bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic impact of LDH and HCG levels in marker-positive seminomas.
Authors: Seidel Christoph Alexander , Daugaard Gedske , Nestler Tim , Tryakin Alexey , Fankhauser Christian Daniel , Hermanns Thomas , Aparicio Jorge , Heinzelbecker Julia , Paffenholz Pia , Heidenreich Axel , De Giorgi Ugo , Cathomas Richard , Lorch Anja , Bremmer Felix , Giannatempo Patrizia , Necchi Andrea , Aurilio Gaetano , Casadei Chiara , Oing Christoph , Bokemeyer Carsten 
Published: February 2020

392 Background: The prognostic impact of LDH and HCG serum levels in marker positive metastatic seminoma patients is uncertain. This analysis evaluated the association between LDH and HCG levels with oncological outcomes in this patient population. Methods: Seminoma patients with elevated HCG levels were retrospectively analyzed. After stratification according to tumor marker levels pre- and post-orchiectomy, outcomes of subgroups were compared using log-rank test and cox-regression analysis. Study endpoints were cancer specific- (CSS) and recurrence-free survival (RFS). Results: In total, 429 HCG-positive metastatic seminoma patients (stage II n=291; stage III n=138) diagnosed between 1981 and 2018 were included. LDH + HCG levels ranged from 124 U/l to 8833 U/l (median: 619; IQR: 955) + 2 IU/l to 283,782 IU/l (median: 20; IQR: 63) pre- and from 107 U/l to 8650 U/l (median: 324; IQR: 481) + 0 IU/l to 36700 IU/l post-orchiectomy (median: 30; IQR: 121), respectively. Five-year CSS and RFS rates were 90% and 79%, respectively. Patients with LDH levels pre-orchiectomy <1.5 UNL (n=142) had a 5-year CSS (RFS) rate of 97% (88%), compared to 86% (81%) for ≥1.5 to 3 UNL (n=40), 83% (77%) for >3 to 5 UNL (n=44) and 83% (72%) for >5 UNL (n=44) (CSS p <0.001; RFS p=0.142). Concerning LDH levels post-orchiectomy this stratification was not significant but patients with LDH levels ≥3 UNL (n=77) displayed an impaired prognosis associated with a 5-year CSS (RFS) rate of 85% (79%) compared to 94% (82%) for levels <3 UNL (n=186) (CSS p=0.025; RFS p=0.447). Patients with HCG levels ≥2000 IU/l (n=17) pre- but not post-orchiectomy had a 5-year CSS (RFS) rate of 73% (60%) compared to 94% (79%) for patients with HCG levels <2000 IU/l (n=855) (CSS p=0.09; RFS p=0.04). In cox-regression analysis LDH ≥1.5 UNL (p=0.037; HR 3.32, CI95%1.08-10.26) and HCG levels ≥2000 IU/l (p=0.044; HR 3.69, 95%CI1.04-13.13) pre-orchiectomy were confirmed as prognostic factors for CSS. Conclusions: LDH levels inversely correlate with survival outcomes, suggesting ≥1.5 UNL pre- and ≥3 UNL post-orchiectomy as potential cut-off values for further risk assessment. Patients with extensive HCG elevations may represent an unfavorable subgroup concerning RFS and CSS, but only few patients were affected.
Germline alterations in patients with testicular cancer.
Authors: Ramamurthy Chethan , Esplin Edward D. , Yang Shan , Liss Michael , Tomlinson Gail Elizabeth , Sonpavde Guru 
Published: February 2020

397 Background: There are limited data for the association of testis cancer (TC) with hereditary cancer genes. We report the prevalence of germline mutations among men with TC completing germline genetic testing through a large, commercial laboratory. Methods: We reviewed a de-identified dataset of men from across the USA with history of TC who underwent testing of 1 to 130 genes via massively parallel sequencing with customized capture bait-sets to analyze exonic regions, flanking intronic sequences, and copy number alterations. Pathogenic (P) and likely pathogenic (LP) were confirmed using orthogonal technology in accordance with Invitae standard operating practices. P/LP variants including single nucleotide variants/indels/copy number variants are reported. Fisher’s Exact test was used to analyze categorical variables. Results: The cohort of 250 men was 84% White/Caucasian. The median number of genes tested was 48. P/LP variants were found in 18% (n = 45) of subjects. P/LP variants occurred in several moderate to high penetrance genes, including CHEK2 (n = 10 [4.0%]), BRCA1/2 (n = 6 [2.4%]), ATM (n = 6 [2.4%]) and Lynch syndrome genes (n = 4 [1.6%]). Heterozygous MUTYH (n = 6) and NTHL1 (n = 1) mutations were also found. DNA damage repair (DDR) mutations were found in 14.8% (n = 37) of subjects. Of the 45 carriers, 18 (40%) had no other personal cancer history while 27 (60%) had an additional primary cancer, but there was no significant association between having another primary and risk of carrying a mutation (p = 0.253). CHEK2 was the single most frequently mutated gene, with 2 of the low penetrance I157T mutations identified, but 8 other higher penetrance variants, including 2 1100delC mutations. Conclusions: A high percentage of hereditary cancer gene mutations were found in testicular cancer patients, many which were not associated with a history of another malignancy. Several mutations were in high penetrance DDR genes such as BRCA1/2 and Lynch genes, which may also serve as actionable targets. CHEK2 mutations were common, supporting prior data suggesting an association with testicular cancer. Further multigene panel testing in unselected patients and the study of association with histologic subtype, race, stage and family history is warranted.
Treatment compliance and early toxicity in SAKK 01/10: Single-dose carboplatin and involved-node radiotherapy for treatment of stage IIA/B seminoma.
Authors: Papachristofilou Alexandros , Bedke Jens , Hayoz Stefanie , Fischer Natalie , Schiel Xaver , Schratzenstaller Ulrich , Krege Susanne , Lorch Anja , Aebersold Daniel M. , Putora Paul-Martin , Berthold Dominik R. , Zihler Deborah , Azinwi Ngwa C. , Zengerling Friedemann , Dieing Annette , Mueller Arndt-Christian , Cathomas Richard 
Published: February 2020

405 Background: Standard treatment options for stage IIA/B seminoma include either extensive paraaortal/pelvic radiotherapy or intensive chemotherapy with 3x BEP or 4x EP. Both treatment modalities are associated with excellent efficacy but also a high rate of acute and late toxicities. Therefore, de-escalation strategies appear warranted for this patient group aiming to minimize acute and long-term toxicities while maintaining efficacy. SAKK 01/10 is a joint project of the Swiss Group for Clinical Cancer Research and the German Testicular Cancer Study Group. Methods: Patients with stage IIA/B seminoma (de novo or relapse on active surveillance) were eligible for participation in this single arm phase II trial. A repeat scan was advised in patients with equivocal lymph node enlargement. Treatment consisted of one cycle carboplatin AUC7 followed by involved-node radiotherapy with 30 Gy in stage IIA and 36 Gy in stage IIB disease. The primary endpoint of the trial is 3-year progression free survival. We report on treatment compliance and early toxicity during treatment and within 30 days. Results: 120 patients with stage IIA/B seminoma were recruited from 10/12 until 06/18 in 20 study centers in Switzerland and Germany. 116 patients were eligible and initiated treatment per protocol (40% stage IIA, 60% stage IIB). All patients received chemotherapy (CT) with a median applied dose of 984 mg (range: 560-1920 mg). The median planning target volume (PTV) for radiotherapy (RT) was 297 cm3 (range: 24-1047 cm3). RT was delayed/interrupted in two patients due to adverse events. During CT, grade 2 and grade 3 adverse events were seen in 21% and 2% of all patients respectively (most common grade 2 events: neutropenia 6%, nausea 5%). During RT, grade 2 and grade 3 adverse events were seen in 26% and 6% of all patients respectively (most common grade 2 events: neutropenia 15%, nausea 6%). One case of transient creatinine increase was reported as a severe adverse event, resolving without sequelae. Conclusions: Treatment with one cycle carboplatin AUC7 and 30-36 Gy involved-node radiotherapy for stage IIA/B seminoma is feasible and demonstrates a very favorable early toxicity profile. Clinical trial information: NCT01593241.
Biomarkers of lung damage with possible predictiveness of ARDS within CS in super high-risk patients with germ cell tumors.
Authors: Rejlekova Katarina , Kalavska Katarina , Celec Peter , Makovnik Marek , Chovanec Michal , Hapakova Nikola , De Angelis Valentina , Obertova Jana , Palacka Patrik , Sycova Zuzana , Mardiak Jozef , Mego Michal 
Published: February 2020

411 Background: Germ cell tumors (GCTs) represent a highly curable disease; however, a small proportion of patients with super-high-risk characteristics (choriocarcinoma, massive lung metastases, choriogonadotropin > 50 000 mIU/ml) can develop choriocarcinoma syndrome (CS) and consecutive acute respiratory distress syndrome (ARDS) shortly after the chemotherapy start with high mortality rate. This study aimed to evaluate biomarkers of lung damage as predictive biomarkers for ARDS development within CS in poor-risk GCTs patients. Methods: This study included 23 poor-risk GCTs treated from November 2000 to May 2018 in National Cancer Institute in Slovakia for whom plasma samples before chemotherapy initiation were available. Plasma levels of lung damage biomarkers (surfactant protein (D-SPD), receptor of advanced glycation end-products (sRAGE), and club cell secretory protein – (CC16)) were evaluated by ELISA assays. Results: Five (22%) of 23 patients developed CS, and all of them died shortly after the chemotherapy start. with median of 7 days (4 - 35 days). Four of them developed ARDS within CS, while one patient died due to massive abdominal hemorrhage. Pre-treatment levels of s-RAGE and SPD but not CC-16 were significantly associated with CS development ( P = 0.03 and P = 0.04). Level of sRAGE and SPD correlated significantly with dyspnea, weight loss, extent of metastatic lung involvement and need of mechanical ventilation after chemotherapy start, as well as with PFS and OS, while CC-16 did not correlate with any of these factors. Conclusions: In this study we identified new predictive biomarkers for CS development in poor-risk GCTs. Abovementioned factors might help to improve the risk stratification of these patients with GCTs as well as discover new treatment approaches preventing ARDS development within CS which may result in enhanced treatment outcome.
Response to olaparib or carboplatin in a real-world cohort of men with DNA damage repair (DDR) deficient metastatic castration-resistant prostate cancer (mCRPC).
Authors: Berchuck Jacob E , Silver Rebecca , Bakouny Ziad , Abou Alaiwi Sarah , Hamid Anis , Sweeney Christopher , Freedman Matthew L. , Pomerantz Mark , Taplin Mary-Ellen 
Published: February 2020

43 Background: PARP inhibitors (PARPi) and platinum chemotherapy cause synthetic lethality and result in clinical benefit in men with mCRPC whose tumors harbor deleterious alterations in DDR genes. BRCA2 is the strongest predictor, but data supports a role for BRCA1, ATM, and other genes. PARPi are more expensive than platinum chemotherapy; whether they are more effective is not known. We evaluated outcomes in men with DDR-deficient mCRPC treated with PARPi or platinum chemotherapy. Methods: We identified men treated at Dana-Farber Cancer Institute who received olaparib or carboplatin for mCRPC and underwent tumor mutation profiling. Progression-free survival (PFS) was determined using Prostate Cancer Working Group 3 guidelines. Pathogenic germline or somatic single-nucleotide variants, insertions/deletions, and copy number loss in BRCA2, BRCA1, and ATM, were identified. Log-rank test was utilized to compare differences in PFS. Results: We identified 27 men who received olaparib: 19/27 (70.4%) received prior taxane chemotherapy and 3/27 (11.1%) prior carboplatin; 16 had mono- or bi-allelic alterations in BRCA2 and 2 had alterations in BRCA1 or ATM. We identified 41 men treated with carboplatin: 39/41 (95.1%) received carboplatin in combination with a taxane; 36/41 (87.8%) received prior taxane chemotherapy and 7/41 (17.1%) prior PARPi; 16 had BRCA2 alterations and 5 had alterations in BRCA1 or ATM. Among men with BRCA2 alterations, there was no significant difference in PFS (HR 0.71, 95% CI 0.45-1.11; p = 0.13) between those treated with olaparib (4.9 months [m]) versus carboplatin (5.4 m). Similarly, no difference in PFS (HR 0.80, 95% CI 0.54-1.16; p = 0.24) was observed among men with BRCA2, BRCA1, or ATM alterations treated with olaparib (3.8 m) versus carboplatin (3.6 m). Conclusions: In a small real-world cohort of men with mCRPC harboring deleterious alterations in BRCA2, BRCA1, and ATM, there was no difference in PFS between those treated with olaparib versus carboplatin. These findings support further investigation into the comparative effectiveness and cost-effectiveness of PARPi and platinum chemotherapy in men with DDR-deficient mCRPC.
Patient-reported outcomes (PRO) from a phase I/II dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration-resistant prostate cancer (mCRPC).
Authors: Vlachostergios Panagiotis J. , Goswami Sukanya , Niaz Muhammad Junaid , Thomas Charlene , Christos Paul J. , Osborne Joseph , Vallabhajosula Shankar , Molina Ana M. , Sternberg Cora N. , Singh Sharon , Tan Angela , Patel Amie , Nanus David M. , Bander Neil Harrison , Tagawa Scott T. 
Published: February 2020

45 Background: We performed the 1st dose-escalation study of PSMA-targeted radionuclide therapy with 177Lu-PSMA-617. Using dose-fractionation, we intended to deliver a dose-intense regimen designed to minimize radioresistance due to repopulation. Radionuclide therapy may be able to treat symptoms due to tumor and therefore may be associated with improvement in PRO. Methods: Inclusion: progressive mCRPC following potent AR-pathway inhibitor (ARPI, e.g. abi/enza) and taxane (or unfit/refuse chemo) without limit of # prior therapies, adequate organ function, ECOG performance status 0-2, without preselection for PSMA expression. Treatment was a single cycle of fractionated dose 177Lu-PSMA-617 on D1 and D15 (7.4 to 22 GBq in phase 1; 22.2 GBq in phase 2). PRO tools included FACT-P and BPI-SF at baseline and follow up. Results: 44 men with median age 69 (range 55-91), median PSA 182.97 (range 0.89-5541) were treated. 93% with bone, 45% nodal, 18% lung, 9% liver, 9% other visceral metastases. 55% with at least 1 prior chemo regimen, 52% >2 prior ARPI, 27% with Ra223, 30% sip-T, 5% 177Lu-J591. 59.1% with >50% PSA decline (66.7% at 22.2 GBq, n=21), median overall survival 16 months (95% CI 11-NR). High grade (Gr) toxicity was rare with 6.8% Gr 3 anemia and 2.3% Gr 3 platelets. Gr 1/2 treatment-emergent AE’s include 81.8% with pain flare, 61.4% xerostomia, 29.5% fatigue, 25% platelets, 25% anemia, 25% pain, 15.5% nausea. FACT-P scores tended to improve in all categories by D22 (1 week later), with overall FACT-P scores improving by mean of 8.9 points (p=0.07) at D22 and remaining improved at 12 wks. All BPI scores also improved, with BPI overall severity score improving by mean of 3.0 at D22 (p=0.008) and remained better than baseline at 12 wks. There was no clear association with any AE and PRO changes, but those with PSA decline tended to have improved pain scores (p=0.1). Conclusions: A single cycle of up to 22.2 GBq of 177Lu-PSMA-617 is safe with fractionated (D1 & D15) dosing, with encouraging early efficacy signals in a population unselected for PSMA expression and improved quality of life and pain scores by validated PRO instruments. Clinical trial information: NCT03042468.
A risk scoring system for African-American (AA) patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with first-line abiraterone (ABA) or enzalutamide (ENZ).
Authors: Brown Jacqueline T , Liu Yuan , LaFollette Jennifer Ann , Kucuk Omer , Moore Melvin R. , Bilen Mehmet Asim 
Published: February 2020

51 Background: AA pts represented < 3% of the COU-AA-302 and PREVAIL trial cohorts that led to the approval of ABA and ENZ in the 1st line treatment of mCRPC. We characterized the clinical outcomes (CO) and developed a risk score for AA pts with mCRPC on these agents. Methods: We retrospectively reviewed 77 AA pts with mCRPC treated with 1st line ABA or ENZ at Grady Memorial Hospital from 2015-2018. The CO included median overall survival (mOS), progression-free survival (mPFS) and PSA response (PSAr) as defined by a ≥ 50% drop in PSA over the 1st 12 weeks of treatment. Cox proportional hazard model and Kaplan-Meier method were used for association with OS and PFS and logistic regression model for PSAr. The risk score was built by regression coefficient-based scoring system using OS as the 1° outcome. Covariates included grade group (GG), baseline (bl) PSA, albumin, and BMI, ECOG status, and age. Results: Median age was 60 years with median follow-up of 11.5 months (mos). 50 pts received ABA; 27 received ENZ. The overall mOS was 45.7 mos, mPFS was 12.9 mos, and PSAr was 84.4%. CO did not differ significantly for ABA vs. ENZ with a 24-month OS of 66.6% vs. 57.7% and PFS of 34.3% vs. 45%. 1 point was assigned for each of the following: GG > 3, bl PSA ≥ 108, or bl albumin ≤ 4.2. The total was classified into low (0-1), intermediate (2), and high (3) risk and associated with CO via univariate (UVA) and multivariate (MVA) analyses (Table). Conclusions: We present the efficacy of ABA and ENZ in a cohort of AA pts with mCRPC. Risk grouping using bl PSA, bl albumin and GG may predict CO in this population. These results should be validated in a larger, prospective study.[Table: see text]
Characterization of the urinary microbiota in bladder cancer patients.
Authors: Oresta Bianca , Hurle Rodolfo , Lazzeri Massimo , Frego Nicola , Saita Alberto , Faccani Cristina , Fasulo Vittorio , Casale Paolo , Pozzi Chiara , Guazzoni Giorgio Ferruccio , Rescigno Maria 
Published: February 2020

535 Background: Mounting evidence indicates that the microbiota plays an important role in carcinogenesis and response to treatments. The dogma that urine is sterile has been overturned and dysbiosis of the urinary microbiota has been linked to urological disorders. We tested the hypothesis that alteration in urinary microbial community composition may be associated to bladder cancer development and progression. Therefore, we performed a study to characterize the urinary microbiota associated with non-muscle invasive and muscle invasive bladder cancer (NMIBC, MIBC). Methods: Urines were collected with a catheter from BC patients before transurethral resection or cystectomy, and age-matched non-neoplastic subjects. Subjects with prior history of sexually transmitted infection, chronic intestinal inflammation, urinary tract infection and recent usage of antibiotic or immunomodulatory agents were excluded. Bacterial DNA was extracted and amplified for 16S rDNA sequencing. Results: We isolated bacterial DNA from urine samples of 12 non-neoplastic control subjects and 27 BC patients. The most abundant phyla in both groups were Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria, with Bacteroidetes being slightly more abundant in bladder cancer at the expense of Proteobacteria. Interestingly, we found that NMIBC displayed a reduction in the abundance of Sphingobacteriaceae, Bifidobacteriaceae and Enterobacteriaceae. High grade NMIBC and MIBC showed decreased Bifidobacterium and Ruminococcus, which are known to protect from inflammation, and increased Corynebacterium, a potential opportunistic bacteria. No correlation with environmental risk factors (i.e. smoking) was investigated. Conclusions: The urinary microbiota of BC patients displayed a significantly different pattern relative to control group, suggesting that the tumor microenvironment can influence dysbiosis. In particular, we found specific bacteria to associate with aggressive tumors. A better understanding of the urinary microbiota could pave the way for exploring new therapeutic options based on the manipulation of the microbial community. Analysis of additional samples is ongoing.
Intravesical anti-PD-1 immune checkpoint inhibition in urothelial bladder cancer in a mouse model.
Authors: Rajkumar Anne , Wang Jian , Neuzil Kevin E. , Kirschner Austin Noah , Chang Sam S. 
Published: February 2020

537 Background: Non-muscle-invasive bladder cancer is treated by resection within the bladder and bladder instillment with BCG or chemotherapy, but the majority of intermediate- and high-risk cases subsequently recur. Systemic administration of anti-PD-1 immune checkpoint inhibitors (anti-PD-1) are approved treatments for metastatic urothelial bladder cancer. We hypothesized that intravesical instillment with an anti-PD-1 inhibitor would treat localized bladder cancer. Methods: We investigated a syngeneic wild-type mouse model of orthotopic urothelial bladder cancer. We instilled MBT2 cells into wild-type C3H mice to compare treatments, which included weekly intravesical administration of chemotherapy and anti-PD-1 antibody alongside intraperitoneal administration of anti-PD1 antibody. Results: Anti-PD-1 antibody administered by bladder instillment (intravesical route) successfully treats the disease, similarly to anti-PD-1 by systemic route. Anti-PD-1 antibody by either route provides significant survival advantage over isotype control antibody given by bladder instillment. Treatment by immune checkpoint inhibitor increases CD8+ cell infiltration in tumors, particularly when administered intravesically. In addition, antibody treatment avoids toxicity observed for intravesical chemotherapy. Mice who cleared their tumors after initial treatment were rechallenged with tumor engraftment 3-9 months later without any additional treatment, showing initial-anti-PD-1 treated mice did not grow tumors but initial mitomycin-treated mice did grow tumors. Conclusions: Intravesical administration of anti-PD-1 is a promising avenue for treatment of localized bladder cancer, with comparable anti-tumor activity compared to systemic anti-PD-1 in this mouse model.
Comprehensive targeted gene profiling to determine the genomic signature likely to drive progression of high-grade nonmuscle invasive bladder cancer to muscle invasive bladder cancer.
Authors: Alkhateeb Abedalrhman , Atikukke Govindaraja , Porter Lisa , Fifield Bre-Anne , Cavallo-Medved Dora , Facca Julianna , El-Gohary Yasser , Zhang Tianmin , Hamzeh Osamah , Rueda Luis , Kanjeekal Sindu Mary 
Published: February 2020

568 Background: Bladder cancer is the fifth most common cancer and eighth leading cause of cancer related-death in North America. It can present as non-muscle invasive bladder cancer (NMIBC) and/or muscle invasive bladder (MIBC). Although genomic profiling studies have established that low-grade NMIBC and MIBC are genetically distinct, high-grade NMIBC can recur and progress to MIBC [ Knowles, M.A. and C.D. Hurst, 2015]. Low grade, non-invasive bladder cancers are characterized by activating mutations in fibroblast growth factor receptor 3 (FGFR3), HRAS or other pathways of receptor kinase activation. High-grade disease, which is often becomes invasive, is characterized by inactivation of TP53 and Rb pathways [Kim, J., et al.]. Finding a subtype of invasive carcinoma with FGFR3 mutation may suggest an alternate pathway by which low grade, non-invasive pathology could transform into invasive disease [Knowles, M.A. and C.D. Hurst, 2015]. Methods: In this study, using a total of 30 bladder cancer (NMIBC and MIBC) patient samples from Windsor Regional Hospital Cancer Program, we performed comprehensive targeted gene sequencing to identify single nucleotide variants, small insertions / deletions, copy number variants and splice variants in over 500 common tumor genes panel. Results: Preliminary data from our study correlates with previously published mutation landscape for NMIBC and MIBC, and includes mutations in EGFR, FGFR3, FGFR4, PIK3CA, CDK6, ALK, JAK, as well as RET. While mutations in AKT1, BRCA1, CCND1, ERBB2, FGFR1, FGFR2, HRAS, and MET appear to be prevalent in NMIBC, mutations in IDH1 and MAP2K2 appear to be more common in MIBC. Three of the samples used in the study are from patients who progressed from high-grade NMIBC to MIBC. Conclusions: Therefore, have the genomic profiling performed at these two stages, which provides a unique ability to identify the potential “genomic triggers” for the transition.