bluuebunny/crossref_metadata_2025 huggingface dataset:
Occult hepatitis B virus infection in patients with chronic liver disease.
Authors: Diniz Paulo Henrique Costa , Faria Luciana Costa , Vidigal Paula Vieira Teixeira , Xavier Marcelo Antonio Pascoal , do Amaral Nayra Soares , Resende Alexandre Prado , Lima Agnaldo Soares , Miranda Debora Marques , Ferrari Teresa Cristina de Abreu
Published: March 2020

e15199

Background: Occult hepatitis B virus (HBV) infection is characterized by persistence of HBV DNA into the tissue of hepatitis B surface antigen-negative individuals. The clinical relevance of this infection is still under debate. In particular, the impact of occult HBV infection in cases of hepatocellular carcinoma (HCC) is uncertain. Methods: We investigated the prevalence of occult HBV in patients with chronic liver disease, with or without HCC, that were submitted to liver transplantation or partial hepatectomy in Alfa Institute of Gastroenterology from Clinical Hospital - UFMG - Brazil. We tested the presence of VHB DNA in liver sample using nested PCR in four different regions of viral genome (pre-S/S, pre –core/core, polymerase and X). We also tested these patients’serum for HVB antigens (HBsAg and HBeAg)and antibodies (anti-HBs, anti-HBe and anti-HBC). Results: Our studied population included 71 patients, 50 (70.4%) were male and had median age of 51±12.5 years. Cirrhosis etiology was alcoholic (22 cases, 32.4%), viral hepatitis (17 cases, 25%), cryptogenic (16 cases, 23.5%), autoimmune (10 cases, 14.7%) and 3 cases of other etiologies. HCC was found in 22 patients (31.4%). Viral DNA was detected in 4 cases (5.6%), three of them with HCC. Among these three cases viral DNA was found in non-tumoral area in two of them and in HCC sample in the other one. Conclusions: The prevalence of occult hepatitis B infection was high in our population of cirrhotic patients submitted to liver transplant, especially with associated HCC.
Salvage high-dose chemotherapy for primary mediastinal nonseminomatous germ cell tumors: Single institute experience.
Authors: Walker John WT , North Scott A. , Basappa Naveen S. , Venner Peter M.
Published: March 2020

e15503

Background: Primary mediastinal non-seminomatous germ cell tumors (PMNSGCT) bear a worse prognosis than stage-matched testicular primaries, with a five year survival rate of 50%. In contrast to relapsed testicular NSGCT, retrospective analyses have not shown benefit to high-dose chemotherapy and autologous stem-cell transplant (HDCT/ ASCT) in PMNSGCT patients. Since publication of these studies, advancements in treatment regimens and supportive care have occurred, with emerging evidence suggesting HDCT/ASCT may benefit patients with PMNSGCT - both as first-line sequential treatment after standard-dose chemotherapy and at relapse. Objectives: Review the experience of patients presenting with PMNSGCT to a regional referral cancer center as a quality control assessment. Assess the benefit of salvage HDCT/ASCT to relapsed PMNSGCT patients. Methods: Patients presenting with PMNSGCT from 1980-2010 were abstracted from a Provincial cancer registry and records were retrospectively reviewed. Data includes patient demographics, cancer treatments and outcomes. Results: Fourteen male patients (median age 29; range: 17-54 years) with PMNSGCT were identified. Seven of 13 (54%) patients remain continuously disease-free with 1 patient lost to follow-up. Mean duration of follow-up in these patients is 57 (34-100) months. Three patients died having received ≤ 1 cycle of chemotherapy; exclusion of these patients results in a treatment failure rate of 30%. Six of the 7 cancer-free patients required salvage surgery. Three patients received tandem HDCT/ASCT (carboplatin 550 mg/m2 and etoposide 150 mg/m2daily for 4 days) at subsequent relapse despite second-line chemotherapy. Two remain disease-free at 45 and 74 months respectively, while the third patient died of their disease 14 months post-transplant. Conclusions: Our experience with PMNSGCT is generally consistent with published outcomes in that ≈50% of patients are cured. However, in this series 2/3 heavily pretreated patients were salvaged with HDCT/ASCT, refuting the published historical experience. This study is limited by its small sample size, but provides impetus to re-examine HDCT/ASCT for high-risk patients.
Effective and less toxic trimodality approach in muscle invasive urinary bladder cancer.
Authors: Abdel-Wahab Reham , Eltaher Ahmed M. , Essa Hoda H. , Eid Samir-Shehata M.
Published: March 2020

e15505

Background: Bladder cancer represents a global health problem. Radical cystectomy considered the standard of care for invasive bladder cancer. Because of the potential morbidity with surgery, organ preservation via trimodality approach has been the subject of investigation. The concurrent use of cisplatin with 5-FU or gemcitabin with local radiotherapy has been studied and the results were better than radical cystectomy. However, this was associated with grade 3-4 (G3-4) toxicity. Recently, similarly effective but less toxic regimen by the use of paclitaxel and cisplatin is under investigation. Methods: We proposed a single-center, single arm, phase II prospective cohort study. 30 patients (22 male and 8 female) with T2-T3 bladder cancer according to the AJCC 2010 were included. All patients were >18y with exclusion of those with bladder capacity < 350cc, hydronephrosis, with previous intravesical therapy, systemic chemotherapy or pelvic radiation, those currently receiving nephrotoxic or ototoxic drugs, and those with other malignancies. All patients treated with maximum transurethral resection (TUR) followed by local radiotherapy 64Gy concurrently with weekly 60mg/m2 Paclitaxel and 20mg/m2 Cisplatin. Results: Cystoscopic re-evaluation 6-8 weeks after the end of treatment revealed that 90% of patients achieve complete response (CR), 6.7% achieve partial response (PR) and 3.3% had stable disease (SD). Mild toxicity was infrequent and easily controlled without interruption of treatment except in one patient. Toxicity was in the form of cystitis G1 in 46.7% and G2 in 3.3%. Diarrhea G1 in 33.3% and G2 in 3.3%. Only one patient who has past history of piles, developed G2 proctitis that leads to irregularity of treatment. Other mild toxicities were: G1 dermatitis (80%), G1 bleeding per rectum (3.3%), G1 anemia (13.3%), G1 and G2 nausea and vomiting (50% and 33.3% respectively), while neutropenia and thrompocytopenia were not seen. Conclusions: Our preliminary results revealed that weekly low dose paclitaxel and cisplatin concurrently with local radiotherapy was effective, tolerable and has acceptable toxicity in the treatment of muscle invasive urinary bladder cancer.
Effect of race on survival of metastatic renal cell carcinoma treated with VEGFR-TKI therapy.
Authors: Kuykendal Adam Rea , Snavely Anna C , Nielsen Matthew Edward , Kim William Y.
Published: March 2020

e15507

Background: African Americans (AAs) with renal cell carcinoma (RCC) have a higher incidence of disease, younger age of onset, and at least in the cytokine era AA have had a shorter progression free survival (PFS) and overall survival (OS) relative to Caucasians (Cs). Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors (VEGFR-TKIs) were approved for advanced RCC based on trials with minimal AA participation. This study was undertaken to examine if VEGFR-TKIs are similarly effective in AA patients. Methods: This was a single institution retrospective cohort study. We examined the medical records from 2004 to 2012 of all C and AA patients with metastatic RCC started on first line VEGFR-TKI therapy with at least one follow up visit. This resulted in 34 C patients and 12 AA patients. We abstracted self- reported race, treatment type, MSKCC prognosis, date of progression as defined by the treating physician, and other demographic and clinical variables. The Social Security Death Index was used to establish date of death. OS and PFS were analyzed using Kaplan-Meier and Cox proportional hazards models. Gene expression data from TCGA was analyzed for biological differences between RCC occurring in AAs and Cs. Results: 54.6% of AAs were classified into the MSKCC poor prognosis group compared with 10.7% of Cs. AAs compared to Cs had a non-significant trend toward worse OS (HR 1.49, p = 0.36) and PFS (HR 1.59, p = 0.27). After adjustment for risk group we found no significant difference between AAs and Cs for OS (HR 1.00, p = 0.99) and PFS (HR 1.26, p = 0.66). Comparison of the RCC gene expression profiles demonstrated significant differences in gene expression with AA tumors showing enrichment for genes involved in ion transport and cell-cell junctions. Conclusions: This is a preliminary study that suggests first line VEGFR-TKI therapy is an effective choice for AA patients as metastatic RCC in AAs responds similarly as Cs to VEGFR-TKI treatment. In addition, there are distinct gene expression differences that distinguish AA and C tumors.
The role of prognostic factors in metastatic renal cell carcinoma (mRCC) treated with targeted therapies (TT): Data from an Italian retrospective multicentric study.
Authors: Barile Carmen , Fraccon Anna Paola , Zustovich Fable , Gaion Fernando , Salvagno Luigi , Massari Francesco , Martellucci Ignazio , Modenesi Caterina , Giusto Mauro , Segati Romana , Bearz Alessandra , Ogliosi Chiara , Macrini Sveva , Maruzzo Marco , Larussa Francesca , Nicolardi Linda , Bonciarelli Giorgio , Menon Daniela , Inno Alessandro , Pasini Felice
Published: March 2020

e15512

Background: Several prognostic factors in mRCC have been largely described in the literature. This study was aimed to verify whether some of these factors maintain their prognostic role in a cohort of pts treated in the community setting outside clinical trials. Methods: 902 pts with mRCC treated with TT from 2007 to December 2012 in 28 Italian centres were included in the analysis. Various potential prognostic factors were correlated with overall survival (OS). Results: Median age was 60 (range 25-89), 75% of pts were males; median OS (mOS) was 24 mo. Histology was clear cell (CC), CC with sarcomatoid component, papillary, NOS, not available in 82%, 6%, 4%, 4% and 4 %, respectively. mOS in the CC subgroup was 28 vs 12.5 mo of the non CC subset (p<0.001). Nephrectomy was performed in 88% of the cases. mOS of these pts was 28 mo vs 6.5 in those without surgery (p<0.001). The number of metastatic sites was >2 in 43% of the pts. mOS of this group was 18 mo vs 31 mo of pts with ≤2 metastatic sites (p=0.0001). MSKCC risk was good in 32%, intermediate in 53% and poor in 15% of the pts. According to MSKCC risk score, mOS was 6.4, 24 and 49 mo in poor, intermediate and good subsets, respectively (p<0.001). The small subset of pts (2%) with both thrombophilia and neutrophilia had a dismal mOS of 3 mo. PS (ECOG) was 0-1 in 90% of the pts; mOS of pts with PS ≥2 was 6 mo (p=0.0001). The findings of multivariate analysis are showed in the Table. Conclusions: The results of our survey confirm that clear cell histology, prior nephrectomy, number of metastatic sites, PS, MSKCC risk, platelets, and neutrophils count maintain their prognostic value also in mRCC pts treated with TT in the everyday clinical practice. [Table: see text]
Targeted therapy for renal cell carcinoma (RCC) with brain metastasis: Overall survival (OS) and safety.
Authors: Bastos Diogo Assed , Molina Ana M. , Jia Xiaoyu , Velasco Susanne , Patil Sujata , Voss Martin Henner , Feldman Darren Richard , Motzer Robert John
Published: March 2020

e15517

Background: Brain metastases (b-met) in RCC are associated with poor prognosis and median OS of about 7 months in the pre-targeted therapy (TT) era (Culine, Cancer 1998). The role of TT in this setting is not well established since patients (pts) with b-met were excluded from most clinical trials. The primary objective was to assess OS and central nervous system (CNS) safety of pts with b-met treated with TT. Methods: Pts with mRCC treated with ≥ 28 days of TT after b-met diagnoses were retrospectively identified. Kaplan-Meier method and Cox proportional hazards model were used to analyze the association between clinical features and OS. Results: 65 pts were identified, 52 (80%) treated with anti-angiogenic agents and 13 (20%) treated with mTOR inhibitors. Most pts had extracranial metastasis (98%) and 54% had ≥ 2 brain lesions. Fifty seven pts (88%) had local therapy for b-met before TT including surgery in 3 (5%), radiation therapy (RT) in 36 (55%) and both surgery and RT in 18 (28%). Median follow-up was 12.3 months (1.1 – 58.8) and median time from RCC diagnosis to b-met was 17.8 months (0 – 192.2). Median TT duration was 3.4 months (0.3 – 31.9) for 1st line and 1.9 months (0.2 – 23.6) for 2nd line. Median OS was 12.2 months (95% CI 8.0 to 15.5). On univariate analysis using various clinical and treatment variables, MSKCC risk group (P= 0.001), histology subtype (clear vs other) (P< 0.0001), and number of b-met at diagnosis (P= 0.004) correlated with OS and retained statistical significance on multivariate analysis (Table). CNS complications were identified in 5 pts (8%), including 2 with radiation necrosis and 3 with b-met hemorrhage. Conclusions: The use of TT in the multimodality treatment of pts with RCC and b-met appears safe with OS that compares favorably to historical results in the pre-TT era. Clear cell RCC, favorable MSKCC risk status, and solitary b-met are associated with better outcome. [Table: see text]
Patience is a virtue: Wait and see strategy for metastatic or recurrent renal cell carcinoma.
Authors: Park Inkeun , Lee Jae-Lyun , Ahn Jin-Hee , Jeong In Gab , Song Cheryn , Hong Bum-Sik , Hong Jun Hyuk , Kim Choung-Soo , Ahn Hanjong
Published: March 2020

e15519

Background: Metastatic renal cell carcinoma (MRCC) often presents with very indolent course without any symptom, and treatment (Tx) for MRCC is mostly palliative rather than curative in a molecular target agents era. There exist several Tx options for MRCC, but all available agents have considerable toxicities, cause economic burden to patients (pts), and impair quality of life. For some cancers like indolent lymphoma, “wait and see” strategy (W&S) is adopted for asymptomatic pts. We retrospectively evaluate clinical outcomes of W&S for asymptomatic MRCC pts. Methods: we enrolled MRCC pts who was followed-up with deferred treatment for the purpose of W&S in our institution between 2000 and 2012. Clinical characteristics, response to W&S, predictive factor for time-to-progression (TTP), and response to succeeding first line Tx were analyzed. Results: Of 44 pts found, 30 pts had recurrent disease and 13 pts initially metastatic disease. Most pts had good Karnofsty PS (KPS), 100% for 26 pts and 90% for 13 pts. Lung (38 pts), lymph nodes (16 pts), kidney (6 pts) were most common site of metastasis. During W&S, stable disease (SD) and progressive disease (PD) were the best overall response for 36 (82%) and 8 (18%) pts, respectively, and 37 pts had PD finally. With a median F/U period of 24.7 months, median TTP and OS were 12.5 months (95% CI, 6.7-18.4) and 91.1 months (95% CI, 41.3-141.0). After univariate and multivariate analysis for TTP, KPS<100%, liver metastasis, time from diagnosis to W&S< 1year, and neutrophilia were found to be predictive factors for TTP during W&S. After PD, 27 pts proceeded to systemic treatment (13 sunitinib, 10 pazopanib, 3 immunotherapy, and 1 temsirolimus). Objective response rate were 54% for sunitinib, and 50% for pazopanib. Conclusions: This study suggests that W&S could be a viable treatment option for the first-line approach in asymptomatic MRCC pts, especially for those who have good performance status without neurtrphilia or liver metastases.
Extent of neutrophil (NTP) infiltration in benign lymph nodes (LNs) to predict survival in patients with muscle-invasive bladder cancer (MIBC).
Authors: Liang Wei , Jove Richard , Yuh Bertram E. , Chan Kevin , Wilson Timothy G. , McConkey David James , Lerner Seth P. , Pal Sumanta Kumar
Published: March 2020

e15522

Background: In preclinical models, NTPs appear to establish a pre-metastatic niche that fosters the invasion of metastases (Kowanetz et al. PNAS 2010). This observation still requires clinical validation in MIBC. Methods: Benign LN tissue was obtained from patients (pts) who had undergone cystectomy and LN dissection for documented MIBC. Immunohistochemical (IHC) staining for CD15 (a NTP marker) was performed. Interleukin-17 (IL-17) and phosphorylated signal transducer and activator of transcription 3 (pSTAT3), putative mediators of NTP recruitment, were assessed through the same method (Laan et al. J Immunol 1999; Fielding et al. J Immunol 2008). Positively staining cells were counted and averaged over 8 high power fields. Pts were stratified by the median cell count for each biomarker. Analyses of overall survival (OS) were performed using the Kaplan-Meier method and log-rank test. Results: Of 55 pts with MIBC, 19 pts received no neoadjuvant chemotherapy (NAC), while 36 pts had received NAC with either GC (n=17) or MVAC (n=19). CD15 and IL-17 expression was significantly lower in pts with prior NAC (P<0.001 for both), while expression of pSTAT3 was similar in both groups. Furthermore, across the whole cohort, a strong association was seen between expression of CD15 and IL-17 (r=0.73, P<0.001). Amongst patients with no prior NAC, median OS was higher in those pts with low CD15 v high CD15 (158.7 mos v 36.9 mos, P=0.02), and low pSTAT3 v high pSTAT3 (NR v 106.4 mos, P=0.04). Median OS was numerically higher in pts with low IL-17 v high IL-17 (114.5 v 36.9 mos; P=0.14). Patients with both low CD15/IL-17 had a particularly favorable outcome. Amongst pts with prior exposure to NAC, no difference in survival was noted based on CD15, pSTAT3 or IL-17. Conclusions: NTP recruitment to benign LNs (potentially mediated by IL-17) may be prognostic of OS in pts with MIBC who have not received NAC. Bolstered by these findings, the prognostic value of NTP recruitment will be examined prospectively in SWOG 1011, a trial comparing limited v extended LN dissection in pts with MIBC.
Sequential salvage chemotherapy for CDDP-refractory advanced testicular cancer: Japanese high-volume center experience.
Authors: Nakamura Terukazu , Kimura Yasunori , Ueda Takashi , Naya Yoshio , Hongo Fumiya , Miki Tsuneharu
Published: March 2020

e15526

Background: Chemotherapy- refractory or resistant GCTs, so called ‘difficult-to-treat’ GCTs would remain continuously disease-free with salvage chemotherapy or surgery. The optimal salvage chemotherapy remains unclear. The aim of this study was to assess the efficacy of ‘sequential’ chemotherapy for advanced testicular cancer. Methods: Salvage chemotherapy was required in 129 patients out of 233 advanced GCTs treated at Kyoto Prefectural University of Medicine from June, 1998 to December, 2011. Clinical outcomes were retrospectively assessed. Results: Median age was 31 year-old (range:17-65y.o.). Non-seminoma was in 111 cases (86.0%). IGCCC showed good in 37 cases (28.9%), intermediate 33 (25.6%), poor 47 (36.4%), and unknown 12 (9.1%). As the 2nd line therapy, VIP/VeIP and TIP/N therapy were done in 43 (33.3%) and 49 cases (38.0%), respectively. With regard to the patients requiring 3rd line or more chemotherapy, 95, 67, 40, 26 cases had 3rd, 4th, 5th and 6th line or more chemotherapy, respectively. TIN therapy was performed in 48 patients as 3rd line and in 24 patients as 4th line. Irinotecan-containing chemotherapy was done in 24 and 36 cased as 2nd +3rd line therapy and 4th line or more, respectively. Gemcitabine-containing therapy was done in 33 cases with 3rdline or more chemotherapy. Overall survival rate at median follow-up period was 71.0%at median follow-up of 48m. Overall survival stratified by IGCCC was shown in the figure. There was no significant difference between any two groups. Clinical outcomes showed no evidence of disease (NED) was obtained in 86.1% with second line therapy. Noteworthy mentioned, about 40% patients had NED even in the 4thline or more chemotherapy group. Conclusions: Relatively good prognosis was obtained in the patients with salvage chemotherapy at Japanese high volume center. Sequential continuous chemotherapy would be very important to manage ‘difficult-to-treat’ advanced germ cell tumors.
Searching for predictors markers in renal cell carcinoma: A regression model.
Authors: Quindós Varela Maria , Medina Villaamil Vanessa , Santamarina Cainzos Isabel , Aparicio Guadalupe , Valladares Ayerbes Manuel , Antón Aparicio Luis M.
Published: March 2020

e15542

Background: Renal cell carcinoma (RCC) is known to be resistant to chemotherapy. The need for the identification of biomarkers capable of determining RCC prognosis factors and metastatic potential that are obtainable from non-invasive or minimally invasive techniques are desirable. The purpose from this analysis was to derive predictive models which could predict more accurately than any one factor alone. Methods: By tissue micro-array (TMA) technology we assessed 29 markers involved in the cascade of events leading to the formation and progression of this disease. The ability of multivariate logistic regression to improve the diagnostic accuracy for RCC by combining determinations of proteins markers and pathological variables was evaluated. Univariate analysis was used to select factors (p<0.05) for entry into a multivariate stepwise logistic regression model using the forward method. Odds ratios with 95% CI were calculated. A p-value of < 0.05 was significant. Results: The regression equations obtained were the next: for lymphatic vessels invasion, Y(x)=6.815- 0.442 (EGFR value); for node status Y(x)=2.07+ 0.494(NOTCH1 value) - 0.269(GLUT5 value); for veins invasion Y(x)=57.61+ 6.01 (NOTCH2 value)- 9.3 (GLUT1 value)+ 1.73 (C-KIT value); for breaking capsule Y(x)=2.713- 0.261(EGFR value)+ 0.407 (NOTCH1 value)- 0.305(NOTCH2 value)+ 0.463 (GLUT1 value); for pelvis invasion Y(x)=8.624-0.198 (EGFR value)- 0.514 (DLL3 value). Receiver-operator characteristic (ROC) curve analyses were made to analyse the accuracy of the best candidate proteins. Should be noted from this analysis NOTCH1 and GLUT5 for node status prediction (AUC=0.833, 95% CI, 0.744-0.922; p<0.001) and EGFR and DLL3 for pelvis invasion (AUC=0.777, 95% CI, 0.631-0.922; p=0.007). Conclusions: In the age of individual therapy, the approach to percutaneous image-guided RCC biopsy procedures plays an expanded role. Applying a 2 mm punch needle for constructing a TMA, thereby mimicking the percutaneous biopsy technique we could describe for the first time how are combined 29 protein markers in regression equations to predict in the most optimal way a number of pathological variables associated with RCC that may help in the diagnosis and prognosis of this disease.
Clinical efficacy of sunitinib as post-operative adjuvant therapy in patients with high-risk renal cell carcinoma.
Authors: Zhang Xu , Yuan Jianlin , Wang Liang , Chen Lijun , Pan Jinhong , Ye Linyang , Xiao Xuren , Qiu Jianhong , Zhang Keqin , Ye Gang
Published: March 2020

e15547

Background: To evaluate the efficacy and safety of Sunitinib as post-operative adjuvant therapy in patients with high-risk renal cell carcinoma (RCC). Methods: A total of 60 patients with resected, histologically confirmed clear cell RCC were enrolled in this study. Patients received orally Sunitinib either at a dose of 50mg on treatment schedule 4/2 (once daily for 4 weeks followed by 2 weeks off) or at a dose of 37.5mg once daily for three 6-week cycles from 1 month after surgery. Results: All 60 patients tolerated Sunitinib treatment well and no patient discontinued treatment due to adverse events. Most adverse events were grade 1 to 2. The most frequently reported adverse events were neutropenia (56.7%), thrombocytopenia (53.3%), leucopenia (48.3%), hand-foot syndrome (46.7%) and hypertension (36.7%). The most frequently reported grade 3 or 4 toxicities were thrombocytopenia (25%), neutropenia (15%), hand-foot syndrome (11.7%) and leucopenia (8.3%). The majority of adverse events occurred within the first 1-2 cycles of Sunitinib treatment, and was ameliorated 1 month after 3 cycles finished. No irreversible adverse event was observed. As of January 31, 2013, recurrence occurred in 3 of 60 (5%) patients except one death due to cerebrovascular accident unrelated to treatment, with 12-month disease-free survival (DFS) rate of 96.6% (RCC recurred 7 months after surgery in 2 patients and recurred 14 months after surgery in 1 patient). Conclusions: Myelosuppression occurred less frequently in high-risk RCC patients treated with Sunitinib as operative adjuvant therapy than in advanced RCC patients, with a better benefit trend. Long-term follow-up data are needed to further confirm the efficacy of Sunitinib in the adjuvant setting.
Phase I study of TH-302, investigational hypoxia-targeted drug, in combination with sunitinib.
Authors: Starodub Alexander , Milhem Mohammed M. , Pennington Kenneth Lee , Kio Ebenezer A. , Bruetman Daniel , Thorne Tracy , Hickingbottom Barbara , Kroll Stew
Published: March 2020

e15557

Background: Tumors often consist of highly hypoxic subregions known to be resistant to chemotherapy and radiotherapy. TH-302 is an investigational hypoxia-targeted drug with a 2-nitroimidazole trigger designed to release the DNA alkylator bromo-isophosphoramide mustard (Br-IPM) when reduced in severe hypoxia. Preclinical models demonstrate that treatment with sunitinib increased the tumor hypoxic fraction, the therapeutic target of TH-302. Initiating TH-302 following sunitinib significantly increased the efficacy of sunitinib in these models. In this phase 1 dose escalation study, TH-302 was combined with standard dose sunitinib. Methods: Eligible patients (pts) for the study (NCT01381822) had advanced RCC, GIST or PNET tumors, evaluable disease by RECIST, ECOG ≤2 and acceptable hematologic, hepatic and renal function. Pts received TH-302 in combination with standard full doses of 50 mg PO sunitinib daily from Day 1 to Day 28 of a 6 week cycle. TH-302 was administered IV on Days 8, 15 and 22. TH-302 starting dose was 240 mg/m2. The study objectives were to determine the MTD, DLTs and RP2D and to evaluate the safety and preliminary efficacy of TH-302 when used in combination with sunitinib. Results: Ten pts were enrolled. Median age: 63 (range 27-72); Female (5)/ Male (5); ECOG 0 (5); ECOG 1 (5); Primary tumor: RCC (6), GIST (4). Median prior chemotherapies: 3 (range: 0-3) including prior sunitinib in 7 pts. No DLTs were observed in the 3 pts at the 240 mg/m2 cohort and 1 pt of 5 DLT evaluable in the 340 mg/m2 cohort had a DLT of stomatitis. Eight pts discontinued (progressive disease (6), pursued other treatment options, adverse event unrelated to study drugs). Three pts had a study drug related SAE (neutropenic sepsis, anemia, hyperthyroidism). Common TH-302 related AEs were nausea and mucosal toxicity and were mostly grade 1 or 2. Grade 3/4 thrombocytopenia and neutropenia were reported in 4 pts and 3 pts, respectively. One of 4 (25%) pts with GIST had a confirmed PR and 3 of 4 (75%) pts with RCC had PRs including 2 with confirmed PRs. Conclusions: TH-302 can be administered in combination with full dose sunitinib. Mucositis was dose limiting. There is preliminary evidence of activity of TH-302 in combination with sunitinib in RCC. Clinical trial information: NCT01381822.
Development of renal cell carcinoma in patients with primary uveal melanoma.
Authors: Valsecchi Matias Emanuel , Asija Aakanksha , Sato Takami , Shields Carol L , Shields Jerry A , Richards-Yutz Jennifer , Ganguly Arupa , Mastrangelo Michael J. , Lin Jianqing
Published: March 2020

e15563

Background: Somatic mutations of BRCA1 associated protein1 (BAP1), a tumor suppressor gene, located on chromosome 3p21.1 is found in 50% of primary uveal melanoma (UM) and has been linked to an aggressive phenotype. It is recently reported that somatic BAP1 mutation is also found in 15% of renal cell carcinomas (RCC). We hypothesize that germ line or somatic mutation of BAP1 may contribute the carcinogenesis of patients (pts) who have both UM and RCC. Methods: Retrospective chart review on patients with primary UM treated at Wills Eye Institute and Thomas Jefferson University between 1997 and 2012 revealed 15 patients with both UM and histologically proven RCC. Clinical information on these patients was analyzed. Tumor tissue and blood specimens were also collected for BAP1 gene mutation analysis. Results: Of the 15 patients, 12 (80%) were males. Median age at diagnosis of UM was 57 years old. Six of these patients developed liver metastasis on follow-up (40%). From 8 patients whose pathology data on RCC were available, 6 of them were clear cell type (75%), one was papillary type-1 and one was multilocular cystic subtype. The diagnosis of RCC proceeded the UM diagnosis in 5 of 15 patients, while the diagnoses were made concurrently in 4 patients. Six patients were diagnosed with UM first. For pts who had genetic testing on UM, chromosome 3 abnormalities are the most common abnormalities found. Peripheral blood specimens were tested for 2 patients and germ-line BAP1 mutation was not discovered. Detailed tumor tissue BAP1 mutation analysis is ongoing. Conclusions: The development of RCC is relative common for UM and the molecular mechanism is being determined. It is male dominant in sex and mostly clear cell type in histology of RCC. Further gene mutation analysis and its association with clinical data will be reported.
Increase in blood pressure with sorafenib exposure: Renal cell carcinoma (RCC) versus other solid tumors.
Authors: Shah Amishi , Motiwala Shweta , Brose Marcia S. , O'Dwyer Peter J. , Flaherty Keith , Keefe Stephen Michael
Published: March 2020

e15564

Background: Tyrosine kinase inhibitors (TKIs) such as sorafenib are widely used in the treatment of solid tumor malignancies. Incident hypertension with angiogenesis inhibitors has been well-documented in the RCC where incident hypertension on treatment is associated with improved clinical outcome. Little has been reported about increases in (BP) with TKIs in other solid tumor malignancies. Methods: We performed a retrospective cohort study examining changes in BP with sorafenib among the 101 patients treated at the University of Pennsylvania on a randomized discontinuation trial examining sorafenib in patients with advanced solid tumor malignancies. Solid tumor diagnoses were established on the basis of tumor histology. Treatment of patients on study with sorafenib was initiated at 400 mg BID. Patients were treated for at least 12 weeks and were evaluated at least every three weeks in the clinic. BP was recorded at each visit. Sorafenib exposure was recorded by patients in a pill diary. The primary endpoint for this study was a maximal change in BP defined as the difference between baseline BP and highest subsequent recorded systolic and diastolic BPs on treatment. Results: 72% of RCC patients developed an increase in systolic BP (SBP) of at least 20 mmHg as compared to 32% of non-RCC patients. The mean increase in SBP on study for RCC patients was 30 mmHg versus 19 mmHg in non-mRCC patients. RCC patients in the top quartile of increased SBP showed a mean increase of 54 mmHg as compared to 35 mmHg for non-mRCC patients. A chi-squared test of proportions and t-tests were used to compare rates and means, respectively. Each of the aforementioned differences were found to be statistically significant with p-values <0.003. These relationships also held true for diastolic BP. There was no difference in SBP between groups in terms of age or sorafenib exposure. Differences in BP were not related to differences in glomerular filtration rate. Conclusions: In these sorafenib-treated patients, the proportion of patients with increased BP and the mean amplitude of change in BP both were significantly greater in the RCC population than in the non-RCC group.
Comparing the efficacies of neoadjuvant non-cisplatin-based and cisplatin-based chemotherapies in obtaining pathologic complete remissions in muscle-invasive bladder cancer.
Authors: Sivakumaran Praveen , Ranpura Vishal Navnitray , Perry David John
Published: March 2020

e15577

Background: Muscle-invasive bladder cancer (MIBC) is an aggressive disease and cisplatin-based neoadjvuant chemotherapy is standard therapy. Because of renal insufficiency, many patients are unfit to receive cisplatin and, instead receive carboplatin-based chemotherapy. The efficacy of carboplatin-based chemotherapy has not been studied in this setting. We performed a study comparing the efficacies of neoadjuvant carboplatin-containing and cisplatin-containing chemotherapies in achieving pathologic complete responses (pCR) in MIBC. Overall survival (OS) was also calculated. Methods: Medical records for all patients who underwent cystectomy at MedStar Washington Hospital Center between January 1, 2002 and December 31, 2011 were reviewed to determine which neoadjuvant chemotherapy was given and whether a pCR was reached at the time of cystectomy. OS was also calculated. Results: 232 patients qualified for study. 13 received neoadjuvant cisplatin-based treatment (Group 1) and 12 received neoadjuvant carboplatin-based treatment (Group 2). pCR rates were 53.8% and 41.7% in Groups 1 and 2, respectively. 5-year OS for Groups 1 and 2 were 69% and 75%, respectively. Conclusions: Given the limitations of this small retrospective analysis, carboplatin-based neoadjuvant chemotherapy prior to cystectomy for MIBC appears to be comparable in efficacy to cisplatin-based neoadjuvant chemotherapy.
Bladder cancer in African-Americans: Defining intrinsic biology and outcome.
Authors: Chism David D. , Damrauer Jeffrey S. , Gallagher Sarah A. , Milowsky Matthew I. , Kim William Y.
Published: March 2020

e15595

Background: Matched for stage and grade, urothelial carcinoma (UC) of the bladder has a higher cancer-specific mortality in African-Americans [AAs] as compared to whites. Gene expression studies in breast cancer have identified a basal-like subtype in AAs associated with a worse prognosis. We sought to use gene expression analysis to determine if the difference in outcome in UC is related to tumor biology. Methods: RNA expression of high-grade, muscle invasive UC tumors was filtered for dynamically expressed genes, hierarchically clustered and used to define the optimal number of gene expression subclasses by the criterion of subclass stability. 2 class Significance Analysis of Microarrays (SAM) was used to define the most differentially expressed genes and this list was analyzed by DAVID and Ingenuity (IPA) pathway analysis. The 50-gene predictor (PAM50) was used to determine correlation to the basal centroid of basal-like breast cancer. Results: Using hierarchical clustering, K=3 was independently found to yield the optimal number of subclasses. 2 class SAM generated a list of approximately 1,800 genes that were most differentially expressed between each molecular subtype and the others. DAVID and Ingenuity (IPA) pathway analysis revealed basal, urothelial, and extracellular matrix (ECM)-rich subtypes based on expression of specific genes or gene pathways. Based on the PAM50 classifier, a significant fraction of the tumors from AA (8/9) were classified as basal-like (P=0.03. Chi square). Conclusions: Our preliminary data suggests that AA patients have a higher rate of basal-like UC of the bladder cancer.
A cytokine and angiogenic factor (CAF) analysis in plasma in testicular germ cell tumor patients (TGCTs).
Authors: Mardiak Jozef , Cholujova Dana , Jurisica Igor , Gronesova Paulina , Miskovska Vera , Obertova Jana , Palacka Patrik , Rajec Jan , Sycova-Mila Zuzana , Usakova Vanda , Vertakova-Krakovska Bibiana , Chovanec Michal , Svetlovska Daniela , Salek Tomas , Bujdak Peter , Spanik Stanislav , Ondrus Dalibor , Mego Michal
Published: March 2020

e15599

Background: We investigated cytokines and angiogenic factors (CAFs) in patients with testicular germ cell tumors (TGCTs). We aimed to link the CAF profile to type of response to chemotherapy and select candidate prognostic and predictive markers for further study. Methods: In the presented study, plasma from 99 patients (pt) with TGCTs treated with first line (95 pt) or salvage (4 pt) chemotherapy was collected. The concentrations of 51 plasma CAFs were measured pre-treatment (n = 80) and on day 22 (n = 60) using multiplex bead arrays (Human Group I and II cytokine panels and TGF beta by Bio-Plex 200 system (Bio-Rad Laboratories, Hercules, CA). We used unsupervised clustering with self-organizing map (SOM) and k-means clustering to analyze CAF expression profiles. Results: Unsupervised clustering with self-organizing maps and k-means identified characteristic plasma cytokine profiles in different subgroups of patients according to response to chemotherapy and other clinical variables. Several cytokines were differentially expressed in patients with favourable and unfavorable response in serum before chemotherapy including IL-1b, IL-15, M-CSF, IL-4, IL-5, b-NGF, IL-10, MCP-3, FGF basic, IL-6, MIP-1a, GM-CSF, IL-17, IL-13, MIP1b, IL-8, SCF, IFN alfa, SCGFb, IL-2RA, IP-10, IL-16, TGFb-3. Similarly, following cytokines were differentially expressed in serum after 1st cycle of chemotherapy IL-1b, TGFb-3, LIF, TGFb-2, IL-16, IL-18, IL-2RA, MCP-3, IFN alfa, HGF, IL1a, MIF, SCF, IL-3, SCGFb, b-NGF, MIG, CTACK. Conclusions: CAF profiling with unsupervised clustering revealed clinically relevant differences in subgroups of TGCTs patients. We suggest that this platform may provide valuable insights into TGCTs biology, and could help to identify plasma cytokine signature for predicting treatment resistance.
High-dose chemotherapy and autologous stem cell transplantation in refractory/metastatic nonseminomatous germ cell-tumors: A retrospective study of the Turkish Oncology Association.
Authors: Ozturk Mustafa , Arpaci Fikret , Ozaydin Sukru , Karadurmus Nuri , Ozdemir Evren , Ataergin Selmin , Erdem Gokhan , Karaca Halit , Cakar Mustafa , Turker Turker , Ozet Ahmet , Kuzhan Okan , Kilic Selim , Komurcu Seref , Ozet Gulsum , Dagdas Simten , Ozturk Bekir , Sivgin Serdar
Published: March 2020

e15623

Background: Testicular cancer is a chemosensitive tumor that may be curable even in relapsed disease. Those patients who do not respond to standard combination chemotherapy or relaps may be treated with high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) as salvage therapy. Methods: Eighty five patients that received HDC and ASCT between Feb 1993 - Dec 2012 in different university clinics of Turkey were retrospectively reviewed and evaluated. Results: Median age of the patients was 24 (range: 11-54 years) and 63 patients (74,1%) had stage III, 21 (24,7%) had stage II disease at initial diagnosis. The primary tumor location was testis in 71 patients (83,5%), and 14 patients (16,5%) had extragonadal region origin. Evaluation of metastatic focuses before HDC and ASCT was as follows: Liver metastasis (n = 23, 27.05%), lung involvement (n = 23, 27.05%) and multiorgan involvement (n =14, 16.47%) and other metastatic involvements (n=4, 4.7%). ICE (ifosfamide, carboplatin, etoposide) regimen was performed as HDC in all patients. Median follow-up was 59 (range: 8-218) months. Pre-ASCT patients’ condition was complete remission (n=28, 32.9%), partial remission (n=36, 42.4%) and never in CR (n=21, 24.7%) respectively. 32 patients (37.6%) relapsed or progressed within 1 year after HDC and ASCT median relaps was time 3 months (range: 0.3 - 36.13). Transplant related mortality was %3.5 and 3 patients died within the engraftment period after HDC. Five-year overall survival rate was 59.7%. Conclusions: HDC and ASCT is an effective and safe approach for patients with metastatic and refractory germ cell testicular cancer patients that do not respond to standard combination chemotherapy.
Prostate cancer management: Racial disparities in the United States.
Authors: Al Dhaybi Omar , Silberstein Peter T.
Published: March 2020

e16012

Background: Racial disparities in prostate cancer management have been reported. Black patients with well–differentiated disease were less likely to receive definitive therapy than whites with similar disease according to Underwood et. al., who included 142,340 patients from the Surveillance, Epidemiology and End Result (SEER) registry (J Urol, Vol. 171, 1504 – 1507, April 2004). Our objective was to identify racial disparities in the management of prostate cancer patients from the National Cancer Database. Methods: Prostate cancer treatment according to race in the USA, obtained from the National Cancer Database, was retrospectively reviewed. 1,497,540 patients with prostate cancer in 1397 US teaching and community hospitals between 2000 and 2010 were included. Chi square and Fisher tests were used for statistical analysis. Results: Black patients with stage II disease underwent radical prostatectomy significantly less than white patients (34.3% versus 43%, p<0.05). 10.9% of blacks with stage II disease did not receive any therapy, versus 6.7% of whites (p<0.05). 0.9% of whites with stage III disease didn’t receive any therapy versus 2% of blacks (p<0.05). The disparity was even more accentuated for stage IV disease, where 13.4% of blacks did not receive any form of treatment versus 10.3% of whites (p<0.05). 44% of blacks with localized disease (stage I and II) received radiation therapy, 34% received surgery. Blacks were less likely to receive radical prostatectomy for stage I and II disease compared to whites (34% versus 43%, p<0.05). Stage IV disease at presentation was more common in blacks (7.2%) than in whites (4.7%, p<0.05). Conclusions: This is the largest study which has analyzed ethnicity and prostate cancer management. Significant racial disparities exist in prostate cancer management between whites and blacks in the USA. Our study reveals that blacks are more likely to receive radiation therapy and less likely to get radical prostatectomy for stage I and II disease. A higher percentage of black patients with stage II, III or IV disease do not undergo any treatment as compared to whites. Blacks are also more likely to present with stage IV disease.
Effects of angiotensin-converting enzyme (ACE) inhibitors on the outcomes of patients receiving primary radiotherapy for prostate cancer (PC).
Authors: Ranasinghe Weranja Kalana Bodhisiri , Williams Scott G. , Sengupta Shomik , Chang Mike , Shulkes Arthur , Bolton Damien M. , Baldwin Graham , Patel Oneel
Published: March 2020

e16016

Background: ACE inhibitors have been linked with an increased incidence of prostate, breast and lung cancer as well as increased recurrence rates in breast cancer. However the effects of ACE inhibitors on patients receiving primary radiation therapy for PC are unknown. Methods: We conducted a retrospective medication review of a prospective cohort of 1956 men who received primary radiotherapy (RT) for PC at the Peter McCallum Cancer Institute, Melbourne, Australia from 2003 -07. A competing risks model was developed for statistical analysis of the data. Results: 56% of patients who received RT also had concurrent salvage androgen deprivation therapy (sADT). A total 502 men had subsequent biochemical failure, 314 had initiated sADT and 125 had died of prostate cancer. Median follow up after RT was 71 months and 41 months after initiation of sADT. Of the 603 men who were on ACE-inhibitors, 160 received sADT. After adjusting for patient age, initial tumor stage, Gleason Score and PSA, along with planned ADT usage and ACE27 co-morbidity score, there were significant association between ACE-inhibitors and PC-specific mortality both from the time of RT and sADT (p= 0.035 and 0.01 respectively), with a strong increase in hazard (HR 1.58 [95%CI 1.03-2.42) and 2.02 [95%CI 1.16-2.90]). No significant association was seen with time to metastasis development, suggesting the impact of ACE inhibitors may be in the post-metastasis phase of the disease. Conclusions: ACE inhibitors may increase the rates of PC-specific mortality in men receiving primary RT for PC. However these results need to be further validated by randomized controlled studies and the mechanisms need to be investigated.
Role of the urologist in whether locoregional prostate cancer patients consult with a radiation oncologist.
Authors: Quek Ruben G. W. , Ward Kevin C. , Master Viraj A. , Lin Chun Chieh , Virgo Katherine S. , Portier Kenneth M. , Lipscomb Joseph
Published: March 2020

e16029

Background: Multiple treatment options exist for prostate cancer patients, and therapeutic recommendations may differ depending on characteristics of the specialist consulted. The clinical judgment of specialists can play a critical role in the initial treatment choice, especially in cases where there is no professional consensus regarding the optimal treatment strategy. We examined the association between prostate cancer patients’ urologists’ practice affiliation with medical schools on the likelihood the patient would consult a radiation oncologist. Methods: Using the Surveillance, Epidemiology and End Results – Medicare linked database and the American Medical Association Physician Masterfile, we conducted a retrospective cohort study of 39,915 patients aged 66 years or older who were diagnosed between 2004 - 2007 with locoregional prostate cancer, and the 2,404 urologists who performed the diagnostic biopsies. Multilevel regression analysis was used to evaluate the influence of patients’ urologists’ practice affiliations with medical schools on the patients’ consultation with a radiation oncologist within 9 months of diagnosis. Results: Overall, 25,110 (62.9%) patients consulted with a radiation oncologist. After adjusting for patient, tumor and urologist characteristics, patients who saw urologists practicing within non-institutional settings were significantly more likely to consult with a radiation oncologist (odds ratio [OR], 1.19; 95% confidence interval [95% CI], 1.05-1.34, p = 0.006) when compared to those who saw urologists practicing within settings with a major medical school affiliation. In addition, patients who saw urologists ≥ 58 years old were significantly more likely to consult with a radiation oncologist (OR, 1.71; 95% CI, 1.16-2.50, p = 0.006) when compared to those who saw urologists < 43 years old. Conclusions: Locoregional prostate cancer patients who received their diagnostic biopsy by urologists practicing in non-institutional settings and those who saw older urologists were significantly more likely to eventually consult with a radiation oncologist. This may have implications on which patient eventually receives radiation as initial therapy.