bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of no treatment vs other nonsurgical treatments in Pancreatic Adenocarcinoma National Cancer Database: 2004-2014.
Authors: Saha Sukamal , Elgamal Mohamed , Cherry Meghan , Buttar Robin , Devisetty Kiran , Gayar Hesham , Wiese David , Grewal Sandeep Singh , Eilender David S. , Arora Madan L.
Published: May 2019

e15795

Background: Surgery remains the only curative treatment option in pancreatic adenocarcinoma, yet in more than 50% of the patients (pts) the disease is too advanced or at very high risk and considered inoperable. They are either managed with no treatment or other nonsurgical methods. Hence, we analyzed a large cohort of pancreatic adenocarcinoma pts undergoing No Treatment vs Chemotherapy, Radiation or Chemoradiation to determine their impact on survival. Methods: Only pancreatic adenocarcinoma pts who had no surgery in the National Cancer Database (NCDB) from 2004–2014 were included. Of that group, patients with unknown or missing data about chemotherapy or radiation treatment or less than 3 years of survival data were excluded. Pts were stratified into 4 groups: Chemotherapy, Radiation Therapy, Chemoradiation and No Treatment. Overall 1-, 2- and 3-year survival was calculated and the groups were compared using Pearson’s chi-squared. Results: Of the total 309,709 pancreatic cancer pts in the NCDB 2004–2014, 111,421 (36.0%) remained after application of the study criteria. Of these, 43,203 (38.8%) received chemotherapy only, 2,453 (2.2%) received radiation only, 15,764 (14.1%) received chemoradiation and 50,001 (40.0%) had no treatment. Overall survival for 1, 2, and 3 years was best in the chemoradiation group with a 1 year survival of (40.0%) compared to chemotherapy only (22.4%), radiation only (14.9%) and no treatment (9.6%). Overall, only (19.0%) of pts survived for 1 year, (5.4%) survived for 2 years and (2.3%) survived for 3 years. (Table) Conclusions: Survival in pancreatic adenocarcinoma pts remains dismal without surgery. Best survival in nonsurgical pts was seen after combination Chemoradiation therapy and worst survival in No Treatment group. Hence, whenever possible, a combination Chemoradiation should be offered even as palliation in non-surgical pancreatic adenocarcinoma pts.[Table: see text]
Role of OncoTherad immunotherapy in the regulation of toll-like receptors-mediated immune system and RANK/RANKL signaling: New therapeutic perspective for non-muscle invasive bladder cancer.
Authors: Fávaro Wagner José , Iantas Sonia Regina , Gonçalves Juliana Mattoso , Dias Queila Cristina , Reis Ianny Brum , Billis Athanase , Duran Nelson , Alonso João Carlos Cardoso
Published: May 2019

e16004

Background: The new modalities for treating patients with non-muscle invasive bladder cancer (NMIBC) for whom Bacillus Calmette-Guerin (BCG) has failed or is contraindicated are recently increasing due to the development of new drugs. In this scenario, a new perspective is represented by OncoTherad immunomodulator. OncoTherad is a nanostructured inorganic phosphate complex associated to glycosidic protein, developed by University of Campinas/ Brazil, which exhibits antitumor properties. This study detailed and characterized the therapeutic effects of OncoTherad based on activation of Toll-Like Receptors (TLRs) signaling pathways and regulation of receptor activator of nuclear factor kβ (RANK)/RANK ligand (RANKL) cytokine system in an animal model of NMIBC, as well as, compared these effects with BCG treatment. Methods: Fisher 344 female rats were submitted to NMIBC induction with N-methyl-N-nitrosourea (MNU). MNU treated animals were further divided into 3 groups (10 animals per group): the NMIBC group received 0.30 mL of saline solution; the NMIBC-BCG group received of 2 mg/mL of BCG; the NMIBC-OncoTherad group received 20 mg/Kg dose of OncoTherad. All animals were treated intravesically every other week for 6 weeks. Results: Our results demonstrated that OncoTherad intravesical immunotherapy led to distinct activation of TLRs 2 and 4-mediated innate immune system, resulting in increased interferons signaling pathway, which was more effective (80.0%) in the NMIBC treatment, when compared to BCG treatment (20.0%). Interferon signaling pathway activation induced by OncoTherad led to increase of iNOS expression, resulting in apoptosis and histopathological recovery. Also, OncoTherad immunotherapy decreased RANK/RANKL expression, resulting in reduced regulatory T (Treg) cells. Conclusions: The decreased of RANK/RANKL expression by OncoTherad was fundamental to up-regulation interferon signaling pathway and in suppresion of abnormal cell proliferation. Thus, OncoTherad immunotherapy could be considered an important therapeutic strategy for NMIBC, as well as, opens a new perspective for treatment of BCG-refractory or relapsed patients.
Single cell analysis of urothelial carcinoma (UC) liver metastases identifies epithelial-mesenchymal transition (EMT) as a potential mechanism of resistance to immunotherapy.
Authors: Lattanzi Michael , Tredwin Lily M. , Deng Fang-Ming , Chiriboga Luis , Zeck Briana , Forcato Claudio , Serrano Jonathan , Mohamed Hussein , Snuderl Matija , Balar Arjun Vasant
Published: May 2019

e16018

Background: UC liver metastases are associated with a low response rate to immune checkpoint blockade (ICB) and short survival. We sought to identify tumor specific factors promoting resistance to ICB. Methods: DEPArray is a dielectrophoresis based cell sorting platform for isolating immunohistochemically-defined cell populations from formalin-fixed paraffin-embedded (FFPE) tissue. Available FFPE tissue blocks of mUC liver metastases from patients (pts) treated with ICB were selected for analysis. Following histologic evaluation, tissue blocks were digested to yield cellular suspensions for immunophenotypic DEPArray sorting by keratin (K) and vimentin (V) to identify carcinoma cells and stromal cells, respectively. Cell pools were further analyzed for recurrent mutations and copy number alterations by a targeted OncoSeek panel and by MiSeq. Results: 12 unique patient samples were profiled. Median age was 73 (range 65-89), 11/12 male, 7 (58%) were platinum-refractory, and 4 (33%) received only ICB. 7 (58%) biopsies were obtained prior to initiation of ICB (1PR, 1SD, 5PD). Routine H&E sections generally revealed tumors completely devoid of immune cells, but admixed with atypical mesenchymal cells ranging from 5% to 60% of cellular composition. DEPArray sorting by K and V identified three discrete cell populations: K+/V- carcinoma cells, K-/V+ stromal cells, and K+/V+ cells that exhibited mesenchymal morphology. Of 8 samples with adequate cell counts (range 75-154 cells), next-generation sequencing (NGS) identified that K+/V- carcinoma cells and K+/V+ double positive cells shared unique somatic alterations in 7 (88%) pts, including point mutations in FGFR3, ERBB2, FBXW7, PIK3CA, FLT3 and STK11, and amplification of CDK4. In one liver responder to ICB, V+ stromal cells carried a putative germline TP53 R248W mutation. Conclusions: Archival FFPE tissue from mUC liver metastases can be digitally sorted by DEPArray to yield pools of ~100 cells suitable for NGS. UC liver metastases exhibit a population of K+/V+ cells with clonal somatic alterations suggestive of an EMT cancer cell phenotype that may be playing a role in ICB resistance.
Programmed death-ligand 1 (PD-L1) expression in small cell carcinoma of bladder.
Authors: Sanguino Angela , Samiei Arash , Pasricha Gurleen , Harinath Lakshmi , Miller Ralph , Lyne John , Silverman Jan F , Mao Shifeng
Published: May 2019

e16019

Background: Small cell carcinoma of bladder (SCCB) is a rare but aggressive variant of bladder neoplasm. There is limited insight for risk prognostication and treatment guidance in this entity. Immune checkpoint inhibitors (ICI), anti-PD-1 or anti-PD-L1 antibodies, have been approved for treating urothelial carcinoma, while the evidence of their efficacy in SCCB is lacking. PD-L1 expression in tumor tissue of urothelial cancer has been postulated to correlate with response to ICI but with controversy. We have studied the expression of PD-L1 in SCCB and its association with patient survival. Methods: Nineteen cases of SCCB diagnosed between 2011 and 2017 in a single center were identified. Formalin-fixed paraffin-embedded tumor samples were stained for PD-L1 (Ventana PD-L1 SP142). Cases showing positive stain in 5% or more of tumor cells and tumor stromal mononuclear cells (TSMC) were considered positive. Results: Among 19 cases of SCCB, 4 (21%) stained positive for PD-L1. All 4 cases had strong PD-L1 staining ( > 30%) seen in the TSMC but barely in tumor cells (focal < 5% cells in 2/4 cases). Except for one patient who died from surgery, all remaining 3 patients with positive PD-L1 staining are still alive. Twelve out of 19 SCCB patients developed metastatic disease; 4 of them were treated with ICI. The only responder of the 4 patients had strong PD-L1 expression in TSMC cells. The overall survival for patients with positive PD-L1 staining was 41 months versus 14 months for those with negative staining (p = 0.09). Age, pathologic stage and treatments were similar between the two groups. Conclusions: In our study, PD-L1 expression was seen in 21% of tumor samples from patients with SCCB, mostly in TSMC, but minimal in tumor cells. The strong expression of PD-L1 in TSMC correlates with a trend of improved survival and potential response to ICI in SCCB. PD-L1 expression in TSMC, rather than tumor cells, could be used as a marker for prognosis in SCCB.
Comparing costs of radical cystectomy versus trimodal therapy for patients diagnosed with localized muscle-invasive bladder cancer.
Authors: Phillips Daniel , Dafashy Tamer , Shan Yong , Ray-Zack Mohamed Danny , Hudgins Hogan K , Jazzar Usama , Tyler Douglas S. , Freedland Stephen J. , Swanson Todd A. , Baillargeon Jacques G. , Hu Jim C. , Kaul Sapna , Kamat Ashish M. , Gore John L. , Mehta Hemalkumar B , Williams Stephen Bentley
Published: May 2019

e16021

Background: Earlier studies on the cost of muscle-invasive bladder cancer treatments lack granularity and are limited to 180 days. The objective of this study is to compare the one-year costs associated with trimodal therapy versus radical cystectomy, accounting for survival and intensity effects on total costs. Methods: This cohort study used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Data analysis was performed from March 5, 2018 through December 4, 2018. A total of 2,963 patients aged 66-85 years diagnosed with clinical stage T2-4a muscle-invasive bladder cancer from January 1, 2002 through December 31, 2011. Total Medicare costs within one year of diagnosis following radical cystectomy versus trimodal therapy were compared using inverse probability of treatment-weighted (IPTW) propensity score models, which included a two-part estimator to account for intrinsic selection bias. Results: Median costs were significantly higher for trimodal therapy than radical cystectomy in 90 days ($83,754 vs. $68,692; median difference $11,805, 95% CI $7,745 to $15,864), 180 days ($187,162 vs. $109,078; median difference $62,370, 95% CI $55,581 to $69,160), and 365 days ($289,142 vs. $148,757; median difference $109,027, 95% CI $98,692 to $119,363), respectively. Outpatient care, radiology, medication expenses and pathology/laboratory costs contributed largely to the higher costs associated with trimodal therapy. On IPTW-adjusted analyses, patients undergoing trimodal therapy had $129,854 (95% CI $115,793-$145,299) higher costs compared with radical cystectomy one year after diagnosis. Conclusions: Compared to radical cystectomy, trimodal therapy was associated with higher costs among patients with muscle-invasive bladder cancer. Extrapolating cost figures resulted in nationwide excess spending of $444 million for trimodal therapy compared with radical cystectomy for patients diagnosed in 2017.
Real-world outcomes of metastatic urothelial carcinoma (mUC) patients (pts) treated with first or second-line immunotherapies (IO) in the United States (US).
Authors: Boyd Marley , Annavarapu Srinivas , Doshi Gurjyot K. , Imai Kentaro , Sbar Eric , Godwin James Luke , Li Haojie , Sonpavde Guru
Published: May 2019

e16025

Background: While clinical trials have affirmed benefit of IO for mUC, limited real-world evidence exists to describe the current treatment landscape and clinical outcomes. This study evaluated these trends in a network of community oncology practices, the US Oncology Network (USON). Methods: This was a retrospective study of adult mUC pts who initiated IO regardless of PD-L1 expression in the first- (1L cohort) or second-line (2L cohort) setting between 5/1/2016-1/31/2018. Using data from USON’s electronic heath record, descriptive and Kaplan-Meier analyses were conducted to evaluate baseline characteristics, treatment patterns and clinical outcomes. Results: Among the 254 pts in the 1L cohort, median (range) age at IO initiation was 74 (42, 90+), 71% were male, 77% were Caucasian, and 18.1% and 5.9% had ECOG performance status (PS) 2 and 3/4, respectively. Among the 179 pts in the 2L cohort, median (range) age at IO initiation was 71 (29, 90+), 76% were male, 76% were Caucasian and 20.7% and 2.2% had ECOG PS 2 and 3/4, respectively. Nearly all pts received IO monotherapy. Median (range) follow-up durations from IO initiation were 4.3 (0, 22; 1L cohort) and 3.6 (0, 19; 2L cohort) months (mo), during which time 39% (1L cohort) and 37% (2L cohort) of pts died. Median overall survival (95% confidence interval [CI]) was 9.9 (7.5, 15.7) mo for the 1L IO cohort and 8.3 (6.4, not reached) mo for the 2L IO cohort. Six-mo survival probabilities (95% CI) were 61.6% (54.5%, 67.9%; 1L cohort) and 60.7% (51.4%, 68.8%; 2L cohort). In total, 52.8% of 1L pts and 53.6% of 2L pts were alive and did not advance to next line of therapy, and 11% of 1L and 13% of 2L cohort pts advanced to the next line of therapy. Median (95% CI) treatment durations were 2.3 (1.9, 3.0) and 3.3 (2.7, 3.9) mos for the 1L and 2L cohorts, respectively. Six-mo ongoing treatment probabilities (95% CI) were 28.9% (23.3%, 34.7%; 1L cohort) and 34.0% (26.1%, 42.1%; 2L cohort). Conclusions: Outcomes of real-world mUC pts receiving IO were as expected, with majority of pts alive and a small minority receiving post-IO therapy. Future research should examine how pt and tumor (PD-L1 expression) characteristics influence treatment and outcomes.
Genomic analysis of urothelial cancer and associations with treatment choice and outcome.
Authors: Sarid David , Berger Raanan , Levartovsky Meital , Gadot Moran , Maurice-Dror Corinne , Collin Maya , Peer Avivit , Perets Ruth , Purim Ofer , Sarfaty Michal , Rosenbaum Eli , Neiman Victoria , Ligumsky Hagai , Rouvinov Keren , Romanov Ialyzaveta , Mermershtain Wilmosh , Shani Shrem Noa , Vainer Gilad Wolf , Leibowitz-Amit Raya
Published: May 2019

e16026

Background: The use of next generation sequencing (NGS) is in a constant rise, without clear evidence to its utility in guiding treatment choices in urologic malignancies. While platinum-based chemotherapy (chemo) is still the mainstay of treatment, anti-PD1/L1 antibodies (IO) and FGFR3 inhibitors are emerging therapeutic options. Here our aim was to retrospectively assess the utility of next-generation sequencing (NGS) in selecting advanced treatment lines and define the response rates (RR) to chemo and IO in a real-life cohort. Methods: Metastatic urothelial carcinoma (UC) patients (pts) receiving first-line chemo were included. Paraffin-embedded pathological samples were subjected to FoundationOne genomic analysis (Roche) and to PD-L1 IHC staining using the FDA-approved Ventana's companion diagnostic test. Reports were anonymized and analysis was performed using Excel (Microsoft Office). Response was defined as either a clinically or radiologically-significant improvement. Results: 60 pts were included in this analysis with a median age of 69, of which 87.7% were men and 70% were current or past-smokers. RR to first line chemo or IO was 66% (95% CI 50-82) and 33% (95% CI 12-64), respectively. RR to second-line IO was 14% ((95% CI 4-40). Median TMB was 10 Mut/Mb (range 1-62) with no difference between smokers and non-smokers. 31% pts had tumor PD-L1 staining of > 5% and 3.7% were MSI-high. 107 genes were altered across all pts. The median number of genomic alterations (mutations (muts), amplifications (amps), deletions (dels) and re-arrangements) was 7 (range 2-17). The most frequent were TERT promotor and TP53 mutations, occurring in in 39 (69.6%) and 30 (53.6%) pts, respectively. FGFR3 alterations were found in 9 (15%) pts (7 mut and 2 fusions), 12 pts (20%) had alterations in ERBB2/Her2 (6 amps, 3 muts, 3 equivocal amps), BRCA1 mutations were found in 6 (10%) pts, and TSC1 alterations were found in 6 (10%) pts (4 muts and 2 dels). Altogether, about 40% of patients had potentially actionable alterations; of these, to date, the treatment of 8 patients (13%) was consequently altered. The RR to IO was non-significantly higher in pts with TMB > 10 (29% VS 20%, p = 0.1) across all pts in this cohort. Conclusions: RR to first-line chemo is higher than to first-line IO, and the association between TMB and response to IO is still debatable in UC. NGS can yield potentially 'actionable' alterations in about 40% of UC pts, and can change the treatment paradigm in the third of them.
Population-based outcomes comparing radical cystectomy with trimodal therapy for patients diagnosed with localized muscle-invasive bladder cancer.
Authors: Dafashy Tamer , Phillips Daniel , Shan Yong , Hudgins Hogan K , Jazzar Usama , Ray-Zack Mohamed Danny , Kaul Sapna , Kerr Preston , Kamat Ashish M. , Tyler Douglas S. , Freedland Stephen J. , Swanson Todd A. , Mehta Hemalkumar B , Williams Stephen Bentley
Published: May 2019

e16029

Background: Radical cystectomy is the guideline-recommended treatment for muscle-invasive bladder cancer; however, use of trimodal therapy, which utilizes a combination of surgery, radiation, and chemotherapy, has increased in recent years with conflicting survival outcomes. Methods: Utilizing data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, a total of 2,963 patients aged 66 years or older diagnosed with clinical stage T2-4a bladder cancer from January 1, 2002 to December 31, 2011 were analyzed. Conventional regression, propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to compare radical cystectomy and trimodal therapy for overall and cancer-specific survival, and cost. Results: Patients who underwent TMT had significantly decreased overall (conventional regression: Hazard Ratio (HR) 1.54, 95% Confidence Interval (CI), 1.39-1.71; PSM: HR 1.49, 95% CI 1.31-1.69; IPTW: HR 1.54, 95% CI 1.39-1.71) and cancer-specific (conventional regression: HR 1.51, 95% CI 1.40-1.63; PSM: HR 1.55, 95% CI 1.32-1.83; IPTW: HR 1.51, 95% CI 1.40-1.63) survival. Median total costs were significantly higher with trimodal therapy than with radical cystectomy at 6-month ($171,401 vs. $99,890, p < 0.001). Conclusions: Using population-based data and different analytic methods to control for imbalance between study groups, we found that trimodal therapy was associated with decreased overall and cancer-specific survival at increased costs compared to radical cystectomy.
Sarcopenia as a predictor of perioperative outcomes following radical cystectomy in a contemporary cohort of patients with bladder cancer.
Authors: Drury Nicholas Brent , Worrilow William Mills , Beano Hamza Mustafa , Robinson Myra M. , Ignatoff Jeffrey , Britt Peter , Wilder Jessica , Hensel Caitlin , Sylvestre Dana , Gaston Kris E , Clark Peter E , Riggs Stephen Boyd
Published: May 2019

e16031

Background: Sarcopenia has gained considerable recognition as an important prognostic factor for complications, longer hospital stay, and survival following cystectomy for bladder cancer. However, inconsistent cutoff values to define sarcopenia have been utilized throughout the literature. Our aim was to evaluate sarcopenia as a predictor of outcomes following radical cystectomy with urinary diversion (RCUD) using the international consensus definition, Martin criteria, and Mayr criteria, as a standardized cutoff value would potentially reduce bias across studies. Methods: A retrospective analysis of patients treated with RCUD at our institution between 2010 and 2017 was performed. Sarcopenia was defined according to the aforementioned criteria and assessed by measuring total psoas area (TPA) on preoperative computerized tomography. The impact of sarcopenia on perioperative outcomes, cancer-specific survival (CSS), and overall survival (OS) was evaluated with univariate and multivariate regression models. Results: Of 258 patients who underwent RCUD, 195 had available computed tomography scans within 90 days of surgery. The median TPA scores among men and women were 578.0 and 459.6 mm2/mm2, respectively. The overall incidence of sarcopenia according to the international consensus definition, Martin criteria, and Mayr criteria was 36.4% (71/195), 24.1% (47/195), and 31.3% (61/195), respectively. Regardless of definition, significant differences were not observed in length of stay, high grade complications, readmissions, and discharge destination (all P > .05). Furthermore, sarcopenia was not significantly associated with CSS or OS. The median follow-up time was 4.1 years (95% CI: 3.6 - 4.4). The 5-year CSS and OS were 46.3% and 66.2%, respectively. Conclusions: Irrespective of definition, we were unable to externally validate sarcopenia as a predictor of perioperative outcomes in our contemporary cohort. Future studies will evaluate the impact of our evolving perioperative care pathway on oncological outcomes, including its ability to mitigate the effects of sarcopenia through reducing the physiological and mental demands of surgery.
Risk factors for renal failure (RF) during high-dose chemotherapy (HDCT) and outcomes for patients (pts) with relapsed germ-cell tumors (rGCT).
Authors: Zhang Kevin Juan , Hanna Nasser H. , Abu Zaid Mohammad Issam , Abonour Rafat , Albany Costantine , Einhorn Lawrence H. , Adra Nabil
Published: May 2019

e16042

Background: Pts with rGCT can be cured with salvage chemotherapy (CT). We evaluated risk factors and outcomes of pts who developed RF during HDCT for rGCT. Methods: All pts were planned to receive 2 consecutive courses of HDCT per protocol (N Engl J Med 2007;357:340-8). Characteristics and outcomes of pts sustaining grade ≥3 RF were analyzed and compared with those not sustaining grade ≥3 RF. Results: 21 (4%) of 473 pts had grade ≥3 RF: median age 38 (range 25-70), median creatinine 1.2 (0.6-1.8), median creatinine clearance (CrCl) 94 (48-216), median body mass index 27.1 (19.9-34.2). Median # prior standard-dose cisplatin-based CT cycles 5 (4-8) and median total dose of cisplatin 1000mg (600-1976). 10/21 pts had history of renal disease prior to HDCT, 4 had hypertension, 2 had diabetes, 2 had solitary kidney and 5 had stent or nephrostomy tube for obstruction. 20/21 pts developed neutropenic fever. 5 required total parenteral nutrition and 18 required hemodialysis (HD) during HDCT. 6 of 21 died during HDCT. 10 of 15 pts who survived HDCT had renal function recover to baseline, 2 came off HD but renal function was not restored to baseline, and 3 continued to be on HD at most recent f/u. In comparison to pts (n = 452) who did not experience grade ≥3 RF, pts (n = 21) who did experience grade ≥3 RF were more likely treated with HDCT ≥ 3rd line setting (38% vs 15%), had ECOG PS 1/2 (53% vs 18%), less likely to receive both courses of HDCT (33% vs 94%), more likely to experience GI (62% vs 11%), hepatic (43% vs 3%), pulmonary (38% vs 2%), and infectious (95% vs 1%) grade ≥ 3 toxicities; treatment-related death was also higher in this group (29% vs 2%). With a median f/u of 10 months after HDCT, 5 pts had no evidence of disease (NED), 3 were alive with disease, 6 died of disease, 6 died from complications of HDCT, and 1 lost to follow up. Conclusions: Irreversible RF during HDCT for rGCT is uncommon, but is associated with higher rates of infectious, GI, hepatic, pulmonary complications and treatment-related death. These pts are more heavily pre-treated, have lower baseline PS, and are likely to have history of renal disease prior to HDCT. However, most surviving pts recovered their renal function and 5/21 remain alive with NED.
High DNA damage levels to predict hematologic toxicity in testicular germ cell tumor (TGCT) patients treated with first-line chemotherapy.
Authors: Mego Michal , Hapakova Nikola , Sestakova Zuzana , Holickova Andrea , Miskovska Vera , Chovanec Michal , Rejlekova Katarina , Svetlovska Daniela , Kalavska Katarina , Obertova Jana , Palacka Patrik , De Angelis Valentina , Sycova Zuzana , Mardiak Jozef , Chovanec Miroslav
Published: May 2019

e16055

Background: TGCTs are an excellent example of chemosensitive disease. However, cisplatin-based chemotherapy has significant side effects, including myelosuppression. Previously, we found endogenous DNA damage level in peripheral blood mononuclear cells (PBMCs) to be an independent prognostic marker. We tested the hypothesis that patients with high endogenous DNA damage levels in PBMCs have an increased risk of developing hematologic toxicity. Methods: 120 chemotherapy-naïve patients with TGCTs treated in the National Cancer Institute and the St. Elisabeth Cancer Institute in Bratislava, Slovakia, from 2012 to 2018 were enrolled. All patients received platinum-based chemotherapy with G-CSF support. On the day of starting treatment, we measured the endogenous DNA damage levels in PBMCs using the Comet assay. We used a cut-off level of 5.25, a value previously found to stratify patients based on their prognosis. We monitored hematologic toxicity during the 1st cycle of chemotherapy. The mean and SEM were calculated for all variables. Results: Patients with high DNA damage levels ( > 5.25) had more significant hematologic toxicity with significantly lower nadir white blood cell count (6.0±1.1×109/L vs 9.8±1.0×109/L p = 0.001), absolute neutrophil count (4.1±1.0×109/L vs 7.0±0.9×109/L p = 0.013) and absolute lymphocyte count (ALC, 1.1±0.1×109/L vs 1.5±0.1×109/L p < 0.001). ALCs on day 0 (1.5±0.1×109/L vs 1.8±0.1×109/L p = 0.005) and day 22 (2.0±0.1×109/L vs 2.4±0.1×109/L p = 0.046) were also significantly lower in patients with high DNA damage levels. There were no significant differences in hemoglobin levels or platelet counts between the two groups. Neutrophil to lymphocyte ratio and systemic immune-inflammation index were lower at nadir in patients with high DNA damage levels, however, these differences were not statistically significant (p = 0.08 and p = 0.10, respectively). Conclusions: This study shows that higher endogenous DNA damage levels correlate with an increased risk of hematologic toxicity. The Comet assay data can be used to select patients for closer monitoring due to a higher risk of acute chemotherapy-related complications.
Delivery of bleomycin among patients with testicular cancer: A population-based study of pulmonary monitoring and toxicity.
Authors: Booth Christopher M. , Raphael Michael J. , Wei Xuejiao , Robinson Andrew George , Bedard Philippe L. , Karim Safiya , Lougheed M. Dianne
Published: May 2019

e16056

Background: Bleomycin is commonly used to treat testicular cancer and can be associated with severe pulmonary toxicity. There is limited information about how clinicians monitor patients during treatment and the incidence of pulmonary toxicity in routine practice. Methods: The Ontario Cancer Registry was linked to electronic records of treatment to identify all incident cases of testicular cancer treated with orchiectomy and bleomycin, etoposide, and cisplatin (BEP) chemotherapy in the province of Ontario during 2005-2010. Health-administrative databases were used to describe use of pulmonary function tests (PFTs), chest imaging and physician visits. Results: 475 patients were treated with orchiectomy and chemotherapy. Complete chemotherapy records were available for 93% (368/394) of men treated with BEP. Bleomycin was omitted among 32% (116/368) of patients. PFTs were performed in 17% (63/368), 17% (61/368) and 29% (106/368) of patients before BEP, during BEP, and within 2 years of finishing BEP, respectively. During chemotherapy, 62% of patients (227/368) had chest imaging. In the two years following BEP, 23% (85/368) had a physician visit for respiratory symptoms; this rate was substantially higher among men with greater exposure to bleomycin; 40% (24/60) for 10-12 doses bleomycin vs 21% (53/250) for 7-9 doses vs 14% (8/58) for 1-6 doses (p = 0.002). Two percent of men (8/368) had visit codes for pulmonary fibrosis. Conclusions: A substantial proportion of men treated with BEP will seek medical attention after chemotherapy for respiratory symptoms and this is associated with cumulative dose of bleomycin. Use of PFTs and chest imaging during treatment is common. Whether PFT test results or clinical symptoms are leading to bleomycin dose omission is uncertain.
Impact of cisplatin-related adverse health outcomes (AHOs) on employment outcomes and self-reported health (SRH) among testicular cancer survivors (TCS).
Authors: Kerns Sarah L. , Fung Chunkit , Fossa Sophie D. , Dinh Paul C , Monahan Patrick O. , Sesso Howard D. , Frisina Robert D. , Feldman Darren R. , Hamilton Robert James , Vaughn David J. , Martin Neil E. , Huddart Robert A , Kollmannsberger Christian K. , Sahasrabudhe Deepak M. , Ardeshirrouhanifard Shirin , Einhorn Lawrence H. , Travis Lois B. ,   The Platinum Study Group
Published: May 2019

e16058

Background: We aim to provide new information on cisplatin-related AHOs and employment status in TCS and evaluate impact on SRH. Methods: 1,815 TCS ³1 year post-chemotherapy underwent physical exam, audiometry, renal function evaluation, and completed questionnaires. Therapy data were obtained from medical records. A cumulative burden of morbidity score (CBMPt) assessed the number and severity of platinum-related AHOs (peripheral sensory neuropathy (PSN), hearing loss, tinnitus, and renal function) with grading per CTCAE v4.03. Multivariable regression assessed relations between CBMPt score, individual AHOs and employment status as well as SRH, adjusting for sociodemographic/clinical factors. Unemployment in TCS was compared with subjects in the Behavioral Risk Factor Surveillance System (BRFSS) of similar age/race/ethnicity. Results: Almost 1 in 10 TCS were either on disability leave (2.4%) or unemployed (6.8%) at a median age of 37 yr (median follow-up: 4 yr). TCS with tinnitus (OR = 3.1, grade 3 vs. 0, P = 0.04), renal dysfunction (OR = 13.5, grade 3 vs. 0, P = 0.01), or pain (OR = 7.2 and 40.9, grade 2 or 3 vs. 0, respectively; P < 0.001 each) had significantly greater odds of disability leave vs. full-time employment after adjusting for sociodemographic/clinical factors; pain was strongly correlated with PSN (Pearson r2= 0.40; P < 0.001). CBMPt score was associated with disability leave (OR = 1.5, P = 0.04), but not with unemployment. A significantly higher percentage of TCS were unemployed vs. BRFSS norms (e.g. 3.6% of TCS age 35-39 vs. 2.0% in BRFSS). PSN (OR = 2.2, grade 3 vs. 0, P = 0.02), self-reported hearing loss (OR = 1.8, grade 2/3 vs. 0, P = 0.04), and pain (OR = 2.8 and 8.5, grade 2 or 3 vs. 0, respectively; P < 0.01 each) were each associated with increased odds of unemployment vs. full-time employment. Cisplatin-related AHOs and pain were associated with significantly worse SRH (P < 0.05). Conclusions: Our findings have new, important implications regarding productivity loss and socioeconomic costs in TCS. Survivorship care strategies should include inquiries about employment status, and every effort made to assist affected TCS in returning to the work force.
Utilization of mental health services among survivors of testicular cancer: A population-based study.
Authors: Booth Christopher M. , Raphael Michael J. , Wei Xuejiao , Soares Claudio , Bedard Philippe L. , Leveridge Michael , Siemens D. Robert , Robinson Andrew George
Published: May 2019

e16062

Background: Testicular cancer survivors may experience long-term psychological distress related to their diagnosis and treatment. Measurement of mental health service use (MHS) is an objective way to quantify the incurred burden of psychological distress. Here we describe patterns of MHS use among survivors of testicular cancer in a single-payer health system. Methods: The Ontario Cancer Registry was linked to electronic treatment records to identify all incident cases of testicular cancer treated with orchiectomy in the Canadian province of Ontario during 2004-2010. Mental health clinical visits were identified from records of hospital admission, emergency room visits and out-patient physician billing records. Results: The study cohort included 1877 patients; mean age was 35 and 61% had pure seminoma. Two thirds of patients (66%, 1230/1877) were initially treated with active surveillance. In the 2-year period prior to orchiectomy, 24% (443/1877) of patients had MHS use. Post-orchiectomy, the prevalence of MHS use was 18% (331/1877), 23% (431/1877) and 30% (572/1877) at 6, 12 and 24 months, respectively. The use of MHS was greatest in the peri-diagnostic/surgical period. Rates of MHS visits, 3 months before, 0-3 months after, 4-6 months after and 2 years after orchiectomy were 11%, 14%, 10%, and 6%, respectively. Post-orchiectomy MHS use was greatest among those with baseline MHS use. The prevalence of MHS use for patients with and without baseline MHS use was 40% (175/443) vs 11% (156/1434, p < 0.001) at 6 months; 51% (225/443) vs 14% (206/1434, p < 0.001) at 12 months; and 61% (271/443) vs 21% (301/1434, p < 0.001) at 24 months post-orchiectomy. Post-orchiectomy MHS use did not vary by initial treatment strategy (active surveillance vs upfront treatment, p = 0.435). Older patients were more likely to have MHS visits at all time periods than younger patients; MHS rates at 6 months were 15% (93/631) vs 18% (112/625) vs 20% (126/621) for ages 16-29, 30-39, and 40+ years respectively (p = 0.035). Conclusions: MHS use among survivors of testicular cancer is common, particularly in the peri-diagnostic and surgical period. The rate of MHS use is highest among those patients with a history of prior MHS use. Clinicians should screen for the presence of psychological distress among survivors of testicular cancer.
The clinical features of extragonadal germ cell tumors: A SEER analysis.
Authors: Alnimer Yanal Mufeed , Katato Khalil
Published: May 2019

e16064

Background: Extragonadal germ cell tumor is an uncommon type of malignancy. We aim to identify the clinical features and the prognosis in various histological subtypes in these patients using the Surveillance, Epidemiology, and End Results Program (SEER) database. Methods: We used the (SEER) database to identify the patients with non-gonadal germ cell tumors between 1998-2015. 1299 patients were identified and included in our analysis. Results: 1299 patients had non-gonadal germ cell tumors between 1998-2015. The mean age was 26 years-old. 568 patients (44%) were females and 731 patients (56%) were males. 276 patients (21%) died after a mean follow up time of 41.16 months (1-60 months). The mean overall survival (OS) was 49.4 months (95%CI 48.21-50.52) with the median being unreached. The Females had better OS compared to the males with a Hazard ratio (HR) = 0.50 (95%CI 0.40-0.63). Age more than 60 years-old at the time of diagnosis was associated with a substantially significant increase in mortality with an HR = 43 (95% CI 19.17-94.41). The mediastinal germ cell tumors were associated with worse OS compared to other sites with a HR = 4.69 (95%CI 3.37-6.52). The median OS for Embryonal cell carcinoma was 22 months, and it was associated with worse OS compared to seminoma and other histological subtypes with a HR = 4.10 (95% CI 1.69-9.72) and 2.77 (95% 1.16-6.58) respectively. On the other hand, Seminoma was associated with better OS compared to other histological subtypes with an HR = 0.66 (95%CI 0.52-0.84). Moreover, tumor size less than 80 mm was associated with better OS with a HR = 0.42 (95%CI 0.30-0.64). In multivariate analysis, patients above the age of 60 had worse OS with an HR = 4.04 (95%CI 1.71-9.58), patients with mediastinal germ cell tumors had poorer OS compared to other sites with an HR = 2.38 (95%CI 1.51-3.79). Furthermore, embryonal carcinoma, mixed germ cell tumors and choriocarcinoma were associated with worse OS compared to seminoma and immature teratoma with an HR = 10.39 (95% CI 4.36-24.72), HR = 2.07 (95% CI 1.23-3.46) and HR = 6.16 (95%CI 2.98-12.74) respectively. Conclusions: Non-gonadal seminoma and immature teratoma carry better prognosis compared to other histological subtypes. Also, among non-gonadal germ cell tumors, non-mediastinal seminoma has the best survival outcome.
Prognostic value of serum C-reactive protein level prior to second-line treatment in intermediate risk metastatic renal cell carcinoma patients.
Authors: Takamatsu Kimiharu , Mizuno Ryuichi , Hayakawa Nozomi , Kikuchi Eiji , Kosaka Takeo , Oya Mototsugu
Published: May 2019

e16065

Background: The later-line treatment of metastatic renal cell carcinoma (mRCC) has been drastically changing by the development of immune-oncology drugs and molecular targeted treatment in recent years. Although the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is useful for second-line setting, this model has the problem that over 50% patients are classified as intermediate risk group. The aim of this study is to evaluate whether the serum C-reactive protein (CRP) levels prior to second-line treatment could divide intermediate risk group patients. Methods: We retrospectively reviewed 150 mRCC patients received second-line molecular targeted therapy. We assessed the prognostic impact of serum CRP levels prior to second-line treatment initiation to predict overall survival (OS) especially in intermediate risk group. Results: The median OS from second-line treatment of whole cohort and intermediate risk group were 24.6 (95%confidence interval, 95%CI:18.2-31.0) and 23.6 (95%CI:15.1-32.1) months. Thirty-three out of 82 (40%) intermediate risk patients demonstrated elevated baseline CRP levels. The median OS of elevated and non-elevated CRP group were 13.4 (95%CI:5.9-20.8) and 29.4 (95%CI:25.5-33.5) months, respectively (p = 0.001). The serum CRP elevation could predict prognosis in intermediate risk patients treated with second-line treatment (HR 2.5,95%CI:1.4-4.2, p = 0.001). Conclusions: The serum CRP levels at second-line treatment initiation could divide intermediate risk mRCC patients into two prognostic subgroups.
Renal cell carcinoma in kidney transplant recipients at Guy’s and King’s College Hospital (UK) between 1987-2018.
Authors: Butt Sabeeh-Ur-Rehman , Chow Barbara , Shah Sapna , MacDougall Iain , Shaw Catriona , Kirmizis Dimitrios , Chowdhury Simon , Rudman Sarah Maria , Josephs Debra Hannah , Zakri Rhana , Olsburgh Jonathon , Enting Deborah
Published: May 2019

e16066

Background: The increased incidence of cancer after renal transplantation is well recognised. Differences in cancer risk depend on the type of cancer but overall the incidence of solid cancer in kidney transplant recipient is at least twofold. Long term immunosuppression, oncogenic viruses and changes in immune surveillance are contributing factors. The incidence of renal cell carcinoma (RCC) is approximately six-fold greater than in the general population. Screening for RCC in the post-transplantation setting is not routine. Methods: Retrospective case series of kidney transplant recipients who underwent transplantation between 1987 and 2018 at Guy’s Hospital (London, UK). Collected data on patients who developed RCC post-transplant included: baseline demographics, renal disease, transplant survival, tumour characteristics, cancer treatment and survival. Results: 2968 patients underwent kidney transplantation between 1987 and 2018 at our Centre. 52 patients (1.8%) developed RCC. 40 (74%) were male with a median age of 51 years. 37% (71%) were white and 12 (23%) were black. The causes of end stage kidney disease included IgA nephropathy, hypertension and polycystic kidney disease. Median time to RCC diagnosis after transplant was 9 years (range 0-27). 86% of patients presented with stage 1/2 tumours, with the majority (72%) occurring in native kidneys. Most underwent radical nephrectomy although 5 patients were managed with radiofrequency-ablation (RFA) or surveillance (donor kidneys). Of 6 patients with metastatic disease, 5 received pazopanib and 1 everolimus. 4 patients continued systemic therapy for over 3 months and all derived clinical benefit with a median drug exposure of 19 months .15 patients required further kidney transplant or dialysis. Overall only 2 patients died from RCC. Conclusions: This retrospective study is the largest single-centre UK study to our knowledge. Kidney transplant recipients experience a marked increased risk of developing RCC. Most diagnosed RCCs are small and disease-specific mortality is low. With a third of tumours arising in donor organs, questions around optimum loco-regional approach and screening of high-risk population remain unanswered.
Real life data from Turkey regarding the impact of first-line sunitinib and pazopanib in metastatic renal cell cancer.
Authors: Isik Ulas , Kostek Osman , Demiray Gokcen , Dirican Ahmet , Simsek Melih , Büyüksimsek Mahmut , Ucar Gokhan , Gunaydin Ulug Mutlu , Sakalar Teoman , Aliyev Altay , Demir Atakan , Turhal Serdar , Pilanci Kezban Nur , Kefeli Umut , Gokyer Ali , Paydas Semra , Uncu Dogan , Okten Ilker Nihat , Uygun Kazim , Cabuk Devrim
Published: May 2019

e16075

Background: Although the distribution in the world varies widely, renal cell carcinoma (RCC) is the ninth most common cancer, especially in males. It’s the seventh most common cancer in Turkey. In this study, the progression-free survival (PFS) and overall survival (OS) of patients with metastatic RCC (mRCC) who were treated at 13 centers in our country were evaluated and the efficacy of first-line treatment approaches was compared. Methods: Data of mRCC patients admitted to 13 outpatient clinics in Turkey between 2008 and 2018 were reviewed retrospectively. Demographic characteristics, pre-treatment clinical evaluations, information about treatment approaches and survival outcomes of the patients were collected. All medical records were collected by a detailed review of the patients’ charts. The median and percentage values were frequently signified for defining of central trends. Kaplan-Meier method was applied for OS analyzes and log-rank test with Cox-regression models were applied for the evaluation of prognostic factors. Results: Data from files of 262 patients were reviewed. Twelve of these patients were excluded from the study because they could not receive treatment due to comorbidities and other reasons at metastatic stage of the disease. Of the patients, 100 (40%) were female and 150 (60%) were male. Median age was 60 (range 21-83). For the entire group, the median PFS (mPFS) was 27.6 months and the median overall survival (mOS) was 46.1 months. In terms of first-line treatment of metastatic disease, 41.3% of the patients received sunitinib, 48.8% of the patients received pazopanib, 15.8% of the patients received other treatments. PFS of the patients receiving sunitinib, pazopanib and the other treatments were 26.3 months, 34.2 months and 14.2 months, respectively. There was no statistically significant difference between PFS of the patients receiving sunitinib and pazopanib (p = 0.05). mOS was 54 months in sunitinib arm, 54.9 months in pazopanib arm and 23.3 months in the other treatment arm. There was no statistically significant difference between two treatment agents in terms of mOS (p = 0.43). Conclusions: Pazopanib was more commonly prescribed in Turkey. There were no statistically significant differences between mPFS and mOS of the patients who received sunitinib and pazopanib for the first-line treatment of mRCC. With increased use of immunotherapeutic agents for the first-line treatment of mRCC in our country, improvement in mOS could be expected.
Immunotherapy with nivolumab in metastatic renal cell carcinoma in resource constraint settings: Impact of increasing intervals between standard doses, and stopping treatment early in responding patients.
Authors: Rauthan Amit , Patil Poonam , Yashas Nitin , Kulkarni Shriniwas Subhash , Sood Tanvi , Nigade Gaurav , Somashekhar S.P. , Zaveri Shabber
Published: May 2019

e16078

Background: Nivolumab is now a standard 2nd line treatment for patients of metastatic Renal cell cancer (mRCC) who progress on 1st line Sunitinib or Pazopanib. Most western centers use Nivolumab for either 2 years duration, or indefinitely, or till severe side effects. Due to high drug cost and lack of insurance, it is difficult for most of our Indian patients to afford this duration of treatment. So, we decided to study the impact of increasing intervals between standard doses of Nivolumab, and stopping treatment early in responding patients of mRCC. Methods: This is a single centre, retrospective study of mRCC patients. Nivolumab was given at either 3 mg/kg or 240mg at 2 weekly intervals for the initial 6 cycles. If the patient were found to have either Complete Response (CR), Partial Response (PR) or stable disease, the interval between cycles was extended to 3 weeks (at same dose). After 9 months, the doses were extended to 4 weekly intervals (at same dose). The treatment was stopped at 18 doses in patients with CR or PR. The endpoints were objective response rate (ORR), overall survival (OS) and adverse events (AE). Results: Between May 2016 and Dec 2018, 28 patients received Nivolumab. 24 patients had received oral TKIs initially- 13 Sunitinib, 10 Pazopanib, and 1 Sorafinib. 4 patients received Nivolumab as 1st line therapy (2 as single agent, 2 with oral TKI). Response was assessed by RECIST criteria. 3 patients (11%) achieved CR, 7(25%) achieved PR, 7 (25%) had stable disease and 11(39%)had progressive disease. Treatment was stopped after 18 doses in the 3 patients who had CR. The duration of followup after stopping treatment ranges from 8 months to 18 months, and all 3 patients continue to be in CR. 3 patients with stable disease have received more that 18 cycles (1 at 22 cycles, 2 at 19 cycles). OS at 1 year is 60% and median OS has not been reached. Conclusions: In our experience, Nivolumab is an effective agent in mRCC, even when the dosage intervals are increased, and when the treatment is stopped early in responding patients. An ORR of 36% and a OS at 1 year of 60% is the best we have seen. Long-lasting responses, even after discontinuing therapy, have been seen. This enables us to reduce the cost of treatment without possibly losing efficacy, and this could be an important step forward for treating more patients with Nivolumab in our resource constraint setting.