bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of care transitions with treatment delay for patients with muscle-invasive bladder cancer.
Authors: Tomaszewski Jeffrey J. , Handorf Elizabeth , Corcoran Anthony , Mehrazin Reza , Canter Daniel , Bekelman Justin E. , Kutikov Alexander , Chen David Y. T. , Uzzo Robert G. , Smaldone Marc C.
Published: February 2017

346

Background: Population-based data suggest an association between timely treatment (<3 months) and improved survival in patients undergoing radical cystectomy (RC). Hypothesizing that care transitions at the time of hospital referral may delay timely treatment in patients with muscle invasive bladder cancer (MIBC), our objective was to identify the association between care transitions and treatment delay ≥3 months using a large national tumor registry. Methods: Using the National Cancer Database, all patients with stage ≥II urothelial carcinoma treated with RC from 2003-2010 were identified. A care transition was defined as a change in hospital from diagnosis to first course of treatment. A logistic regression model was used to test the association between care transition and treatment delay (from diagnosis to RC or initiation of neoadjuvant chemotherapy), adjusting for year, demographic, clinicopathologic, and hospital characteristics. Results: Of 22,251 patients identified, 14.2% of patients experienced a treatment delay of ≥3 months. Further, this proportion increased over the study period (13.5% [2003-2006] versus 14.8% [2007-2010], p=0.01). 19.4% of patients undergoing a care transition experienced a delay to definitive treatment compared to 10.7% of patients diagnosed and treated at the same hospital (p<0.001). The proportion of patients experiencing a care transition increased over the study period (37.4% [2003-2006] versus 42.3% [2007-2010], p<0.001). Following adjustment, patients were more likely to experience a treatment delay when undergoing a care transition (OR 2.0 [CI 1.8-2.2]). Additional covariates associated with treatment delay included African American race (OR 1.5 [CI 1.3-1.7]), Hispanic ethnicity (OR 1.6 [CI 1.3-1.9]), insurance status (Medicaid OR 1.4 [CI 1.1-1.7], Medicare OR 1.2 [CI 1.08-1.34], no insurance OR 1.3 [CI 1.07-1.54]), and Charlson comorbidity count ≥2 (OR 1.3 [CI 1.08-1.45]). Conclusions: Patients with MIBC who experienced a care transition between diagnosis and treatment hospitals were more likely to experience a treatment delay of ≥3 months. Strategies to expedite care transitions at the time of hospital referral may be a means to improve quality of care.
The significance of protocol biopsy after intravesical BCG treatment in patients with non-muscle–invasive bladder cancer.
Authors: Maruyama Satoru , Shinohara Nobuo , Murahashi Norihiro , Suzuki Hidetaka , Matsumoto Ryuji , Akino Tomoshige , Miyajima Naoto , Tsuchiya Kunihiko , Abe Takashige , Nonomura Katsuya
Published: February 2017

356

Background: Currently, there are few well-validated data of the optimal schedule of follow-up after BCG intravesical instillation. The objective of the study were to elucidate the ability of conventional exams (cystoscopy, urine cytology) to diagnose presence of carcinoma and the significance of protocol biopsy after BCG intravesical treatment in patients with high-risk non-muscle-invasive bladder cancer (NMIBC). Methods: The study included patients treated with BCG intravesical treatment. From January 2002 to October 2012, we retrospectively reviewed a total of 72 patients (61 men and 11 women). The median age was 72 years (range 47-84). The pathological stages were Tis in 4 patients (6%), Ta in 29 (40%) and T1 in 39 (54%) (T1 with CIS in 30 [42%]). Tumors were multifocal in 56 (78%) and second TUR had been performed in 53 (74%) patients. We investigated the prognosis and accuracy of tumor existence by conventional exams referring with the protocol biopsy. A protocol biopsy was performed within 5 to 9 months after the final TUR. CTCAE v4.0 was used to grade adverse events. Results: Of 72 patients, we performed protocol biopsy in 62 patients and 9 (15%) had cancer. The conventional methods had a sensitivity of 78%, specificity of 81%, positive predictive value of 41% and negative predictive value of 96% in diagnosing cancer. Although three (5%) had grade2 adverse events, there were no grade 3 or greater adverse events. Of 53 patients with no cancer in protocol biopsy, 8 (8%) patients experienced a recurrence but 51patients (96%) were alive with no evidence of disease. Of 9 patients pointed out cancer in protocol biopsy, 7patients (78%) had no evidence of disease recurrence at last follow-up. The 5-year recurrence-free survival rate and overall survival rate were 77% and 95%, respectively. Conclusions: To the best of our knowledge, this is the first report of the ability of conventional exams for follow-up after BCG treatment. Our findings revealed that conventional exams were limited for meticulous follow-up, so that the protocol biopsy will be recommended to obtain the better survival in high-risk NMIBC patients.
Outcomes of radical cystectomy in potential candidates for bladder-preservation therapy.
Authors: Pietzak Eugene J. , Smith Zachary L. , Malkowicz S. Bruce , Guzzo Thomas J.
Published: February 2017

357

Background: Outcomes for Bladder Preservation Therapy (BPT) in urothelial-type bladder cancer (UBC) are often compared to those achieved by Radical Cystectomy (RC). However, BPT patients are usually “carefully selected” which may limit comparisons. Our objective was to analyze the outcomes of RC within a “carefully selected” patient cohort. Methods: We identified 471 consecutive patients with UBC who underwent RC with curative intent from 1987 to 2008 at a single academic center. Patients were considered eligible for BPT if tumors were clinical T2 without carcinoma in-situ (CIS), hydronephrosis, multiple invasive tumors, or mixed histology. Patients with ≥1 contraindications were considered ineligible. Renal function was not factored into eligibility. Clinicopathologic characteristics and survival outcomes for BPT eligible patients were compared to ineligible patients. Results: 275 patients had cT2 tumors, of which 157 (57.1%) were ineligible for BPT (CIS=54; hydro=77; multiple tumors=29; mixed histology=55; ≥2 contraindications=51). BPT eligible and ineligible patients did not statistically differ with regards to age, gender, race, BMI, smoking, ASA score, or neoadjuvant chemotherapy. At time of RC, BPT eligible patients were less likely to have positive lymph nodes (p=0.01), pathologic LVI (p=0.02), & upstaging to pT3/pT4 (p=0.002). 2 and 5 year overall survival (OS) for all cT2 patients was 65.2% and 40.3%. 2 and 5 year OS was 76.7% and 44.2% for BPT eligible patients, but only 57.1% and 37.4% for ineligible (p=0.07). No statistical difference was seen in distant Recurrence Free Survival (RFS) (p=0.9), but BPT eligible patients had better local-RFS (p=0.05). 2-year Cancer Specific Survival (CSS) for all cT2, BPT eligible, and BPT ineligible patients was 71.8, 85.4%, and 62.3% respectively. Fine-Gray competing risk analysis revealed significantly better CSS for BPT eligible patients compared to those ineligible (Sub-HR=0.46 [CI=0.29-0.72] p=0.001). Conclusions: RC provides excellent CSS for patients potentially eligible for BPT. This should be included in an informed discussion of treatment options. In the absence of randomized trials, comparisons between RC and BPT must factor in selection bias.
Trends of multimodal therapy in high-stage penile cancer.
Authors: Ferry Elizabeth Kate , Zhu Hui
Published: February 2017

370

Background: Penile cancer (PC) is associated with high mortality and treatment failure in higher stage disease. While no prospective data exists, small anecdotal reports advocate the use of perioperative chemotherapy and/or radiotherapy for advanced disease. The 2013 National Comprehensive Cancer Network (NCCN) guidelines advocate the use of multimodal therapy for advanced disease. This study aimed to examine the trend in the use of perioperative chemotherapy or radiotherapy for advanced stage PC in the U.S. from 2000 – 2011. Methods: The National Cancer Database (NCDB) Datalinks Portal was queried. Diagnosis by year, first course treatment by stage, in all hospitals from 2000 – 2011 was obtained. Percentages of men treated with surgery alone, surgery with radiation, and surgery with chemotherapy in stages III and IV by year were determined to assess trends. Results: From 2000 – 2011, there were 1,028 and 440 men diagnosed with stage III and IV PC, respectively, who were recorded as having either surgery alone, surgery with radiation (+XRT), or surgery with chemotherapy (+Chemo). Addition of radiation therapy was variable, but low. Addition of chemotherapy has gradually increased, most dramatically in stage III PC. Conclusions: Consistent with the 2013 NCCN guidelines on penile cancer, the use of multimodal therapy for higher stage PC has increased, though modestly. Surgery with chemotherapy is the most common multimodal therapy. Further studies are needed to determine if this corresponds to a change in PC mortality. [Table: see text]
Enhancing risk stratification in primary mediastinal nonseminomatous germ cell tumors (PMNSGCT): A 27-year experience at a tertiary cancer center.
Authors: Necchi Andrea , Lo Vullo Salvatore , Giannatempo Patrizia , Farè Elena , Raggi Daniele , Nicolai Nicola , Piva Luigi , Biasoni Davide , Torelli Tullio , Catanzaro Mario , Stagni Silvia , Maffezzini Massimo , Scanagatta Paolo , Gianni Alessandro M. , Mariani Luigi , Salvioni Roberto , Pastorino Ugo
Published: February 2017

373

Background: Mediastinal GCTs and PMNSGCTs poorly benefit from CT and half of patients (pts) still die for disease. Enhancing the risk stratification may result in tailoring a personalized treatment strategy since diagnosis. Methods: Between 1985 and 2012, 87 pts with PM-GCT were treated at our center. Of them, pure seminomatous histology was excluded. Cox proportional hazards regression analysis was conducted to examine the prognostic impact of these candidate factors on overall survival (OS): type of 1st-line CT (high [HDCT] vs conventional dose [CDCT]), post-CT surgery, type of baseline elevated serum tumor marker (STM), presence of lung or liver-bone-brain metastases (LBB), STM response (still elevated vs normal or normalized), and histology (viable cancer [VC] vs necrosis/teratoma [NT]). OS curves were compared by Kaplan Meier method with the log-rank test. Results: The study included 68 cases with PMNSGCT. Median age was 28.5 yrs (IQR: 23-35). 12 pts (17.7%) presented with mediastinal syndrome, 23 (33.8%) had lung and 7 (10.3%) LBB metastases. 12 pts received upfront HDCT and 45 pts (66.2%) underwent post-CT surgery. The final model of poor prognostic factors included no surgery (HR: 8.74, 95%CI, 1.77-43.01), surgery + VC (HR: 6.97, 95%CI, 1.46-33.30), and lung metastases (HR: 2.92, 95%CI, 0.99-8.64). The model demonstrated moderate discriminatory ability for OS (c-statistic=0.68). A risk stratification model based on the combination of these factors and accounting for a 50% five-year survival cutoff identified 2 groups (poor prognosis, N=28 vs good prognosis, N=26) with distinct overall survival curves (p<0.001). Pre-operative STM and final histology were not associated (p=0.574 at Chi squared test). 5-yr OS after receiving 2nd line CT (n=25) was 18.7% (95%CI, 7.9-44.5). Results are limited by small numbers. Conclusions: Pts with PMNSGCT classified as having a good prognosis in this model had a fairly high survival estimate, while a strategy of consolidation CT for pts with poorest risk features warrants investigation, once the model is confirmed. The effect of surgery on survival was independent of post-CT STM, which also poorly predicted final histology.
Surgical management trends of penile cancer in the United States between 2000 and 2010.
Authors: Ferry Elizabeth Kate , Zhu Hui
Published: February 2017

379

Background: Penile cancer may cause significant morbidities to those who are treated with aggressive surgery. Conversely, there has been no improvement in penile cancer survival rates since 1990. While the causes for this stagnation may be multifactorial, one potential cause is undertreatment of high-risk disease. This study aimed to examine both the trend in the stage-dependent surgical treatment for penile cancer from 2000 to 2010 and the patterns of possible over and/or undertreatment during this period. Methods: The National Cancer Database (NCDB) Datalinks Portal was queried. Diagnosis by year, first course surgery by stage, in all hospitals from 2000-2010 was first obtained. Data was grouped into no surgery, penile sparing, and radical surgery. Data was also obtained for first course surgery by stage in community hospitals (C), comprehensive centers (CC), and teaching research hospitals (TR), individually. Groups were similar as above, with the exclusion of the no surgery group. Results: There were 1,405 patients with recorded first course surgical treatments in community hospitals, 3,930 in comprehensive hospitals, and 3,667 in teaching research hospitals from 2000 to 2010. Graphically, there has been no change in the trend in the pattern of surgical management of penile cancer from 2000 to 2010 in high or low stage penile cancers. Consistent overtreatment of stage I penile cancer with radical surgery was observed in all hospitals during this period. A variable, but high, percentage of penile-sparing surgery was observed for advanced stages among all hospital types. Conclusions: Corresponding to the stagnation in the survival rates of penile cancer, the surgical management trends ded not change between 2000 and 2010. Contrary to the 2013 National Comprehensive Cancer Network (NCCN) Guidelines, penile-sparing surgery continues to be performed in all types of treating hospitals for higher stage penile cancers, which may represent an undertreatment of potentially fatal penile cancers. Conversely, there was a persistent pattern of overtreatment of stage I penile cancer. [Table: see text]
Stage I testicular tumor: How frequently to scan?
Authors: Ramamurthy Sindhu , Mahtab Najibah , Showler Helen , Frew John A. , Pedley Ian D. , Azzabi Ashraf , Brown Jolene , McMenemin Rhona Margaret
Published: February 2017

380

Background: Testicular malignancy is the most common cancer affecting men aged between 15 and 44 years. In our centre, almost all low-risk seminoma (LRS) stage-I and non-seminomatous germ cell tumours (NSGCT) stage I (high and low-risk) tumours are followed-up on a surveillance program (SP) for a minimum of 5 years. LRS patients are scanned at 4, 6, and 12 monthly intervals during years 1, 2, and 3 to 5 years respectively. NSGCT undergo computer tomography (CT) scan at 3 monthly intervals in years 1 and 2, 4 monthly in year 3 and 6 monthly thereafter. Clinical examination, Chest X-ray (CXR) and tumour markers (TM) are performed at each visit. This retrospective audit examined if relapses were first detected by raised TM or radiologically, and if there was any difference in detection rate between these investigations to recommend reducing the frequency of CT scans, especially in lower risk groups, and therefore cumulative radiation exposure. Methods: The patient population was obtained from hospital electronic database. Metastatic patients, clinical trials patients and those who received adjuvant treatment upfront were excluded. Results: 396 patients were enrolled from 1999 to September 2013. 153 patients were followed-up in SP. 33 relapses (mean age 37 years, range 17-56) detected in SP. The mean relapse free survival period was 55.3 months (range 9.6-43.3) from date of diagnosis. No relapses were first detected on CXR. 4 patients had only TM elevated and 6 had CT abnormality found post TM elevation. 11 had simultaneous CT and TM abnormalities. For 12 patients, CT abnormality was detected with no TM raise. Of these, 8 were high risk (7 NSGCT and 1 pure seminoma) and 4 were low risk NSGCT. Patients were treated with standard BEP/EP chemotherapy regimen on relapse. All patients are alive to date and continue to be followed-up regularly. Conclusions: 12 patients in our study had relapses detected radiologically with no TM rise. 25% of these patients had low risk NSGCT. Without the CT scan, these patients would have faced potential delay in diagnosis and treatment. Results of prospective randomised trials are awaited to produce evidence to place confidence in less number of CT-scans for these patients during follow- up. Until then we recommend the current standard protocol be followed.
Impact of extrascrotal symptoms on treatment outcome in patients with nonseminomatous germ cell tumor with intermediate or poor prognosis.
Authors: Yamada Shigeyuki , Saito Hideo , Mitsuzuka Koji , Ito Akihiro , Arai Yoichi
Published: February 2017

384

Background: The International Germ Cell Consensus (IGCC) classification is based on primary tumor localization, presence of non-pulmonary visceral metastases, and serum tumor marker levels, not the general condition of patients. The present study aimed to identify novel prognostic factors for nonseminomatous germ cell tumors (NSGCTs) with IGCC intermediate or poor prognosis. Methods: We retrospectively analyzed 399 patients with germ cell tumors (GCT) treated at Tohoku University Hospital between 1979 and 2011. Of these, 52 and 61 patients with NSGCTs were classified as having intermediate and poor prognosis, respectively. Several clinical parameters were reviewed, including age, IGCC prognosis group, kind of induction chemotherapy, and extra-scrotal symptoms at presentation. Extra-scrotal symptoms were defined as symptoms other than scrotal swelling, such as abdominal pain, lumbago, and dyspnea. Survival was estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to assess potential predictors of outcome. Results: The median age of the 113 patients was 30. Median length of follow-up was 57 months. At presentation, 12 (23%) patients with intermediate prognosis and 32 (52%) patients with poor prognosis had extra-scrotal symptoms. In the intermediate prognosis group, the five year overall survival (OS) of patients with extra-scrotal symptoms was significantly worse than that of patients without symptoms (95% vs. 63%, p= 0.0008), but there was no significant difference in five year OS between patients with and without extra-scrotal symptoms in the poor prognosis group (60% vs. 66%, p= 0.265). On multivariate analysis, the presence of extra-scrotal symptoms (hazard ratio [HR] = 2.48, p= 0.0184) and induction chemotherapy not including etoposide (HR = 12.0, p< 0.0001) were independent predictors of inferior OS. Conclusions: The presence of extra-scrotal symptoms was associated with inferior OS, particularly in patients with intermediate prognosis. Intermediate-prognosis patients with extra-scrotal symptoms should be recognized as having poor prognosis.
Nonseminomatous germ cell tumor of the testis: Prognostic factors for a lethal phenotype.
Authors: Tu Shi-Ming , Bilen Mehmet Asim , Tu Zachary H. , General Raphael , Ward John Francis , Pisters Louis L. , General Rosale , Chen Adrienne H. , Nieto Yago , Pagliaro Lance C. , Yeung S. J. , Logothetis Christopher , Lin Sue-Hwa , Gorlov Ivan
Published: February 2017

390

Background: Cancer is a heterogeneous disease. Studying cancer heterogeneity may enable us to elucidate the various subtypes of a particular cancer, and improve the diagnosis, prognostication, and therapy of cancer. Nonseminomatous germ cell tumor (NSGCT) is a prime example of a heterogeneous disease. We determined potential lethality of NSGCT by characterizing the histological makeup of primary testicular tumors, the tumor burden, psychosocial issues, and surgical factors. Methods: From November 1997 to October 2012, 142 consecutive patients diagnosed with a NSGCT of the testis were evaluated for this study. The log-rank test was used to identify prognostic factors in univariate Kaplan-Meier analysis. A multivariate Cox regression model was used to evaluate predictive factors for overall survival. Results: Patient and tumor characteristics: median (range) age 25 (12 to 53); pathology – embryonal carcinoma 15%, teratoma 6%, and mixed NSGCT 79%; stage – I 46%, II 32%, and III 21%. Ten (7%) patients died from their NSGCT. Seven (5%) patients had incurable NSGCT. Multivariate analysis showed that presence of seminoma (p=0.007), presence of yolk sac tumor (p=0.019), clinical stage (p=0.027), and psychosocial issues (p=0.04), have unfavorable prognostic significance. Conclusions: Certain subtypes of NSGCT containing yolk sac tumor and seminoma are inherently chemotherapy resistant and potentially lethal. Psychosocial factors can delay the diagnosis and treatment of patients with such tumors and adversely affect their clinical outcome. Results of this study need to be validated in another data base or a prospective clinical trial.
Development and validation of a prognostic nomogram for progression-free and overall survival in patients with advanced renal cell carcinoma (aRCC) treated with pazopanib.
Authors: Kattan Michael W. , Sternberg Cora N. , Mehmud Faisal , Bhatt Kamalnayan , Chakrabarti Debasis , McCann Lauren , Motzer Robert John
Published: February 2017

405

Background: Pazopanib, an oral multikinase inhibitor, demonstrated noninferiority to sunitinib in patients with aRCC in COMPARZ (NCT00720941), a randomized, phase III trial (NEJM 2013;369:722). The purpose of this study was to develop and validate prognostic nomograms based on outcome data from COMPARZ for predicting the probability of 12-month progression-free survival (PFS) and 30-month overall survival (OS) for aRCC patients who received pazopanib. Methods: Statistical modeling was performed on a dataset consisting of 557 patients from the pazopanib arm of COMPARZ. A Cox proportional hazards regression model was fit using predictors thought to be prognostic. These predictors included neutrophil count, platelet count, LDH, and alkaline phosphatase, all relative to ULN; calcium; albumin; hemoglobin; Karnofsky score; months from diagnosis to treatment; number of metastatic sites; and presence of lung, liver, and bone metastases. Data from patients on the sunitinib arm of COMPARZ and the pazopanib arm of the VEG105192 trial (NCT00334282; J Clin Oncol 2010;28:1061) were used for validation. Missing values were imputed using chained equations. For validation with the VEG105192 dataset, bootstrap-corrected estimates of discrimination and calibration were calculated following 1000 resamples. The Cox model was plotted as a nomogram. Results: Prognostic nomograms were developed and validated for predicting the probability of 12-month PFS and 30-month OS in aRCC patients based on a Cox regression model. Calibration plots suggested reasonable correspondence between predicted probabilities and actual proportions of PFS and OS. The concordance index for 12-month PFS was 0.636 with sunitinib patients and 0.635 for pazopanib patients; the concordance index was 0.692 for 30-month OS (sunitinib patients). When examining the PFS and OS nomograms, albumin, calcium, and LDH levels appeared to be the most influential predictors of outcome. Conclusions: The nomograms predict, with reasonable accuracy, treatment outcomes in patients with aRCC receiving pazopanib, based on their baseline clinical characteristics.
Toxicity analysis of lymph node irradiation for prostate cancer patients treated with IMRT.
Authors: Johnson Matthew E. , Li Tianyu , Kutikov Alexander , Buyyounouski Mark K. , Sobczak Mark L. , Viterbo Rosalia , Horwitz Eric M.
Published: February 2017

41

Background: The radiation target for intensity modulated radiation therapy (IMRT) in high-risk prostate cancer (HRPC) includes both the prostate and seminal vesicles (SV). Inclusion of the regional lymph nodes (LN) has considerable variation in daily practice. Currently used prescriptions are 80 Gy to prostate and proximal SV, with 56Gy to the distal SV with (P/SV+LN) or without the pelvic LN (P/SV). The same P/SV prescription is used for intermediate risk prostate cancer (IRPC). We report the association between inclusion of the LN and toxicity for men treated from 2001 to 2009. Methods: 1,160 men treated for HRPC and IRPC with IMRT were identified in our clinical database. All patients had simulation with both CT and MRI, and utilized daily image guidance. Toxicity data were obtained from chart review. Statistical analysis was performed utilizing log rank test. Results: 408 patients were in the P/SV+LN group. There was no difference between the groups in regard to age, race, RT duration, or smoking. Median prescription dose was 78 Gy in both groups. Median follow-up was 44 months. A higher rate of late GI toxicity was seen in the group of patients treated to P/SV+LN (p<0.01), see Table. No difference was seen in toxicity >grade 2 for acute GU (33.1% vs. 30.2%, p=0.31), acute GI (5.9% vs. 3.5%, p=0.05), or late GU toxicity (13.7% vs. 13.0%, p=0.74) for P/SV+LN vs. P/SV alone at 5 years. MVA was performed for late GI toxicity controlling for radiation dose, length of radiation course, and use of androgen deprivation. Inclusion of LN RT remained a significant predictor of late GI toxicity (HR=2.0, p=0.02). For those with late GI toxicity, the most common symptoms were bleeding (69.5%), increased frequency of bowel movements (26.6%), fecal incontinence (15.7%), and proctitis (14.9%). Conclusions: Delivery of 56 Gy to the pelvic LN results in a significant increase in grade 2 or higher late GI toxicity with a HR of 2.0 in the setting of treatment with IMRT. A decision to treat the pelvic LN in HRPC should be weighed against the increase in late GI toxicity. [Table: see text]
Loss of BAP1 and PBRM1 protein expression and its association with clear cell renal cell carcinoma-specific survival.
Authors: Joseph Richard Wayne , Kapur Payal , Serie Daniel , Eckel-Passow Jeanette , Ho Thai Huu , Brugarolas James , Parker Alexander S.
Published: February 2017

414

Background: While mutations in PBRM1 (~40%) and BAP1(~10%) are associated with clinical outcomes and pathologic features in clear cell renal cell carcinoma (ccRCC), the impact of protein expression of these genes remains unknown. Herein, we quantify PBRM1/BAP1 protein expression in a large cohort of patients with localized ccRCC and associate expression with cancer-specific survival (CSS) and pathologic features. Methods: We utilized the Mayo Clinic Renal Registry and identified 1,416 patients who underwent nephrectomy to treat clinically localized ccRCC between 1/3/1990 and 4/14/2009. We used immunohistochemistry (IHC) to detect PBRM1/BAP1 expression, and a central pathologist blinded to the outcomes scored tumors as either positive or negative. Tumors with heterogeneous or equivocal staining were excluded from this analysis. We generated Cox proportional hazard regression models for associations with ccRCC-SS, and we employed Mann-Whitney U tests for associations with pathologic features. Results: Of the 1,416 samples, 1,232 (87%) were PBRM1/BAP1 positive or negative, 163 (11%) had heterogeneous staining, and 21 (1%) could not be assessed. The distribution and association of PBRM1/BAP1 phenotypes with clinical outcomes are listed in the table below. PBRM1+/BAP1+ tumors have the best CSS, and PBRM1-/BAP1- have the worst. In addition, PBRM1/BAP1 expression strongly associated with the tumor size, stage, grade, and tumor necrosis (p<0.0001). Conclusions: This study is the first and largest to quantify PRBM1/BAP1 protein expression in ccRCC tumors. We were able to quantify PBRM1/BAP1 through IHC in the vast majority of tumors (87%), and PRBM1/BAP1 expression strongly associates with both CSS and pathologic tumor characteristics. Our data confirms our previous findings of the importance of PRBM1/BAP1 in the molecular pathogenesis of ccRCC. [Table: see text]
Positive surgical margins after partial nephrectomy for renal cell carcinoma: Results from Canadian Kidney Cancer Information System database.
Authors: Bansal Rahul K. , Kapoor Anil , Finelli Antonio , Rendon Ricardo A. , Moore Ronald Brian , Breau Rodney H. , Lacombe Louis , Kawakami Jun , Drachenberg Darrel E , Black Peter C. , Pautler Stephen E. , Liu Zhihui , Tanguay Simon
Published: February 2017

420

Background: Partial nephrectomy (PN) is the standard of care for small renal masses (SRMs) whenever feasible. The occurrence of a positive surgical margin (PSM) on a pathological specimen is not uncommon and an ideal management is unknown. We conducted this study to examine the rate of PSM, predictors of PSM and their oncological outcomes after PN for renal cell carcinoma (RCC), using the Canadian Kidney Cancer information system (CKCis) database. Methods: We accessed the prospectively maintained CKCis database for 1066 patients who underwent PN for RCC in major academic centers all across Canada. Demographics, clinical, pathological and follow-up data were noted for patients with PSM and negative surgical margins (NSM). Multivariate logistic regression analysis was performed to assess predictors of PSM. Results: Out of 1066 patients, 59 (5.5%) had PSM, 928 (87%) had NSM and records of 79 (7.4%) patients were not available. Mean patient age was 61 years and 59 years in the PSM and NSM group respectively, and in each group 63% of the patients were males. Mean tumor size was 3.6cm (range 1.1 – 9.5) and 3.3cm (range 0.5 – 16.2) in PSM and NSM group respectively. PSM group had 5 (8%) grade 1, 28 (47%) grade 2, 16 (27%) grade 3 and 5 (8%) grade 4 tumors as compared to 127 (14%), 458 (50%), 207 (23%) and 27 (3%) respectively in NSM group. Four (6.7%) patients from the PSM group and 49 (5.3%) patients from the NSM group had local and/or systemic progression of disease. There were two cancer specific deaths in NSM group and none in PSM group. Fifty two (88%) and 861 (93%) patients were alive at mean follow-up of 18.5 (range 0 – 91.7) and 28.9 months (range 0 – 315.5) in PSM and NSM group respectively. For the multivariate logistic regression analysis; Fuhrman grade 4 predicted presence of PSM whereas age, operative technique, tumor size, tumor stage did not. Conclusions: Results from the CKCis database suggest that PSM after PN are common but does not result in adverse oncological outcomes. Presence of Fuhrman grade 4 may be associated with PSM on final pathological specimen.
Interpreting first-line options in mRCC: A look into the German RCC-registry.
Authors: Goebell Peter J. , Mueller Lothar , Overkamp Friedrich , Lueck A. , Vogt Michele , Marschner Norbert
Published: February 2017

429

Background: During the last few years, several efficacious therapeutic options have been developed for patients with metastatic renal cell carcinoma (mRCC). Due to the variety of multiple new targeted therapeutic options evidence based solely on randomized clinical trails is lacking. Registry data represents an important supplement providing insight into the treatment course and evidence on various outcomes. However, results provided by registry data may be influenced by many factors such as patient characteristic and comorbidities. Matched-pair analyses provide an interesting tool to compare different treatment options. Material & Methods: Over 100 oncology and urology outpatient centers in Germany are actively participating in this registry. The enrolment of the first 1000 mRCC patient data-sets with a maximum follow-up of three years has recently been completed. Among other information, data on patient and tumor characteristics, all systemic antineoplastic treatments, dosages, as well as response rates, progression free survival and overall survival are documented. Results: At the start of systemic therapy mean age were 66.2 years for male and 69.0 years for female patients, respectively. For all patients at least one comorbidity was indicated (Charlson Comorbidity Index 1.0). More than 94% of patients had metastases at inclusion. Investigating the most prominent TKIs used in sequential treatment in the registry, we identified time from initial diagnosis to treatment start as one of the most important factors predicting overall survival. Surprisingly, when controlling for this factor in a matched-pair analysis together with age, gender and risk, outcome in terms of progression-free survival appears to be similar in first line treatment with either Sunitinib or Sorafenib. Conclusions: Registry data can provide missing pieces of evidence on treatment outcomes. The registry demonstrates once more its hypothesis generating character and thus adds to the body of evidence as established from clinical trials. A direct comparison of efficacy can only be provided by clinical trails whereas registry data represent effectiveness of real-life treatment.
Prognostic impact of C-reactive protein (CRP) in metastatic prostate cancer (MPC): A systematic review and meta-analysis.
Authors: Naik Gurudatta , Morgan Charity , Rocha Pedro Filipe Simoes da , Templeton Arnoud J. , Pond Gregory Russell , Sonpavde Guru
Published: February 2017

43

Background: Serum C-reactive protein (CRP), a marker of inflammation, appears to demonstrate a prognostic impact in small studies of metastatic prostate cancer (MPC). We conducted a meta-analysis to better quantitate its prognostic impact. Methods: A systematic review was conducted to identify publications and presentations exploring the association of baseline serum CRP and overall survival (OS) in MPC, both castration-sensitive and castration-resistant. The hazard ratio (HR) and 95% confidence interval (CI) with P values were pooled. HRs were selectively extracted from multivariable analyses. Estimates of HRs were weighted and pooled using the generic inverse variance and random-effect models. Heterogeneity among trials was assessed using Cochrane’s Q statistic and the I2 statistic was used to quantify inconsistency among trials. The assumption of homogeneity was considered invalid for P<0.1. All statistical tests were two-sided, and P<0.05 was considered significant Results: Six studies comprising 659 evaluable patients were eligible. The first authors were Prins (N=119), Pond (N=112), Ito (N=80), Nakashima (N=126), Beer (N=160), and McArdle (N=62). The Nakashima and McArdle studies evaluated castration-sensitive men, while the remaining four studies evaluated castration-resistant men receiving docetaxel-based chemotherapy. The primary endpoint was OS except the McArdle study, which used cancer specific survival. All HRs were derived from multivariate analyses except the Pond study, which was a bivariate analysis. Men with higher CRP had significantly worse OS than those with lower CRP (HR = 1.42, P<0.001, 95% CI: 1.17 to 1.73; I2 = 72.6%, p = 0.003). In trials of castration-sensitive men receiving hormonal therapy, high CRP yielded a HR = 1.92 (P=0.005, 95% CI: 1.22 to 3.03; I2 = 0). In castration-resistant men receiving chemotherapy, high CRP yielded HR=1.35 (p=0.003, 95% CI: 1.11 to 1.65; I2 = 79%), P for subgroup difference=0.20. Conclusions: This meta-analysis suggests a strong prognostic impact for CRP on OS in men with both castration-sensitive and castration-resistant prostate cancer. Prospective validation is justified, given the affordability, ready availability and large dynamic range of CRP.
Surgeons’ preferences and practice patterns regarding intra-operative frozen section during partial nephrectomy.
Authors: Sidana Abhinav , Donovan James , Gaitonde Krishnanath
Published: February 2017

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Background: Intra−operative frozen section (FS) evaluation for tumor margin during partial nephrectomy (PN) is a matter of controversy in urologic oncology. We evaluate the preferences and practice patterns of urologists regarding intra−operative FS during PN. Methods: A 17 item questionnaire was designed to collect information on surgeons’ preferences and practice patterns regarding FS during PN. The survey was sent to the members of the Society of Urologic Oncology and the Endourological Society. Univariate and multivariate logistic regression analysis was done to identify the predictors determining the preferences. Results: 197 responses were received. 69% and 58% of respondents chose to obtain FS (always or sometimes) during Open Partial Nephrectomy (OPN) and Laparoscopic Partial Nephrectomy (LPN) respectively. There was a strong correlation between surgeons’ preferences during OPN and LPN. Younger surgeons are less likely to obtain FS during OPN (p<0.05). For surgeons who did not routinely obtain FS, “confidence about complete resection” was the most common reason (79%), followed by “no change in management with positive margins” (35%). Majority (75%) believed the margins to be negative if surgical margin was free of tumor microscopically by one cell layer. Older surgeons considered negative margins to be free of tumor microscopically by >= 5mm. Surgeons who performed more than 25 PNs annually were less likely to fulgurate the tumor bed after resection (p=0.025) while more likely to send an additional specimen from tumor bed for FS analysis (p=0.007). 54% and 42% of respondents would repeat FS for positive microscopic margins during OPN and LPN respectively. 95% of the respondents would not recommend additional treatment for positive margins on final pathology. Conclusions: Despite recent literature pointing to low clinical utility of intraoperative FS analysis, more than half of the surgeons still opt for intraoperative FS. Surgeon’s age and volume influence preferences and practice pattern in regards to FS analysis to some extent. Fellowship training, surgical approach and region of practice do not appear to dictate a surgeon’s preferences in regards to intra-operative FS during PN.
EVERSUN: A phase II trial of everolimus alternating with sunitinib as first-line therapy for advanced renal cell carcinoma (aRCC) (ANZUP trial 0901).
Authors: Davis Ian D. , Long Anne , Martin Andrew , Espinoza David , Yip Sonia , Kichenadasse Ganessan , Thompson Jennifer F. , Harrison Michelle L. , Lowenthal Raymond M. , Pavlakis Nick , Azad Arun , Kannourakis George , Steer Christopher , Goldstein David , Shapiro Jeremy David , Stockler Martin R. ,   Australian & New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: February 2017

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Background: We hypothesized that alternating inhibitors of the VEGFR and mTOR pathways would delay the development of resistance in aRCC. Methods: Single-arm, two-stage, multicenter, phase II trial to determine the activity, feasibility, and safety of sunitinib 50mg daily 4 weeks (wk) on / 2wk off, alternating with everolimus 10mg daily for 5 wk on / 1 wk off. Participants had aRCC of MSKCC good or intermediate risk. Primary endpoint: proportion alive and free of progression at 6 months (PFS6m). Secondary endpoints included feasibility, tumour response, overall survival (OS), and adverse events (AE). Imaging was done every 6 wk till wk 24, then q12wk. Planned sample size of 55 allowed distinction between a PFS6m rate of ≤64% versus ≥84% with type 1 and type 2 error rates of 5%. Results: We recruited 55 eligible participants from Sept 2010 to Aug 2012: mean age 61, male 71%, good risk 16%, intermediate risk 84%. Feasibility: 80% could start cycle 2 within 14 weeks; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 wks of any treatment. Efficacy: PFS6m was 29/55 (53%; 95% CI: 40%-66%). The OR rate was 7/55 (13%; 95% CI 4%-22%, all partial). After a median follow-up of 20 months, 47 of 55 had progressed with a median PFS of 8 months (95% CI: 5 to 10), and 30 of 55 had died with a median OS of 17 months (95% CI: 12 to undefined). Safety: AEs were consistent with those expected for each single agent. The most common grade 3 or 4 AE (number of participants) were hypertension (13), anaemia (9), oral mucositis (7), fatigue (n=7), GGT increase (n=6), pain (n=5), and platelet count decreased (n=5). Conclusions: The EVERSUN regimen was feasible and safe, but its activity did not meet prespecified values to warrant further research. This study supports the current approach of continuing first line anti-VEGF therapy until progression or prohibitive toxicity before switching to another drug. EVERSUN is an ANZUP Cancer Trials Group Ltd. trial coordinated by the NHMRC Clinical Trials Centre (ACTRN12609000643279). Clinical trial information: ACTRN12609000643279.
Phase II trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma.
Authors: Karam Jose A. , Devine Catherine E , Urbauer Diana L , Lozano Marisa , Ahrar Kamran , Tamboli Pheroze , Tannir Nizar M. , Wood Christopher G.
Published: February 2017

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Background: Previous studies have shown minimal impact of tyrosine kinase inhibitors on primary renal tumors. In this phase II trial, we investigate the safety and role of the axitinib in downsizing tumors in patients with non-metastatic clear cell renal cell carcinoma (RCC) prior to surgical resection. Methods: Patients with clinical stage T2-T3b N0 M0 biopsy-proven RCC were eligible for this study. Patients received axitinib daily for 12 weeks prior to surgery. The primary outcome was objective response rate. Secondary outcomes included safety, tolerability, feasibility of administration of axitinib and quality of life (using FKSI-15). A dedicated radiologist independently reviewed all CT scans to evaluate for response using RECIST. Results: Twenty-four patients were treated between 2011 and 2013. All patients had biopsy-proven clear cell RCC. Twenty-three patients continued axitinib for 12 weeks, and underwent surgery as planned without delay. One patient stopped treatment before 12 weeks due to adverse events (AEs) and was taken to surgery early. Median reduction of primary renal tumor size was 28.3% (range 5.3-42.9%). Eleven patients (45.8%) experienced a partial response by RECIST, and 13 patients had stable disease. There was no progression of disease while on axitinib. The most common AEs were hypertension, fatigue, oral mucositis, hypothyroidism, and hand-foot syndrome. No grade 4 AEs were observed. Intraoperatively, no complications or unusual bleeding were encountered. Postoperatively, 2 grade 3 and 13 grade 2 complications were noted, while no grade 4 or 5 complications occurred. FKSI-15 did change over time (p < 0.0001), with quality of life worsening in comparison to the screening assessment by week 7 (p = 0.0004). However, by week 19, quality of life was not found to be statistically different from screening (p = 0.3344). Conclusions: Axitinib was clinically active and well tolerated in the neoadjuvant setting in patients with locally advanced non-metastatic ccRCC. Clinical trial information: NCT01263769.
Dovitinib in first-line renal cell carcinoma: An investigation into tumour gene status and correlation with efficacy: A phase II clinical trial.
Authors: Broom Reuben James , Duffey Steven , Fraser-Browne Carol , Wilson Georgia , Thompson Kerin , Hanning Fritha , Mitchell Nicola Jane , Zwi Jonathan , McKeage Mark James , Dranitsaris George , Oei Paul , Fong Peter C.C.
Published: February 2017

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Background: Dovitinib is an anti-VEGFR tyrosine kinase inhibitor, differentiated by its inhibition of FGFR-1,-2,-3 and PDGFRβ. We evaluated its activity as 1st-line therapy in patients with metastatic clear-cell renal cell carcinoma (mCCRCC) in correlation with status of genes relevant to its mechanism of action. Methods: 31 treatment-naïve patients with mCCRCC were enrolled in this single-arm, single-site, phase II study (ACTRN12612000140853) and received dovitinib at 500mg 5 days on/2 days off until progression. Patients were offered an optional post-treatment biopsy to elucidate resistance mechanisms. The primary endpoint was progression free survival (PFS) using RECIST 1.1. Secondary endpoints include response rate (RR) and efficacy by FGFR gene status (FISH and DNA sequence using Sequenom OncoCarta panel). Results: Accrual occurred over 15 months from March 2012. Median patient age was 64 years and 72% were male. ECOG performance status was 0 in 45% and 1 in 55%. Heng prognostic group was favorable-risk in 38%, intermediate-risk in 52% and poor-risk in 10%. 38% of patients had bone metastases. Four patients stopped treatment due to toxicity and 1 patient withdrew (investigator decision). Median PFS was 6.2 months (inter quartile range: 3.3 to 8.2). Of 28 evaluable patients, best response was; PR (29%), SD (53%) and PD (18%). All-cause grade 3/4 adverse events (AE’s) occurring in ≥5% of patients were; fatigue (16%), abdominal pain (13%), pancreatitis (10%), gout (7%), diarrhea (7%), bone pain (7%), hypercalcaemia (7%), elevated lipase (7%) and pulmonary embolism (7%). No Grade 5 AE’s occurred. Pre-treatment tumor tissue is available for analysis from primary and metastatic sites from 93% and 54% of patients respectively. To date, 6 patients have donated post-progression tumor tissue. Gene status (FISH) for FGFR-1,-2,-3, PDGFβ and PDGFRβ is available for 20 primary and 17 metastatic specimens. Conclusions: Dovitinib has activity when administered in the 1st-line setting of mCCRCC with a tolerable safety profile at this dosing schedule. Correlation of this activity to relevant gene status in tumor samples from study patients will be presented. Clinical trial information: ACTRN12612000140853.
Impact on clinical prognosis using DNA methylation of the SLC16A3 promoter and expression of the human lactate transporter MCT4 in renal cancer.
Authors: Bedke Jens , Fisel Pascale , Winter Stefan , Kruck Stephan , Scharpf Marcus , Nies Anne , Fend Falko , Stenzl Arnulf , Schaeffeler Elke , Schwab Matthias
Published: February 2017

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Background: The monocarboxylate transporter 4 (MCT4) is a metabolic target in tumor biology because it mediates lactate transport across membranes resulting in antiapoptotic effects. Cell experiments support the importance of MCT4 in clear cell renal cell carcinoma (ccRCC). In this study, we assessed the prognostic potential of MCT4 expression in ccRCC and its epigenetic regulation by DNA methylation as novel predictive marker for patient outcome using independent ccRCC cohorts. Methods: MCT4 protein expression was quantified in 207 ccRCC and corresponding nontumor tissues. Data of an independent ccRCC cohort from The Cancer Genome Atlas (TCGA) were analyzed on MCT4 mRNA (n = 482) and DNA methylation (n = 283) level. The findings on MCT4 expression and DNA methylation in the SLC16A3 promoter were validated in a third cohort (n = 64). Promoter activity assays were conducted in four RCC cell lines. Results: MCT4 protein expression was upregulated (p < 0.0001) in ccRCC and showed significant association with cancer-related death. Upregulation of MCT4 mRNA expression (p < 0.00001) was confirmed in the TCGA cohort. Single CpG sites correlated inversely with mRNA expression and were associated with overall survival in Kaplan-Meier analyses [HR = 0.39; 95% confidence interval (CI), 0.24-0.64; P[log-rank] = 1.23e(-04)]. Promoter activity studies confirmed MCT4 regulation by DNA methylation. The significant correlation between MCT4 protein and gene expression or DNA methylation at single CpG sites was validated in a third cohort. Again, higher methylation at individual CpG sites was associated with prolonged survival [HR = 0.05; 95% CI, 0.01-0.40; P[log-rank] = 6.91e(-05)]. Conclusions: This study identified SLC16A3 promoter DNA methylation as a novel epigenetic mechanism for MCT4 regulation in ccRCC. First evidence of a biological rationale for prognosis and clinical outcome is supported by this specific SLC16A3 promoter DNA methylation.