bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized trial of 72-hour infusional bleomycin in BEP (cisplatin, etoposide, and bleomycin) versus conventional weekly bleomycin in patients with metastatic IGCCCG good prognosis disease.
Authors: Vinnicombe Sarah , Harland Stephen John , Joffe Johnathan K. , Huddart Robert , Mazhar Danish , Birtle Alison J. , White Jeff D. , Wilson Peter , Marshall Marita , Sarker Shah-Jalal , Shamash Jonathan 
Published: March 2020

4535 Background: Bleomycin is an integral part of combination chemotherapy in germ cell tumours. Pulmonary symptoms often dictate drug cessation and death occurs in 1-2% of patients. Circumstantial evidence suggests that continuous infusion may be less toxic. Methods: We conducted a randomized phase 3 study to see whether infusional bleomycin was associated with less pulmonary toxicity. Patients were stratified for smoking, renal dysfunction and age and were randomized to receive either conventional BEP with weekly bleomycin (3,0000 units /week iv over 30min) or the same doses but administered as a 90,000 unit infusion on day 1 over 72 hours. The primary endpoint was CT proven lung toxicity, secondary endpoints included PFS and changes in lung function testing. CT scans and lung function testing were conducted after 1 cycle, end of treatment and 1 year post treatment. Sample size of 210 was calculated to detect a difference of 16% Bleomycin damage with 80% power at the 5% level of significance using 2-sided test. Results: The median follow-up was 2.5 years. At day 21 of the treatment, 52% patients in the infusional arm had grade 1 or above toxicity compared to 55% in the conventional. At the end of treatment the results were 84% vs. 60% and at one year it was 65% vs. 59%. Repeated measures mixed effects model shows no significant difference in percentage of grade 1 and above toxicity between the two arms (Difference=1.63, P=0.09, 95% CI: -0.28, 3.54). However, there was a significantly higher level of grade 2 and above toxicity in patients in the infusion arm (difference=0.8; 95% CI 0.11 to 1.49). Toxicity level was the highest at the end of treatment and in older patients (Age>30). Lung function testing between the two arms failed to show any differences. Two-years PFS rate was 93% in both arms (hazard ratio infusion vs conventional was 0.91; 95% CI 0.33 to 2.52). There was an association between toxicity after 1 cycle and subsequent toxicity at end of treatment and at 1 year (p=0.003). Conclusions: Infusional bleomycin has no advantage over standard administration of bleomycin. Clinical trial information: 08648791.
Stomach cancer risk following radiotherapy for testicular cancer.
Authors: Morton Lindsay M , Fossa Sophie D. , Stovall Marilyn , van Leeuwen Flora E. , Johannesen Tom B. , Rajaraman Preetha , Aleman Berthe M , Dores Graca , Gilbert Ethel S. , Hall Per , Holowaty Eric J. , Joensuu Heikki , Kaijser Magnus , Lynch Charles , Pukkala Eero , Storm Hans H , Smith Susan A , Fraumeni Joseph F , Travis Lois B. , Hauptmann Michael 
Published: March 2020

4536 Background: Testicular cancer (TC) is a highly curable malignancy occurring most commonly among men aged 15-34 years. Survivors are at increased risk for adverse late effects of therapy. Previous studies have reported more than 4-fold risks of stomach cancer after TC, although the potential role of radiotherapy and chemotherapy for TC in these associations is unclear. Methods: We evaluated stomach cancer risk in an international cohort of 23,982 men diagnosed with TC during 1959-1987. Using detailed radiotherapy records, doses to the stomach tumor location were estimated for 92 stomach cancer patients and 180 individually matched controls. Chemotherapy drugs and doses also were recorded. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. Results: Fifty-seven percent of patients with stomach cancer were diagnosed with TC before age 40 years, 65% had seminoma, 95% had stage I or II disease, and 37% were diagnosed with stomach cancer ≥20 years after TC diagnosis. Patients who received radiotherapy [87 (95%) cases, 151 (84%) controls] had a 5.9-fold (95%CI 1.6-21.3) increased risk of stomach cancer compared with patients who did not receive radiotherapy. Risk increased with increasing radiation dose to the stomach (P-trend<0.001), with ORs of 3.6 (95%CI 1.3-10.6), 4.4 (1.2-16.4) and 13.3 (2.5-70.0) after 20-39.9 Gy, 40-49.9 Gy, and ≥50 Gy radiation to the stomach, respectively, compared with <10 Gy. Radiation-related stomach cancer risk did not vary by calendar year of treatment, age at exposure, or TC histology. The OR for having received any chemotherapy was 1.3 (14 cases, 23 controls, 95% CI 0.6-2.8). Stomach cancer risk was not significantly elevated among patients given cisplatin-based chemotherapy (7 cases, 10 controls, OR=1.7, 95% CI 0.6-5.1). Conclusions: Patients administered radiotherapy for TC in the past are at increased risk of developing stomach cancer, particularly those who received ≥20 Gy to the stomach. The study results warrant consideration in radiation risk assessment and long-term follow-up. Future studies should further investigate a possible role for chemotherapy in stomach cancer risk.
Impact of response to prior chemotherapy (RTPC) on outcomes in second-line therapy for advanced urothelial carcinoma (UC): Implications for trial design.
Authors: Pond Gregory Russell , Bellmunt Joaquim , Fougeray Ronan , Choueiri Toni K. , Qu Angela Q. , Salhi Yacine , Niegisch Guenter , Albers Peter , Di Lorenzo Giuseppe , Galsky Matt D. , Necchi Andrea , Sonpavde Guru 
Published: March 2020

4539 Background: Performance status (PS), hemoglobin (Hb), liver metastasis (LM), and time from prior chemotherapy (TFPC) are significant prognostic factors in second-line therapy for advanced UC. Setting of prior chemotherapy, i.e., metastatic or perioperative, has not appeared significant. However, the impact of prior chemosensitivity is unclear, which may confound trial interpretation. Hence, we examined the prognostic impact of RTPC, when prior therapy was given for metastatic disease. Methods: Six phase II trials evaluating second-line chemotherapy and/or biologics (n=504) were pooled. Patients who received prior therapy for metastatic disease were eligible for analysis if data regarding Hb, LM, PS, and TFPC were available. Response by RECIST to first-line therapy was recorded. Progression-Free Survival (PFS) and overall survival (OS) were calculated from the date of registration using the Kaplan-Meier method. Results: 275 pts were evaluable for analysis. Patients received gemcitabine-paclitaxel, cyclophosphamide-paclitaxel, pazopanib, docetaxel plus vandetanib/placebo or vinflunine (2 trials). Those with prior response (n=111) had a median (95% CI) OS of 8.0 (6.8-9.4) months (mo) and PFS of 3.0 (2.6-4.0), compared with OS and PFS of 5.9 (5.0-6.6) mo and 2.6 (2.0-2.8) for those without prior response (n=164). Multivariable analysis did not reveal an independent impact of RTPC on PFS or OS (Table). Conclusions: RTPC in patients receiving prior chemotherapy for metastatic disease did not confer an independent prognostic impact with second-line therapy for advanced UC. Patients who received prior chemotherapy in peri-operative or metastatic settings may be enrolled in the same second-line trial stratified for PS, anemia, LM and TFPC. [Table: see text]
Expression of PD-L1 in primary urothelial carcinoma (UC).
Authors: Zhang Jingsong , Dickinson Shohreh I , Clark Noel D , Flaherty Amber Lea 
Published: March 2020

4541 Background: Engagement of programmed cell death-1 (PD-1), expressed on CD8+ T cells, with it ligand PD-L1(B7H1), expressed on tumor cells, results in T cell suppression and tumor protection. Antibodies against PD-1 or PD-L1 have reported impressive anti-tumor activities in phase I/II trials and are being tested in the phase 3 setting. Exploratory analysis indicated that expression of PD-L1 could be a predictive marker for response. Of note, urothelial carcinoma (UC) was not included in the early phase anti-PD1 or anti-PD-L1 studies. To explore anti-PD-L1 as a new treatment for this lethal disease, we assessed PD-L1 expression in UC. Methods: The relative mRNA abundance of PD-L1 mRNA in UC was studied in the Oncomine Bittner Multi-cancer dataset, which included a total of 1911 tumor samples. PD-L1 immunohistochemistry (IHC) was performed with rabbit monoclonal antibody against human PD-L1 on tissue microarrays with 83 formalin fixed paraffin embedded T1, T2 and T3 UC. IHC slides were reviewed by a genitourinary pathologist. A positive staining is defined when ≥ 5% of cancer cells had positive PD-L1 membrane and/or cytoplasmic staining. The IHC slides were scanned with the Aperio ScanScope XT and the immunopositivity of PD-L1 was quantitatively scored using commercial algorithms from the Aperio Toolbox and TissueStudio. The 1+, 2+, and 3+ score of each core was based on the dominant IHC staining intensity. Results: In the Bittner multi-cancer dataset, the log2 median mRNA intensities of PD-L1 in prostate cancer, clear cell renal cell carcinoma, colon cancer, UC of the bladder, ureter and squamous cell carcinoma of the bladder were 0.245, 0.528, 0.61, 0.81, 0.802, and 1.202 respectively. The overall PD-L1 IHC staining positivity was 45% in 83 primary UC samples. All six 3+ PD-L1 staining cores were grade 3 urothelial carcinomas and each core had more than 60% of cancer cells with 3+ PD-L1 membrane staining. Grade 3 cores also had the highest percentage of 2+ and 3+ PD-L1 positivity. No association was observed between T staging and PD-L1 staining intensity. Conclusions: PD-L1 is expressed in primary UC. We have obtained additional UC samples to correlate its expression with survival and its expression pattern with the pattern of tumor infiltrating lymphocytes.
Investigation of a novel irreversible pan-HER inhibitor combined with chemotherapy in bladder cancer models.
Authors: Grivas Petros , Day Kathleen C. , Daignault Stephanie , Shakir Nazia , Paul Alyssa , Kunju Priya , Smith David C. , Hussain Maha , Day Mark L. 
Published: March 2020

4545 Background: Human Epidermal Receptors (HER) play an important role in bladder cancer (BCa) progression and may mediate chemotherapy resistance. Dacomitinib (Dac) is a novel, potent, irreversible pan-HER inhibitor with activity in several solid tumors, currently in phase III trials in NSCLC. We showed that Dac has single agent anti-tumor activity in human BCa models in vitro and in vivo, inducing apoptosis and G1 arrest. We hypothesized that Dac has additive effects with Gemcitabine (G) and Cisplatin (C) in BCa xenografts. Methods: UM-UC-6 (UC6) or UM-UC-9 (UC9) xenografts were established in age-matched NOD/SCID mice. A week after injection, mice had small tumors, were randomized and treated with i. G 50mg/kg + C 2mg/kg via 3 weekly intra-peritoneal injections (IPI) + daily p.o. buffer for 3 weeks; ii. Dac 6mg/kg p.o. daily for 3 weeks + 3 weekly IPI (saline); iii. GC (same dose/schedule) + Dac starting 1 day after GC (based on cell cycle effect and kinetics); iv. no treatment (control). Mice were monitored daily, weighed weekly, sacrificed at 4 weeks and tumors were weighed. 3 tumors/group were stained for EGFR, HER2, Ki67, E-cadherin, ALDH, p-EGFR, p-ERK, p-Akt. 3rd GC dose in UC6 model was given at 50% due to weight loss; all GC doses were given at 50% in UC9 model. Mann-Whitney test with multiple comparison adjustments was used for analysis. Results: Dac- and GC+Dac-treated mice had no significant weight loss. UC6 tumor weights were significantly lower in Dac and GC+Dac vs control (p<0.0001) or GC (p<0.0001), corresponding to decreased p-ERK %cell expression and staining intensity. GC and control had similar tumor weights (p=0.19). 5 Dac and 3 GC+Dac UC6-injected mice had no tumor at 4 weeks. UC9 tumor weights were significantly lower in Dac (p=0.002, 6x reduction) or GC (p=0.0006; 7x reduction) vs control. GC+Dac had significantly lower tumor weights vs GC (p=0.005), Dac (p=0.06) or control (p<0.0001; 17x reduction). Conclusions: Dac had dramatic singe-agent activity in UC6 xenograft that was GC-resistant. Dac+GC was superior to GC in UC9 xenograft, supporting clinical evaluation. Further investigation of Dac anti-tumor activity and predictive biomarker discovery in additional bladder cancer models is pursued.
Aggressive surgical management of germ cell tumors with somatic-type malignancy: Pathologic features, prognostic factors, and survival outcomes.
Authors: Rice Kevin R , Magers Martin J , Beck Stephen , Einhorn Lawrence H. , Ulbright Thomas M. , Foster Richard 
Published: March 2020

4554 Background: Germ cell tumors (GCT) with somatic-type malignancy (SM) are rare occurring in approximately 3-8% of GCT cases. Prognostic factors and optimal management remain poorly-defined. Methods: The Indiana University (IU) testis cancer database was queried from 1979 to 2011 for patients demonstrating atypical histology at orchiectomy or subsequent resection of metastatic disease. Patients with transformation to PNET only were excluded due to distinct management. Chart review, pathologic review, and survival analysis were performed. Results: 122 patients met study inclusion criteria. Primary tumor site was testis in 112, retroperitoneum in 8, groin in 1, and pineal gland in 1. The most common SM histologies were sarcoma (71) and carcinoma (32). At GCT diagnosis, 24, 44, 45 patients had stage I, II, and III disease, respectively. Stage was unknown in 9. Median time from GCT diagnosis to SM was 13 months (Range, 0-397). This interval was longest for carcinomas (94.5 months) and sarcomatoid yolk sac tumors (113 months). Only 11 of 83 patients (13.3%) receiving cisplatin-based chemotherapy for measurable disease demonstrated an initial complete response. First resection at IU was reoperative in 45 patients (36.9%). 69 patients (56.6%) required extirpation of abdominal viscera/vascular structures or distant metastases. At a median follow-up of 71 months, the 5-year cancer specific survival (CSS) was 63%. Predictors of poorer CSS included SM diagnosed at late relapse (p = 0.014), referral to IU for reoperative RPLND (p = 0.022), and tumor grade (p = 0.043). SM histology subtype, stage, risk category, and number of resections for SM were not predictive of CSS. Conclusions: GCT with SM is associated with poorer CSS than traditional GCT. Established prognostic factors for GCT lose their predictive value in the setting of SM. SM can occur at any point in the course of GCT, but has a propensity for delayed presentation with later onset being associated with poorer CSS. Aggressive and serial surgical resections are often necessary to optimize CSS. Tumor grade is an important prognostic factor, particularly in sarcoma cases.
Comparing diagnosis, management, and outcomes of synchronous versus metacrhonus brain metastases from testicular germ cell tumors (TGCT): Multinstitutional experience from the Spanish Germ Cell Cancer Group (SGCCG).
Authors: Aparicio Jorge , Girones Regina , Roure Pere , Germa-Lluch Jose R. , Vazquez-Estevez Sergio , Saenz Alberto , Sastre Javier , Arranz Arija Jose Angel , Gallardo Enrique , Gonzalez-Billalabeitia Enrique , Sanchez-Hernandez Alfredo , Terrasa Josefa , Hernandez Ana , Santander Carmen , Cillan Elena , Sagastibelza Naira , Almenar-Cubells Daniel , Lopez Brea Marta , Maroto José Pablo ,   Spanish Germ Cell Cancer Group (SGCCG)
Published: March 2020

4560 Background: Metastases of testicular germ cell tumors (TGCT) to brain are a rare event. Prognostic is poor and there is little evidence on optimal management of these patients. Methods: A retrospective review of case records of germ cell tumor patients within the Spanish Germ Cell Cancer Group from 1994 to 2012 was conducted. Results: Thirty-tree cases of testicular germ cell tumors from 17 institutions were reported. Nineteen patients (57%) presented with brain metastases at primary diagnosis (group 1: synchronous), thirteen (40%) developed brain metastases at relapse (group 2: metachronous) and only one patient developed brain metastasis during cisplatin based-chemotherapy (3%) (excluded from the analysis). Main demographics and comparison between series are shown on table. Median serum BHCG levels at initial diagnosis were higher in group 1(279.083 versus 175.873), whereas those of AFP were higher in group 2(1320 versus 4181). The most common histology in the primary tumor was choriocarcinoma for group; versus embryonal carcinoma for group 2. Patients had neurological symptoms at diagnosis of brain metastases (63% synchronic/93% metachronus). Performance status was also poor (PS 2-3: 52,6%group 1-62,2% group 2). Four patients (21%) in group 1 had a solitary brain lesion vs seven (54%) on group 2. Median time since last dose of cisplatin to development of brain metastases on group 2 was 6 months (3-22).Median overall survival was 16 months (95% CI 5,3-26,6): group 1: 16 (95% CI 13,9-18);23 group 2 (95% CI 0-165). We have not found significant differences in survival between both groups. Overall 37,5% of patients achieved long-term survival (38,9% in group 1 versus 38,5% in group 2). Patients achieving complete response of brain metastases had a better survival (log rank p:0,003). Conclusions: Long term survival can be achieved in approximately 1/3 of patients with brain metastases. Chemotherapy remains the cornerstone of treatment. Selection bias because of the retrospective nature of review should make us be careful with the conclusions.
Testosterone (T), luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels in testicular cancer survivors (TCSs) 11 and 19 years after orchiectomy.
Authors: Sprauten Mette , Brydoy Marianne , Haugnes Hege Sagstuen , Langberg Carl Wilhelm , Dahl Olav , Klepp Olbjorn Harald , Bremnes Roy M. , Cvancarova Milada , Fossa Sophie D. , Oldenburg Jan 
Published: March 2020

4562 Background: Hypogonadism, i.e., low T-, high LH- and/or FSH-levels, is frequently observed in TCSs and is associated with cardiovascular disease, osteoporosis and reduced quality of life. Little is known about the impact of aging on hypogonadism in TCSs. Methods: T, LH, and FSH levels were retrieved twice from 874 TCSs median 11 (S11) and 19 (S19) years after orchiectomy and categorized based on cut-offs calculated from 570 healthy controls (C), separately for each decadal age group. Treatment was categorized into surgery (S), radiotherapy (RT) or cisplatin-based chemotherapy (CT). Impact of treatment and aging on T, LH and FSH levels was assessed by comparing proportions of TCSs grouped into the C quartiles by ordinal logistic regression and expressed with odds ratios (OR) and 95% confidence interval (CI). Results: TCSs had lower T and higher LH and FSH levels than C at S11 and S19 (p<0.05, except for LH after S at S11) (Table).Approximately 50% of TCSs had T levels in the lowestquartile at S11 and S19. The proportion of TCSs with T below the 2.5% cut-off threshold for C increased from S11 to S19, for the S (9.7 - 12.5%), RT (9.4 - 16.3%) and CT group (12.5- 19.9%). Conclusions: TCSs had lower T and higher LH and FSH levels than C of similar age indicating an impact of treatment. Importantly, proportions of TCSs in the highest LH quartile and below the 2.5% cut-off for T-level increased from S11 to S19, indicating an accelerated hormonal aging. Continued follow-up of hormone levels is important. [Table: see text]
Rates of dose adjustment in patients treated with tivozanib versus sorafenib in the phase III TIVO-1 study.
Authors: Hutson Thomas E. , Nosov Dmitry , Harza Mihai , Esteves Brooke , Strahs Andrew Louis , Berkenblit Anna , Motzer Robert John 
Published: March 2020

4564 Background: Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half-life. Superior progression-free survival (PFS) and overall response rate (ORR) with tivozanib versus sorafenib were demonstrated in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma (PFS: 11.9 vs 9.1 months in ITT population, 12.7 vs 9.1 months in patients who received no prior systemic treatment for mRCC; ORR: 33% vs 23% in ITT population). Hypertension was more common with tivozanib, while lower rates of certain off-target adverse events (AEs) relative to sorafenib were reported (J Clin Oncol 2012;30[suppl]:Abstract 4501). Here we present detailed dose adjustment data. Methods: In total, 517 patients were enrolled and randomized 1:1 to tivozanib 1.5 mg/d (once daily 3 weeks on, 1 week off) or sorafenib 400 mg/d (twice daily, continuously). Treatment duration and AEs leading to discontinuation and dose adjustment were assessed in these patients. Results: Median duration of treatment with tivozanib was 12.7 months vs 9.5 months with sorafenib; fewer patients in the tivozanib arm experienced drug reduction or dose interruption due to AEs (see Table). Treatment-related AEs, as defined by the investigator, led to drug discontinuation in 3.9% of tivozanib patients and 5.4% sorafenib patients. Conclusions: Lower rates of dose adjustment due to related AEs were observed in patients with metastatic RCC who received tivozanib compared to sorafenib. Clinical trial information: NCT01030783. [Table: see text]
Outcome of metastatic sarcomatoid renal cell carcinoma (sRCC): Results from the International mRCC Database Consortium.
Authors: Chittoria Namita , Zhu Hui , Choueiri Toni K. , Kroeger Nils , Lee Jae-Lyun , Srinivas Sandy , Knox Jennifer , Bjarnason Georg A. , MacKenzie Mary J. , Wood Lori , Vaishamayan Ulka N. , Agarwal Neeraj , Pal Sumanta Kumar , Tan Min-Han , Rha Sun Young , Yuasa Takeshi , Donskov Frede , North Scott A. , Rini Brian I. , Heng Daniel Yick Chin 
Published: March 2020

4565 Background: Sarcomatoid differentiation in metastatic RCC (sRCC) is associated with poor prognosis. Robust data regarding outcome in the targeted therapy era is lacking. Methods: Clinical features, prognostic factors, and treatment outcomes in mRCC patients with and without sarcomatoid histology treated with targeted therapy were retrospectively analyzed and compared. Results: 2,286 patients were identified (non-sRCC(n=2,056); sRCC(n=230)). sRCC patients had significantly worse Heng prognostic group distribution compared to non-sRCC (11% vs 19% favorable risk, 49% vs 57% intermediate risk, and 40% vs 24% poor risk; p<0.0001). Time from original diagnosis to relapse (excluding synchronous metastatic disease) in the sRCC patients was 18.8 months compared to 42.9 months in non-sRCC group; p<0.0001. There was no significant difference in the incidence of CNS metastases (6-8%) or underlying clear cell histology (87-88%). Greater than 93% of patients received VEGF inhibitors as first line therapy; 21% achieved an objective response in the sRCC group as compared to 26% in the non-sRCC group with significantly more sRCC patients (43% vs. 21%) having primary refractory disease (p<0.0001, for both). sRCC patients had significantly less use of second-line (p=0.018) and third-line (p=0.0004) systemic therapy. The median PFS / OS was 4.5 months / 10.4 months in sRCC patients and 7.8 months / 22.5 months in non-sRCC patients (p<0.0001 for both). Sarcomatoid histology was associated with a significantly worse PFS and OS after adjusting for the individual Heng risk factors in multivariable analysis (HR 1.5, p<0.0001 for both). Conclusions: Patients with sRCC have worse baseline prognostic criteria, a shorter time to relapse and worse clinical outcome to targeted therapy compared to patients with non-sRCC. Additional insight into the biology of sRCC is needed to develop alternative therapeutics.