , Bottaro Donald P. , Linehan W. Marston , Srinivasan Ramaprasad
Published: February 2017

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Background: Foretinib is an oral multi-kinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations and/or amplifications in MET have been described in patients (pts) with papillary renal cell carcinoma (PRC). The aim of this study was to evaluate the efficacy and safety of 2 dosing regimens of single agent foretinib bisphosphate (foretinib) in pts with PRC and to explore modulation of plasma proteins indicative of target inhibition.

Methods: Pts were enrolled in 2 cohorts with different dosing schedules of foretinib: 240 mg/day on days 1–5 of every 14 days (intermittent arm) or 80 mg/day (daily dosing arm). The primary endpoint was overall response rate (ORR) targeting an ORR of at least 25%. Pts were stratified based on status of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, chromosome 7 gain or none of these). Plasma markers reflecting potential target effects of MET and VEGFR inhibition were also analyzed.

Results: Overall, 74 pts were enrolled with 37 in each dosing cohort. ORR was 13.5%, progression-free survival 9.3 months, 1 year overall survival (OS) was 70% and median OS was not reached. The median duration of response was 18.5 months. Of 68 pts with adequate tumor assessment data available, 50 experienced some reduction in the sum of the longest tumor diameters (SLD) ranging from −2% to −75%. The most frequent grade 3/4 adverse events related to foretinib were fatigue (6.8%), hypertension (50%), and diarrhea (6.8%). A high rate of non-fatal pulmonary embolism was observed (11%). There were no significant differences in efficacy or safety between the two cohorts. In both arms, plasma sMET and VEGF increased and sVEGFR2 decreased after 2 cycles indicating target inhibition, but these changes were not associated with response or PFS. Outcomes based on molecular characterization are presented separately at this meeting.

Conclusions: In the largest clinical trial devoted to papillary RCC, foretinib demonstrated anti-tumor activity in patients with PRC, modulation of several target indicator plasma proteins, and a manageable toxicity profile.