bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic profiling of muscle invasive bladder cancer to predict response to bladder-sparing trimodality therapy.
Authors: Miyamoto David Tomoaki , Gibb Ewan , Mouw Kent William , Liu Yang , Wu Chin-Lee , Drumm Michael , Lehrer Jonathan , Ashab Hussam Al-Deen , Erho Nicholas , Du Plessis Marguerite , Ong Kaye , Shipley William U. , Davicioni Elai , Efstathiou Jason A.
Published: February 2018

513

Background: Trimodality therapy with TURBT followed by chemoradiation is an acceptable alternative to cystectomy for muscle invasive bladder cancer (MIBC). Genomic profiling has demonstrated MIBC can be divided into molecular subtypes with differing responses to chemotherapy. We explored the utility of genomic data to select patients for bladder-sparing trimodality therapy. Methods: Transcriptome wide gene expression profiles were generated for 189 MIBC TURBT samples from patients treated with trimodality therapy at a single institution. Of these, 103 passed microarray QC. Molecular subtype and expression of bladder cancer genes were assessed for association with overall and disease-specific survival. Transcriptome wide differential expression analysis was used to explore gene set enrichment in trimodality therapy response groups. Results: The chemoradiation cohort (n = 103) had a median followup of 6.9 years for alive patients, and was classified into four subtypes: basal (n = 44), basal claudin-low (n = 12), infiltrated luminal (n = 17) and luminal tumors (n = 30). There was no significant difference in overall or disease-specific survival by subtype. However, higher expression of the luminal-associated PPARG was correlated with increased survival after adjusting for subtype and clinical factors (HR = 0.52, p = 0.002). In contrast, a p53 signature predicted worse survival after adjusting for clinical factors (HR = 1.92, p = 0.022). Elevated mRNA expression of the DNA damage repair gene MRE11 was associated with improved survival in the trimodality cohort (HR = 0.69, P = 0.031), consistent with its potential role as a predictive biomarker for radiation response. Gene set enrichment revealed differential regulation of immune pathways in trimodality therapy responders relative to non-responders, including enrichment of interferon gamma signaling (p = 0.01) and CXCL9 (p = 0.031), suggestive of an interplay between tumor immunologic microenvironment and response to chemoradiation. Conclusions: Transcriptional profiling of MIBC revealed gene signatures correlated with response to chemoradiation, suggesting the potential of genomics to guide use of trimodality therapy.
Centralization of radical cystectomy for bladder cancer in a universal healthcare system: Early results from a Canadian academic center.
Authors: Rudzinski Jan Krzysztof , Jacobsen Niels , Ghosh Sunita , North Scott A. , Basappa Naveen S. , Kolinsky Michael Paul , Estey Eric , Fairey Adrian S
Published: February 2018

516

Background: Radical cystectomy for bladder cancer is a complex surgical oncology procedure. Centralization of this procedure to high volume, fellowship-trained surgeons may improve clinical outcomes. Our objective was to compare outcomes of radical cystectomy before and after centralization of care. Methods: A retrospective analysis of data from the University of Alberta Radical Cystectomy Database was performed. Eligible subjects were those with histologically proven urothelial carcinoma of the bladder (cTanyN1-3M0) undergoing curative intent surgery. Patients were classified into pre-centralization era (1994-2007; N = 523) and post-centralization era (2013-present; N = 134) cohorts for analyses. Pre-centralization era patients were treated by 1 of 11 urologic surgeons at 2 academic teaching hospitals. Post-centralization era patients were treated by 1 of 2 fellowship-trained urologic oncologists at 1 academic teaching hospital. Outcomes were overall survival, 90-day mortality rate, positive surgical margin (R1) resection rate, total number of lymph nodes evaluated, and 90-day blood product transfusion rate. The Kaplan-Meier method and multivariable regression analyses were used to analyze survival outcomes. Statistical tests were two-sided (p≤0.05). Results: The median follow-up duration in the pre- and post-centralization era was 33 months and 16 months, respectively. The predicted 2-year overall survival rate was 62% in the pre-centralization era and 84% in the post-centralization era (Log rank P = 0.0007; multivariable HR 0.40, 95% CI 0.24 to 0.68, P < 0.0001). Treatment in the post-centralization era was associated with lower 90-day mortality (6.3% versus 1.5%, multivariable OR 0.23, 95% CI 0.06 to 0.99, P = 0.049), R1 resection (13.0% versus 1.5%; multivariable OR 0.07, 95% CI 0.01 to 0.51, P = 0.009), and 90-day blood product transfusion (59% versus 6%, P < 0.0001) as well as higher total number of lymph nodes evaluated (7 versus 30 lymph nodes, P < 0.0001). Conclusions: Surgical treatment in the post-centralization era was associated with superior survival, cancer control, and perioperative outcomes.
Perioperative nutrition status of radical cystectomy patients.
Authors: Metcalf Meredith , Hamilton-Reeves Jill , DeRuyter Martin , Bishop David , Hand Lauren , Holzbeierlein Jeffrey M. , Lee Eugene
Published: February 2018

517

Background: Radical cystectomy patients are a vulnerable population, with up to 65% suffering complications and 26% readmitted within 90 days. Patients with aggressive bladder cancer are at high risk for malnutrition. Furthermore, malnutrition is a recognized risk factor for poorer outcomes following radical cystectomy. Unclear is the longitudinal assessment of malnutrition during the entire perioperative time frame of the radical cystectomy. Methods: We initiated a prospective, feasibility pilot trial (NCT NCT02942121) evaluating the usage of a healthcare application in the perioperative management of patients undergoing radical cystectomy. As a secondary aim of this prospective trial, we evaluated the perioperative malnutrition status of each participant using the validated Patient-Generated Subjective Global Assessment (PG-SGA). This assessment was administered by registered dieticians at baseline prior to radical cystectomy and at postoperative visits: 2 week, 6 weeks, and 12 weeks. No nutrition interventions occurred during the course of the trial in order to evaluate the natural longitudinal nutritional status of this patient population. Results: Enrollment has been completed with twenty patients. Thus far, 18 patients have completed baseline PG-SGA evaluation: 13 (72%) patients were well nourished, 3 (17%) had moderate malnutrition, and 2 (11%) were severely malnourished. 11 participants have completed their 2 week visit with all but one having decrease in their PG-SGA score. Interestingly, all six patients who have completed the 12 week visit have returned to their baseline rating of the PG-SGA score. Conclusions: Patients undergoing radical cystectomy for bladder cancer are already at risk for malnutrition, which is exacerbated post-operatively. The recovery to baseline is a slow process and may be a window for impactful nutritional interventions designed to lessen the burden of surgery. Clinical trial information: NCT02942121. [Table: see text]
Clinical and molecular characterization of urothelial cancer developing after pelvic radiation.
Authors: Rose Tracy Lynn , Kardos Jordan , Wobker Sara , Milowsky Matthew I. , Kim William Y.
Published: February 2018

518

Background: The development of urothelial cancer (UC) after pelvic radiotherapy (RT) is an increasingly recognized phenomenon. Numerous studies show a relationship between ionizing radiation and urothelial dysplasia and DNA damage. It is not known if UC that develops after pelvic RT is associated with a distinct molecular signature, which could have treatment implications for this subset of UC. Methods: The University of North Carolina (UNC) Genitourinary Oncology Database was queried for cases of UC between 01/2012 and 06/2016 in patients with prior pelvic RT. Demographics, clinical stage, and details of prior RT were collected. Patients with available archival FFPE tumor tissue underwent next generation targeted exome sequencing per the UNCSeq pipeline. Somatic mutations and copy number alterations were analyzed. Total mutation burden (TMB) (mutations per total Megabase region of 30X coverage, mut/Mb) and insertion-to-deletion (indel) ratio was calculated. Wilcoxon rank sum was used to compare TMB and indel ratio of RT-associated cases with all cases of UC sequenced at UNC. Results: 38 patients with UC developing after prior pelvic RT were identified. 68% had muscle-invasive UC. Median age was 76. Prior RT was for the purpose of prostate cancer treatment in all patients. 26% had received external beam radiotherapy, 29% brachytherapy, and 16% both (29% unknown). Median time from RT to diagnosis of UC was 8 years. Ten patients with muscle-invasive UC had tumors available for sequencing. The most commonly identified somatic alterations were TP53 in 60%, RB1 40%, CREBBP 30%, ELF3 30%, HLA-DRB1 30%, KDM6A 30%, and MLL2 30%, including co-occurrence of TP53 and RB1 mutations in 30% of patients. The median TMB was 12.1 mut/Mb, significantly lower than the median TMB of 25.6 mut/Mb in all cases of UC sequenced at UNC (p = 0.006). The indel ratio was not different between the two groups (p = 0.11). Conclusions: UC that develops after pelvic RT is a frequent entity that occurs years after RT. Tumors of patients who received prior RT had a lower overall TMB than other UC tumors, suggesting that RT-induced UC may be a different entity than carcinogen-induced UC. Further studies should expand our analysis to confirm these findings.
A new 50-gene molecular subtype classifier: An evaluation of subtype stability and association with response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.
Authors: Choi Woonyoung , Plimack Elizabeth R. , Siefker-Radtke Arlene O. , Dinney Colin P.N. , McConkey David James
Published: February 2018

519

Background: The bladder cancer basal and luminal molecular subtypes have been associated with differential progression patterns and responses to neoadjuvant chemotherapy. However, they are typically identified by whole transcriptome expression profiling, which may be impractical for most academic centers. To make subtype classification more accessible, we developed a 50-gene basal and luminal subtype classifier and examined its performance in matched tumor specimens, including pretreatment biopsies from patients treated with neoadjuvant chemotherapy. Methods: We refined a 50-gene subtype classifier derived from a oneNN classifier containing >~2000 genes that we previously developed using unsupervised methods. We compared its accuracy against calls made using the original oneNN classifier, including 148 tumors from a neoadjuvant chemotherapy meta dataset. To test subtype stability, tumors in 2 different datasets (30 sets of matched primary and lymph node tumors and 43 sets of matched pre- and post-chemotherapy tumors) were assigned using 50-gene subtype classifier with Linear Discriminator Analysis (LDA) prediction algorithms. Results: In the NAC cohort, patients with tumors assigned to the basal subtype by the 50-gene classifier had better survival outcomes compared to the luminal tumors, consistent with the conclusion generated with the parent classifier (p<0.05). Basal subtype assignments were stable in 62.5 % of pairs, whereas luminal tumors displayed 100% stability. In matched pre- and post-chemotherapy tumors, basal tumors displayed 78% stability while luminal tumors showed 94% stability. Conclusions: Based on these preliminary data, it appears that basal tumors display higher plasticity than luminal tumors with these specific contexts. This plasticity may interfere with precise subtype predictions with tumors assigned to the basal subtype at biopsy.
Using grade of tumor recurrence after BCG to guide further therapy.
Authors: Li Roger , Metcalfe Michael J. , Tabayoyong William , Guo Charles , Nogueras-Gonzalez Graciela M. , Navai Neema , Grossman H. Barton , Dinney Colin P.N. , Kamat Ashish M.
Published: February 2018

523

Background: Tumors that recur after BCG therapy are considered to be high risk and patients are often recommended to undergo radical cystectomy (RC). However, the nuances associated with the grade of tumor recurrence after BCG treatment are not well understood. We aimed to characterize the pattern of bladder cancer progression and cancer specific survival (CSS) in patients with recurrences dichotomized by low grade versus high grade after intravesical BCG treatment. Furthermore, to assess the safety of continued bladder sparing therapy in these patients. Methods: We performed an IRB approved review of our bladder cancer database. Overall, 146 NMIBC patients were found to have tumor recurrence after induction BCG with/without maintenance therapy, 38 with LG and 108 with HG tumors. Baseline clinicopathologic characteristics including age, gender, primary tumor grade, stage, size, multiplicity and concurrent CIS were collected and compared between the two groups. The primary endpoint was PFS, with progression defined as the development of MIBC/distant metastasis. In addition, RFS, HG RFS, CFS, and CSS were also compared. Multivariable analysis was performed using the Cox regression model. All tests were two-sided and p < 0.05 was considered statistically significant. Results: As dichotomized by grade of recurrent tumor, estimated 5-year PFS was 85.6% (95% CI 60.8 - 95.2%) for those with LG recurrence and 67.9% (95% CI 54.1 – 78.4%) for those with HG recurrence. On KM analysis, patients whose initial LG recurrence on BCG therapy had improved subsequent RFS (5.2 vs. 2.8 yrs, p = 0.007), HG RFS (9.4 vs. 3.0 yrs, p < 0.001), CFS (p < 0.001), and compared to those who had a HG initial recurrence; CSS benefit approached significance (3.7 vs. 2 yrs, p = 0.12). Grade of tumor recurrence after BCG was an independent predictor of PFS (HR 3.7, 95% CI 1.3-10.9, p = 0.016). Conclusions: Grade of tumor recurrence after intravesical BCG is an important predictor of bladder cancer progression to MIBC/MUC. However, patients who have low grade recurrences on BCG still may progress and hence should be carefully counselled on bladder sparing therapy.
The role of metastatic burden in cytoreductive/consolidative radical cystectomy.
Authors: Li Roger , Kukreja Janet Baack , Petros Firas G. , Campbell Matthew T. , Nguyen Justin , Nogueras-Gonzalez Graciela M. , Kamat Ashish M. , Pisters Louis L. , Dinney Colin P.N. , Navai Neema
Published: February 2018

524

Background: The strategy of surgical extirpation of the primary tumor in the setting of metastatic disease has gained acceptance for a variety of solid tumors. The role of cytoreductive/consolidative radical cystectomy (CCRC) for metastatic urothelial cancer (UC) is unknown. We aimed to describe our institutional experience with CCRC for metastatic UC and to investigate clinicopathologic features predicting prolonged cancer specific survival (CSS) following CCRC. Methods: We performed IRB approved review of our bladder cancer database, and identified 32 patients with metastatic cancer originating from the lower urinary tract who underwent CCRC. Of these, two patients had non−UC histology. Baseline demographics, regimen of chemotherapy, clinicopathologic features, and perioperative complications were collected. Progression free survival (PFS) and cancer specific survival (CSS) were estimated from the time of CCRC. Univariate and multivariate Cox regression models were used to identify predictors of improved CSS after CCRC. Results: Of the 32 patients, 19 (59%) had clinical evidence of distant metastases, while 13 were found to harbor occult metastases on the surgical specimen. The most common site of metastasis was the retroperitoneal lymph nodes, found in 17 patients. Solitary metastases were found in 19 patients (59%). Twenty−eight (88%) patients received chemotherapy prior to CCRC. Disease progression was detected in 29 patients after CCRC (median PFS 4.5 mo), while 28 died of metastatic cancer (median CSS 11.7 mo). On multivariate analysis, patients with solitary metastases were found to have improved CSS compared to those with multiple metastases (HR 2.51, 95% CI 1.06−5.92, p = 0.04), with median CSS of 16.9 mo vs. 5.6 mo (p = 0.003). Median postoperative LOS was 10 days. Overall, 59% suffered postoperative complications, including one perioperative mortality. Conclusions: CCRC is feasible in the setting of metastatic UC, with comparable perioperative morbidity and mortality to RC with curative intent. Patients with solitary metastasis demonstrated longer CSS than those with multiple metastases, and should be considered candidates for future trials evaluating the role of CCRC for metastatic UC.
Distress prevalence and associated risk factors within the urothelial cancer population.
Authors: Ralston Laurel , Grivas Petros
Published: February 2018

526

Background: Prevalence of distress has been estimated as high as 40% in some cancer populations, but minimal literature exists regarding distress in bladder cancer patients. Distress has been linked with multiple negative clinical outcomes, with the Commission on Cancer now requiring standardized distress screening for cancer program accreditation. The purpose of this study is to identify prevalence of distress, associated clinical risk factors and psychosocial referral trends in the urothelial cancer population. Methods: This was a retrospective review of distress screening outcomes in bladder cancer patients seen in oncology outpatient clinic at an academic medical center between January 1, 2016-October 1, 2017. Established oncology patients are screened for distress every 30 days using the Patient Health Questionnaire-9 (PHQ-9) and/or the NCCN Distress Thermometer (DT). Questionnaires are completed on an electronic tablet at the time of check-in and linked to the Epic electronic medical record in real time. A data capture program was used to query screening outcomes and identify those who met the threshold scores (PHQ-9 > 8, DT > 4). Results: Of 153 patients with a primary diagnosis of bladder, 81 (53%) completed the PHQ-9 (n = 67) or NCCN distress thermometer (n = 16). The overall incidence of distress was 13.6% with an average score of 12.3 on PHQ-9 (n = 10) and 9 on DT (n = 1). Of the patients with elevated distress, there were 7 males and 4 females with an average age of 64 and 77, respectively. All were either married or widowed. Metastasis was documented in 45%. Five were on an antidepressant and only one had mood disorder previously documented in the history. Social work referral occurred for 73% of the patients. One patient had elevated distress in the 6 months subsequent to diagnosis. Of the seven now deceased patients, all had elevated distress within 6 months of death. Conclusions: At 13.6%, the prevalence of distress in urothelial cancer patients was less than that in general oncology. Metastatic disease and female gender were risk factors while documentation of a psychiatric condition was not. One unexpected finding was that all now deceased patients had endorsed elevated distress within 6 months of death.
Serum miRNA to predict post-chemotherapy viable disease in testicular non-seminomatous germ cell tumor patients.
Authors: Leao Ricardo Romao Nazario , Van Agthoven Ton , Figueiredo Arnaldo , Fadaak Kamel , Castelo-Branco Pedro , Jewett Michael A.S. , Sweet Joan , Ahmad Ardalan , Anson-Cartwright Lynn , Bedard Philippe L. , Chung Peter W. M. , Hansen Aaron Richard , Warde Padraig Richard , O'Malley Martin , Looijenga Leendert , Hamilton Robert James
Published: February 2018

546

Background: Retroperitoneal lymph node dissection (RPLND) is recommended for residual masses > 1cm post-chemotherapy (pc) for nonseminomatous germ cell tumors (NSGCT). There is no reliable predictor for pcRPLND histology and up to 50% will harbour necrosis/fibrosis only, thus rendering a potentially morbid surgery to be of limited therapeutic value. Objective: To evaluate the ability of defined serum microRNA (miRNA) using the ampTSmiR test to predict residual viable NSGCT after chemotherapy. Methods: Serum miRNA levels (miR-371a-3p, miR-373-3p and miR-367-3p) were measured in 82 patients (cohort A = 39, cohort B = 43) treated with orchiectomy, chemotherapy and pcRPLND to predict viable GCT post-chemotherapy. Outcomes, measurements and statistical analysis: miRNA levels were compared to clinical characteristics, serum tumor markers and correlated with presence of viable GCT (vs. teratoma; vs. necrosis/fibrosis). miRNA-discriminative capacity was determined by receiver operating characteristic (ROC) analysis. Results: Serum miRNA were associated with stage at the time of chemotherapy and declined significantly post-chemotherapy. Patients with fibrosis/necrosis and teratoma had a significant decline in all three miRNA levels after chemotherapy, while those with viable disease had very little change. Patients with necrosis/fibrosis demonstrated similar miRNA levels as patients with residual teratoma. miR-371a-3p demonstrated the highest discriminative capacity [area under the curve (AUC) 0.874, CI 95% 0.774 - 0.974 p < 0.0001] for viable disease post chemotherapy. If considering a more relaxed cut-point of 3cm before consideration of pcRPLND, miR-371a-3p correctly stratified all patients with residual retroperitoneal lesions ≤ 3 cm ( p= 0.02; 100% sensitivity). Conclusions: Our study is the first to explore a miRNA-based serum test to determine histology in post-chemotherapy residual masses and we demonstrated the value of miR-371a-3p to predict presence of viable GCT. Prospective studies are required to confirm its clinical utility.
Collateral damage: Molecular aging and p16INK4a senescence protein in testicular cancer survivors treated with chemotherapy.
Authors: Bourlon Maria Teresa , Velazquez Hugo Eduardo , Orozco Bello Luis Arturo , Hinojosa Juan , Rios-Corzo Ricardo , Lima Guadalupe , Llorente Luis , Atisha-Fregoso Yemil
Published: February 2018

548

Background: Cytotoxic chemotherapy can cure patients with advanced germ cell tumors. Nevertheless, cancer treatment may induce cellular senescence and accelerate molecular aging. The aging process implies an increase of cells expressing p16INK4a and changes in lymphocyte subpopulations. Our aim was to study the potential induction of premature immunosenescence in testicular cancer patients exposed to chemotherapy. Methods: Case-control study of testicular cancer survivors (TCS) treated with chemotherapy (≥3 BEP cycles, disease-free ≥ 3 months) matched by age with healthy controls. Peripheral blood mononuclear cells were isolated, and lymphocyte subpopulations were analyzed by flow cytometry. p16INK4a expression was measured using real-time polymerase chain reaction, and the 2-ΔΔCt method was used for the p16INK4a expression analysis. Groups were compared with Mann-Whitney U test. Results are expressed as median (IQR) unless otherwise indicated. Results: We included 15 cases and 15 controls. Mean age 32.5 yo (24-54), mean time since last chemo 49.5 months (3-192). TCS had a lower percentage of CD3+ (62 (57-68) vs 72 (65-82) p = 0.026) and CD4+ (35 (27-41) vs 42 (38-53) p = 0.013) cells in total lymphocytes. TCS also had a lower % of naïve CD4+ (32 (15-44) vs 39 (32-55) p = 0.041), CD4+CD28+ (90 (85-97) vs 98 (95-99) p = 0.029) and CD8+ naïve (15 (8-26) vs 27 (22-42) p = 0.023) cells. TCS had an increased % of memory CD4+ (18 (13-26) vs 9 (6-11) p = 0.001) and memory CD19+ B cells (76 (62-88) vs 70 (64-79) p = 0.004). The relative expression of p16INK4a in CD3+ cells was higher in TCS compared to controls (1.29±0.36 vs 0.85±0.54; p = 0.035). Conclusions: TCS showed an increase in the expression of the aging biomarker p16INK4a and a lymphocyte phenotype associated with immunosenescence; characterized by a decrease in naïve cells, and concomitant increment of memory and CD28- cells. This phenomenon is believed to contribute to the development of an immune risk profile in the elderly, associated with an increased rate of infections and a diminished effect of vaccines. This is the first time this finding is reported in TCS. Further studies are warranted to define the clinical implications of this alteration.
Long-term sexual functioning in germ-cell tumor survivors.
Authors: Chovanec Michal , Vasilkova Lucia , Setteyova Lucia , Obertova Jana , Palacka Patrik , Rejlekova Katarina , Sycova-Mila Zuzana , Kalavska Katarina , Svetlovska Daniela , Mladosievicova Beata , Mardiak Jozef , Mego Michal
Published: February 2018

549

Background: Treatment for germ-cell tumors (GCT) may lead to long-term consequences in GCT survivors. This study aimed to evaluate a long-term sexual functioning after curative treatment for GCT. Methods: GCT survivors (N = 155) from a national cancer centre completed a Sexual Function Questionnaire that was modified from PROMIS Sexual Function and Satisfaction Questionnaire at a median 10 years of follow up (range 5-32) as a primary exploratory aim. Seventeen survivors (11%) had orchiectomy alone (controls), while 138 (89%) survivors received treatment beyond orchiectomy. The study group consisted of survivors receiving a cisplatin-based chemotherapy, radiotherapy to the retroperitoneal lymph nodes or both, while the control group included survivors treated with orchiectomy only. Results: Survivors treated with both chemotherapy and radiotherapy or any treatment had difficulty maintaining erection during the intercourse compared to the controls (both P = 0.04). Moreover, patients who received chemotherapy and radiotherapy reported difficulty in achieving orgasm during the intercourse ( P = 0.04) and they were disappointed with their overall quality of sex life ( P = 0.002). No difference in education, employment, marital status and parity was observed between the study groups (all P > 0.05). GCT survivors reported no differences in their sexual desire and in the number of attempts to initiate sexual intercourse in the last month. Survivors from all treatment groups reported none or mild anxiety resulting from sexual relationships and the desire to be sexually active was moderate among all subgroups, with no significant difference. Conclusions: Our prospective study shows that an impairment insexual function is a significant issue for long-term GCT survivors. Treatment with chemotherapy plus radiotherapy had the highest impact on the quality of sex life.
Outcomes of multidisciplinary treatment in penile cancer: Experience from Thailand.
Authors: Sirithanaphol Wichien , Pachirat Kachit , Rompsaithong Ukrit , Kiatsopit Pakorn , Lumbiganon Supanut , Sookprasert Aumkhae , Chindaprasirt Jarin
Published: February 2018

555

Background: Penile cancer is relatively more common in Thailand compared to western countries. We report multidisciplinary treatment outcomes of penile squamous cell carcinoma at a regional center in northeast of Thailand. Methods: Using an institutional database, a total of 68 patients with squamous cell carcinoma of penis treated during 2009-2015 were identified. Patient demographics, pathological data, and treatment modality were reviewed. Survival data was calculated using the Kaplan-Meier method. Results: Median age was 53 years (25-89 years) and the median follow-time was 2.7 years. At presentation, 39 patients (57.4%) were node positive, and 9 (13.2%) had metastatic disease. Management was penile preserving surgery in 13 patients, partial penectomy in 36 patients, total penectomy in 15 patients, and palliative with radiation and/or chemotherapy in 4 patients. The 3-year overall survival for patients with N0-1 and N2-3 was 86% and 35% respectively. For those with high risk (N2/N3) non-metastatic disease, multimodality treatment improved overall survival significantly compared with surgery alone (13.7 mo vs 8.6 mo; HR 0.32, p-value = 0.04) Conclusions: Patients present with locally advanced disease had a poor prognosis. Multidisciplinary management improved overall survival N2/N3 patients.
A qualitative analysis of the impact of Carboplatin AUC 10 on physical, work functioning, and bone marrow toxicity, in patients with metastatic seminoma: A single centre experience.
Authors: Milic Marina , Sharma Anand , Gogbashian Andrew , Hawkins Annette , Rustin Gordon J. S. , Hall Marcia
Published: February 2018

558

Background: We studied the efficacy, safety and tolerability of dose dense Carboplatin AUC10 chemotherapy and explored the HRQoL (health-related quality of life) in metastatic seminoma patients receiving this regimen. Methods: 46 patients with metastatic seminoma treated with Carboplatin AUC10 were identified in our centre. Carboplatin dosing at AUC 10 was used and calculated based on Calvert formula and EDTA clearance. Treatment was administered as a single dose every 21 days for 3 or 4 cycles. Response to treatment was determined by radiological imaging and serum tumour markers. Toxicities were evaluated using the CTCAE Version 4.0. Quality of life (QOL) and long-term treatment related toxicities were assessed post treatment using a self-designed telephonic questionnaire consisting of 4 questions about toxicity, which included- hair loss, hearing impairment, days absence from work and neuropathy. Results: Clinical characteristics are as follows: median age 44 (range 26-77), 34 patients had stage II and 12 stage III seminoma; average dose of carboplatin administered was 1240mg per cycle. 4.3% patients received 2, 87% 3 and 8.7.% 4 cycles of chemotherapy. 93% of patients achieved a complete remission (CR), 4 (all stage IIC) patients required a fourth cycle of chemotherapy, 2 undergoing RPLND and 2 watchful waiting. There was no disease relapse at median follow-up of 27.5 (range 4-84) months. 13 patients (28%) had grade 3 and 2 (4%) grade 4 neutropenia, thirteen (28%) grade 3/4 thrombocytopenia, Nine (19.5%) patients required prophylactic filgrastim. Commonest non-heamatological toxicities were fatigue in 28 (50%) and nausea 14(28%) patients. QOL data was available for 35/46 (76%) of patients. 40/46 (87%) patients had no residual tinnitus, one had residual grade 1 peripheral neuropathy. Eight patients continued to work throughout treatment, 16(45%) took < 5 days off work during chemotherapy, 4 took 5 to 21 days, 13 > 21 days, two were retired. Conclusions: Carbo AUC10 is a safe and effective treatment. Our results suggest the lack of negative impact of Carbo AUC10 on short and intermediate QOL without compromising treatment outcomes.
Testicular Cancer Review Panel: Multidisciplinary specialist review of a rare cancer at Kaiser Permanente, Northern California.
Authors: Harzstark Andrea Lynne , Kong Max , Brinsko Robert , Mamtora Kavita , Herrinton Lisa J. , Liu Liyan , Kumar Sonali , Kolevska Tatjana , Baer David M. , Dinesh M. Kotak , St. Lezin Mark , Presti Joseph C
Published: February 2018

561

Background: Testicular cancer is a rare disease; multidisciplinary management by experienced clinicians is recommended. Methods: Multidisciplinary specialized review of all new testicular cancer cases was established in a community setting by creating a twice monthly Testicular Cancer Review Panel, comprised of two subspecialized medical oncologists and two surgical urologic oncologists, at Kaiser Permanente in Northern California. An early ascertainment list of new testicular cancer diagnoses was obtained and review of the history, labs, pathology reports, and all relevant imaging was performed via a web-based conference. Urologic cancer fellowship trained pathologists and body fellowship trained radiologists were available for secondary review when requested. All recommendations were documented in patient charts. Results: From June 2016 to June 2017, 131 cases were reviewed. Review by the panel resulted in significant changes in care in 19 of 131 patients (14.5%). Pathology and radiology re-reviews were the most common sources of changes in treatment recommendations. Embryonal predominant T1 disease was referred for GU pathology review in 14 cases; in 8, lymphovascular invasion was identified, upstaging 6.1% of patients from 1A to 1B, changing treatment from observation to chemotherapy. Radiology re-review changed the stage and treatment in 11 patients (8.4%), identifying lymphadenopathy not previously noted in 7 patients and reassessing previously identified lymphadenopathy as a non-pathologic finding in 4 patients. The percentage of patients with stage I seminoma observed rather than undergoing adjuvant therapy increased from 11/15 (73.3%) over the first six months of the panel to 18/20 (90%) over the second six months. Convening the panel also resulted in dissemination of oncologic knowledge among treating physicians. Conclusions: Multidisciplinary specialized case review for a rare disease is feasible in the community setting and frequently alters care.
Development of multi-institutional nation-wide tumor board system for testicular cancer in Japan.
Authors: Kawahara Takashi , Kawai Koji , Kojima Takahiro , Kishida Takeshi , Shinohara Nobuo , Kondo Yukihiro , Nonomura Norio , Kakehi Yoshiyuki , Nishiyama Hiroyuki
Published: February 2018

562

Background: The standard treatments have been established for metastatic germ cell tumors and the cure rates are quite improving. Cumulative experience by centralization is required for expertise in all aspects of care but it is quite difficult due to its rarity and the present medical situations in Japan. To resolve this problem, we established the nation-wide internet tumor board system for testicular cancer from 2012. Methods: To start with, 28 members from 14 institutions were registered in the internet mailing list (ML) for this tumor board, then the members who wanted to join this system were added to this ML. The tumor board was operated in semi-closed system and with no consultant fee. The member can present the case by e-mail at any time when he encounters the difficult case. Then the other members replied and commented their opinions or experiences against his questions by e-mail. All members could read his case-presentation and comments of consultants in e-mail. In this study, we summarized the initial 5-year experience and the discussed contents and the usage status were analyzed to assess the quality of this internet nation-wide reference system. Results: The number of members and discussed cases increased gradually. At the present, this ML consists with 179 members from 79 institutions all over Japan. We discussed 100 testicular cancer cases during 5 years. Discussed cases were categorized into 10 categories. 44% of the cases discussed in the ML were poor prognostic cases or extragonadal cases. In 63 cases, the consultants were replied within 24 hours when the case was presented in ML, and some comments were replied within at 5 days in all cases. The median number of comments was 6, and active discussions with 10 or more comments were performed in 26 cases (26%). Conclusions: The nation-wide internet tumor board system for testicular tumor was growing in Japan and useful to decide treatment strategy for difficult cases. It might be helpful for members in low volume centers to gain cumulative experience.
Refractory testicular pure seminoma (PS) and non-seminomatous(NS) germ cell tumors (GCT): A comprehensive genomic profiling (CGP) study.
Authors: Jacob Joseph M , Ferry Elizabeth Kate , Shapiro Oleg , Millis Sherri Z. , Chung Jon , Elvin Julia Andrea , Vergilio Jo-Anne , Ramkissoon Shakti , Suh James , Severson Eric Allan , Daniel Sugganth , Ali Siraj Mahamed , Schrock Alexa Betzig , Miller Vincent A. , Stephens Philip J. , Gay Laurie M. , Bratslavsky Gennady , Ross Jeffrey S.
Published: February 2018

565

Background: Although PSand NS testicular GCT have a favorable prognosis, on occasion these tumors can be refractory to conventional systemic treatments. Methods: FFPE tissues from 22 PS and 86 NSunderwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mutations (mut) per megabase (Mb) and microsatellite instability (MSI) was determined on 114 loci. Results: PS patients were older than NS (P=0.007). The primary tumor was sequenced in 41% of PS and 18% of NS with a metastasis sample in 59% of PS and 82% of NS.Four (18%) of PS had syncytial trophoblast cells identified. The mean GA frequency at 4.1 mut/case for NS was higher than that seen in PS and this difference reached near significance (P=0.08). The KRAS, TP53, CCND2 and FGF6/23 GA frequencies were similar in both tumor types (Table). GA in KIT, PIK3CA/ MTOR, PTEN and BRCA2 were more frequent in PS than NS whereas BRAF and ERBB2 GA were more frequent in NS (Table). MSI-High status was absent in in PS (0%) and identified in 2% of NS. Higher levels of TMB were not encountered in PS (0% TMB ≥10 mut/Mb), but higher TMB levels were more frequent in NS (5% ≥ 10 mut/B and 1% ≥ 20 mut/Mb). Conclusions: The GA found in refractory PS and NS differ significantly. PS features a lower GA frequency with slightly higher potential for targeted therapies in kinase (KIT) and MTOR pathways but, has very low TMB predicting limited opportunities for immunotherapy for these patients. For NS targeted therapy biomarkers appear even more uncommon than seen in PS with only extremely rare kinase inhibitor opportunities. However, based on rare high TMB and MSI-High status, immunotherapies may be of benefit in a small subset of NS patients. Further study of genomic findings in relapsed and clinically aggressive PS and NS appears warranted. [Table: see text]
Management of growing teratoma syndrome (GTS): Results of the German Testicular Cancer Study Group.
Authors: Paffenholz Pia , Pfister David , Busch Jonas , Dieckmann Klaus Peter , Schmelz Hans U. , Heidenreich Axel
Published: February 2018

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Background: Growing teratoma syndrome (GTS) is an infrequent clinical phenomenon constituting only about 2 to 8% of all testis cancer patients. Data in the literature on the therapy of GTS are sparse, reflecting the rarity of the disease. The objective of was to determine the diagnostic, surgical and oncological outcome of patients with GTS treated in the 21st century. Methods: Between 01/2000 and 01/2010 post-chemotherapeutic retroperitoneal lymph node dissections (PCRLND) were performed in 296 patients with advanced NSGCT. We analysed the peri- and postoperative outcome of 16 patients (5.4%) that fulfilled the criteria of a GTS: enlarging metastatic mass in the retroperitoneum or visceral organs during systemic chemotherapy with normalized or decreasing tumour markers. Results: Mean patient age was 31 years (17-57). Initially, all patients had NSGCT with a good or intermediate prognosis according to IGCCCG; one patient had a poor prognosis. In all cases the primary tumour predominantly contained mature teratoma; two patients had a clinical stage IIb, nine and three presented with clinical stage IIc and III respectively. Median tumour diameter at time of surgery was 8.1 cm (1.5-32). Tumour markers were plateauing or normalized in all patients. Tumour masses were localized in the retroperitoneum in 15 patients; one patient demonstrated a pulmonary mass. After a median follow-up of 4.2 years, 2 patients developed outfield recurrences; all but one patients are alive. Conclusions: GTS is a rare disease among patients with advanced NSGCT and necessitates complete surgical resection of the masses with curative intention. Surgery should be considered at time of progression to facilitate complete removal of the growing teratoma and be performed in tertiary referral centers only.
Adjuvant etoposide plus cisplatin (EP) for pathologic stage (PS) II nonseminomatous germ cell tumor (NSGCT).
Authors: McHugh Deaglan Joseph , Funt Samuel , Silber Deborah , Knezevic Andrea , Patil Sujata , O'Donnell Devon , Tsai Stephanie , Reuter Victor E. , Sheinfeld Joel , Carver Brett Stewart , Motzer Robert J. , Bajorin Dean F. , Bosl George J. , Feldman Darren R.
Published: February 2018

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Background: The risk of relapse after primary retroperitoneal lymph node dissection (RPLND) for patients (pts) with PS IIA NSGCT is 10-20% and increases to over 50% for pts with PS IIB NSGCT. Cisplatin-based chemotherapy reduces the relapse risk to approximately 1%. Standard adjuvant chemotherapy regimens consist of 2 cycles of EP or 2 cycles of bleomycin plus EP (BEP). Methods: From March 1989 to April 2016, 156 pts with PS II NSGCT seen at Memorial Sloan Kettering Cancer Center and assigned to two cycles of EP chemotherapy following RPLND were included. Pts from a prior analysis (Kondagunta, JCO, 2004) were included with updated survival outcomes and expanded histopathologic parameters. Each cycle consisted of cisplatin 20mg/m2 and etoposide 100mg/m2 administered on days 1 to 5 at 21-day intervals. Demographics, histopathologic features, therapeutic and survival outcomes were recorded. Results: Median age was 28 years (range 15-52). 30 pts (19%) had pN1 disease, 122 (78%) pN2 disease and 4 (3%) pN3 disease. Median number of positive lymph nodes was 3 (range 1-37) and median size of the largest positive node was 2.0cm (range 0.4-7.0cm). 69 pts (45%) had extranodal tumor extension. Embryonal carcinoma, seminoma, mature teratoma and yolk sac were the predominant histological subtypes in the RPLND pathology in 115 (90%), 8 (6%), 4 (3%) and 1 (1%) pts respectively. 150 pts (96%) received 2 cycles of EP, 5 (3%) received 1 cycle of EP and one received 4 cycles of EP due to a transient marker increase following his first cycle. Dose delays occurred in 54 (38%) pts, mostly due to neutropenia (44/54 delays). With a median follow-up of 9 years, 2 pts (1 pN2 and 1 pN3) relapsed; both achieved a complete response to paclitaxel, ifosfamide and cisplatin (TIP), remaining disease-free at 65 and 143 months respectively. 3 pts died, all unrelated to GCT or treatment, for 10-year relapse-free and overall survival rates of 98% and 99%, respectively. Conclusions: This is the largest series reported to date on adjuvant chemotherapy with EP for PS II NSGCT. With 100% disease-specific survival and acceptable toxicity, these data confirm the efficacy of 2 cycles of EP and suggest that inclusion of bleomycin (e.g. BEP) in this setting is not necessary.
Clinical characteristics and treatment outcomes of patients (pts) with advanced germ cell tumor (aGCT) treated at a tertiary cancer center in Brazil.
Authors: Vasconcellos Vitor Fiorin de , Bastos Diogo Assed , Pereira Allan Andresson Lima , Pereira Bruno Rodriguez , Silva Jamile Almeida , Muniz David Queiroz Borges , Guglielmetti Giuliano , Nahas William Carlos , Dzik Carlos
Published: February 2018

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Background: Reported treatment outcomes for pts with aGCT are largely based on series from developed countries. Data from less developed countries are lacking. Methods: From 2000 to 2015, a retrospective analysis identified 302 pts with aGCT treated at Instituto do Cancer do Estado de São Paulo (ICESP). Kaplan-Meier methods were used for analysis of progression-free survival (PFS) and overall survival (OS) according to the International Germ Cell Consensus Classification Group (IGCCCG). Results: Median follow-up was 46 months and median age was 28 years old. Clinical features and management are detailed in the Table. 54 pts (18%) had ECOG performance status (PS) ≥ 2 at baseline. According to the IGCCCG, 57% were good-, 18.3% intermediate-, and 24.7% poor-risk disease. Median AFP was 2.9, 243, and 3.998 and HCG was 0.4, 113 and 301 in IGCCCG good-, intermediate-, and poor-risk groups, respectively. 5-year PFS and OS were 69% and 85%, respectively, including 83% and 95.3% in good-risk, 70.9% and 83.6% in intermediate-risk and 35.1% and 62.2% in poor-risk pts. Only 3 pts (3%) received high-dose chemotherapy (HDCT) as first salvage therapy. Conclusions: Brazilian pts with advanced GCT in this cohort had similar outcomes as pts in the IGCCCG database. In comparison to contemporary series, pts with intermediate- and poor-risk GCT had slightly inferior PFS and OS, possibly due to a high percentage of pts with poor PS and less use of HDCT. [Table: see text]
Plasma miR371 for the detection of viable germ cell tumor in testicular cancer patients with enlarging or post chemotherapy residual nodes.
Authors: Nappi Lucia , Thi Marisa , Eigl Bernhard J. , Chi Kim N. , Gleave Martin , So Alan I. , Khalaf Daniel , Black Peter C. , Nichols Craig R. , Kollmannsberger Christian K.
Published: February 2018

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Background: The pathological constitution of post-chemotherapy residual disease (PCRD) or enlarged nodes in clinical stage I (CSI) patients (pts) with germ cell tumor (GCT) is guesswork, especially when tumor markers (β-HCG, AFP, LDH) are negative. Currently, accurate assessment requires clinical follow-up with imaging to establish patterns of growth or pathological confirmation with RPLND. A blood-based approach reliably to identify patients with non teratoma viable GCT (NTVGCT) would be valuable. Methods: miR371 extracted from plasma of 44 pts with GCT was analyzed by RT-PCR and relative expression calculated by the 2-ΔΔCt method. Plasma from healthy male volunteers was used as negative control while miR-93-5p as internal positive control. The sensitivity and specificity of miR371 were calculated correlating miR371 overexpression to the presence of relapsed/residual NTVGCT. Results: Fifty eight samples (20 CSI, 20 metastatic, 18 PCRD) were analyzed. Ten CSI pts presented with suspicious enlarging nodes (≥ IIA) and miR371 was overexpressed in 5/6 pts with confirmed tumor relapse. Neither CSI pts with unconfirmed enlarging nodes (n = 4) or with no signs of relapse (n = 10) presented high miR371 levels. miR371 was overexpressed in all the pre-chemotherapy metastatic pts (n = 10) and negative after chemotherapy (n = 10), with 4 pts presenting PCRD. miR371 was negative in all the pts with PCRD and no residual NTVGCT was detected in those pts by either pathology (n = 10) or clinical follow-up (n = 8). Sensitivity and specificity were 93.3% and 100%, respectively. Conclusions: Elevated plasma levels of miR371 correlate with the presence of NTVGCT and may lead to biological rather than radiographic assessment of active GCT. Since chemotherapy is first line option for NTVGCT while is inactive in teratoma, miR371 status may be used to select pts for chemotherapy or surgery. These encouraging findings inform upcoming North American trials for further definition of miR371 operating characteristics in all stages, sites of origin, gender and age specific GCTs. [Table: see text]