bluuebunny/crossref_metadata_2025_split huggingface dataset:
MSKCC and Heng prognostic risk assessment for synchronous metastatic renal cell carcinoma (syncmRCC) and the tumor in place treated in the targeted therapy era.
Authors: Noe Allard , Blank Christian U. , Horenblas Simon , Haanen John B. A. G. , Bex Axel 
Published: March 2020

e15525 Background: SyncmRCC is heterogenous and selection for cytoreductive nephrectomy (CN) and targeted therapy is required. MSKCC and Heng models for overall survival (OS) are validated for targeted therapy. However, they were developed from predominantly metachronous mRCC patients. It is unknown how they perform in syncmRCC and if they can be used to decide about CN. Methods: Retrospective study of pretherapeutic MSKCC and Heng scores and outcome from 146 patients with syncmRCC and the primary tumor in place treated at a single institute with targeted therapy since 2006. CN was performed in patients WHO 0-1 and low metastatic burden. Results: Table: distribution of risk and OS compared to Heng et al., JCO 27:5794, 2009 . Only n=2 were favorable risk. Overall, n=117 were treated by sunitinib, others by temsirolimus or sorafenib. CN was performed in n=94 (64.3%). Among Heng poor risk 46% (n=29) were intermediate risk by MSKCC. Of Heng poor risk n=37 (58.7%) had CN with a median OS of 8.5 months; 2y OS was 18.9% and higher than for MSKCC poor risk. Of Heng intermediate risk n=57 (69.5%) underwent CN (median OS 15.5 months (1-68); 2y OS 36.8%). Conclusions: In syncmRCC MSKCC and Heng intermediate risk patients have shorter OS than previously reported for each model in the targeted therapy era. However, 25-30 % of intermediate risk patients live >2 y and a potential benefit of CN may be apparent in this group. A discrepancy exists between Heng and MSKCC poor risk percentage. We speculate that the primary tumor in place may influence thrombocyte and neutrophile counts resulting in significantly more Heng poor risk among patients with MSKCC intermediate risk. Especially MSKCC poor risk carries a dismal median and 2y OS in syncmRCC. MSKCC risk assessment performs well in identifying poor risk patients unlikely to benefit from CN. [Table: see text]
Baseline high-sensitivity C-reactive protein to predict progression-free survival in metastatic renal cell carcinoma patients treated with first-line sunitinib.
Authors: Mizuno Ryuichi , Kimura Go , Kondo Tsunenori , Ueda Takeshi , Hara Hidehiko , Kishida Takeshi , Kume Haruki , Sohji Sunao , Hatano Takashi , Morita Jun , Kawata Nozomu , Matsumoto Kazuhiro , Ishida Masaru , Takahashi Shunji , Tanabe Kazunari , Nakazawa Hayakazu , Horie Shigeo , Oya Mototsugu ,   Tokyo Metropolitan Study Group
Published: March 2020

e15527 Background: Predicting the efficacy of tyrosine kinase inhibitors (TKI) would be of clinical value in patients with metastatic renal cell carcinoma (mRCC). We tested the hypothesis that serum inflammatory markers are associated with clinical outcome in mRCC patients at favorable or intermediate prognostic risk treated with first-line sunitinib. Methods: Eighty-nine mRCC patients were prospectively monitored at baseline (day 0) during sunitinib treatment. Serum interleukin-6 and 8 levels were determined by CLEIA and ELISA, respectively. A high-sensitivity C-reactive protein (hs-CRP) levels were measured using laser nephelometry. Correlations between baseline interleukin-6, 8, hs-CRP levels and response to sunitinib, and progression-free survival (PFS) were examined. Results: Median PFS was 9.2 months. Clinical benefit rate (CBR; percent complete responses+partial responses +stable disease 24 weeks) was 57.3%. Baseline interleukin-8 (P=0.0240) and hs-CRP (P=0.0060) was associated with CBR. No association between baseline interleukin-6 and 8 with PFS was observed. However, baseline hs-CRP were associated with PFS (P=0.0016; unit risk 1.010; 95% CI 1.004 to 1.017). Conclusions: Baseline serum inflammatory markers could be of clinical interest in sunitinib-treated mRCC patiens to predict outcome. Baseline hs-CRP serum levels warrant further study. Clinical trial information: UMIN000009622.
Association between guideline-adherent imaging and overall survival following second-line targeted therapy for metastatic renal cell carcinoma.
Authors: Lin Peggy L. , Pal Sumanta Kumar , Jonasch Eric , Signorovitch James E. , Liu Zhimei , Culver Kenneth W. , Scott Jeffrey A. , Vogelzang Nicholas J. 
Published: March 2020

e15538 Background: NCCN guidelines recommend imaging at 2-6 months after initiation of targeted therapy for metastatic renal cell carcinoma (mRCC). This study assessed the association between guideline-adherent imaging and overall survival in mRCC. Methods: Thirty-six community-based medical oncologists/hematologists reviewed charts for ≤ 15 mRCC patients each. Included patients were aged ≥ 18 years and initiated 2nd targeted therapy in 2010 or later. Patients alive up to month 6 were categorized into 3 groups based on time of first imaging test: early (0-60 days), guideline-adherent (61-180 days), and delayed(> 180 days). Overall survival (OS) was compared using multivariable Cox proportional hazards models adjusted for age, gender, duration of mRCC, prior treatments, comorbidities, metastatic sites, 1st targeted therapy, ECOG and MSKCC status, 2nd targeted therapy, and progression status (based on symptoms or imaging) in the first 6 months on 2nd line therapy. Reasons for imaging were also assessed. Results: Among the 192 patients included in the analysis, 25 received early imaging, 136 received guideline-adherent imaging, and 31 received delayed imaging. First imaging tests were more likely due to worsening symptoms or changes in a palpable mass, as opposed to routine monitoring, among patients with delayed vs. guideline adherent imaging (20.0% vs. 7.1%, P = 0.005). After adjusting for baseline characteristics, guideline-adherent imaging was associated with a 64% lower hazard of death compared to delayed imaging (hazard ratio (HR) = 0.36, 95% confidence interval (CI) 0.14 to 0.93, P = 0.035). Adjusted 1-year survival was 82% in the guideline-adherent compared to 67% in the delayed imaging group. The hazard of death did not differ between those with early vs. guideline-adherent imaging (HR = 1.05, 95% CI 0.35-3.12, P = 0.927). Conclusions: Among patients surviving 6 months after the initiation of 2nd targeted therapy for mRCC, timely first imaging within 2-6 months, consistent with guidelines, was associated with significantly prolonged overall survival compared to delayed imaging. Further investigation is warranted with larger samples.
A novel polymer-coated nanoparticle (NP) for urothelium penetration and drug delivery.
Authors: Hoimes Christopher J. , Martin Darryl T , Kaimakliotis Hristos K , Cheng Christopher J , Kelly William Kevin , Tew Gregory N , Wheeler Marcia , Weiss Robert M , Saltzman W. Mark 
Published: March 2020

e15543 Background: Up to 40% of patients with non-invasive bladder cancer (BC) will develop invasive disease progression despite locally-directed therapy. Overcoming the urothelial barrier is a challenge for intravesical drug delivery. We designed a biodegradable poly(lactide-co-glycolide) (PLGA) NP coated with a novel cell penetrating polymer, poly (guanidinium oxanorbornene) (PGON) for testing against BC in vitro and in vivo. We chose to deliver the HDAC inhibitor belinostat (bel) for its BC cell cytotoxicity and inhibition of invasion & migration pathways; key mechanisms that enable progression of BC. Methods: Fluorophore (C6) or bel was encapsulated in PLGA using an oil/water nanoemulsion method, and surface coated with PGON, and then characterized for morphology, size, and loading. BC cell lines UM-UC-3 and T24 were treated with belinostat or NP-bel-PGON vs controls for assessment of cytotoxicity and acetyl-H4 histone expression over time. In vivo murine bladder and ex vivo human ureter were treated with NP-C6-PGON, and compared to NPs coated with chitosan or PEG for urothelial penetration using FACS analysis, tissue extraction, and fluorescence microscopy. UM-UC-3 murine flank xenografts were treated locally biweekly with NP-bel-PGON or controls and assessed for tumor size and acetyl-H4 expression. Results: C6 extraction of intravesically treated mouse bladder and ex-vivo human ureter showed uptake improved ten-fold in NP-C6-PGON compared to other NPs and corroborated by fluorescent microscopy. In vitro, NP-bel-PGON and bel had similar IC50 of ~2.0 μM in UM-UC-3 & T24 lines, and no effect from PGON. Significantly, the NP-bel-PGON treated groups retained 30% of max H4 hyperacetylation whereas bel groups declined to basal at 12hr post wash, which supports a mechanism of intracellular NP release and activity. In vivo, xenografts treated with NP-bel-PGON showed tumor volume reduced 70% and had 2.5 fold higher intratumoral acetyl-H4 expression compared to vehicle three days post final treatment. Conclusions: NP-bel-PGON penetrates the urothelium, is taken up by BC cells, sustains HDAC inhibition, and causes tumor regression. These data demonstrate the potential for NP-bel-PGON as an intravesical nanotherapy of BC.
A new equation to predict glomerular filtration rate one year after radical nephrectomy in Japanese patients.
Authors: Shimada Shuichi , Saito Hideo , Ito Akihiro , Ioritani Naomasa , Kawamura Sadafumi , Tochigi Tatsuo , Yamaguchi Takuhiro , Arai Yoichi 
Published: March 2020

e15570 Background: Strong associations have been reported between chronic kidney disease (CKD) and outcomes such as the development of ischemic cardiovascular disease and heart failure, as well as all-cause mortality. In many patients, CKD develops immediately after radical nephrectomy (RN) for renal cortical tumors and the prevalence of CKD after RN increases steadily thereafter. Therefore, it is important to predict postnephrectomy renal function. To evaluate renal function one year after radical nephrectomy for renal cortical tumors (RCT), predictive factors for postnephrectomy renal function were investigated, and an equation to predict estimated glomerular filtration rate (eGFR) one year after RN was developed. Methods: A total of 525 patients who underwent RN between May 2007 and August 2011 at Tohoku University Hospital and its affiliated hospitals were prospectively evaluated. Overall, 429 patients were analyzed in this study, of whom 257 were randomly selected as the training dataset, and the remaining 172 patients constituted the validation dataset. The prediction equation was developed by stepwise regression applied to the training dataset. Results: Independent factors associated with postnephrectomy eGFR included tumor size (cm), preoperative serum creatinine (mg/dL), sex, and age (years), but body mass index (BMI) and body surface area (BSA) were not significant factors. An equation to predict eGFR one year after RN was developed: Predicted eGFR mL/min/1.73m2=211 × Age -0.454 × Pre SCr -0.841 × Tumor size 0.069 × 0.90 (if female). The equation was validated with the validation dataset (R2=0.55, P<0.0001). Conclusions: The equation developed provided predicted postnephrectomy GFR and will be helpful for preoperative patient counseling and selecting the type of surgical procedure, especially in elective partial or radical nephrectomy cases.
Prognostic factors in patients (pts) with mediastinal nonseminomatous germ cell tumors (MNGCT).
Authors: Bulanov Anatoly , Fedyanin Mikhail , Tryakin Alexey , Pokataev Ilya , Zakharova Tatiana , Polockii Boris , Garin August , Tjulandin Sergei 
Published: March 2020

e15585 Background: According to IGCCCG, pts with MNGCT belong to poor prognostic group. But, there are no independent prognostic factors which could determine prognosis in this group of pts. We retrospectively studied prognostic factors in pts with MNGCT. Methods: We analyzed data on 61 pts with MNGCT, who were treated in our department during 1986-2011. Median age was 23 years (range: 18-44). Median follow-up time was 52 months (range 4-180). Biopsy was performed in 35/61 (57.4%) pts before treatment. At the beginning of therapy median AFP was 3,360 IU/ml (range: 1-300,000), HCG – 4.5 mIU/ml (range: 0.1 to 326210), LDH – 791 U/l (range: 249-4,475). Conventional induction chemotherapy (CT): classical BEP regimen – 23 (37.8%) pts, T-BEP – 17 (27.8%) pts, CPOB – 17 (27.8%) pts, accelerated (two-weekly) BEP – 4 (6.6%) pts. After CT, residual tumor was resected in 28 (45.9%) pts. Multivariate Cox regression analysis was performed to determine independent factors, which influenced on overall survival (OS). Results: Marker-negative objective response was revealed in 40/61 (65.6%). Progression disease during induction CT was detected in 21 (34.4%) pts. 5-years OS was 44% for all pts. Multivariate analysis revealed the following independent negative prognostic factors: age ≥ 24 (р=0.08, HR 1.9, 95%CI 0.92-4.1), size of the primary mediastinal tumor ≥ 19 cm (р= 0.03, HR 5.8, 96%CI 1.85-18.67). Median OS hasn’t been reached and 3-year OS was 62% in pts with good prognosis (age < 24 years and/or size of mediastinal tumor < 19 cm) vs. 15 months and 30% in pts with poor prognosis (р=0.02, HR 0.42, 95%CI 0.19-0.87) respectively. Conclusions: Age ≥ 24 and size of the primary mediastinal tumor ≥ 19 cm are independent negative prognostic factors in pts with MNGCT. These factors could be used as strata in clinical trials. However, this tendency has to be confirmed in large series of pts.
Adjuvant cancer peptide vaccine treatment with intravesical BCG therapy for non-muscle-invasive bladder cancer.
Authors: Obara Wataru 
Published: March 2020

e15587 Background: We previously reported safety and high immunogenicity of peptide vaccine treatment using two novel peptides derived from oncoantigens, M phase phosphoprotein 1 (MPHOSPH1) and DEP domain containing 1 (DEPDC1), for patients with advanced bladder cancer. We further conducted a multi-center phase II clinical trial using the same peptides to investigate the effectiveness to prevent recurrence after TURBt for patients with non-muscle invasive bladder cancer (NMIBC). Methods: The key eligibility criteria were patients with intermediate or high risk for NMIBC, with tumors having expression of MPHOSPH1 and/or DEPDC1, and with HLA class I expression on tumor cells. HLA-A24-restricted MPH and/or DEP derived peptide were subcutaneously administered in combination with intravesical BCG therapy after TUR-Bt. All enrolled patients had received the vaccination without knowing HLA-A status, and the HLA genotypes were used for a key-open marker. The primary endpoint was to examine effect on recurrence free survival (RFS) and secondary endpoint was induction of peptide-specific CTL response, injection site of reaction (ISR) and adverse effect. Results: A total of 133 patients were enrolled. RFS rates at 2 years in all patients were 74.4 %. Although the difference in RFS between the A24(+) and A24(-) groups (77.2% vs. 70.4%) was not statistically significant (p=0.24), that in the ISR-positive group was significantly better than that in the ISR-negative group (81.6% vs. 54.3%, p=0.0004). The peptide vaccine treatment was well-tolerated without any treatment- associated severe adverse events, while the bladder irritability caused by BCG treatment was observed in 64 cases (48.1%). The MPHOSPH1 and DEPDC1 peptide-specific CTL responses in the 24(+) group were observed in 82 % and 83 % of patients, respectively. Four (7.4%) cases in the 24(-) group revealed the peptide-specific CTL response, indicating some cross-reactivity against the vaccinated peptides on other HLA allele(s). Conclusions: Combination immunotherapy of intravesical BCG and cancer peptide vaccine demonstrated the promising clinical effect on recurrence prevention for NMIBC as well as good immunogenicity and safety. Clinical trial information: 00633204.
Importance of performance status, corrected calcium, and microvascular invasion in predicting overall survival in patients with metastatic renal cell carcinoma at the era of molecular targeted therapy.
Authors: Eto Masatoshi , Kamba Tomomi , Miyake Hideaki , Fujisawa Masato , Kamai Takao , Uemura Hirotsugu , Tsukamoto Taiji , Azuma Haruhito , Matsubara Akio , Nishimura Kazuo , Nakamura Tsuyoshi , Ogawa Osamu , Naito Seiji ,   Japan Immunotherapy SNPs-Study Group for Kidney Cancer
Published: March 2020

e15588 Background: We have recently reported that the single nucleotide polymorphisms (SNPs) in signal transducer and activator 3 (STAT3) gene are significantly associated with better response to interferon (IFN)-α in patients with metastatic renal cell carcinoma (mRCC) in our prospective trail (Eur Urol 2012, Epub ahead). In the present study, we further evaluated which clinical and pathological factors correlated with overall survival (OS) in the trial. Methods: In the multicenter, prospective study, patients with histologically confirmed RCC that was metastatic, measurable disease, age > 20 years, ECOG performance status (PS) 0-1 and adequate organ function received 3 dosages of 5 million U per week of IFN-α treatment. After the failure of IFN-α, molecular targeted drugs were used. We followed the patients for 2 years to define the date of death or loss to follow-up to calculate OS. Association between OS and clinical, pathological factors, such as age, PS, TNM classification, grade, infiltrating type, sarcomatoid component, microvascular invasion, lactate dehydrogenase (LDH), corrected Calcium (Ca), hemoglobin (Hb), C-reactive protein (CRP), platelet (Plt), etc, was analyzed using the Log-rank test. For multivariate analysis, the Stepwise test was used. Results: Two hundreds three eligible pts were enrolled between December 2006 and October 2009. All pts had prior nephrectomy, and 88.7% had ECOG PS 0. Ninety-four percent of patients had clear cell RCC, and 5% had papillary RCC. The response rate of IFN-α was 13.8% (28/203, 9 CR, 19 PR). Median OS was 42.8 months in mRCC patients initially treated with IFN-α. In univariate analysis, PS, TNM classification, grade, infiltrating type, microvascular invasion, corrected Ca, Hb, CRP, and Plt were significantly associated with OS. Among them, PS, microvascular invasion, and corrected Ca were significantly correlated with OS in multivariate analysis. Conclusions: This prospective study demonstrates that PS, corrected Ca, and microvascular invasion are important in predicting OS in mRCC patients initially treated with IFN-α at the era of molecular targeted therapy. Clinical trial information: UMIN000000731.
Proof of concept of correlation between progression-free survival (PFS) and overall survival (OS) in treatment-naive patients with advanced renal-cell carcinoma (mRCC): Final results of a randomized phase II study comparing sorafenib plus interleukin-2 (IL-2) versus sorafenib alone: The ROSORC trial.
Authors: Verzoni Elena , Bracarda Sergio , Ricci Sergio , Sacco Cosimo , Ridolfi Laura , Porta Camillo , Miceli Rosalba , Zilembo Nicoletta , Bajetta Emilio , Procopio Giuseppe ,   Italian Trials in Medical Oncology (ITMO)
Published: March 2020

e15589 Background: The outcome analyses of the randomized phase 2 ROSORC trial, did not show any difference in terms of PFS between mRCC patients undergoing first-line treatment with sorafenib plus IL-2 versus sorafenib monotherapy (7.3 versus 6.9 months in favour of the combination arm; p= 0.109). (Procopio et al BJC 2011). Overall survival analyses are here reported. Methods: In this open-label phase 2 prospective study, 128 treatment-naïve patients with mRCC were randomized to receive either sorafenib 400 mg twice daily plus subcutaneous IL-2 4.5 MIU five times a week for 6 weeks every eight weeks (Arm A), or sorafenib alone (Arm B). The primary endpoint was PFS, while the secondary endpoint was OS. Survival analyses were evaluated by Kaplan-Meier plots and compared by two-sided log-rank test. Results: After a median follow up of 58 months (interquartile range 28-63), the median OS was 38 and 33 months in arm A and B respectively (p= 0.667). The 5-year OS was 26.3 % (95% CI: 15.9-43.5) and 23.1% (95 % CI: 13.2-40.5) in the combination and single agent arm, respectively. Overall we observed 85 deaths and among them, 42 occurred in the Arm B. Overall, 49 (74 %) and 48 (77 %) patients in the Arm A and B, respectively, received at least one targeted therapy (TT) after disease progression, including sunitinib, everolimus, axitinib or temsirolimus. Most common adverse events (AEs) included fatigue, hand-foot syndrome, hypertension and diarrhea and were mild in grade (Grade 1-2). Grade 3-4 AEs were documented in 38 % and 25 % of patients receiving combination and single agent treatment, respectively. Conclusions: While the PFS observed was in keeping with previous literature data regarding sorafenib, either as a single agent or in combination, the OS dramatically improved results reported so far in prospective randomized trials. This outcome suggests lack of correlation between PFS and OS and a synergistic effect of sequential TTs following sorafenib failure. Clinical trial information: NCT00609401.
Antineoplastic effects of specific inhibition of Notch-2 in bladder cancer.
Authors: Hayashi Tetsutaro , Gust Kilian , Jaeger Wolfgang , Awrey Shannon , Li Na , Altamirano-Dimas Manuel , Buttyan Ralph , Li Estelle , Fazli Ladan , Black Peter C. 
Published: March 2020

e15590 Background: Notch signaling guides cell fate decisions, establishment of cell lineages, stem cell maintenance and differentiation during early development. Notch is re-activated in many malignancies where it has been shown to regulate tumor growth and progression. We report effects of Notch-2 knockdown and treatment with a specific Notch-2 inhibitor, NRR2Mab, in pre-clinical models of bladder cancer. Methods: UM-UC3, UM-UC13 and UM-UC16 cells, representing invasive bladder cancer cells with high Notch-2 expression, were stably transduced with Notch-2 or non-targeting shRNA in a lentiviral vector. A Notch-2-inactivating monoclonal antibody, NRR2Mab, and an isotype-matched, non-targeting antibody were provided by Genentech, Inc. (San Francisco, CA). Cells were grown under adherent (AH) or anchorage-independent conditions (AI) and the effects of Notch-2 silencing or NRR2Mab inactivation were quantitatively assessed for changes in proliferation, migration and invasive activities using in vitro assays, and for expression of Notch-2 or other common stem cell-related genes using quantitative RT-PCR, Western blotting and immunohistochemistry. In vivo effects were evaluated in an orthotopic bladder cancer xenograft model with bioluminescence imaging. Results: Cells transduced with the Notch-2 shRNA or treated with NRR2Mab demonstrated markedly decreased Notch-2 expression. Both treatments diminished cell proliferation under AI but not AH conditions in UM-UC3 and UM-UC13. When grown in AI conditions, UM-UC3 and UM-UC13 were found to be enriched for expression of stem cell genes. Notch-2 silencing or treatment with NRR2Mab diminished the expression of these genes. Both treatments significantly inhibited cell migration and invasion of these cells. In vivo, stable Notch-2 knockdown significantly inhibited xenograft growth for all 3 cell lines. NRR2Mab treatment also inhibited UM-UC13 xenograft growth and metastasis. Conclusions: Our results provide preclinical evidence that Notch-2 may be a useful target to inhibit growth and progression of bladder cancer. Targeting Notch-2 with a specific inhibitory monoclonal antibody warrants further evaluation in this context.