bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bone metastases in patients with relapsed/refractory germ cell tumors (GCT) undergoing first salvage chemotherapy: A retrospective analysis of a large international database.
Authors: Oechsle Karin , Oing Christoph , Honecker Friedemann , Berger Lars Arne , Bokemeyer Carsten , Beyer Joerg , Lorch Anja ,   for the International Prognostic Factor Study Group (IPFSG)
Published: March 2020

4597 Background: Bone metastases (mets) are rare events in GCT patients (pts) and data on characteristics, risk factors, treatment and outcome in these pts are largely missing. Methods: A subgroup of 104 ptswith bone metsfrom the IPFSG database was analyzed. All patients experienced unequivocal relapse/progression after > 3 cycles of cisplatin-based chemotherapy and received conventional-dose (CDCT) or high-dose salvage chemotherapy (HDCT). Results: 104 / 1594 pts presented with bone mets (6,5%) at first relapse. Histology was pure seminoma in 26%, and non-seminoma in 74%. At initial diagnosis, 54% of pts had presented with "poor risk" according to IGCCCG. Overall response rate (ORR; CR+PR) to 1st-line chemotherapy was 89%. Median PFS after primary treatment was 3 months (range 0 - 140). Bone mets at first relapse were accompanied by abdominal, lung, mediastinal, liver and brain mets in 54%, 48%, 28%, 36%, and 14%, respectively. Tumor marker profiles were heterogeneous (elevation of AFP / ß-HCG: 51% / 37%). Salvage treatment was CDCT in 34%, and HDCT in 66% of pts. ORR to salvage chemotherapy was 68% for the total cohort, and 43% vs. 81% for CDCT vs. HDCT (p<.01). For the total cohort, 2y-PFS and 5y-OS were 24% and 16%, respectively. 2y-PFS and 5y-OS were significantly higher in pts after HDCT compared to CDCT (2y-PFS 29% vs. 14%, p=.01; 5y-OS 19% vs. 9%, p=.04). Conclusions: Pts relapsing with bone mets after platinum-based CTX were characterized by "poor risk" disease at initial diagnosis, but characteristics at first relapse were heterogeneous. Treatment response and outcome was improved in pts with HDCT compared to CDCT. Further prospective evaluation of characteristics and treatment approaches in GCT pts with bone mets is warranted.
Metastatic malignant transformation of teratoma to primitive neuroectodermal tumor (PNET): Results with PNET-based chemotherapy.
Authors: Jain Amit , Einhorn Lawrence H. , Brames Mary J. 
Published: March 2020

4598 Background: Metastatic germ cell cancers are highly chemosensitive and have 80% cure rate with cisplatin based chemotherapy. Post-chemotherapy teratoma can usually be surgically resected. However, teratoma, which is pleuripotent tissue, can undergo malignant transformation along mesodermal elements to PNET. Unlike teratoma, PNET can metastasize and render a patient unresectable and incurable. We report the results of treatment of patients with PNET with cyclophosphamide + doxorubicin + vincristine (CAV) alternating with ifosfamide + etoposide (IE). Methods: We reviewed 81 patients with histologically confirmed PNET transformed from testicular teratoma at Indiana University from 1998 to 2011. We identified 13 cases who were treated with chemotherapy comprising cyclophosphamide 1000-1200 mg/m2, doxorubicin 50-75 mg/m2, and vincristine 2 mg alternating with ifosfamide 1.8 grams/m2 plus etoposide 100 mg/m2 for 5 days. Treatment was given every 3 weeks with a maximum of 6 cycles or until progression or undue toxicity. Hematopoeitic growth factors were usually incorporated. The remaining 68 patients underwent surgical resection. Results: Ten patients had unresectable disease and 3 were treated in an adjuvant setting. Median age was 31 years (range 20-53). Ten of 13 patients had received prior platinum based chemotherapy. Eight of 10 evaluable patients achieved objective response. Five of those were rendered with no evidence of disease(NED) with further surgery. Although 4 of the 5 patients subsequently relapsed, 1 patient remains alive with NED at 69 months. The 3 patients who received adjuvant treatment after retroperitoneal lymph node dissection (RPLND) are alive with NED at 1, 4 and 8 years. Conclusions: CAV and IE alternating chemotherapy has high objective response rate for PNET transformed from teratoma and results in occasional long term disease free survival when combined with subsequent resection. We recommend adjuvant CAV alternating with IE chemotherapy for patients with PNET after RPLND due to the high probability of recurrent disease and their high chemosensitivity to this regimen.
Phase I results of a phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma (mRCC) patients previously treated with VEGFR tyrosine kinase inhibitors.
Authors: Hutson Thomas E. , Dang Long H. , Lauer Richard C. , Starodub Alexander , Hauke Ralph J. , Galsky Matt D. , Bylow Kathryn A. , Logan Theodore , Cowey Charles Lance , Bibby David C. , Kremmidiotis Gabriel , Doolin Elizabeth E. , Lavranos Tina C. , Sonpavde Guru , Hahn Noah M. , Sweeney Christopher , Sarantopoulos John ,   Hoosier Oncology Group
Published: March 2020

4603 Background: BNC105P is an investigational agent that destabilizes tubulin polymers leading to selective damage of tumor vasculature, causing disruption of blood flow to tumors, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Preclinical investigations have demonstrated that BNC105P is effective at selectively damaging the vasculature in both primary and metastatic lesions. Up regulation of the mTOR pathway has been identified as a survival response by the tumor to hypoxic insult. It follows that the combined use of BNC105P with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to VEGFR-directed tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. Using a classic 3+3 design, the phase I component of this study enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6, 16 mg/m2; IV infusion Days 1 and 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. Results: The phase I component has been completed. The BNC105P / everolimus combination was well tolerated. No DLTs (drug-related, during cycle 1) were observed in any of the phase I subjects. Toxicities on study deemed to be drug-related (either single agent or combination) included single grade 3 events of anemia and pericardial effusion. Grade 2 events (more than 1 occurrence) of fatigue, anemia and oral mucositis were also observed. Seven phase I subjects achieved at least disease stabilization with a minimum time on therapy of 18 weeks (6 cycles). Across all subjects a median of 6 cycles (range: 1-15) was administered. PK analysis confirmed no drug-drug interaction. The randomized phase II component of the study continues and will compare everolimus given in combination with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: The MTD of BNC105P (16 mg/m2) can be combined with full dose everolimus and is being evaluated in the randomized phase II study.
Safety and efficacy of AMG 386 in combination with sunitinib in patients with metastatic renal cell carcinoma (mRCC) in an open-label multicenter phase II study.
Authors: Atkins Michael B. , Ravaud Alain , Gravis Gwenaelle , Drosik Kazimierz , Demkow Tomasz , Tomczak Piotr , Kracht Karolyn , Puhlmann Markus , Weinreich David Michael 
Published: March 2020

4606 Background: AMG 386, an investigational peptide-Fc fusion protein, inhibits angiogenesis by disrupting the angiopoietin/Tie2 axis. We evaluated the safety and efficacy of AMG 386 plus sunitinib in patients (pts) with mRCC. Methods: Adults with mRCC who were naïve to angiogenesis inhibitors were sequentially enrolled to 2 cohorts: sunitinib 50 mg PO QD (4 wks on, 2 wks off) plus AMG 386 at 10 mg/kg (A) or 15 mg/kg (B) IV QW. Primary endpoints: adverse events (AEs), dose interruptions/reductions due to AEs in the first 12 wks of treatment; secondary endpoints included: progression-free survival (PFS) and response rate (ORR). Results: 85 pts received ≥1 dose of study medication (A/B, n=43/42). In A/B, 88%/76% were male and 30%/36% were age ≥65; MSKCC risk scores were low (40%/36%) or intermediate (60%/62%). For A/B: median follow-up time was 19.6/12.0 mos; AMG 386 discontinuations due to AEs were 16%/29%; and grade ≥3 treatment-related AEs occurred in 72%/74% with virtually all attributed to sunitinib. Grade 3 AEs occurring with >5% frequency were hypertension, hand foot syndrome, asthenia, fatigue, elevated lipase, diarrhea, mucositis, vomiting, thrombocytopenia, and neutropenia, with no distinction between dose levels. The percentage of pts with sunitinib dose interruptions within the first 12 wks (A/B, 58%/57%) met the prespecified criteria. One pt in B had fatal acute pulmonary edema. No pt developed anti-AMG 386 antibodies. The Kaplan-Meier estimate (95% CI) of PFS was 13.9 (10.4, 19.2) mos in A; PFS in B is not yet mature with only 21% of pts having disease progression. ORR (95% CI) was 58% (42, 73) in A including 1 CR, and 59% (42, 74) in B. Conclusions: In pts with mRCC, AMG 386 at 10 and 15 mg/kg combined with sunitinib appeared to be tolerable. Reported sunitinib dose modifications for the observation period were within the prespecified range. Efficacy results suggest potential benefit for the addition of AMG 386 to sunitinib.
Prospective exploratory analysis of the association between genetic polymorphisms and sunitinib toxicity and efficacy in metastatic renal-cell carcinoma.
Authors: Farfan Carlos Alberto , Sepulveda Juan , Benitez Julio , de Velasco Guillermo , Villacampa Felipe , de la Rosa Federico , Canamares Irene , Rodriguez de Antona Cristina , Cortes-Funes Hernan , Castellano Daniel E. ,   Uro-Oncology Unit, Hospital Universitario 12 de Octubre
Published: March 2020

4620 Background: Sunitinib (SU) is a multi-targeted receptor tyrosine kinase inhibitor treatment that is approved for metastatic renal cell carcinoma (mRCC). However, several patients either do not respond to treatment or they experience significant toxicity.Our study aims to find genetic markers of toxicity and efficacy using a commercially available DNA microarray genotyping system. Methods: 30 patients with newly diagnosed mRCC, from January 2010 to May 2011, were evaluated prospectively at Hospital 12 de Octubre (Madrid, Spain). Pts received SU 50 mg/day, 4 wks on / 2 wks off treatment schedule. A total of 92 of single nucleotide polymorphisms (SNPs) in 34 genes in the pharmacokinetic and pharmacodynamic pathways of drugs were analyzed using Drug inCode pharmacogenetic service. SNPs in candidate genes, together with clinical characteristics were tested univariately for association with the number of days of SU treatment until the first reduction of dose, PFS and OS. Results: Complete analysis was possible in 25 pts. Pts with CYP1A2*1/*1.a low metabolizing genotype, had an increased risk of dose reductions due to toxicity compare to allele *1F (Median time to dose reduction : 2.33 months vs NR; p<0.006). Pts with CYP2C19*1/*1 , wild type genotype, had an increased risk of dose reductions due to toxicity vs. other genotypes (Median time to dose reduction: 2.8 vs 9.73 months; p<0.021). Catechol-O-methyltransferase (COMT) V158M polymorphisms, was associated with PFS and OS (Met/Met carriers median PFS and OS NR; Met/Val pts PFS= 15 months; OS=17.2 months and Val/Val pts PFS=3.3 months; OS= 4.4 months ; p=0.005 for PFS and p=0.003 for OS). Conclusions: This preliminary analysis suggests that CYP1A2 and CYP2C19 SNPs may be associated with toxicity in patients with RCC treated with SU. As CYP1A2 and CYP2C19 activity could be affected by a variety of non-genetic factors, if these is confirmed, it could lead to the necessity of controlling toxic and dietary habits of pts treated with SU. SNPs associated with toxicity and survival in this preliminary analysis are being validated in an independent cohort of RCC treated with SU (García-Donas J, et al. Lancet Oncol 2011).
Trends in the use of cytoreductive nephrectomy for metastatic renal cell carcinoma in the VEGFR tyrosine kinase inhibitor era.
Authors: Tsao Che-Kai , Small Alexander C. , Kates Max , Gartrell Benjamin Adam , Wisnivesky Juan P. , Sonpavde Guru , Palese Michael , Hall Simon , Oh William K. , Galsky Matt D. 
Published: March 2020

4623 Background: Two large randomized trials (SWOG, EORTC) published in 2001 established the role of cytoreductive nephrectomy (CyNx) for the treatment of metastatic renal cell carcinoma (mRCC) in the cytokine era. A paradigm shift occurred in 2005 with the approval of VEGFR tyrosine kinase inhibitors (TKIs). We hypothesized that uncertainty regarding the role of CyNx in the VEGFR TKI era has resulted in a change in practice patterns. Methods: Using the Surveillance, Epidemiology and End Results (SEER) registry, we identified 2780 patients with histologically-confirmed mRCC between 2000 and 2008 who underwent CyNx or no surgery. Patients were separated into pre- or VEGFR TKI-eras (2000-2005 vs. 2006-2008). Differences in baseline characteristics between these patient groups were assessed and controlled for in a logistic regression analysis to determine the likelihood of undergoing CyNx. Results: Overall, 1202 of 2780 patients (43%) underwent CyNx. CyNx increased from 41% in 2000 to 49% in 2005, and decreased to 35% in 2008, with a 20% decreased likelihood of undergoing CyNx in the VEGFR TKI era compared to the pre-VEGFR TKI era. Logistic regression analysis showed that tumor size, age, race, marital status and pre- versus post-2005 periods were independent predictors of CyNx (Table). Patients who were non-Caucasian, single, with primary tumor <3cm, or older were less likely to undergo CyNx. Conclusions: Use of CyNx increased after supporting level I evidence was published in 2001, and decreased after regulatory approval of VEGFR TKIs in 2005. Racial and demographic differences exist in the utilization of CyNx. The results of pending randomized trials evaluating the role of CyNx in the TKI-era are awaited to optimize use of this modality and address potential disparities. [Table: see text]
Molecular characterization of SETD2, a histone methyltransferase, in clear cell renal cell carcinoma (ccRCC).
Authors: Ho Thai Huu , Monzon Federico A. , Hoang Anh , Tamboli Pheroze , Furge Kyle A. , Dykema Karl , Petillo David , Teh Bin Tean , Tannir Nizar M. , Hung Mien-Chie , Jonasch Eric 
Published: March 2020

4624 Background: Although the von Hippel-Lindau (VHL) tumor suppressor is mutated in 60% of ccRCC, deletion of VHL in mice is insufficient for tumorigenesis. Sequencing of ccRCC tumors identified mutations in SETD2, a histone H3 lysine 36 (H3K36) trimethyltransferase. We hypothesize that loss of SETD2 methyltransferase activity decreases H3K36 trimethylation (H3K36Me3) in ccRCC, and contributes to the cancer phenotype. Methods: H3K36Me3 immunohistochemical (IHC) staining was quantitated in wild-type and mutant SETD2 nephrectomy tissue. To establish frequency of SETD2 loss of heterozygosity (LOH), genomic DNA was isolated from 51 VHL deficient ccRCC specimens and analyzed with Affymetrix single-nucleotide polymorphism (SNP) arrays. To evaluate alterations of histone modifications in advanced ccRCC, H3K36Me3 IHC was quantitated on tissue microarrays (TMAs) representing 28 paired ccRCC specimens with unaffected kidney parenchyma and 40 metastases. To identify kidney-specific H3K36Me3 binding sites, chromatin immunoprecipitation (ChIP) sequencing was performed on nephrectomy specimens. Results: Nephrectomy specimens with SETD2 truncating mutations have decreased H3K36Me3 (>50%) compared to uninvolved kidney tissue. Using SNP arrays, LOH at chromosome 3p (location of VHL and SETD2 genes) was detected in >90% of the tested tumors. IHC reveals a 27.4% and 52.0% decrease in H3K36Me3 positive nuclei in primary ccRCC and metastases, respectively, when compared to matched adjacent unaffected kidney tissue (p <0.0001). Using ChIP sequencing, 421 and 1,718 genomic regions were upregulated in the tumor and unaffected kidney tissue. Conclusions: SETD2 truncating mutations in patient-derived tissue have decreased H3K36Me3 indicating that SETD2 is a non-redundant H3K36 methyltransferase. LOH of VHL and SETD2 occurs in >90% of tested ccRCC tumors. Genomic regions enriched for H3K36Me3 binding are being validated in additional patient-derived tissues. H3K36Me3 is decreased in primary ccRCC and even more in metastases, suggesting that SETD2 methyltransferase activity is progressively misregulated in RCC. Loss of SETD2 activity may cooperate with VHL silencing to promote tumorigenesis.
Updated results on long-term overall survival (OS) of the French randomized phase II trial TORAVA in metastatic renal cell carcinoma (mRCC) patients.
Authors: Bay Jacques-Olivier , Negrier Sylvie , Pérol David , Gravis Gwenaelle , Chevreau Christine , Delva Remy , Blanc Ellen , Geoffrois Lionnel , Legouffe Eric , Ferlay Celine , Escudier Bernard J. 
Published: March 2020

4625 Background: Temsirolimus combined with bevacizumab (T+B) failed to improve the progression rate in treatment naive mRCC pts when treated in parallel to sunitinib (S) or B + Interferon (B+I) combination (Lancet Oncol 2011; 12:673-80). Long term updated survival and data on 2d line treatments were analyzed. Methods: 171 pts were treated with T+B (n=88), S (n=42) and B+I (41) respectively. Updated survival data (December 2011) and 2d line therapy after failure of the randomly assigned treatment were updated. OS was defined from the date of randomization until the date of death due to any cause, or the date of last contact. A two-tailed log-rank test was used to compare the OS distribution between the 3 arms with a 5% alpha level. Results: The median follow-up is 35.1 months (range 24.2 to 44.7). In an intent-to-treat analysis, 35-month OS rates were 37% (95% CI 27 to 48), 55% (95% CI 40 to 69) and 62% (95% CI 47 to 76) in arms T+B, S and B+I respectively (3-arm global comparison: p-value=0.0279). OS was not significantly lower in T+B arm than S arm (HR = 0.67, 95% CI 0.40 to 1.12), but significantly lower in T+B arm than B+I arm (HR = 0.48, 95% CI 0.27 to 0.86). Tyrosine kinase inhibitors were administered in 55 (79.7%), 19 (79.2%) and 23 (63.9%) pts in arms T+B, S and B+I respectively, without significant difference between arms (Fisher’s exact test: p=0.20). To note, 21% pts in S arm and 15% pts in B+I arm received an mTOR inhibitor in 2d line therapy. Conclusions: A large majority of pts in all treatment groups received a 2d line therapy after initial treatment failure. The OS rates confirm the absence of synergy or addictive effect of the B+T combination as well as the prolonged survival of pts treated with B+I.
Overall survival (OS) in metastatic renal cell carcinoma (mRCC) sequentially treated with different targeted therapies (TTs): Results from a large cohort of patients.
Authors: Procopio Giuseppe , Verzoni Elena , Iacovelli Roberto , Testa Isabella , Salvioni Roberto , Nicolai Nicola , Porcu Luca , De Braud Filippo G. 
Published: March 2020

4629 Background: Targeted Therapies (TTs) have definitely improved survival in patients with mRCC. However the optimal therapeutic strategy is not shared. This study was performed to assess the overall survival (OS) in a consecutive series of mRCC patients receiving TTs. Methods: Characteristics and outcomes of 336 patients affected by mRCC receiving TTs were collected from the database of Istituto Nazionale Tumori of Milan. The main characteristics of patients were: ECOG PS 0/1/2 186 (55%)/131 (39%)/19 (6 %); clear-cell histology 291 (87%); previous nephrectomy 293 (87%). According to Motzer criteria 32% of patients showed low risk, 48% intermediate risk and 20% poor. Overall, 167 (50%) patients received one TTs, while 116 (34%), 42 (13%) and 11 (3.3%) received 2, 3 and 4 TTs, respectively. 245 (73%) patients received sorafenib (So), 212 (63%) sunitinib (Su), 33 (10%) a bevacizumab regimen and 73 (22%) other TTs, including everolimus, temsirolimus and axitinib. The Kaplan Meier curves were used to describe the survival.The uni- and multi-variate analyses for OS were carried out by means of Cox proportional hazard regression analysis. Results: Ata median follow-up of 43 months, 199 patients (57 %) had died. The median OS was 24 months (95%CI: 20.0-27.0) and the 5-year OS was 24.6 % (95 %CI: 18.7-30.8). In univariate analyses, there were no significant differences in the hazard ratios (HR) for So followed by Su compared to Su followed by So (HRSU-SO / SO-SU = 1.16; 95%CI: 0.57-2.33) or compared with other therapies (HROther sequential th. / SO-SU = 1.21; 95%CI: 0.78-1.88; p=0.674).In the multivariate analysis, in terms of OS any statistical difference was reported as regards the sequence used (Su/So vs So/Su; p>0.05) or bevacizumab regimen as compared to Su and/or So used sequentially (p>0.05). In the uni and multivariate analysis ECOG PS, nephrectomy, Fuhrman grade and number of sites of disease are independent predictive factors of outcome (p< 0.01). Conclusions: These data suggest that TTs improve OS in mRCC without any statistical difference when using different sequences of TTs. No cross-resistance between several sequences of TTs was documented.
Longitudinal serum testosterone levels (T) in long-term testicular cancer survivors (TCSs) in relation to testicular cancer (TC) treatment, aging, and TC diagnosis itself.
Authors: Sprauten Mette , Cvancarova Milada , Fossa Sophie D. , Brydoy Marianne , Haugnes Hege Sagstuen , Oldenburg Jan 
Published: March 2020

4637 Background: Low T may increase the risk of cardiovascular disease, osteoporosis, and reduced quality of life. T might be reduced by TC, its treatment, ageing, and particularly their combination. Methods: T was retrieved from 311 TCSs after orchiectomy and prior to subsequent management with either surveillance/surgery only (S), radiotherapy (RT) or cisplatin based chemotherapy (CT). Human Chorionic Gonadotropin (hCG) was available for 211 TCSs. T was reassessed at surveys performed 9 (S9) and 18 years (S18) after treatment. T values were categorized into quartiles according to cut-off values derived from 570 healthy controls (C) for each decadal age group. Statistical associations were assessed with Chi2 tests. Results: In TCSs about to receive RT or CT, T and hCG were higher when compared to those subsequently managed by S. TCSs were more likely to belong to the lowest T quartile, more so with increasing treatment intensity (table). The proportions of TCSs belonging to the corresponding T quartiles displayed no significant changes from S9 to S18. Conclusions: TCSs had lower T than C of similar age already after orchiectomy, possibly related to removal of the affected testicle and/or testicular dysgenesis syndrome. TCSs who were to receive RT or CT had slightly increased T when compared to S, probably due to hCG stimulation. T reduction by RT or CT has been described previously but rarely in longitudinal studies. Of note, longitudinal assessment of T without comparison to C might result in overestimation of the treatment burden. Relatively stable age adjusted T levels from S9 to S18 for the TCSs independent of treatment are encouraging. [Table: see text]