bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between high microRNA-200C expression and the risk of death from disease in muscle-invasive urothelial carcinoma of the bladder.
Authors: Navai Neema , Williams Michael Brandon , Wen Sijin , Siefker-Radtke Arlene O. , McConkey David James , Dinney Colin P.N. , Adam Liana
Published: February 2017

279

Background: Bladder cancer represents both a common and highly morbid disease with limited tools for prognostication. Recently molecular studies have led to promising targets to inform disease behavior, including microRNAs (miRNA). miRNAs are non-coding RNAs, with widespread effects on cellular function. Our group has demonstrated that the miR200 family members play an integral role in epithelial to mesenchymal transition (EMT) via an inverse relationship with ZEB1 and a direct relationship with E-cadherin. EMT is seen as a necessary step for invasion and metastasis, however, studies have indicated a significant role for mesenchymal to epithelial transition (MET) to drive proliferation after cells have reached metastatic locations. Members of the miR200 family have been shown to induce MET and we hypothesize that miR200c, as a surrogate marker for MET, and will predict disease survival in muscle invasive urothelial carcinoma (MIUC).

Methods: A clinically diverse sample set was obtained consisting of 101 unique specimens upon which real-time PCR miRNA analysis was performed. Regression tree analysis and best-fit modeling was used to establish the most discriminating relative miR200c expression level to predict disease specific survival. Fisher exact test was carried out to compare clinical variables, Kaplan-Meier estimate of survival distribution based on miR200c expression and univariate log-rank test was used to compare survival distributions between groups. Multivariate analysis was done via the proportional hazards model. A p-value of <0.05 was considered significant for all statistical analyses.

Results: Patients with high miRNA200c had significantly more deaths (69 vs. 47%). In multivariable analysis of patients with MIUC miR200c expression was associated with the highest risk of death (RR 2.7). Lymph node involvement (RR 2.0) and age > 65yrs (RR 2.4) were also strong predictors of survival. High miR200c had lower median survival for all patients (59 vs 16 months; p = 0.039) and those with MIUC (41 vs 8 months; p = 0.0004).

Conclusions: High miR200c expression is associated with a higher risk of death from bladder cancer in patients with muscle invasive disease.
Bladder cancer patterns of pelvic failure: Implications for adjuvant radiation therapy.
Authors: Baumann Brian Christopher , Guzzo Thomas J. , He Jiwei , Vaughn David J. , Keefe Stephen Michael , Vapiwala Neha , Deville Curtiland , Bekelman Justin E. , Tucker Kai , Hwang Wei-Ting , Malkowicz S. Bruce , Christodouleas John Paul
Published: February 2017

293

Background: Local-regional recurrences (LF) after radical cystectomy with or without chemotherapy are common in patients with locally advanced disease. Adjuvant radiation (RT) could reduce LF, but toxicity discouraged its use. Modern RT with reduced morbidity has rekindled interest but requires knowledge of pelvic failure patterns to design appropriate clinical target volumes.

Methods: 5-yr LF rates after radical cystectomy plus pelvic lymph node dissection with or without chemotherapy were determined for 8 pelvic sites among 442 patients with urothelial carcinoma of the bladder. The impact on the pattern of failure of pathologic stage, margin status, nodal involvement, and extent of node dissection was assessed using competing risk statistical methods. The percentage of patients whose sites of LF would be completely encompassed within various hypothetical clinical target volumes for post-operative radiation were calculated.

Results: Stage pT3-4 patients had higher 5-yr LF rates in virtually all pelvic sites compared to pT0-2 patients. Among pT3-4 patients, margin status significantly altered the pattern of failure while extent of node dissection and pathologic nodal involvement did not. Stage pT3-4 patients with negative margins failed predominantly in the iliac/obturator nodes. Failures in the cystectomy bed and presacral region were significantly higher in pT3-4 patients with positive rather than negative margins. 76% of pT3-4 patients with negative margins who failed would have had all sites of LF included within clinical target volumes encompassing the iliac/obturator nodes, but only 57% of pT3-4 patients with positive margins would have their LF sites covered by such target volumes. Including the cystectomy bed and presacral region in the clinical target volume when margins were positive increased the percentage of encompassed failures to 91%.

Conclusions: In adjuvant RT protocols, the obturator and iliac regions should be targeted in pT3-4 tumors with negative margins; coverage of presacral region and cystectomy bed is advised for pT3-4 with positive margins.
Neoadjuvant chemotherapy for muscle-invasive bladder cancer at the University of Southern California.
Authors: Fairey Adrian Stuart , Daneshmand Siamak , Dorff Tanya B. , Dorin Ryan Paul , Leiskovsky Gary , Quinn David I. , Schuckman Anne , Cai Jie , Miranda Gus , Skinner Eila C.
Published: February 2017

301

Background: There is a paucity of data on neoadjuvant GC (gemcitabine, cisplatin) chemotherapy in patients with muscle-invasive bladder cancer (MIBC). Our aim was to compare pathologic and survival outcomes of neoadjuvant GC and M-VAC (methotrexate, vinblastine, doxorubicin, cisplatin) chemotherapy in patients with MIBC.

Methods: A retrospective analysis of prospectively collected data from the University of Southern California (USC) Bladder Cancer Database was performed. Between 1985 and 2011, 116 patients received neoadjuvant chemotherapy prior to radical cystectomy and extended pelvic lymph node dissection for clinical stage T2-T4N0M0 bladder cancer. The outcomes were pathologic complete response (pT0N0), pathologic tumor downstaging (pT0N0, pTaN0, pT1N0, or pTisN0), overall survival (OS), and recurrence-free survival (RFS). The Kaplan-Meier method and Cox proportional regression models were used to analyze survival data.

Results: The median follow-up duration was 4.5 years (range, 0 to 19.8 years). Fifty-eight patients each received GC and M-VAC chemotherapy. There were no statistically significant differences between the GC and M-VAC groups with regard to pathologic complete response (27.3% versus 17.1%, p=0.419) or pathologic tumor downstaging (45.5% versus 37.1%, p=0.498). The predicted 5-year OS (29% versus 38%, Log rank p=0.634) and RFS (36% versus 35%, Log-rank p=0.891) rates did not differ between the GC and M-VAC groups. However, in a subset of 37 patients with pathologic lymph node positive disease, the predicted 1-year RFS rate differed between the GC and M-VAC groups (0% versus 32%, log rank p=0.019). Multivariable analysis showed a trend toward an independent association between type of neoadjuvant chemotherapy and RFS (GC versus M-VAC: HR 1.64, 95% CI 0.93 to 2.89, p=0.089).

Conclusions: Pathologic complete response, pathologic tumor downstaging, and survival did not differ in patients who received neoadjuvant GC and M-VAC chemotherapy. However, GC was associated with poorer RFS in a subset of patients with pathologic lymph node positive disease. Randomized controlled trials comparing neoadjuvant chemotherapy regimens are urgently needed.
Preliminary results of perioperative outcomes and oncologic efficacy from a single-institution randomized controlled trial of open versus robotic-assisted radical cystectomy.
Authors: Messer Jamie Christopher , Fitzgerald John Patrick , Ercole Barbara , Svatek Robert Scott , Parekh Dipen J.
Published: February 2017

305

Background: In the past decade minimally invasive robotic assisted approaches have emerged as a viable option for the treatment of many urologic malignancies. Robotic-assisted radical cystectomy (RARC) for bladder cancer has been reported with the potential for lower blood loss, less transfusion requirement, and shorter hospital stay in prior studies. We present preliminary data from a single institution prospective randomized clinical trial of open radical cystectomy (ORC) versus RARC.

Methods: Prospective randomized single institution series evaluating the feasibility of ORC versus RARC for consecutive patients was performed from July 2009 to June 2011. Oncologic efficacy was assessed based on the surrogates of total number of lymph nodes removed and positive surgical margins. Perioperative morbidity was assessed evaluating for estimated blood loss, transfusion requirements, length of stay and perioperative morbidity.

Results: To date 46 patients have been randomized with data available on 39 patients for analysis. Each group was similar with regards to age, sex, race, BMI, comorbidities, and previous abdominal procedures, operative time, and final pathologic stage. We observed no significant difference between oncologic outcomes of positive surgical margins (5% vs 5.263%, p 0.48) or number of LN removed (11 vs 23, p 0.40) for the RARC versus ORC groups respectively. The RARC group was noted to have decreased estimated blood loss (400 mL vs 800 mL, p 0.008) and a trend towards decreased rate of excessive length of stay (>5 days) (65% vs 84%, p 0.17) for the RARC versus ORC groups. The robotic group had a trend towards decreased rate of transfusion however this was not statistically significant (40% versus 53%, p 0.26).

Conclusions: Our preliminary findings from a single institution randomized trial of RARC versus ORC indicates that RARC has equivalent oncologic outcomes as measured by positive surgical margins and total number of lymph node removed. RARC demonstrates Perioperative benefits of decreased blood loss, fewer excessive hospital stays, and a trend toward fewer transfusions that was not significant.
Intravesical (IVe) valrubicin for treatment of carcinoma in situ (CIS) of the bladder: Use in clinical practice.
Authors: Cookson Michael S. , Lihou Christine Francis , Harper Samira Q. , Lang Zhihui
Published: February 2017

317

Background: IVe valrubicin is indicated for bacillus Calmette-Guérin (BCG)-refractory CIS when cystectomy is not an option. An ongoing retrospective clinical-practice chart review is being conducted to examine use of valrubicin since its reintroduction (Oct 2009).

Methods: Records were analyzed for adults with non-muscle invasive bladder cancer (NMIBC) treated with valrubicin.

Results: In this ongoing study, 62 patients received valrubicin (date range; 10/7/2009-6/10/2011). Most were male (52, 84%) and white (49, 79%); median age was 79 y (range, 49–89). 49 patients (79%) had a history of CIS + papillary tumors, 8 had CIS (13%), 4 had papillary (7%), 1 had NMIBC unspecified (1%). 57 patients (92%) received prior IVe therapy (median [range], 2 [0–11] courses); 13 patients (21%) received 1 course, 16 (26%) 2 courses, and 28 (45%) ≥3 courses. Immunotherapy (eg, BCG, unspecified) was the most common prior treatment (54 patients, 87%; median [range], 2 [0–7] courses); 17 patients (27%) received 1 course, 15 (24%) 2 courses, and 22 (35%) ≥3 courses. Prior IVe chemotherapy was less common (21 patients, 34%). 47 patients (76%) had ≥1 transurethral resection of the bladder tumor (median [range], 2 [0–9] for n=62 patients). Fewer had undergone ≥1 fulguration procedures (27, 44%). Most valrubicin courses (49/67, 73%) used the recommended 6 instillations (median [range], 6 [2–7]). Retention time (median [range], 120 [0–180] min) was recorded for 89/381 instillations (23%). Adverse events (AEs) were observed for 31 patients (50%); most AEs (102/106, 96%) were mild or moderate. 3 patients (5%) had serious AEs (treatment-relationship unknown). Median followup for all patients was 5.2 mo (range, 0–13.9). 13 patients (21%) underwent cystectomy at a median of 5.3 mo (range, 1-13) from the last valrubicin dose. 2 patients died, at 1.1 (metastatic disease) and 11.9 mo after finishing valrubicin.

Conclusions: Patients treated with valrubicin in clinical practice often had concomitant papillary tumors and were heavily pretreated. One in 8 patients had no record of previous immunotherapy. Drug administration adhered closely to labeled instructions and was well tolerated. Funding: Endo Pharmaceuticals.
Paclitaxel-based high-dose chemotherapy (HDCT) for relapsed or refractory germ cell tumors (GCTs): Clinical outcome and quality of life (QOL) in long-term survivors.
Authors: Pal Sumanta Kumar , Sun Virginia , Carmichael Courtney , Ferrell Betty R. , Frankel Paul Henry , Margolin Kim Allyson
Published: February 2017

325

Background: HDCT is a viable and potentially curative approach for patients with relapsed or refractory GCTs. However, no comparative data exist to define the optimal chemotherapeutic strategy. Herein, long-term follow-up data and QOL assessments are provided for an expanded cohort of patients treated with high-dose paclitaxel, etoposide, carboplatin, and ifosfamide (TECTIC).

Methods: Details of the TECTIC regimen and clinical follow-up data for an initial 33 patients have been previously reported (Margolin Biol Blood Marrow Trans 2005). Surviving patients were surveyed using a modified EORTC Quality of Life Questionnaire-30 (QLQ-C30) and the Functional Assessment of Cancer Therapy-Taxane (FACT-T) questionnaire; results were compared to relevant historical cohorts using a 2-sample t-test. Cardiovascular morbidity (CM) was ascertained through queries regarding use of antihypertensive (AH) or cholesterol-lowering (CL) agents, and presence/absence of diabetes mellitus (DM).

Results: Forty-six patients received protocol-based therapy. Of these, 17 patients were progression-free at a median of 112.7 mos (49.5-170.2), and 6 patients remain alive following progression with a median overall survival (OS) of 64.4 mos (43.6-147.1). Median progression-free survival (PFS) and OS were 11.8 mos (95%CI 5.8-NR) and 21.7 months (95%CI 12.7-NR), respectively. Of the 23 patients still alive, 18 patients were accessible and consented to telephonic interview. As compared to historical cohorts (Rossen J Clin Oncol 2009), survivors had a higher global health scale score (87.04 v 75.62; P=0.02) but a lower physical functioning score (68.89 v 92.66; P=0.0001) by the QLQ-C30 scale. No difference in FACT-T scores were observed as compared to historical cohorts (Cella Cancer 2003). Four patients (22%) had DM. Three patients (17%) and 4 patients (22%) reported use of AH and CL agents, respectively.

Conclusions: HDCT with the TECTIC regimen produces durable remissions in patients with relapsed or refractory GCTs, with acceptable QOL and CM in long-term survivors.
Long-term outcomes of radiotherapy for stage II testicular seminoma: The Mayo Clinic experience.
Authors: Hallemeier Christopher Leigh , Pisansky Thomas Michael , Davis Brian , Choo Richard
Published: February 2017

327

Background: To report long-term outcomes of patients (pts) treated with radiotherapy (RT) for stage II testicular seminoma.

Methods: Between 1974 and 2007, 52 pts received RT for clinical stage II testicular seminoma after radical inguinal orchiectomy; 3 pts were excluded due to no clinical follow-up. CT staging was used for 46 pts (94%). Estimates of overall (OS), relapse-free (RFS), and cause-specific (CSS) survival were determined using the Kaplan-Meier technique. Major cardiac event (MCE) was defined as myocardial infarction, coronary artery bypass grafting or stenting, or valve replacement. Second malignancy (SM) was defined as biopsy-confirmed malignancy occurring in the RT field.

Results: The median pt age was 35 years. AJCC stage was IIA (n=23), IIB (n=7), IIC (n=15), and unknown (n=4). Three pts were treated for paraortic recurrence during surveillance for stage I seminoma. Four pts with IIB (n=1) or IIC (n=3) disease were treated with chemotherapy in addition to RT. The median total RT dose was 30.4 Gy. Prophylactic mediastinal/supraclavicular (MSCV) RT was given to 24 pts (49%). The median follow-up was 18 years (range 0.4-37). Estimates of OS, RFS, and CSS at 10 and 20 years were 94% and 81%, 79% and 70%, and 96% and 96%, respectively. OS, RFS, and CSS were not significantly different between stage groups. Recurrence occurred in 9 pts (18%); sites were MSCV (n=6), para-aortic (n=1), lung (n=1), and peritoneal cavity (n=1). Seven pts were successfully salvaged, while 2 pts died of seminoma. No patient with stage IIA/B that received prophylactic MSCV RT (n=11) experienced MSCV relapse. Among patients that did not receive prophylactic MSCV RT, 2 of 13 (15%) with stage IIA and 3 of 6 (50%) with stage IIB experienced MSCV relapse. MCE occurred in 10 pts (20%) at a median of 18 years (range 7-30) after RT. SM occurred in 5 pts (10%) at a median of 27 years (range 20-34) after RT.

Conclusions: Infradiaphragmatic RT alone was associated with a significant risk of MSCV failure, particularly in patients with stage IIB disease, suggesting that chemotherapy may be the optimal treatment in this patient cohort. Most MCE and SM events occurred more than 20 years after RT, highlighting the importance of vigilant long-term follow-up.
Genetic variants in antioxidant genes, Gleason grade, and prostate cancer recurrence after radical prostatectomy.
Authors: Richman Erin L , Weinberg Vivian K. , Sosa Eduardo V , Song Xiaoling , Carroll Peter , Witte John S , Chan June M.
Published: February 2017

33

Background: Laboratory and genomic data suggest that the antioxidant defense system is important in prostate carcinogenesis, and that this relation may vary by plasma antioxidant status.

Methods: Among 567 radical prostatectomy (RP) patients with non-metastatic prostate cancer (CaP), we examined genetic variants in SOD1(5 SNPs), SOD2(6), SOD3(6), TXRND1(5), TXRND2(21), GPX1(3), GPX3(8), GPX4(5), CAT(9), XRCC1(2), SELENBP1(5), SEP15(4), SEPP1(4), SEC14L2(8), and TTPA(4) and risk of high pathologic Gleason sum (8+ or 7 with primary 4+) using logistic regression, and CaP recurrence (PSA rise, second treatment, metastasis) using Cox proportional hazards regression. We also examined whether the genetic variants interacted with plasma selenium, alpha-tocopherol, or gamma-tocopherol in relation to risk of high grade CaP.

Results: 21% (n = 117) of men had high grade CaP, and 47 recurrences occurred (median follow-up of all participants = 3 y). Men with 1+ of the less common allele (CT or TT) in rs4880 (SOD2) had a 49% reduced rate of recurrence (hazard ratio (HR): 0.51; 95% confidence interval (CI): 0.28, 0.92), independent of grade, stage, and PSA. In contrast, men with 1+ of the less common allele in 3 of the TXRND1, 4 of the TXRND2, and 1 of the SEP15 SNPs had 2-fold increased rate of recurrence (HRs: 1.93-2.95; p-values: 0.002-0.04), and men with 2 of the less common allele in 2 of the GPX3 SNPs had 3-fold increased rate of recurrence (p-values from additive models: <0.01). For high grade CaP, men with 1+ of the less common allele in 1 of the SOD3 SNPs or 2 of the less common alleles in 2 of the TXRND2 SNPs had 2-fold increased risk (p-values = 0.007-0.02), while men with 1+ of the less common allele in 1 of the GPX1 SNPs had 37% reduced risk (p-value = 0.04). Among men with certain genotypes in 3 TXRND2, 1 GPX3, or 2 CAT SNPs, high plasma selenium reduced risk of high grade CaP by 50-76%. Among men with certain genotypes in 1 SOD1 or 1 SOD2 SNP, high plasma alpha-tocopherol reduced risk of high grade CaP by 65-68%.

Conclusions: Genetic variants in antioxidant genes may be associated with CaP recurrence after RP, and may interact with plasma selenium and alpha-tocopherol in relation to risk of high grade CaP.
Adjuvant surgery in patients with testicular cancer undergoing post-chemotherapy retroperitoneal lymph node dissection.
Authors: Djaladat Hooman , Nichols Craig R. , Daneshmand Siamak
Published: February 2017

335

Background: Up to 50% of patients who undergo induction chemotherapy for metastatic germ cell cancer have significant residual retroperitoneal disease in whom post chemotherapy RPLND is indicated with intent to cure. Since complete resection is a critical component in PC-RPLND, meticulous dissection of the retroperitoneum with resection of involved organs or structures (adjuvant surgery) should be considered whenever feasible to ensure optimal outcome.

Methods: From 2004 to 2010, 85 testicular cancer patients underwent PC-RPLND by a single surgeon (SD). A bilateral template approach was utilized with nerve sparing technique whenever feasible. The clinico-pathologic and outcome of patients who underwent adjuvant surgery during PC-RPLND were reviewed.

Results: Of 85 patients undergoing PC-RPLND, 28 (33%) required adjuvant procedures. Thirteen (15%) required vascular procedures including cavotomy/ caval resection in six, aortic resection in eight, common iliac vessels resection in four and renal vessels resection/reimplant in two. Twelve patients (14%) required adjuvant nephrectomy (10/12 left sided). There was 1 ureteral resection with appendiceal substitution, 1 partial duodenectomy, 2 cholecystectomy, 2 thoracotomies, 4 liver resection/ biopsy, and 1 neck dissection. There were 8 early complications (28%) including vocal cord paralysis, brachial plexus injury, lower extremities compartment syndrome, thigh numbness, UGI bleeding, retroperitoneal hematoma and alcohol withdrawal. No peri-operative death was reported. Retroperitoneal pathology revealed mature teratoma in 11 (39%), fibrosis in 8 (28%) and viable germ cell tumor (GCT) in 9 (32%) patients. 75%, 82% and 66% of patients with fibrosis, teratoma and viable GCT had no evidence of recurrence in mean follow up of 18 months.

Conclusions: A significant number of patients undergoing PC-RPLND require adjuvant surgery including vascular procedures and nephrectomy. The excellent outcomes associated with low operative morbidity/mortality validate such aggressive surgical approaches performed by experienced surgeons.
Changes in body fat and lipid metabolism in testicular cancer patients undergoing curative chemotherapy.
Authors: Willemse Peter-Paul Michiel , van der Meer Rutger W. , van Elderen Saskia , Burggraaf Jacobus , Lamb Hildo J , de Roos Albert , Osanto Susanne
Published: February 2017

337

Background: Testicular cancer (TC) survivors are at increased risk to develop metabolic syndrome and cardiovascular disease. We assessed the utility of proton magnetic resonance spectroscopy (H1-MRS) and aortic Pulse Wave Velocity (aoPWV) with MRI to detect the early effects of chemotherapy-induced changes in lipid metabolism on liver fat storage and vascular function in testicular cancer patients undergoing curative treatment.

Methods: Nineteen 19 chemo-naïve TC patients (age 20–54 years) were studied before, shortly after (<3 months), and 9 months after the start of three or four cycles of cisplatin-based chemotherapy. At each visit, fasting blood samples for serum glucose, insulin, HbA1c, and lipids were collected, and abdominal subcutaneous (scFat) and visceral fat (visFat) volume, hepatic triglyceride content (HTgC), and aoPWV were assessed by MRI. All measurements were performed using validated methodology. Data were analysed using RM-ANOVA.

Results: Shorty after cessation of chemotherapy there was an increase in fasting serum insulin (5.7±4.4 vs. 9.6±6.3; p=0.05), HOMA-index (1.3± 0.3 vs. 2.3± 0.4; p=0.006), HbA1c (5.2±0.3 vs. 5.3±0.6; p=0.03), total cholesterol (4.88±1.31 vs. 5.61±1.50; p=0.002) and LDL-cholesterol (3.31±1.16 vs. 3.73±1.41; p=0.02). This coincided with relative volume increases of scFAT (6.9%; 95%CI 0.4–13.4%) and visFAT (18.7%; 95%CI 2.4–35.1%), a unsignificant increase in HTgC (47.4%; 95%CI −5.4–129.5%). AoPWV did not change (0.2%; 95%CI −0.5–0.8%). All parameters that were increased at 3 months returned to baseline at 9 months, but the increases in scFAT and visFAT remained.

Conclusions: Cisplatinum-based chemotherapy in TC patients is associated with disturbances of glucose and lipid metabolism shortly after therapy but returns to baseline later. These changes did not translate into significant increases in HTgC and aoPWV, suggesting that these measures are of limited value to detect early chemotherapy-induced changes. Interestingly, scFAT and visFAT showed sustained increases, and this may explain the observed higher incidence in metabolic syndrome and (ensuing) cardiovascular disease in chemotherapy-treated TC patients.
Salvage treatment for metastatic penile cancer after first-line chemotherapy with paclitaxel, ifosfamide, and cisplatin: Analysis of response and survival outcomes.
Authors: Wang Jennifer , Pettaway Curtis A. , Pagliaro Lance C.
Published: February 2017

340

Background: There are few effective salvage treatment options for men with advanced metastatic penile cancer. Patients who remain disease-free for 2 years after surgical removal of regional lymph node metastases are likely cured of the disease, but the survival is short for those who recur. Our objective was to estimate the efficacy of salvage treatments for metastatic penile cancer after neoadjuvant paclitaxel, ifosfamide, and cisplatin.

Methods: Patients are from a 30-patient cohort who we saw between April 2000 and September 2008 presenting with stage TxN2-3M0 squamous cell carcinoma of the penis. All were treated with 1 to 4 courses of neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy prior to planned lymphadenectomy. For the patients who had progression or recurrence of disease, we retrospectively evaluated the salvage therapies given, response data, and survival times from the date of first progression.

Results: Nineteen of the 30 patients (63.3%) had tumor progression and 17 received one or more salvage therapies. Median age at diagnosis was 57 years (range 24-72 years). The median survival from time of first progression was 5.8 months (range 3.7 to 30.9 months). Two of five patients (40%) who had received bleomycin, methotrexate, and cisplatin experienced an objective response (1 complete and 1 partial), and one (20%) developed pneumonitis. Two patients had received gemcitabine combinations without response. Two patients had received epidermal growth factor receptor-targeted therapy with gefitinib or cetuximab and cisplatin, both without response. Three patients had received chemo-radiotherapy, one with stable disease for 13.5 months and 2 with no apparent benefit. Five patients underwent salvage surgery, and they all progressed within 2 months with one case of fatal hemorrhage.

Conclusions: Men with metastatic penile cancer that progresses through or recurs after front-line neoadjuvant chemotherapy have poor responses to the described salvage treatments, and median overall survival is less than 6 months. Emphasis should be placed on clinical trials for development of effective therapy in this setting.
Combination of paclitaxel, cisplatin, and gemcitabine (TPG) as third- to fourth-line therapy for male germ cell tumors (GCT).
Authors: Necchi Andrea , Nicolai Nicola , Giannatempo Patrizia , Raggi Daniele , Napoli Giuseppa , Catanzaro Mario , Biasoni Davide , Torelli Tullio , Milani Angelo , Stagni Silvia , Piva Luigi , De Braud Filippo G. , Gianni Alessandro M. , Salvioni Roberto
Published: February 2017

341

Background: Rescue of patients (pts) who fail to be cured following 2–3 chemotherapy (CT) combinations ± high dose CT (HDCT) or who are cisplatin-refractory is still an unmet need. The identification of novel active agents/combinations is a priority.

Methods: We reviewed the characteristics of consecutive pts who received TPG combination at our Institution for relapse/progression after 2 or 3 previous platinum-based CT lines. Treatment consisted of the administration of paclitaxel 80 mg/m2 IV, cisplatin 50 mg/m2 IV and gemcitabine 800 mg/m2 IV on days 1 and 8 q3w. Program provided up to 8 administrations of TPG followed by surgery of all resectable masses. Paraffin slides of all cases with residual viable cancer after TPG were retrieved: CD30 staining and somatic mutation analysis by Sequenom OncoCarta Panel v.1.0 were planned.

Results: From 04/1999 to 07/2011, 74 pts have been treated with TPG, 64 in 3rd and 10 pts in 4th line. Median age was 32 (20–55), median number of prior CDDP cycles was 7 (4–10), 10 pts (13%) had already received HDCT, 4 pts had primary mediastinal GCT, 42 (57%) were CDDP-refractory/abs refractory, 25 pts (34%) had either liver, bone or brain metastases before TPG. 40% developed G3-4 hematologic and 2 pts G3 renal toxicity, none of them being dose-limiting. No treatment delays have been observed. Median number of administrations was 7 (1–10). 8 complete responses (CR), 28 partial responses with normal markers (PRm-) and 13 incomplete response/stable disease have been recorded, for a major response rate (CR+PRm-) of 49%. 34 pts (46%) underwent post-CT surgery which was radical in 15 cases (44%) and led to 7 pathologic CR. 3-, 6- and 12-month PFS was 68% (95% CI 55–76%), 31% (21–42) and 20% (12–30), respectively. 1-yr PFS after HDCT only was 24% (4–53). 12- and 24-month OS was 46% (34–57) and 26% (16–37), respectively. Median PFS and OS were 5 (1–104) and 12 mos (1–116).

Conclusions: TPG combination rates first among salvage therapies for refractory GCT, even after failure of HDCT. Benchmark survival endpoints for trials on new agents/combinations have been set. Results of the biomarker analysis will be available in Feb 2012 and may help to corroborate a window of opportunity for targeted agents in GCT.
A prospective randomized phase II trial evaluating maintenance GM-CSF in an intermittent chemotherapy (chemo) regimen for metastatic castration-resistant prostate cancer (mCRPC): A DoD prostate cancer clinical trials consortium trial.
Authors: Small Eric Jay , Weinberg Vivian K. , Ryan Charles J. , Higano Celestia S. , Lin Amy Mimi , Maruca Yvonne , Alumkal Joshi J. , Yu Evan Y. , Rosenberg Jonathan E. , Beer Tomasz M.
Published: February 2017

35

Background: The optimal number of cycles of docetaxel for patients (pts) with mCRPC is not known, and in practice, treatment breaks are common. The current study was designed to test the safety and efficacy of utilizing 6 cycles of standard docetaxel with chemo free intervals in patients who achieve and maintain a response to docetaxel.

Methods: Pts with mCRPC, no prior chemo, and KPS > 60% were eligible. Pts were treated with “induction” docetaxel 75 mg/m2 q 3 weeks, and prednisone 5 mg po bid. PSAWG1 criteria were used to define response and progression. After 6 cycles, responding pts stopped chemo and were randomized to observation (Obs) or to GM-CSF, 250 mcg/m2 daily for 14 days out of every 28-day cycle. Pts were followed with monthly PSA and imaging every 2 cycles until progression, at which point docetaxel was reinitiated for another 6 cycles, followed by the same “off chemo” regimen. The primary endpoint was the time to progression while on chemo (time to chemo resistance).

Results: 114 pts have been enrolled: 3 are undergoing induction, and 111 are therefore evaluable. Of these pts, 82 completed induction, (10 did not due to PD, 9 due to adverse events (AE), 10 due to pt or MD choice). Of 111 evaluable pts, 48 (43%) had a response to chemo and were eligible for randomization. 22 were randomized to Obs and 26 to GM-CSF. Of 48 randomized pts, 25 restarted chemo, all for PSA PD. (23 pts did not re-start chemo because of AE, other therapy being started, or pt choice; 1 pt is still on GM-CSF.) 6/25 (24%) pts experienced a response to the 2nd series of chemo, and 1/6 (17%) to the 3rd. The time to chemo re-initiation (n=25) was 3.1 mos in Obs pts and 4.2 mos in GM-CSF pts.

Conclusions: 43% of patients met criteria for undergoing intermittent chemo. The response proportion to the 1st, 2nd, and 3rd series of docetaxel was 43%, 24% and 17%, respectively. GM-CSF may modestly delay the time to chemo re-initiation, but the sample size is small and insufficient to assess the impact of GM-CSF on time to chemo resistance.
A multicentered population-based analysis of outcomes of patients with metastatic renal cell carcinoma (mRCC) who do not meet eligibility criteria for clinical trials.
Authors: Heng Daniel Yick Chin , Choueiri Toni K. , Lee Jae-Lyun , Harshman Lauren Christine , Bjarnason Georg A. , Knox Jennifer J. , MacKenzie Mary J. , Vaishampayan Ulka N. , Tan Min-Han , Rha Sun Young , Donskov Frede , Agarwal Neeraj , Kollmannsberger Christian K. , North Scott A. , Rini Brian I. , Wood Lori ,   International mRCC Database Consortium
Published: February 2017

353

Background: Clinical trials have strict eligibility criteria to maintain internal validity. These criteria exclude many patients to whom the trial results are later applied to in clinical practice. Patients that do not meet eligibility criteria are poorly characterized.

Methods: mRCC patients treated with VEGF targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky Performance Status (KPS) < 70%, brain metastases, non-clear cell histology, hemoglobin ≤ 9 g/dL, creatinine > 2x the upper limit of normal, platelet count of < 100x103/uL, neutrophil count < 1500/mm3 or corrected calcium ≤ 12 mg/dL.

Results: 894/2076 (43%) patients were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression free survival (PFS) and median overall survival of first-line targeted therapy were 21% vs 29%, 5.2 vs 8.8 months and 14.5 vs 28.8 months (all p < 0.0001), respectively. Second-line PFS (if applicable) was 3.2 months in the trial ineligible vs 4.4 months in the trial eligible patients (p = 0.0074). When adjusted by the Heng et al prognostic categories, the hazard ratio for death between trial ineligible vs trial eligible patients was 1.621 (95% CI = 1.431–1.836, p < 0.0001). If only KPS, brain metastases and non-clear cell histology were used as exclusion criteria, 672 (32%) patients were excluded and the results were similar.

Conclusions: The number of patients that are ineligible for clinical trials is high and their outcomes are inferior. Designing more inclusive clinical trials for this “ineligible” patient population are needed.

[Table: see text]
Evolving trends in non-clear cell renal cell cancer (RCC) epidemiology: A large registry analysis of 4,483 patients.
Authors: Pai Ashok P. , Brown Monica , Pan Chong-xian , Lara Primo
Published: February 2017

374

Background: Non-clear cell (ncc) RCC is uncommon but includes a heterogeneous group of histologic subtypes such as papillary, chromophobe (Chr), medullary (Med), and collecting duct (CD) cancers. We used a large cancer registry to define nccRCC clinical features and outcomes, identify prognostic variables, and to generate hypotheses for further study.

Methods: Invasive RCC tumors in the California Cancer Registry from 1998–2009 among adults > 18 years of age (n=38,251) were analyzed. Baseline clinical and tumor variables were collected. Primary outcome measures were 3-year cause-specific (CSS) and overall survival (OS). Uni- and multivariate survival analysis were used to identify predictors of CSS and OS.

Results: Of 38,251 RCC cases, 19,149 (50%) were of clear cell type; 14,619 (38.2%) were “unclassified”. Thus, 4,483 (11.7%) nccRCC cases were identified and included in this analysis. Of these, 3304 (73.7%) were diagnosed in 2004–09, suggesting a shift to more precise coding of histologic subtypes starting in the early 2000s. Histology distribution (n, %): papillary − 2,863 (63.9%); Chr − 1,507 (33.6%); and other including Med and CD − 113 (2.5%). Variables associated with significantly better OS and CSS (univariate analysis) were Chr histology, female sex, and higher socioeconomic status (SES). Significantly worse OS and CSS were seen in Med+CD, age > 65 yrs, no nephrectomy (Nx), and higher stage. Non-hispanic blacks had significantly worse OS and CSS, while the “targeted therapy era” (2004–2009) was associated with better OS. Multivariate analysis showed the following to be independently associated with outcomes (all p <0.001; Hazard Ratios [HR] shown for CSS and OS): Chr histology (0.48, 0.56), Med+CD histology (2.99, 2.42), no Nx (2.84, 3.18), regional stage (5.84, 1.98), distant stage (25.7, 7.67); and non-hispanic blacks (1.5,2 p=0.006; 1.25, p=0.03). Age > 65 yrs (HR 1.78, p<0.001) and high SES (HR 0.88, p=0.001) were associated with OS but not CSS.

Conclusions: This is among the largest registry analyses of nccRCC ever performed, showing emerging trends in this uncommon RCC subset. Clinical variables associated with CSS and OS were identified that can inform the design of future clinical trials in nccRCC.
Cytoreductive radical nephrectomy (cRN) and level II-IV infereior vena cava (IVC) thrombectomy for metastatic renal cell carcinoma (mRCC).
Authors: Klink Joseph C. , Westesson Karin E. , Rini Brian I. , Rabets John C. , Campbell Steven C. , Ghoneim Islam , Stephenson Andrew J. , Krishnamurthi Venkatesh
Published: February 2017

382

Background: cRN for mRCC is associated with a modest improvement in survival when combined with cytokine therapy in patients with good performance status. A level II-IV IVC thrombus renders cRN technically challenging with increased risks of perioperative morbidity and mortality. The outcome of these patients relative to the overall cRN population is poorly defined.

Methods: Clinical information and follow-up data were obtained from an institutional retrospective data base for patients who underwent cRN and IVC thrombectomy between 1990–2011.The operative outcomes, complications, and cancer outcomes were compared.

Results: cRN was performed on 56 patients with mRCC and level II (N =19), III (N =25) or IV (N =12) IVC thrombus. Age ranged from 23 to 84 years old and 36 (64%) were male. Predominant sites of metastases were: lung, 22 (39%); liver 3 (5%); mediastinum 3 (5%); multiple sites 17 (30%). Local clinical stage was T3a in 2 (3.6%), T3b in 38 (68%), T3c in 12 (21%), and T4 in 4 (7%). Twenty (36%) patients were clinical N1. Median tumor size was 10.2 cm (range, 1.4–21). Histologic classification was clear cell in 40 (71%), papillary in 4 (7%), and unclassified in 12 (21%). Intraoperatively, 2 patients had embolization of thrombus. Postoperatively, Clavien grade 3–5 complications occurred in 3 (5%) patients, including two (3.6%) mortalities. Follow-up information was available for 49 patients and the median follow-up was 13 months (IQR: 6–33). Of these patients, 31 (63%) received postoperative systemic therapy with cytokines (14), targeted agents (16), or both (1). The overall median survival was 13 months (95% CI: 10–16), and was similar before (median 12 months) and after (median 13 months) the introduction of targeted therapy.

Conclusions: Among patients with mRCC with level II–IV IVC thrombus managed at a high-volume kidney center, cRN and IVC thrombectomy is associated with acceptable perioperative morbidity and mortality. The median survival of patients in our cohort is similar to the overall population of patients managed with cRN and cytokine therapy though less than those managed with cRN and targeted therapy based on data from published randomized trials.
Nodal disease in the setting of metastatic renal cell carcionoma: Can a lymph node dissection alter outcomes?
Authors: Chapin Brian Francis , Delacroix Scott Edward , Kenney Patrick Aloysius , Nogueras Gonzalez Graciela M , Tamboli Pheroze , Jonasch Eric , Tannir Nizar M. , Wood Christopher G.
Published: February 2017

386

Background: The impact of lymph node dissection (LND) in patients with metastatic renal cell carcinoma (mRCC) undergoing cytoreductive nephrectomy (CN) is unclear. The aims of this study were to determine the predictive ability of LN status for overall survival (OS) in patients treated with CN in the targeted therapy era and if LND increases the morbidity of CN.

Methods: We performed a retrospective review of all patients with mRCC treated with CN at a single institution between 2004–2010. Patients participating in open or unpublished trials were excluded, leaving 173 patients for analysis. LNs >1cm by long axis diameter were considered clinically positive (cN+). OS was calculated using COX proportional hazard regression. Complications were classified using the modified Clavien system.

Results: Sixty-five (37.6%) patients were clinically node positive (cN+). Median OS was significantly worse for the cN+ patients compared to cN0 patients [17.5 vs 29.1 mos;HR 1.8;(1.3-2.6)]. Clinical node status remained an independent predictor of OS on multivarible analysis (MV) [HR 1.7;CI 1.1-2.7]. LND was performed in 61/65 (93.4%) cN+ patients and in 56/108 (52%) of cN0 patients. Pathologic node positive disease (pN+) was more common in cN+ compared to cN0 patients (75% vs. 23%,p <0.001). pN+ patients had worse median OS than pN0 patients [16.0 v 35.5 mos;HR 2.3(1.5-3.6)]. Among pN+ patients (n=54), complete resection of all identifiable nodal disease was associated with an improved OS compared to patients with unresectable nodal disease (n=4) [16.0 v 5.6 mos;HR 2.9(1.0-8.3)]. On univariate analysis LND patients were more likely to have a post-operative complication (64% vs 43%,p=0.008) and more specifically chylous ascites (12 v 0,p=0.01). Despite this association, LND did not reach statistical significance when MV analysis was performed [OR 1.9;(0.9-3.8)].

Conclusions: Among patients undergoing CN, those with cN+ disease had worse OS. Likewise, pN+ patients have worse OS than pN0 patients. LND is associated with higher morbidity than CN alone. Further efforts are needed to determine removal of pathologic nodes alters the natural history of the disease, and if the benefit offsets the increased morbidity.
A population-based overview of sequences of targeted therapy in metastatic renal cell carcinoma (mRCC).
Authors: Heng Daniel Yick Chin , Lee Jae-Lyun , Harshman Lauren Christine , Bjarnason Georg A. , Razak Albiruni R , MacKenzie Mary J. , Wood Lori , Vaishampayan Ulka N. , Tan Min-Han , Rha Sun Young , Donskov Frede , Agarwal Neeraj , Kollmannsberger Christian K. , North Scott A. , Rini Brian I. , Choueiri Toni K. ,   International mRCC Database Consortium
Published: February 2017

387

Background: There are several types of targeted therapy (TT) available to treat mRCC and data on outcomes and different sequences of therapies are required.

Methods: Consecutive series of patients with mRCC treated with TT were examined. Multivariable analysis was performed when significant differences on univariable analysis were seen.

Results: 2106 patients were included with a median follow-up of 36 months. 907 (43%) and 318 (15%) patients received subsequent second-line and third-line TT, respectively. Baseline characteristics of the groups below were not different except there were more patients with non-clear cell histology in the VEGF to mTOR group compared to the VEGF to VEGF group. When adjusting for the Heng et al poor risk criteria and non-clear cell histology, the hazard ratio of death for the VEGF to mTOR group vs the VEGF to VEGF group was 0.833 (95%CI 0.669-1.037, p=0.1016). When adjusting for poor risk criteria, the hazard ratio of death for the sunitinib to everolimus vs sunitinib to temsirolimus sequences was 0.774 (0.52-1.153, p=0.2086).

Conclusions: The sequence of TT may not have a substantial effect on outcome but results of prospective randomized studies are awaited.

[Table: see text]
Analgesic use and the risk of renal cell carcinoma (RCC): Results from a large up-to-date meta-analysis.
Authors: Cho Eunyoung , Je Youjin , Choueiri Toni K.
Published: February 2017

395

Background: Analgesics have been linked to an increased risk of developing renal cell carcinoma (RCC), but the evidence is mixed. Using a meta-analysis design of all available studies, we investigated the association between analgesic use and RCC risk.

Methods: We searched the MEDLINE database to identify eligible case-control or cohort studies published in English from 1966 to July 1, 2011 for 3 categories of analgesics: acetaminophen, aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). Study-specific effect estimates were pooled to compute an overall relative risk (RR) and its 95% confidence interval (CI), using a random effects model, for each category of the analgesics. Analyses were conducted according to regular/any use and high dose or long-duration of use, separately.

Results: We identified 18 studies (12 for acetaminophen, 12 for aspirin, and 5 for other NSAIDs) that were performed in 6 countries. Regular/any use of acetaminophen and other NSAIDs were each associated with an increased risk of RCC: pooled RR, 1.33 (95% CI 1.18-1.49) for acetaminophen and 1.26 (95% CI, 1.09-1.44) for other NSAIDs, respectively. For use of aspirin, we found no significant increased risk (pooled RR, 1.14 [95% CI, 0.98-1.33]). Similar risk trends were seen with high dose of analgesics intake. No significant difference in associations was found by study design (case-control vs. cohort), type of controls in case-control study (population based vs. hospital based), outcome (RCC vs. kidney cancer), and gender (male vs. female). There was no indication of publication bias for the 3 analgesics.

Conclusions: In this meta-analysis of analgesics use and RCC risk, we found that use of acetaminophen and non-aspirin NSAIDs was associated with a significant increased risk of developing RCC.
Tumor burden as an independent prognostic factor in metastatic renal cell carcinoma (mRCC).
Authors: Escudier Bernard J. , Iacovelli Roberto , Lanoy Emilie , Albiges Laurence , Fizazi Karim
Published: February 2017

397

Background: During the last ten years, several classifications have been used to assess the prognosis in mRCC. In none of them, tumor burden (TB) has been considered. This study investigates the prognostic role of baseline TB in terms of progression free survival (PFS) and overall survival (OS), in patients with mRCC.

Methods: All patients with clear cell mRCC enrolled in our center, in 2 second-line trials, post cytokine, with sunitinib and sorafenib or placebo (Escudier JCO 2009, Escudier NEJM 2007), were selected for this analysis. TB was defined as the sum of the longest unidimensional diameter of each target lesions assessed using RECIST criteria. PFS and OS were estimated using Kaplan-Meier method and compared using the log-rank test. Association between TB and PFS or OS was evaluated using the Cox proportional hazards model. Multivariable analyses were adjusted for modified MSKCC risk class and treatment. Non-parametric Spearman rank test (rs) was used to assess the correlations between TB and MSKCC risk groups or ECOG Performance Status (PS).

Results: Final population included 124 patients: 66% received sorafenib or sunitinib and 34% received placebo; median follow up was 80.1 months (IQR: 68.8 – 88.0). Baseline TB was divided into 3 tertiles (1.3 - 9.4 cm; 9.5 - 19.0 cm; 19.1 - 47.3 cm). TB was related to PFS and OS and, when adjusting for modified MSKCC risk class and treatment, these associations remained significant: each 1 cm increase in TB increased the progression risk by 5% (HR: 1.05; 95%CI, 1.02 – 1.07; p < 0.0001) and the death risk by 5% (HR: 1.05; 95%CI, 1.03 – 1.08; p < 0.0001). OS decreased with TB: the median tertiles OS values were: 42.1 months (95%CI: 24.0 – 60.2), 20.1 months (95%CI: 14.5 – 25.7), and 11.2 months (95%CI: 4.8 – 17.6), respectively (p < 0.0001, figure 2). The TB was positively related to ECOG PS (rs = 0.357; p < 0.0001) and to MSKCC risk score (rs = 0.478; p < 0.0001). Patients with higher TB had shorter PFS, shorter OS, poorer MSKCC score and increased ECOG PS.

Conclusions: TB is easy to calculate with standard CT and significantly relates to OS and PFS in patients with mRCC. We report for the first time the independent prognostic role of baseline TB in mRCC.