bluuebunny/crossref_metadata_2025 huggingface dataset:
Examination of genomic copy number alterations in renal cell carcinoma with sarcomatoid features.
Authors: Ito Timothy , Pei Jianming , Dulaimi Essel , Menges Craig , Abbosh Philip , Chen David Y. T. , Greenberg Richard E. , Viterbo Rosalia , Kutikov Alexander , Smaldone Marc C. , Uzzo Robert G. , Testa Joseph R.
Published: February 2017

478

Background: Sarcomatoid differentiation is an uncommon histological finding in renal cell carcinoma (RCC) that may develop from any RCC subtype and is associated with a very poor prognosis. The identification of genetic alterations that drive this aggressive phenotype could aid in the development of more effective targeted therapies. In this study, we aimed to identify unique copy number alterations (CNAs) in patients with sarcomatoid RCC when compared to those with other RCC subtypes. Methods: Genomic copy number analysis was performed using single nucleotide polymorphism (SNP)-based microarrays on tissue extracted from the tumors of 80 patients (9 with sarcomatoid features (sRCC), 39 clear cell (ccRCC), 26 papillary (pRCC) and 6 chromophobe RCC (chRCC)) who underwent renal mass excision between 2010 - 2014. Statistical analysis was performed using Kaplan Meier (KM) survival analysis, t-tests and Fisher exact tests where appropriate. Results: sRCC tumors exhibited significantly higher numbers of CNAs when compared to ccRCC, pRCC and chRCC (mean 20.1 vs. 6.6 vs. 7.0 vs. 6.3, respectively; p <0.0001). The most common copy number losses occurred in chromosome arms 1p, 3p, 9q, 15q, 18q, 21q, and 22q, with losses of 9q (88%), 15q (77%), 18q (66%), and 22 (77%) being unique among sRCC tumors when compared to the other 3 histologies. The most common copy number gains were in chromosome arms 1q, 8q, 17q, and 20p/q, with 1q (55%) and 8q (66%) gains unique when compared to the other 3 histologies. Of the sRCC tumors, 3 arose from ccRCC, 2 from pRCC and 4 from unclassified RCC. sRCC was associated with worse survival compared to ccRCC, pRCC and chRCC on KM analysis (p=0.0006), and higher rates of lymph node positivity (77% vs. 3% vs. 12% vs. 0%, respectively; p<0.0001) and metastases (100% vs. 13% vs. 4% vs. 0%, respectively; p<0.0001) on presentation were observed with sRCC. Conclusions: Sarcomatoid differentiation in RCC is associated with a high rate of chromosomal changes with unique copy number alterations including losses of 9q, 15q, 18q and 22q and gains of 1q and 8q. Identification and validation of candidate driver genes or tumor suppressor loci within these chromosomal regions may help identify targets for future therapies.
Circulating cytokines and angiogenic factors (CAFs) in patients with advanced non-clear cell renal cell carcinoma treated with sunitinib: Results from a phase II clinical trial.
Authors: Bilen Mehmet Asim , Zurita Amado J. , Ilias-Khan Nasreen A. , Chen Hsiang-Chun , Wang Xuemei , Hodges Sherie , Lim Zita D. , Jonasch Eric , Khakoo Aarif Yusuf , Tannir Nizar M.
Published: February 2017

483

Background: Development of hypertension (HTN) during VEGF-directed therapies is associated with improved overall survival (OS) in patients (pts) with clear-cell renal cell carcinoma. There is paucity of data about the molecular determinants of response and survival outcomes in non-clear cell renal cell carcinoma (nccRCC) pts treated with targeted therapies. We investigated CAFs and correlated them and HTN with outcomes of nccRCC pts treated with sunitinib in a phase II trial. Methods: Using a bead-based multiplex assay (Luminex), levels of 30 CAFs (including mediators of inflammation, angiogenesis, immunity, and metastasis) were measured prior to start of sunitinib therapy (baseline) and at 4 weeks after completion of cycle 1. Sunitinib benefit was defined as having partial response (PR) or stable disease (SD) by RECIST lasting ≥4 months. Cox proportional hazards regression models were used to assess the association between CAFs, HTN, and survival outcomes. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and OS. Results: Fifty-seven pts [papillary (27), chromophobe (5), unclassified (8), collecting duct/medullary carcinoma (6), sarcomatoid (7), others (4)] were evaluable. Median follow up was 59.1 months (range, 30.6-82.6); 43 pts (75%) have died and 14 (25%) were alive at last follow up. Sunitinib benefit was seen in 21 pts (8 papillary, 4 chromophobe, 3 unclassified, 3 others, 2 collecting duct/medullary carcinoma, 1 sarcomatoid); 2 pts were not evaluable for response. Median PFS was 2.9 months (95% CI, 1.4-5.5) and median OS 16.8 months (95% CI, 10.7-27.4). 29 pts developed HTN during the first cycle, but there was no significant association between HTN and OS, PFS or sunitinib benefit. Elevated baseline levels of GRO, TGFα, sTNF-RI, sVEGF-R2 and IL-8 were correlated with higher risk of death. Conclusions: In this phase II trial in pts with advanced nccRCC, we found no significant association between HTN and PFS, OS, or sunitinib benefit. Candidate CAFs were identified that could be incorporated into prognostic and predictive models for validation in future studies in nccRCC.
Prognosis and outcome of patients with pancreatic metastases from renal cell carcinoma: When the site matters.
Authors: Grassi Paolo , Doucet Ludovic S. , Grünwald Viktor , Melichar Bohuslav , Galli Luca , De Giorgi Ugo , Guida Annalisa , Ortega Cinzia , Santoni Matteo , Bamias Aristotelis , Verzoni Elena , Iacovelli Roberto , Derosa Lisa , Studentova Hana , Pacifici Monica , De Braud Filippo G. , Escudier Bernard J. , Procopio Giuseppe
Published: February 2017

484

Background: Pancreatic metastases from renal cell carcinoma (PmRCC) are uncommon and their prognostic value in the era of targeted terapies (TTs) is not well defined. We evaluated the outcome of a cohort of PmRCC patients (pts) who were treated with either surgery and TTs. Methods: PmRCC pts treated between 1993 and 2014 were identified from the databases of 10 European centers. Clinical records were retrospectively reviewed and pts characteristics, including demographics and clinical outcome, were analyzed. Kaplan-Meier methods and log-rank test were used to evaluate progression-free survival (PFS) and overall survival (OS). Cox’s proportional hazard models were used for OS analysis. Results: A total of 232pts were evaluated. Median age was 61 years, sex ratio M/F was 147/85, and PmRCC were synchronous in 69 pts (30%). Pts treated with pancreatic surgery (including radiosurgery) were 67 (29%), while patients receiving systemic treatment were 210 (91%). Pts with only PmRCC were 23 (11%), whereas in the other 201 cases: lung (25%), lymphnodes (16%), and liver (13%) were the most common metastatic sites. The majority of pts (94%) received nephrectomy (Nx). Median time from Nx to PmRCC occurrence was 92 months (IQR 50-143). First-line TTs included: sunitinib (42%), sorafenib (12%), pazopanib (9%), interferon+bevacizumab (8%), and temsirolimus (1%), 30% of pts received cytokines and 65% of pts received subsequent lines of TTs. Best response to first-line treatment were complete response (5%), partial response (41%), and stable disease (36%) with a disease control rate (DCR) of 82% and a median PFS of 12 months (IQR 9-13). Median OS (calculated from the time of PmRCC occurrence to death) was 73 months (IQR 61-90) with a 5-yr OS of 59%. Median OS for pts treated with surgical resection was 114 months (IQR 90-204) with a 5-year OS of 81%. At univariate analysis only Motzer/Heng prognostic score were significantly associated with OS (p=0.006). Conclusions: PmRCC are associated with long-term survival, usually occur many years after Nx and seem to lead to a less aggressive disease. Surgery should be considered in oligometastatic disease as it can be associated with prolonged survival. TTs are active in these pts and achieve high DCR.
Adrenalectomy for malignant disease: Utilization and outcomes by surgeon specialty and surgical approach.
Authors: Faiena Izak , Tabakin Alexandra , Leow Jeffrey , Patel Neal , Modi Parth K , Salmasi Amirali H. , Chung Benjamin I. , Chang Steven L. , Singer Eric A.
Published: February 2017

489

Background: Adrenal cancers have traditionally been treated using an open surgical approach. With advances in minimally invasive surgery (MIS), adrenal tumors have become more amenable to MIS resection. We report a study on the utilization and outcomes of surgery for adrenal cancers on a national level. Methods: Data on patients who underwent open, laparoscopic, or robotic adrenalectomy for adrenal cancer (ICD-9 code 194.0) from 2003-2013 were extracted from the nationally representative Premier Hospital Database. Surgeon specialty, patient demographics, hospital characteristics, intraoperative and perioperative data, and complications were compared. Data were analyzed using univariate and multivariate logistic regression analyses. Results: 4,781 adrenalectomies were performed for malignant disease. Surgery was more commonly performed in patients >50 years of age (83%), men (64%), and white race (80%). There was no significant difference in rate of adrenalectomy with regards to comorbidities, insurance status, teaching vs. non-teaching hospital, hospital bed size, or geographic region. Adrenalectomy for malignant disease was more commonly performed by non-urologists (66 vs. 34%; p=0.011). Among non-urologists, open surgery was most common followed by laparoscopic and robotic approaches (56.3% vs. 37.4% vs. 6.4%, respectively) as compared to urologists (48.8% vs. 38.4% vs. 12.9%, respectively). There was no difference in complication rate or operative time between surgeon types. On multivariate regression analysis, the best predictor of major complication was a Charlson Comorbidity Index (CCI) >2 (OR 6.1, 95% CI 2.9-12.5; p<0.0001). Surgical approach and surgeon specialty were not predictors of complications. Conclusions: Adrenalectomy for malignant disease was more commonly performed by non-urologists via an open approach. Patient CCI >2 was associated with a higher rate of post-op complications, while surgical approach did not influence complication rate. These findings indicate that MIS can be performed safely for adrenal cancers. Prospective study of MIS for adrenal cancer is needed to evaluate its oncologic efficacy.
Effect of sunitinib treatment on mutations and methylation in metastatic renal cancer.
Authors: Stewart Grant , Van Neste Christophe , Meynert Alison , Semple Colin , O'Mahony Fiach , Laird Alexander , Mackay Alan , Trooskens Geert , Van Criekinge Wim , De Meyer Tim , Powles Thomas , Harrison David James
Published: February 2017

492

Background: The effect of VEGF targeted agents on DNA mutations and epigenetic expression in metastatic clear cell renal cancer (mccRCC) has not been reported. We hypothesise that significant DNA mutations and methylation changes occur with treatment which may be associated with resistance. Methods: DNA was extracted from sequential frozen pairs of primary tumour tissue from 14 mccRCC patients, in the SuMR clinical trial (NCT01024205), at presentation (biopsy) and after 3-cycles of sunitinib (nephrectomy). Multiple biopsies were taken to assess for heterogeneity. Biopsy and nephrectomy samples were compared in untreated tumours as controls. Array CGH, Ion Torrent sequencing (48 key ccRCC genes were assessed [Table]), and methylCap-seq DNA methylation analysis were performed. Results: aCGH hierarchical clustering showed that samples from 2/14 patients clustered together (13%). There were no significant increase in copy number variations (CNVs) following treatment with sunitinib. For somatic mutations of the 48 key genes, there were no patients in whom all samples clustered together. Conversely, at methylation level, all samples for each patient clustered. Mean frequency of mutations in the key genes relative to normal kidney was identical for biopsy and nephrectomy samples (n=14 mutations). 12/48 genes had CNVs or mutations in ≥2 patients following treatment with sunitinib (table). VHL was the only gene with significant difference in methylation pre- and post-sunitinib therapy (FDR=0.077; logFC=-0.8734, hypermethylated following sunitinib therapy); there was no difference in VHL methylation pre- and post-renal artery clamping. Conclusions: Intratumoral heterogeneity was not apparent in DNA methylation, unlike DNA. This may facilitate in biomarker research. The significant increase in VHL methylation following sunitinib gives insight into possible mechanisms of resistance at an epigenetic level. [Table: see text]
Hospital re-admission patterns and outcomes following major urologic cancer surgery.
Authors: Nayak Jasmir G. , Holt Sarah , Gore John L.
Published: February 2017

497

Background: Peri-operative morbidity and mortality varies considerably among hospitals. Given the highly complex surgery required for urologic cancer, post-operative adverse event management may be superior if treated in the same institution as the index surgery. Methods: We accessed the Washington State Comprehensive Hospital Abstract Reporting System from 2009-2013 to identified patients who underwent radical nephrectomy (RN), partial nephrectomy (PN), radical cystectomy (RC) or retroperitoneal lymph node dissection (RPLND) for malignant disease. Mortality rates were assessed in those with an adverse outcome requiring hospital re-admission within 90 days of surgery. The primary hospital (PH) was the institution where the main surgery took place. Secondary hospitals (SH) were all other hospitals. Relationships with mortality were examined using multi-variate modeling. Results: 4,542 patients were identified who underwent major urologic cancer surgery, of which 56% were RN, 26% PN, 15% RC and 2% RPLND. Overall, 795 (18%) experienced an adverse event following surgery requiring hospital admission. 64% of patients returned to their PH for management, but was dependent on the surgery performed (60% RN, 65% PN, 67% RC and 83% RPLND). When stratified by hospital volume, patients were more likely to present to their PH (p=0.0005), with more patients returning to their PH if it was a low vs. high volume center (72% vs 55%). Comorbidities and length of stay on index surgical admission did not affect whether patients chose to present to their PH or a SH for adverse event management. The overall mortality rate was 5%. On multi-variate analysis, patients who underwent surgery at a high-volume PH and presented to a SH for adverse event management had higher rates of mortality (p=0.03). Conclusions: Adverse events within 90 days of surgery of major urologic cancer surgery are associated with a low mortality rate, and most patients present to their PH for management. However, patients presenting to a SH experienced a higher mortality rate following an adverse event. These findings require further investigation and may aid in future quality improvement initiatives to reduce the morbidity associated with these complex surgeries.
Medical therapy for renal cell cancer with pancreatic metastases: Experience of the Gustave Roussy Institute.
Authors: Doucet Ludovic S. , Derosa Lisa , Albiges Laurence , Massard Christophe , Loriot Yohann , Fizazi Karim , Escudier Bernard J.
Published: February 2017

503

Background: The prognosis of renal cell carcinoma (RCC) patients with pancreatic metastases has been reported to be better amongst patients with metastatic disease in several series. However, the benefit of medical treatments, especially antiangiogenic (AA) therapy, is still poorly reported. Methods: We retrospectively reviewed clinical outcomes of RCC patients with pancreatic metastases treated with systemic treatments between 2000 and 2014. Results: Eighty-four patients (pts) were recorded, among which 24 underwent local treatment of pancreatic metastases (83% surgery). Clear cell histology accounts for 92%. At the initiation of systemic treatment, prognostic score according to IMDC was good, intermediate, or unknown in 36%, 50%, and 13% respectively. Median overall survival (OS) was 83,2 months (mo) (55.6-29.4). Median OS was 127 mo (106.6-not reached [NR]) for patients who underwent a local treatment on the pancreas vs. 56.5 (39.8-NR) for those who did not (p=0.04). Cytokines used as first-line systemic therapy (n=27, 52% interleukin-2-based, 22% good prognostic group, 59% intermediate, 19% unknown) yielded an overall response rate (ORR) of 26%, a median treatment duration of 5.4 months (mo) (4.7-5.9) and a time to treatment failure (TTF) of 14.5 mo (12-32.2). Patients who received AA (n=77, previous cytokines 25%) showed, for the first use of AA, an ORR of 61%, with a median treatment duration of 11.5 mo (9-14.7) and a TTF of 18.2 mo (12.4-25.8). OS from the time of first systemic therapy was 107 mo (63.8-140.4) in patients who received AA vs. 30 mo (5.4-NR) in those who did not (p=3.10-5). Conclusions: This study confirms the more favorable prognosis of patients with pancreatic metastases from RCC. ORR to both cytokines and AA is higher than that observed in a general population of patients with metastatic RCC. The molecular basis for this observed better outcome deserves further investigation.
Phase II clinical trial of low-dose interleukin-2, interferon-alpha, and low-dose tegafur uracil therapy for advanced renal cell cancer.
Authors: Kato Tomoyuki , Iwamura Masatsugu , Fujita Tetsuo , Saito Seiichi , Ohshiro Yoshinori , Imai Tomoyuki , Kawata Nozomu , Tomita Yoshihiko , Sejima Takehiro , Kishida Takeshi , Tochigi Tatsuo , Kawamura Sadafumi
Published: February 2017

508

Background: The objective of this trial was to evaluate the efficacy and safety of immunochemotherapy with very low-dose interleukin-2, interferon-alpha and tegafur uracil (IAT therapy) in treatment naïve metastatic renal cell carcinoma (RCC) patients with pulmonary metastasis only. Methods: Previously untreated metastatic renal cell cancer patients only with pulmonary metastasis were enrolled in this multicenter, open-label, single arm, phase II trial. Eligibility criteria included ECOG performance status (PS) 0-2, low or intermediate risk per MSKCC score, and adequate organ function. The primary endpoint was the overall response rate (ORR) per RECIST v1.1. Secondary endpoints were time to progression (TTP), response duration, overall survival (OS), ECOGPS and safety. Safety was assessed by CTCAE, v4.0. Low dose (0.7-2.1 MIU/ day) IL-2 was administered intravenously in the first five days of the first and third week. IFN-alpha (500 MIU/day) was administered 3 times per week in week 2. From 4th to 7th weeks, patients received IFN- alpha 3 times per week and 100 mg tegafur uracil t.i.d. Results: Twenty-eight eligible patients were enrolled from Apr 2009 through Dec 2013. Twenty-one patients were evaluable for ORR. Three patients had partial response (PR) 11 stable disease (SD), and 7 progressive disease (PD). ORR was 14.4% and median duration of PR was 18.0 months. TTP and OS were not reached to median and 3-year OS rate was 76.3%. Twenty-seven patients (96.4%) had an ECOGPS of 0 and 1 (3.6%) had PS of 1. Three patients experienced exacerbation in PS (PS 0 to 1). The most common adverse events (AEs) were elevation of ALT (35.7%) and fever (32.1%). AEs grade 3 included rash (14.3%), depression (3.2%), syncope (3.2%), fever (3.2%), elevation of ALT (3.2%). Four patients discontinued therapy at the time of ORR analysis due to AEs (3 rash, 1 depression). Conclusions: IAT therapy for RCC patients with only pulmonary metastasis is safe and appears to have clinical benefit as reflected by ORR rate and long OS. Clinical trial information: 00002222.
How reliable is a negative MRI/TRUS fusion biopsy? The predictive value of targeted biopsy for prostate cancer.
Authors: Fascelli Michele , Sussman Rachael , Frye Thomas P , George Arvin Koruthu , Abboud Steven , Chelluri Raju , Ho Richard , Brown Anna Mary , Sankineni Sandeep , Merino Maria J , Turkbey Baris , Choyke Peter L. , Wood Bradford J. , Pinto Peter A.
Published: February 2017

51

Background: Multiparametric MRI (mpMRI) has been shown to improve clinically significant prostate cancer (CaP) detection. Targeted biopsy using MRI/transrectal ultrasonography (TRUS) fusion is a novel diagnostic tool. The negative predictive value (NPV) of an MRI/TRUS fusion targeted biopsy of a suspicious lesion on mpMRI was determined. Methods: 30 of 181 men who underwent prostatectomy from 2008-2014 were retrospectively identified and had at least one lesion on mpMRI negative for cancer on MRI/TRUS fusion biopsy. Whole mount pathology specimens, gold standard for CaP detection, were aligned with MRI to assess true histopathology of all identified targets. Lesions negative for CaP on biopsy and not identified as cancer on pathology were considered true negatives (TN). Lesions biopsied negative but later found to possess foci of CaP on whole mount were considered false negatives (FN). Calculations of NPV were then made per biopsy year, MRI suspicion score, and lesion size on MRI. Results: 48 lesions of a total 81 identified on mpMRI were reported negative for CaP in the 30 patients who underwent fusion biopsy. Of these, 37 lesions were found to be truly negative on histopathology, while 11 lesions had CaP foci on whole mount specimen. Overall NPV was 77% (37/48). The NPV increased over time (Table 1), and was as high as 85.7% most recently. Conclusions: This series demonstrated a NPV of 77% for targeted MRI/TRUS fusion biopsy of lesions seen on mpMRI. The increasing NPV trend noted over time may have further applications to assess the learning curve for this diagnostic method. Not surprisingly, NPV is higher for low and moderately suspicious lesions than for highly suspicious lesions. This data may help physicians interpret the clinical implications of a negative fusion biopsy. [Table: see text]
Inferior vena cava thrombus recurrence after radical nephrectomy in renal cell carcinoma.
Authors: Kauffmann Caroline , Pfister David A. , Porres Daniel , Heidenreich Axel
Published: February 2017

511

Background: Local recurrence after radical nephrectomy in renal cell carcinoma occurs in about 2-4% of the patients. An isolated intracaval thrombus is described in only very few cases. We report about our experience in the diagnosis and theapy of this random entity. Methods: 5 patients (2f, 3m) were referred to our institution with the diagnosis of an IVC thrombus recurrence. All patients had underwent a radical nephrectomy 1-9 years before the relapse. In 3 patients, the thrombus was diagnosed within the routine follow up, another 2 presented with swelling/deep vein thrombosis. The staging showed no other metastases. Results: The mean patient age at time of diagnosis was 73.8 (70-81) years. 2 patients presented with a level II thrombus, 2 with level III and one with a level IV thrombus. We could resect the thrombus completely in 4 cases and close the cava with a running suture. In one case we had to resect the inferior vena cava completely and replace it with a gortex prosthesis. The mean blood loss was 1.7 (0-8) liters at an operating time of 5.5 (4.3-7.6) hours. The mean follow up was 3.5 (0.5-8) years, until today occured one case of pulmonal metastatic disease. Significant perioperative complications classified after Clavien-Dindo occured in one case with an intraoperative bleeding and rupture oft he spleen that required a mass-transfusion. Conclusions: Although it is a technical demanding procedure, the surgical resection of a recurrent vena cava thrombus is the method of choice with only a little perioperative morbidity and high oncological effectivity. This random type of recurrent disease illustrates the importance of an adequate primary therapy as well as a regularly follow up after cava-involvement.
Performance of CCP assay in an updated series of biopsy samples obtained from commercial testing.
Authors: Crawford E. David , Shore Neal , Scardino Peter T. , Davis John W. , Tward Jonathan D. , Harrison Lowndes , Evans Brent , Fitzgerald Lisa , Stone Steven , Brawer Michael K.
Published: February 2017

64

Background: The cell cycle progression (CCP) score is an RNA-based expression assay which has improved the prediction of prostate cancer aggressiveness in nine separate retrospective cohorts. In this analysis, we characterized the patient population and CCP score performance in commercial testing. Methods: Formalin-fixed prostate biopsy samples from 4,261 patients were submitted by 930 physicians to Myriad Genetic Laboratories for CCP test analysis. Patient clinicopathologic data was obtained from the test request form. The CCP score was calculated based on RNA expression of 31 cell cycle progression genes normalized to 15 housekeeping genes. Patients were sorted in to AUA risk categories and assigned a relative classification of cancer aggressiveness based on the CCP score. Results: Of the 4,261 samples that contained sufficient carcinoma (>0.5mm linear extent), 4,218 (99.0%) provided quality RNA for analysis. The CCP score distribution ranged from -2.9 to 3.4. Correlation with Gleason score was r=0.35 and the correlation with PSA was r=0.16. Based on the CCP score, 36.8% of men had a less aggressive cancer and 21.2% of patients had a more aggressive cancer than expected based on clinicopathologic prediction. Conclusions: The CCP test can improve risk stratification for men with prostate adenocarcinoma independent of other clinicopathologic variables. Fifty-eight percent of men tested in the commercial assay were assigned to a different risk category than predicted by their clinicopathologic features.
Biochemical failure after treatment for localized prostate cancer: Does original therapeutic modality affect long-term survival?
Authors: Reichard Chad A. , Kovac Evan , Ciezki Jay P. , Tendulkar Rahul D. , Klein Eric A. , Stephenson Andrew J.
Published: February 2017

65

Background: Mortality among men with biochemical failure (BF) after treatment is variable. We examined the long-term survival of men with BF to determine if differences exist, depending on original treatment modality. Methods: Between 1995 and 2008, 6,084 patients underwent treatment for clinically localized prostate cancer at our institution (4,276 underwent radical prostatectomy (RP); 1,808 underwent EBRT). Clinical information and follow up data was obtained from prospectively maintained databases. Survival was assessed using log rank test. Results: 526 (12%) patients had BF defined by PSA > 0.4 after RP. 326 (18%) patients had BF after EBRT, defined as PSA nadir +2. 197 (60%) of EBRT patients received ADT as neoadjuvant/concurrent/adjuvant therapy. Median overall survival was 154 months (95%CI 148-157) versus 129 months (95%CI 123-135) for RP and EBRT respectively (p<.0001). Median prostate cancer specific survival was 125 months (95%CI 93-148) versus 107 months (95%CI 92-123) for RP and EBRT respectively (p=0.17). There was no difference in prostate cancer specific survival between treatments among patients in D’Amico intermediate and high risk groups. Conclusions: In patients with biochemical recurrence after definitive treatment, patients treated with RP have improved overall survival compared to patients treated with EBRT. However, there is no difference among treatment groups in prostate cancer specific survival.
Effect of neoadjuvant systemic therapy prior to radical prostatectomy in high-risk prostate cancer on surgical morbidity: Contemporary results utilizing the Clavien System.
Authors: Williams Stephen Bentley , Davis John W. , Achim Mary F. , Zurita Amado J. , Matin Surena F. , Pisters Louis L. , Ward John Francis , Pettaway Curtis Alvin , Chapin Brian Francis
Published: February 2017

66

Background: There is limited evidence definingthe morbidity of radical prostatectomy (RP) with curative intent for patients with high risk prostate cancer. Multimodality treatment for men with high risk prostate cancer using neoadjuvant systemic therapy followed by surgery is being increasingly explored. Methods: We analyzed 215 consecutive patients with high risk and very high risk prostate cancer who underwent robotic or open RP with extended pelvic lymph node dissection previously untreated or received neoadjuvant systemic therapy between 2006 and 2010 at a single tertiary care academic center. Univariable and multivariable logistic regression analyses were used to identify predictors of complications. Results: Baseline characteristics were similar between patients who underwent neoadjuvant systemic therapy followed by RP versus RP alone except for PSA (PSA< or equal to 4 ng/ml: 75.4% vs. 15.5%, p<0.001) and preoperative hemoglobin (13.8 g/dl vs. 14.4 g/dl, p=0.003), respectively. Twenty nine percent of patients (63 of 215 patients) experienced a complication of any grade ≤90 d after surgery 6% experienced Grade ≥3, with no significant difference between either cohort (p=0.50). On multivariate analysis, estimated blood loss [Odds Ratio (OR) 1.10; 95% CI, 1.0 to 1.2, p=0.03), length of stay (OR 1.75; 95% CI, 1.3 to 2.4, p=0.001) and preoperative hemoglobin (OR 0.71; 95% CI, 0.53 to 0.94, p=0.02) were independent predictors of the occurrence of any grade complication. Considering grade 3 or 4 complications, procedure time (OR 2.20; 95% CI 1.0 to 4.8, p=0.05) and estimated blood loss (OR 1.39; 95% CI, 0.98 to 1.96, p=0.06) were significant predictors of major complications. Conclusions: Postoperative morbidity in patients with high risk prostate cancer following RP with or without the use of neoadjuvant systemic therapy is comparable to contemporary RP series of low to intermediate risk disease reporting outcomes in a similar fashion. Use of neoadjuvant systemic therapy prior to RP was safe and did not appear to increase the risk of having a perioperative complication.
Association between a 17-gene genomic prostate score and multiparametric prostate MRI in men with low- and intermediate-risk prostate cancer (PCa).
Authors: Leapman Michael S. , Westphalen Antonio C. , Ameli Niloufar , Lawrence H. Jeffrey , Febbo Phillip G. , Cooperberg Matthew R. , Carroll Peter
Published: February 2017

83

Background: A biopsy-based RT-PCR assay (Oncotype DX Prostate Assay) providing a Genomic Prostate Score (GPS) as a measure of tumor aggressiveness and multi-parametric prostate MRI (mpMRI) are clinically utilized predictors of adverse pathology at prostatectomy. These tests have not been directly compared and it remains to be determined whether they provide independent information. Methods: We evaluated the association between GPS results (scale 0-100) and baseline endorectal mpMRI in men with clinically localized PCa. MR studies were reviewed to a five-tier scale of increasing suspicion of malignancy. Mean apparent diffusion coefficient (ADC) was calculated from a single dominant lesion. Mean rank of the GPS (0-100) and GPS-predicted likelihood of favorable pathology among MRI strata were compared with the Kruskal-Wallis test. Regression analysis was performed between mean ADC and scaled GPS within CAPRA risk groups. Results: Of 332 patients who received GPS testing at a single institution, 94 were identified with low (n=59) and intermediate (n=35) CAPRA risk prostate cancer who received mpMRI within a two-year interval of prostate biopsy. A broad distribution of GPS was observed across categories defined by mpMRI criteria. Among intermediate risk patients both GPS and the GPS-predicted likelihood of favorable pathology were associated with MR score (p=0.01 and p<0.01, respectively). For low risk patients, neither GPS nor likelihood of favorable pathology were significantly different across MR findings (p=0.12 and p=0.21, respectively). Mean ADC was not significantly associated with GPS or likelihood of favorable pathology for either low (p=0.24) or intermediate (p=0.91) risk categories. Conclusions: While a broad distribution of GPS was observed across mpMRI criteria, increasing GPS was associated with highly suspicious MRI findings in men with intermediate risk PCa. No significant associations were observed between MRI categories and either GPS or likelihood of adverse pathology in low risk patients.
Evaluation of early clinical experience of a novel prognostic proteomics prostate cancer biopsy test.
Authors: Choudhury Sibgat , Trock Bruce J. , Benson Skone Rene , Nardone Julie , Dunyak James , Shipitsin Michail , Epstein Jonathan I
Published: February 2017

88

Background: Standard clinical and pathological parameters derived from diagnostic biopsy are insufficient to accurately assess final prostate tumor pathology of patients with biopsy Gleason grades 3+3 or 3+4. We developed a novel assay (ProMark) that performs quantitative measurements of 8 protein markers from prostate biopsy FFPE sections. In the validation study, assay risk scores were strongly predictive of final prostate tumor pathology with a C-stat of 0.69 (95%CI = 0.63 – 0.76) (p<0.0001). By design, the train-test (N=381) and validation (N=274) studies were enrichment studies, with a higher % of aggressive disease than in the intended use population. Here we study 293 needle biopsy cases that have come to our CLIA lab for ProMark testing over a four month period. The objective of this study is to establish the ProMark score distribution for these ‘real world’ clinical use patients, and to confirm that this distribution matches our clinical validation study. Methods: To establish prevalence of aggressive disease in the intended use population, we used the Institutional Urology Prostate Cancer Database at Johns Hopkins. Among 9,305 men with biopsy Gleason 3+3 or 3+4 and prostatectomy from 2004-2014 the distribution of favorable (GS<4+3 & organ confined) and unfavorable (GS≥4+3 or non-organ confined) based on surgical pathology is 73.1% vs. 26.9%. The adjusted risk score distribution from the validation trial (N=274) is then compared to the CLIA lab samples (N=293), based on cumulative distributions and binomial confidence intervals. Results: Comparison of the risk score distribution of early clinical data with the population-adjusted validation score distribution shows good agreement based on 95% CIs. Table shows expected and measured frequencies in Low, Intermediate and High risk categories. The K-S test for comparison of distributions has p-value=0.44, supporting equivalence of distribution. Conclusions: The results of our study show that early clinical practice closely matches expectations from controlled clinical studies. [Table: see text]
Association of ERG-PTEN expression profile of prostate biopsy with PSA velocity.
Authors: Algotar Amit , Cress Anne , Nagle Ray , Sokoloff Mitchell , Singh Parminder , Behnejad Roxanna , Stratton Steven
Published: February 2017

92

Background: Although ERG and PTEN expression has demonstrated to have a role in prostate carcinogenesis, its association with important clinical markers such as PSA velocity (rate of prostate specific antigen [PSA] change over time) is currently unknown. This novel pilot study presents the results of the above association with the aim of understanding its clinical utility. Methods: Data for this study was obtained from men enrolled in a phase 2 clinical trial conducted to determine the effect of selenium supplementation on prostate cancer progression. All men in this trial were diagnosed with prostate cancer and opted for watchful waiting as their treatment modality. Biopsy tissue collected at randomization was stained for ERG and PTEN using immunohistochemistry techniques. PSA was measured at baseline and at each follow-up visit (every three months). PSA velocity was calculated using mixed effects regression models and the study group was divided into three tertiles. Results: Data from 77 subjects indicates ERG and PTEN expression is independently associated with lower PSA velocity (p = 0.02 and 0.037 respectively). Joint effect of ERG and PTEN expression on PSA velocity was also analyzed using logistic regression. As compared to the wild type (ERG+/PTEN-), ERG-/PTEN- and ERG-/PTEN+ subjects demonstrated increased risk for high PSA velocity. Odds ratios (95% confidence intervals) are: 4.05 (0.68, 24.1) and 1.71 (0.12, 23.1), respectively. These models were adjusted for age, race and Gleason score. Conclusions: This is the first study to report on an association between ERG-PTEN expression and PSA velocity, an important clinical marker of aggressive prostate cancer. Results of this study are counterintuitive to the current understanding of ERG-PTEN mechanism in prostate carcinogenesis indicating presence of yet undiscovered molecular pathways. Hence further research is needed to delineate these pathways and determine clinical utility of ERG and PTEN expression in prostate cancer.
The effect of connexin 36 deletion on chemotherapy-induced peripheral neuropathy (CIPN).
Authors: Sterman Adam , Hanstein Regina , Spray David C.
Published: February 2017

1

Background: CIPN is a debilitating side effect and dose limiting toxicity of many chemotherapeutic agents. CIPN induces pathological changes in dorsal root ganglia (DRG), leading to increased cross-talk among the glia that surround sensory neurons (Satellite Glial Cells, SGC’s) and between sensory neurons and their adjacent SGCs via gap junctions. Since Connexin 36 (Cx36) is the main neuronal gap junction protein, we investigated CIPN in mice with deletion of Cx36. Methods: To induce CIPN, mice were given two i.p. oxaliplatin (oxa) injections 2 days apart. Controls received saline (sal). We used transgenic mice, which were either heterozygous for Cx36 or complete Cx36 knockouts (Cx36 Het or Cx36 KO), and littermate controls (Cx36 wildtype), 6-14 per group. Tactile sensitivity of the hindpaws was assessed prior to and every week after injections for 4 weeks using von Frey filaments. The number of paw withdrawals to 10 stimulations with each filament and pain thresholds (corresponding to filament that elicits 8/10 responses) were recorded. Results: Oxa-injected wildtype mice had higher response rates to filaments compared to sal-injected controls (p < 0.05), and lower tactile thresholds (at 9 days: sal 6.0±0.0g vs. oxa 1.9±0.5g, p < 0.0001), indicating hypersensitivity. Compared with wildtype, mice lacking Cx36 (Cx36 KO) displayed significantly less tactile hypersensitivity after oxa (tactile threshold at 9 days: WT 1.9±0.5g vs. KO 4.0±0.4g, p < 0.01), whereas oxa induced tactile hypersensitivity occurred in a similar fashion in Cx36 Het mice (tactile threshold at 9 days: WT 1.9±0.5g vs. Het 1.5±0.1g). At 9 days, there were fewer responses to filaments in oxa-injected Cx36 KO mice compared to oxa-injected wildtype mice (p < 0.05), but not in oxa-injected Cx36 Het mice. Conclusions: We found that oxaliplatin induces transient CIPN, represented by tactile hypersensitivity, in wildtype mice. Deletion of the gap junction protein Cx36, as displayed in the Cx36 KO mice, resulted in significantly less CIPN. This is the first report that a neuronal gap junction protein may modulate pain sensitivity, and points to a new molecule (Cx36) as a potential novel target for CIPN therapy.
Recovery of cancer patients' social lives upon referral to palliative care units.
Authors: Terui Takeshi , Hirayama Yasuo , Machino Takayuki , Kusakabe Toshiro , Nakamura Kenji , Mihara Hiroyoshi , Itoh Satoko , Ishitani Kunihiko
Published: February 2017

107

Background: Our hospital is a cancer-specific facility that treats patients from diagnosis to terminal care. We evaluate the possibility of effective cancer chemotherapies for patients referred to our palliative care unit from other hospitals through case conferences in our institution. Even the patients referred to the palliative care unit of our institution are sometimes assessed as “very likely to be improved by standard or semi-standard treatment” by the palliative care and oncologic teams in our institution. We surveyed inappropriate cases that were mistakenly assessed as indicated for terminal care in their previous hospital. Methods: We reviewed 1535 patients referred to our palliative care unit from other hospitals because of anticancer chemotherapy contraindications over a 3-year period. We determined the number of the patients who were thought to actually have indications for cancer chemotherapy. Results: During the case conferences, 31 (2.0%) of the 1535 patients were thought to have indications for cancer chemotherapies. Standard chemotherapies were administered in our hospital to 6 patients. Four of the 6 patients were alive at one year and recovered their social life. Conclusions: Prudent assessment using updated guidelines are needed at the time of patient referral of a hospice. Ethical problems clearly exist with patients who were mistakenly assessed as indicated for terminal care in their previous hospital. There remains room for discussion of whether it is an ethical problem to overturn the will of a patient having chosen best supportive care (including those for whom it was presented as the only option by previous doctors or those who made positively the choice themselves) and proceed with cancer treatment.
Psychosocial distress in vulnerable patient populations: What happens after screening?
Authors: Cimino Theora , Albert Margot , Safier Leslie , Harris Heather A. , Kinderman Anne
Published: February 2017

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Background: The Commission on Cancer mandates psychosocial distress screening for patients with cancer, as well as documentation of referrals made to address sources of distress. Patients in safety net settings, who are vulnerable to significant economic and social stressors, may benefit from such screening; however, it is unclear if patients can access needed services and if their needs change over time. We examined the experience of cancer patients in an urban safety-net healthcare system to identify areas of improvement in the provision of support services. Methods: We performed a retrospective cohort analysis of patients screened for psychosocial distress during 2015. We reviewed medical records from initial oncology visits for results of screening and referrals made at that time. Those who reported a distress score of ≥ 4 were eligible for telephone follow up, which occurred 1-12 months after initial screening. Patients who agreed to participate completed a telephone survey that assessed current distress and referral status. Results: Of 113 patients who completed a psychosocial distress screen, 60% (n=68) reported a distress score of ≥ 4 and were called for follow up. Of these 68 patients, 17 (25%) had died or enrolled in hospice, 16 (25%) could not be reached after 3 attempts, 7 (10%) had transferred care, and 1 declined to participate. 26 patients (38%) completed telephone follow up. Patients reported an average distress score of 3.8, compared to 6.2 at their first visit. While “worry” was the most commonly reported problem at baseline, “pain” was the most common problem at follow up. For these 26 patients, a total of 69 referrals were made at their first visit, 59% of which were not accessed. 58% of the reasons given for not accessing referrals cited factors other than lack of interest, including requiring more information, not hearing back from the organization, and transportation issues. Conclusions: Significant barriers, such as difficulty with referrals and follow up, may interfere with providing care to a diverse, underserved population of patients who report high levels of distress at their first oncology visits. Alternative approaches, including primary or specialty palliative care, may be needed in this population.
Referral patterns and characteristics of uninsured versus insured patients referred to the outpatient supportive care center (SCC) at a comprehensive cancer center.
Authors: Azhar Ahsan , Yennu Sriram , Ramu Aashraya , Zhang Haibo , Haider Ali , Williams Janet L. , Bruera Eduardo
Published: February 2017

116

Background: Multiple barriers exist in providing quality palliative care to low-income patients with cancer. Such disparities may negatively influence effective management of symptoms including pain. Our objective was to compare referral patterns and characteristics (level of symptom distress) of uninsured vs insured patients. Methods: We reviewed randomly selected charts of 100 Indigent (IND) and 100 Medicaid (MC) patients and compared them with a random sample of 300 patients with insurance (INS) referred during the same time period (1/2010 to 12/2014) to our SCC. Data was collected for date of registration at the cancer center, diagnosis of Advanced Cancer (ACD), first visit to the SCC (PC1), symptom assessment (Edmonton Symptom Assessment Scale-ESAS) at PC1. We excluded self-pay patients. Results: Results for IND, MC and INS (n = 481) respectively are as follows: Mean (SD) Age in yrs. was 50 (12), 48 (11) and 63 (13); p < 0.001. Percentage of non-white was 44%, 51% and 19.5%; p < 0.001. Percentage of unmarried patients was 64%, 68% and 33%; p < 0.001. Mean (SD) ESAS score at PC1 for pain was 5.6 (3.2), 6.7 (2.5), 4.9 (3.2); p < 0.001. Percentage of patients on opioids upon referral was 86%, 62%, and 54%; p < 0.001. Mean (SD) for referral time in months from ACD to PC1 was 8.7 (SD 10.4), 12.3 (SD 18.1) and 12 (SD 19.9) p = 0.31; for no. of encounters with SC per month were 0.46 (0.45), 0.41 (0.46) and 0.3 (0.55); p = 0.01; for survival in months (PC1 to last contact) was 6.4 (5.8), 5.6 (6.4) & 6 (7.22) p = 0.77. Conclusions: Uninsured patients had significantly higher levels of pain, were more frequently on opioids, younger, non-white and not married. They also required a larger number of SCC encounters. Insurance status did not impact timing of SCC referral or SCC follow ups at our cancer center.
Palliative care consultation and advance care planning for adults with poor-risk leukemia admitted to an academic medical center.
Authors: Freeman Ashley , Wood William A , Fox Alexandra , Hanson Laura C.
Published: February 2017

13

Background: Despite high mortality for certain patients with hematologic malignancies, integration of palliative care (PC) and documentation of advance care planning (ACP) is lacking. Our primary objective was to determine the frequency of PC consultation and ACP for inpatients with poor-risk leukemia at our institution. Our secondary objectives were to describe the content of goals of care (GOC) discussions and to characterize PC and end-of-life quality measures. Methods: Chart reviews were conducted for patients with poor risk leukemia (acute leukemia ≥ 65 years or relapsed leukemia > 18 years) admitted to the University of North Carolina from October 1, 2015 to March 31, 2016. The following was abstracted from the chart: demographic data, disease characteristics, presence of a PC consultation, frequency and content of ACP (written advance directive, documented GOC discussion, identified surrogate decision maker), PC quality measures (assessment of pain, dyspnea, nausea, constipation), and end-of-life quality measures (chemotherapy within 14 days of death, ICU stay within 30 days of death, hospice referral less than 3 days prior to death). Results: Thirty-eight subjects were identified. Fifty percent of patients were over age 65 with a new diagnosis of acute leukemia and 50% had relapsed leukemia. The majority of patients (66%) reported pain and 45% reported dyspnea on admission. Sixteen percent of patients died within 30 days of discharge. Eleven percent of patients received PC consultation and 16% had all elements of ACP documented in the chart. GOC discussions without a surrogate decision maker were documented for 37%; content included discussion of values (11%), prognosis (37%), treatment choices (21%), life sustaining preferences (16%), and hospice (21%). Conclusions: In this descriptive study of inpatients with poor-risk leukemia, we found that despite a poor prognosis and high symptom burden, only 11% of patients received PC consultation and 16% had all elements of ACP present in the chart. While our data are limited by documentation, we believe this represents missed opportunities for the delivery of high-quality care.