bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential response of primary or secondary exon 13/14 and exon 17 c-kit mutant to nilotinib and sunitinib: Findings from a cell-based drug-screening platform
Authors: Chan C. , Chen L. , Hsueh Y. , Chuang W. , Lee H. , Huang M. , Heieh R. , Weng W.
Published: August 2020

e15636

Background: Gastrointestinal stromal tumors (GIST) are frequently associated with mutation of c-kit oncogene that is accompanied with constitutional activation of c-kit protein. At present, imatinib is the drug of choice for unresectable or metastatic GIST, however, primary or acquired resistance to imatinib is frequently associated with the presence of an exon 13, 14 or 17 c-kit mutation. The current recommendations for GIST refractory to standard (400 mg/day) imatinib treatment include increasing dose of imatinib to 600–800 mg/day for tumors with primary exon 9 mutation or sunitinib. Several molecular targeted agents are also under investigation. With so many potential agents, personalized therapy based on c-kit mutant genotype for imatinib-resistant GIST deserves to explore. Methods: We prepared a series of c-kit cDNA constructs encoding mutant exon 9 (502AY insertion), 11 (V560D substitution and Δ555–576 deletion), 13 (V654A substitution), 14 (T670I substitution) and 17 (D820G and N822K substitutions) either alone or in combination to simulating the frequently occurred primary ± secondary c-kit mutants in GIST. We expressed these constructs in COS-1 cells to study the efficacy of different tyrosine kinase inhibitors (TKIs) on the autophosphorylation of various single or double mutant c- kit. Results: The efficacy of imatinib on single c-kit mutant was V560D > Δ555–576 > 502AY > D820G or N822K, and ineffective for single and double mutants containing V654A or T670I. Sunitinib is a more potent inhibitor for single 502AY, D820G and N822K mutant than imatinib and nilotinib; while single V654A and T670I c-kit mutant are more sensitive to nilotinib. Interestingly, double exon 11 (V560D or Δ555–576)/V654A or T670I mutant c-kit are more sensitive to sunitinib; while exon 11 (V560D or Δ555–576)/D820G or N822K double mutant c-kit are more sensitive to nilotinib. Conclusions: Our system provides a useful platform to select/screen effective TKIs for GIST with single or double mutant c-kit. The findings of differential response of c-kit mutant to nilotinib and sunitinib may help to select therapy for GIST with primary or secondary exon 13 / 14 and exon 17 mutations.

[Table: see text]
The predictive role of CA 19–9 kinetics for time-to-progression (TTP) and overall survival (OS) in patients receiving palliative first-line chemotherapy for advanced pancreatic cancer
Authors: Haas M. , Boeck S. , Stieber P. , Laubender R. P. , Buchner H. , Klose C. , Kullmann F. , Bruns C. J. , Mansmann U. , Heinemann V.
Published: August 2020

e15637

Background: Previous studies showed contradictory results for a predictive role of CA 19–9 kinetics during chemotherapy in patients (pts) with pancreatic cancer (PC). Methods: We performed a retrospective, multicenter study in order to evaluate the role of CA 19–9 as a biomarker for TTP and OS in PC. Main inclusion criteria: histological confirmed diagnosis of PC, treatment with first-line chemotherapy for advanced disease, pre-treatment CA 19–9 level of > 5.2 U/ml. As CA 19–9 measurements were conducted in different laboratories using different commercial assays, we defined a subgroup of pts where CA 19–9 was assessed exclusively by the Elecsys assay (Roche Diagnostics). For the analysis of CA 19–9 kinetics, at least one follow-up measurement between day 20 and 64 during first-line chemotherapy had to be available. Pts were divided into two subgroups of CA 19–9 responders and non-responders by cut-offs of a 25% and 50% decline, respectively. OS and TTP were estimated with the Kaplan-Meier-Method, differences between the subgroups were analyzed by using the log-rank test. Results: One hundred and eighty-six pts were included, 83 of them were tested with the Elecsys method. Median age was 63 years, 90 % of the pts were treated within prospective clinical trials. Median pre-treatment CA 19–9 was 1076 U/ml (range 5.7–100,000 U/ml), the median bilirubin was 0.6 mg/dl. Median OS and TTP were 9.8 months (mo) and 5.4 mo, respectively. In univariate analysis, pts with a CA 19–9 decline of at least 25% during chemotherapy lived significantly longer (11.9 mo vs. 8.2 mo, p=0.003) and had a significantly prolonged TTP (5.8 mo vs. 4.4 mo, p=0.018) than those with a lower decline or even CA 19–9 increase. Data for the Elecsys-measurements were comparable (OS: 13.4 mo vs. 8.6 mo, p=0.004; TTP: 7.0 mo vs. 2.6 mo, p=0.003). None of the analyses demanding a CA 19–9 drop of at least 50% reached the level of statistical significance. Conclusion: An early CA 19–9 decline of 25% during first-line chemotherapy may predict OS and TTP in pts with advanced PC. Innovative statistical methods are required to improve our understanding of the utility of CA 19–9 as a predictive biomarker in PC.

[Table: see text]
PhaseI/II clinical trial of dose escalation using daily on-line cone beam CT guided radiotherapy combined with active breath control after transcatheter arterial chemoembolization for hepatocellular carcinoma
Authors: Yue J. , Yu J. , LI S. , Yin Y. , Liu T. , Zhu J. , Lu J.
Published: August 2020

e15654

Background: The radiation dose is the key factor to improve survival of patients with hepatocellular carcinoma (HCC). The optimal way to increase radiation dose is to reduce uncertainties of target mainly due to respiratory motion and setup error in radiotherapy. Our previous study demonstrated that lipiodol can be a reliable surrogate of direct tumor targeting in Kv- cone beam CT(CBCT) for patients with good lipiodol embolization. Relying on lipiodol,the daily on-line CBCT guidance with ABC is feasible. By reducing geometric position uncertainty, as well as liver movement, the technique of ABC combined with on-line CBCT guidance can permit CTV(clinical target volume)-PTV(planning target volume) margin reduction and dose escalation. The purpose of the study is to apply the new technique for clinical application and investigate the dose escalation, toxicities and response of liver tumors with the technique combined with chemoembolization(TACE). Methods: 20 HCC patients with Child-Pugh A liver function score were treated by daily on-line CBCT guided radiotherapy relying on lipiodol combined with ABC after TACE. After current doses of 45Gy/ 9 fractions,3 fractions/weeks were delivered,the scheduled dose escalation ranged from 5 to 20Gy. Each mean liver dose not reached 23G y, V30 ( the percentage of normal liver volume with radiation dose≥30 Gy) less than 28%. Results: The planned dose escalation was finished in all subgroups. None of these patients developed Grade 2 or greater liver toxicity except two patients developed Grade 2 gastrointestinal complications and one had grade 1 acute liver toxicity.The overall immediate tumor response rate was 76.3%. 1-year overall survival rate was 80.5%. Conclusions: The technique of daily on-line CBCT guided radiotherapy combined with ABC after TACE is a safe and effective treatment which can reduce CTV-PTV margin significantly and increase target precision greatly. With the technique combined with TACE, the total irradiation dose above 65Gy is feasible in daily fraction of 5Gy.

No significant financial relationships to disclose.
Leptomeningeal carcinomatosis of gastric cancer: Multicenter retrospective analysis of 54 cases
Authors: Oh S. , Kim S. , Kwon H. , Kim H. , Hwang I. , Kang J. , Lee S. , Lee J. , Kang W.
Published: August 2020

e15658

Background: Leptomeningeal carcinomatosis occurs in approximately 5% of patients with cancer. The most common cancers involving the leptomeninges are breast and lung cancer. However, gastric adenocarcinoma has been rarely reported with leptomeningeal carcinomatosis (LMC). Methods: We analyzed 54 cases of cytological confirmed gastric LMC at 4 institutions from 1994 to 2007. Results: Male to female ratio was 1.5:1. Median age of these patients was 49 years. The majority of patients had advanced disease at the initial diagnosis of gastric cancer. The clinical or pathologic TNM stages of the primary gastric cancer were IV in 38 patients (70%). The median interval from the diagnosis of the primary malignancy to the diagnosis of LMC was 6.3 months (range, 0 - 73.1 months). Of the initial endoscopic finding available 45 patients, Bormann type III and IV were 23 (51%) and 15 (33%) patients, respectively. Headache (85%) and nausea/vomiting (58%) were most common presenting symptoms of LMC. The intrathecal (IT) chemotherapy was administered to 36 patients - mainly with methotraxate alone (59%) or combination with ara- C/hydrocortisone (41%). Median IT treatment number was 7 (range, 1–18). Concomitant radiotherapy or chemotherapy was done in 25 patients and 10 patients, respectively. 17 patients (46%) were achieved cytological negative conversion. Median OS duration from diagnosis of LMC was 6.7 weeks (95% CI; 4.3–9.1 weeks). Clinically, initial advanced stage was predictive value of poor prognosis (P=0.009). But, Cytology negative conversion was predictive value of relatively longer survival duration (P=0.005). And, not only IT chemotherapy but also intravenous chemotherapy had been shown improvement of survival duration (P=0.010, P=0.005, respectively). Conclusions: Although gastric LMC has dismal prognosis, IT and IV chemotherapy could be help to extend survival duration of gastric LMC.

No significant financial relationships to disclose.
The optimal threshold of 18F-FLT PET and 18F-FDG PET to estimate the length of gross tumor volume in patients with squamous cell carcinoma of the thoracic esophagus verified by pathological examination
Authors: Yu J. , Han D. , Zhong Xiaojun , Mu Dianbin , Fu Zheng , Zhan g Baijiang , Zhang Limin , Zhang Weidi
Published: August 2020

e15665

Background: To determine the optimal method of using 3-deoxy-3-18F-fluorothymidine (FLT) positron emission tomography (PET) to estimate gross tumor length in esophageal carcinoma, and compared with that of 18F- fluorodeoxyglucose(FDG) PET. Methods: Twenty patients with esophageal squamous cell carcinoma treated with radical surgery were enrolled and detected by FLT PET, eighteen of them underwent FDG PET scan. Gross tumor volumes (GTVs) were delineated using seven different methods with FLT PET: visual interpretation, standardized uptake value (SUV) 1.3, SUV 1.4, SUV 1.5, and 20% of maximum standard uptake value (SUVmax), 25% SUVmax,30% SUVmax, on FLT PET imaging, and three different methods with FDG PET: visual interpretation, SUV 2.5, and 40%SUVmax on FDG PET imaging. The length of tumors on FLT PET scan were measured and recorded as LFLTvis, LFLT1.3, LFLT1.4, LFLT1.5, LFLT20%, LFLT25%, and LFLT30%, and FDG PET scan were measured and recorded as LFDGvis, LFDG2.5, and LFDG40%, respectively, and compared with the length of gross tumor in the resected specimen measured by pathological examination (LPath). Results: The mean (±SD) LPath was 5.16±2.19cm. The mean LFLTvis, LFLT1.3, LFLT1.4, LFLT1.5, LFLT20%, LFLT25%, and LFLT30%were 5.17±2.40cm, 5.55±2.43cm, 5.17±2.41cm, 4.95±2.44cm, 5.82±2.23cm, 5.32±2.31cm, and 5.04±2.28cm, respectively. Compared with the LPath, the P value were 0.971, 0.045, 0.972, 0.255, 0.066, 0.644, and 0.714, respectively. The correlation coefficients were 0.952, 0.944, 0.959, 0.948, 0.763, 0.783, and 0.800, respectively. The mean LFDGvis, LFDG2.5, and LFDG40% were 5.41±2.27cm, 5.38±2.25cm, and 4.02±1.57cm, respectively. Compared with the LPath, the P value were 0.098, 0.085 and 0.000, respectively. The correlation coefficients were 0.984, 0.990 and 0.932, respectively. On FLT PET, LFLT1.4, and on FDG PET, L FDG2.5 seem more approximate to LPath. The difference between LFLT1.4 and LFDG2.5 was not significantly (P=0.442), the correlation coefficients was 0.960. Conclusions: An SUV cutoff of 1.4 on FLT PET, and an SUV cutoff of 2.5 on FDG PET, provided the closest estimation of GTV length in this study

No significant financial relationships to disclose.
Recurrence patterns of Chinese patients with gastric cancer after complete resection
Authors: Lu M. , Shen L.
Published: August 2020

e15667

Background: Recurrence after radical resection was the most important factor that influence the prognosis of patients with gastric adenocarcinoma. Focusing on the clinicopathologic features and recurrence patterns, this study aims to find the characteristics of recurrence pattern and the predictive factors of gastric cancer patients in China. Methods: This is a retrospective analysis of the gastric adenocarcinoma patients who accepted adjuvant treatment and follow up in our medical department after R0 resection. From June 1995 through June 2007, among 845 patients with R0 resection, 773 cases with detailed information of follow-up enrolled in this study. The location of first recurrence were reviewed. Recurrences location were categorized as locoregional, peritoneal, or distant. Locoregional recurrence was defined as dominant masses in the gastric bed, regional nodes or anastomotic recurrence. Peritoneal recurrence was documented by positive cytology in ascitic fluid, peritoneal nodules or ovaries with tumors involved. Distant metastases were defined as the specific organ or distant lymph nodes involved. Univariate and multivariate analyses were performed to identify predictive factors of recurrence patterns. Results: Till the last follow-up date in November 2008, 426 patients (55.1%) recurred, and 303(71.1%) recurred within 2 years after resection. The pattern of recurrence was locoregional in 240 patients (31%), distant in 261 patients (33.8%) and peritoneal in 88 patients (11.4%). On multivariate analysis, proximal location, the rate of positive lymph node > 0.33, number of lymph node dissetion<15 and operated in general hospital increase the risk of locoregional recurrence. Distant recurrence was significant associated with male gender, advanced T-stage, positive lymph nodes and number of lymph node dissection<15; female gender, poor differentiation and advanced T-stage were high risk factors of peritoneal recurrence. Conclusions: Different recurrence pattern has remarkable relationship with various clinicopathologic factors. It is noteworthy that both locoregional recurrence and distant recurrence are associated with the number of lymph node dissection, confirming the importantace of lymph node dissection.

No significant financial relationships to disclose.
Pharmacokinetics of intraperitoneal docetaxel and S-1 in patients with gastric cancer with peritoneal carcinomatosis
Authors: Hayashi K. , Kamikozuru H.
Published: August 2020

e15672

Background: One of the most causes of death from gastric cancer is peritoneal cartinomatosis. Intraperitoneal docetaxel infusion is expected to be a new strategy for a treatment of peritoneal carcinomatosis. The purpose of this study is to evaluate the plasma and peritoneal pharmacokinetic of intraperitoneal docetaxel infusion in combination with oral administration of S-1. Methods: Eight patients with peritoneal carcinomatosis of advanced gastric cancer were enrolled. Docetaxel was dissolved in an isotonic saline to a final 1 liter solution and administered in 2 hour via an implanted intraperitoneal catheter at dosage of 40mg/m2. Five of eight patients were administered S-1 orally at dosage of 80mg/m2. Blood and peritoneal fluid were collected before administration, on completion of the docetaxel infusion(hour 0) and at hours 1,2,4,6,12,24,48,and 72 after completion of the infusion of the docetaxel. Plasma and peritoneal fluid concentrations of docetaxel and 5FU were evaluated. Results: The mean peak peritoneal and plasma concentrations of docetaxel were 18.6×103 ng/ml (at hour 0) and 45 ng/ml (at hour 0 to 2), respectively. The peritoneal concentrations of docetaxel were remained even after 24 and 72 hours (24 hours: 1150ng/ml, 72 hours: 74ng/ml). In seven out of eight patients, plasma concentrations of docetaxel were disappeared after 24 hours, but in only one patient with severe ascites, concentration of plasma docetaxel at hour 24 could be obtained (20 ng/ml). The mean peritoneal and plasma areas under the curves (AUC) of doceta×el were 141x103 ng/ml×hr and 480 ng/ml×hr, respectively. The mean peritoneal concentrations of 5FU kept over 60% of plasma concentrations (plasma: 164.3ng/ml, peritoneal: 105ng/ml). Conclusions: Intaperitoneal docetaxel kept relatively high concentrations even after 72hours. 5FU concentrations were well transfered in peritoneal fluid from plasma via oral S-1 administration. Intraperitoneal docetaxel in combination with S-1 orally may be a useful regimen to the patients with carcinomatosis of advanced gastric cancer.

No significant financial relationships to disclose.
Assessment of serum concentrations of Dkk1 as potential biomarker for esophageal squamous cell carcinoma
Authors: Zer C. , Dong X. , Kernstine K. , Zhong L.
Published: August 2020

e15675

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common fatal cancers worldwide due to the lack of an early disease screening strategy. Identification of diagnostic markers will greatly improve the morbid outcome. Dickkopf 1 (Dkk1) is a secreted antagonist of Wnt signaling pathway, an important pathway in tumorigenesis. The expressions of Dkk1 seem to be tumor-specific: reduced expressions have been seen in colorectal cancer, but elevated levels were reported for hepatoblastomas. In ESCC, the situation is less clear, for both elevation and reduction of Dkk1 were reported. The serum concentrations of Dkk1 have also been shown to be higher in ESCC patients’ sera in one study. In view of the varied outcome from Dkk1 tissue expressions and the scarce reports on Dkk1 serum concentration from ESCC patients, we therefore sought to determine the tissue expression and serum concentrations of Dkk1 as our first step to evaluate the potential of Dkk1 as a diagnostic marker for ESCC. Methods: The expression levels of Dkk1 in ten ESCC tumor and adjacent non-tumor tissues were examined by Western blot. Serum Dkk1 level of 168 samples were quantified in a double-blind fashion by ELISA (Dkk1 Duoset ELISA development kit from R & D Systems, Minneapolis, MN). To ensure that the serum Dkk1 detection was not affected by autoantibodies against Dkk1 present in sera, we also measured serum Dkk1 autoantibody levels by ELISA with modifications to the ELISA kit. Results: Seven out of ten of the tumors showed elevated Dkk1 level, while only two out of ten of the control normal tissue showed elevation. Surprisingly, after decoding of our serum samples into 80 patients and 88 normal controls, we found that Dkk1 level was significantly lower in patient sera (2.99ng/ml) than the normal samples (5.32ng/ml) (p=0.0001; t-test). The measurements were not obscured by the presence of Dkk1 autoantibodies, as they were not different between patient and control samples. Conclusions: Contrary to previous published results, we found Dkk1 is suppressed in patient sera, and thus our result undermines the potential of serum Dkk1 level as a predictive marker for ESCC. Further investigations will be needed to explain the discrepancies between the studies.

No significant financial relationships to disclose.
Diagnostic yield of nonfunctional pancreatic neuroendocrine tumor using endoscopic ultrasound-guided fine needle aspiration biopsy
Authors: Matsumoto K. , Sawaki A. , Kobayashi Y. , Mizuno N. , Hara K. , Takagi T. , Sawai Y. , Shimizu Y. , Yatabe Y. , Yamao K.
Published: August 2020

e15680

Background: Radiological examinations including computed tomography (CT) and endoscopic ultrasound sonography (EUS) are important for the diagnosis of pancreatic neuroendocrine tumors (PNETs). Pathological diagnosis is not needed with functional PNETs because the diagnosis is made by biochemical testing. Therefore, pathological diagnosis is essential for the non-functional PNETs (nf-PNETs). In this study, we examined the diagnostic yield of radiological examinations and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for nf-PNETs. Methods: From January 1997 to December 2007, consecutive 38 cases were pathologically diagnosed from as nf-PNETs at Aichi Cancer Center Hospital. Of these 33 patients was diagnosed with surgical specimen, 5 patients with EUS-FNA specimen. Of 33 patients, 16 patients underwent EUS-FNA preoperatively, and were examined further: their EUS-FNA specimens were submitted for additional immunohistochemical examination for CD 56, chromogranin A, synaptophysin, somatostatin receptor 2A (SSTR2A) and Ki-67 using cell block method. Staging of PNETs was performed according to WHO classification. Results: 16 patients (10 men and 6 women) who ranged in age from 23 to 81 years. The mean of tumor size was 2.2 cm and ranged from 0.7 to 4.4 cm. Diagnosis by CT and EUS was 12 (75.0%) PNETs, two pancreatic cancer, one solid papillary tumors and one malignant lymphoma. Accurate diagnosis by cytology and immunohistochemistry was 75.0% and 93.8%, respectively. The Ki-67 in specimens of malignancy tended to be higher than those of benign or uncertain behavior. If we assumed that a tumor with Ki-67 of more than 2% was malignancy, the diagnostic accuracy was 75.0%. Positive reaction to SSTR2A was up to 14 out of 16 nf-PNETs. Conclusions: The EUS-FNA is a useful tool for diagnosing nf-PNETs with immunohistochemical staining compared to cytology and radiological examinations. Ki-67 may be also effective to predict the degree of malignancy.

No significant financial relationships to disclose.
Modulation of regulatory T cells and myeloid-derived suppressor cells by sorafenib and sunitinib in renal cell carcinoma patients
Authors: Floercken A. , Takvorian A. , Singh A. , Hopfenmüller W. , Pezzutto A. , Dörken B. , Westermann J.
Published: August 2020

e16002

Background: Induction of regulatory T (Treg) and myeloid-derived suppressor cells (MDSC) is a major mechanism for the escape of tumors from immunological control. Increased levels of Treg cells have been described in renal cell cancer (RCC) patients and seem to correlate with an adverse outcome. Furthermore, reduction of Treg has been reported for RCC patients under sunitinib therapy. The aim of our study was to analyse the influence of sorafenib and sunitinib on the frequency of Treg and MDSC in patients with metastatic RCC (mRCC). Methods: The number of T reg, MDSC and lymphocyte subpopulations was analysed by flowcytometry in peripheral blood (pb) of patients (n=19) with histologically confirmed mRCC under treatment with either sunitinib (50 mg/d, n=11) or sorafenib (800 mg/d, n=8). After informed consent blood samples were taken before and during the 1st, 2nd, and 3rd month of therapy. Flowcytometric analysis was performed using fluorochrome labeled antibodies against CD3, CD4, CD8, CD25, CD127, FOXp3, CD33, C14, CD11b and HLA-DR. Results: The baseline level of Treg did not differ from healthy controls. However, there was a significant increase of CD3+CD4+CD25+FOXp3+Treg (13,5% vs. 36,3% of gated cells, p= 0.02) and the ratio FOXp3+/FOXp3- CD3+CD4+ T cells (0,16% vs. 0,56% of gated cells, p= 0.02) in the group of sorafenib-treated patients compared to sunitinib-treated patients during the 1st month of therapy and thereafter. This effect was confirmed in an intragroup analysis. There was no influence of Sunitinib on the frequency of Treg. Analysis of CD33+/HLA-DR-/11b+ MDSC did not reveal any change under treatment with sorafenib or sunitinib. Conclusions: Sorafenib, but not sunitinib, leads to an early and sustained increase of Treg in pb of mRCC patients. A negative influence of sorafenib on primary immune responses has been described and has mainly been attributed to functional impairment of dendritic cells (DC). Whether altered DC function under sorafenib is responsible for the induction of Treg in RCC patients will have to be addressed in future studies. In immunoresponsive tumors such as RCC, immunological effects of kinase inhibitors are particularly relevant for the design of combination trials with immunotherapeutic agents.

No significant financial relationships to disclose.
Prediction of survival by immunohistochemical stains (IHC) in stage D2 prostate cancer patients (pts): The importance of pTEN overexpression
Authors: Kasimis B. , Chang V. , Gounder S. , Gonzalez M. , Finch-Cruz C. , Blumenfrucht M. , Srinivas S. , Cogswell J. , Morales E. , Ahmed S.
Published: August 2020

e16019

Background: Several signal transduction pathways,important for apoptosis and angiogenesis were idendified and their expression and correlation with survival was studied by IHC in archival prostate cancer biopsies. All pts has androgen deprivation for stage D2 disease and were followed at 3 month intervals. Methods: In an IRB approved study,42 pts had adequate tissue preserved between 1992 and 2006 and their charts were reviewed retrospectively.IHC stains to detect tumor expression of S6(ribosomal),p70s6,pTEN,AKT-1,BCL-1(Cyclin D1),VEGF,c-KIT,PDGFR-alpha and PDGFR-beta were performed by US Labs(Irvine,CA).All results were independently evaluated by two pathologists.Immunoreactivity was scored using a semiquantitative system combining intensity of staining(0–3+) and percentage of cells staining positive(0–3+).The total score was obtained by adding the scores for indensity and the percentage of positive cells,then averaging the resuts obtained by each reader.For the purpose of this study, stain intensity of 0–1+ was considered negative and the intensity of 2–3+ was considered positive.A Cox regression survival model for each stain was developed with variables known to predict survival :Gleason score,Hemoglobin(Hgb),Alkaline Phosphatase(Alk Phos),Prostate Specific Antigen(PSA),Lactate Dehydrogenase(LDH) levels. Results: The median values were: age 70yrs(56–92),Gleason score 8(6–10), LDH 171 IU/L(97–350),Hgb 12.9gm/dl (6.8–16.3), PSA 188ng/ml(2–5677),Alk Phos 139U/L(60–1756),survival 851 days(163- 6102).In univariate analysis,VEGF staining was predictive of survival (p<0.037) but not in multivariate analysis.The pTEN staining correlated with survival (p<0.0367) and a hazard ratio of 0.040 in multivariate analysis. Conclusions: In this small sample of pts, overexpression of S6,p70s6,AKT-1,BCL-1,VEGF,c-KIT,PDGFR-alpha and PDGFR-beta by IHC staining did not predict survival independently.The pTEN staining,however was strong predictor of survival in the multivariate analysis.

No significant financial relationships to disclose.
Phase II trial of bevacizumab (B) and oral satraplatin (S) and prednisone in docetaxel pretreated metastatic castrate resistant prostate cancer (CRPC)
Authors: Vaishampayan U. N. , Heilbrun L. K. , Heath E. I. , Smith D. W. , Dickow B. , Baranowski K. , Powell I. , Fontana J.
Published: August 2020

e16028

Background: In metastatic CRPC, second line therapy after docetaxel, remains a currently unmet need. Based on the efficacy and tolerability of S and B in prostate cancer, and the clinical synergy noted between chemotherapy and B, a phase II trial of the combination was conducted. Methods: Metastatic CRPC patients, with prior docetaxel based chemotherapy were eligible to receive S 80 mg/m2 orally for days 1–5, and B 10 mg/kg on day 1, and 15mg/kg on day 15 of each 35 day cycle. Prednisone was administered at a dose of 5 mg twice daily. Response was assessed every 2 cycles. Toxicity was assessed weekly during cycle 1 and on days 1 and 15 of each subsequent cycle. Primary endpoint was time to progression defined as a skeletal event, new areas of metastases on bone scans or per RECIST criteria for measurable disease. Results: 19 of 28 patients have been enrolled to date; 7 African American and 12 Caucasian,, with median age of 68.5 years and median pretherapy PSA of 137.8 ng/mL (range 16.8–994 ng/mL). 7 (44%) had bone pain, Gleason score of 7 and ≥ 8 in 7 and 12 patients respectively. Measurable disease progression was noted in 5 patients, bone scan progression in 6 patients, progression of both in 3 patients, and PSA only progression in 5 patients. 76 cycles have been administered; 7 patients continued on therapy beyond 6 cycles. The only grade 4 toxicity noted was pulmonary embolism in 2 patients, after 2 and 6 cycles of therapy. Grade 3 neutropenia, gastrointestinal toxicity, and electrolyte abnormalities were noted in 1 patient each. There were no treatment related deaths. 16/19 patients are response evaluable. 7 patients had a PSA decline of which 4 patients had a ≥30% PSA decline. 3 of 6 patients had a measurable disease response. 11 of 16 patients have progressed to date after median of 6 cycles of therapy. Time to progression and survival data will be reported. Conclusions: The combination was well tolerated, and revealed preliminary evidence of clinical efficacy in docetaxel pretreated metastatic CRPC.

[Table: see text]
Salvage chemotherapy with gemcitabine, paclitaxel, ifosphamide, and cisplatin (Gem-TIP) for relapsed germ cell tumours (GCT)
Authors: Wheater M. J. , Huddart R. , White J. , Rustin G. , Abab J. , Mead G. M.
Published: August 2020

e16031

Background: Patients with relapsed metastatic GCT following treatment with cisplatin based combination chemotherapy, may be cured with further intensive chemotherapy. A Medical Research Council trial of TIP achieved 1 year progression free survival (PFS) of 38% with 65% survival (Br J Cancer. 2005;93:178). A more dose intense schedule of TIP with growth factors achieved 2-year PFS of 91% (Proc Am Soc Clin Oncol. 22:2003 [abstr 1537]). Gemcitabine has activity in the treatment of multiply relapsed disease. This study aims to investigate the feasibility of adding gem to TIP with the addition of growth factor support, while maintaining TIP dose intensity, with a view to improving the outcome from TIP alone. Methods: A phase I dose escalation study of Gem-TIP was carried out in patients at first relapse from metastatic GCT following cisplatin chemotherapy. All patients received TIP without dose reduction (paclitaxel 175 mg/m2 d1, cisplatin 20 mg/m2 d1–5, ifosphamide 1 g/m2 d2–6) with GCSF days 7–18 of a 21 day cycle for maximum 4 cycles. 3 dose levels of gem were investigated, 600 mg/m2 d1, 900 mg/m2 d1 and 1,200 mg/m2 d1. Dose limiting toxicity (DLT) was non-haematological grade 3 or 4, except nausea, vomiting and alopecia. Results: 13 patients treated, 12 male, 1 female, age 21–48 years. Baseline histology seminoma 8, non-seminoma 5. Cohort 1: 4 patients treated, 1 withdrew after 1 cycle. No DLT observed. Cohort 2: 3 patients completed treatment with no DLT. Cohort 3: 1 patient treated suffered allergic pneumonitis at cycle 1 complicated by a malignant pleural effusion. A further 5 patients were treated at this dose level. The minimum course duration was 63 days. The mean duration for each cohort was 69 days for cohort 1 and 2, 64 days for cohort 3. Grade 3/4 haematological toxicity was; neutropaenia 9 patients, thrombocytopaenia 10 patients, with 2 episodes of febrile neutropaenia but no bleeding. 10 platelet transfusions were required. 10 patients were assessable for response, 5 CR, 3 PR, 2 PD. At median follow up 18 months the median PFS is 10 months. Conclusions: Gem-TIP can be delivered with 1200mg/m2 gem with manageable toxicity in the context of growth factor support. This dose will be taken forward to a phase II study.

No significant financial relationships to disclose.
Role of obesity and race in predicting recurrence rates and survival in renal cell carcinoma
Authors: Ritch C. , Lee D. J. , Desai M. , McKiernan J. M.
Published: August 2020

e16052

Background: Two in three Americans are obese or overweight, and African-Americans are 1.4 times as likely to be obese than whites. However, the relationship between obesity, race, and renal cell carcinoma (RCC) is highly debated. We sought to explore the relationship between BMI and race, and determine the predictors for survival and recurrence after nephrectomy (Nx) for RCC. Methods: A retrospective analysis of the Columbia Urologic Oncology Database found that 1118 consecutive patients underwent partial or radical Nx for RCC between 1988 and 2008. Of these, 499 patients had BMI and race data available. 379 (76%) were white, 51 (10.2%) were black, 37 (7.4%) were Hispanic, and 32 (6.4%) were Asian. 341 (68.3%) were male compared to 158 (31.7%) females; 215 (50.3%) had partial Nx while 284 (56.9%) had a radical Nx. Overweight and obesity were defined as having a BMI > 25 kg/m2 and a BMI > 30 kg/m2, respectively. Cox proportional hazards models were used to assess the relationship between BMI, race, and recurrence- free survival (RFS). Results: The 499 patients had a median age of 63 years were followed for a mean of 25 months. Asians had significantly lower BMI than the other races (p=0.02), but the other ethnicities had similar BMI distributions. The two year cancer-specific survival was 89.6%, 92.7%, and 96.1% for normal weight, overweight, and obese patients, respectively (p=0.036). Race did not have a significant impact on predicting RFS. A multivariate Cox regression found that male sex, BMI, size of tumor removed, tumor stage, and margin were independent predictors of RFS. Overweight and obese patients were more likely to survive from RCC without recurrence than normal weight patients (p=0.04). An analysis assessing the effect of an interaction between race and BMI demonstrated that hazard ratios for increased BMI did not differ significantly by race. Conclusions: BMI is an independent predictor of RFS in patients undergoing partial or radical Nx for RCC. Recurrence free-survival did not differ significantly among the different ethnicities, and the impact of race on recurrence-free survival did not vary among different BMI classes. The importance of these findings needs to be addressed in large multi- institutional analyses.

No significant financial relationships to disclose.
A phase I study of everolimus plus sorafenib in patients with metastatic renal cell carcinoma (mRCC)
Authors: Cen P. , Daleiden A. , Doshi G. , Amato R.
Published: August 2020

e16056

Background: Everolimus, a mTOR inhibitor and Sorafenib, a Raf kinase inhibitor had shown their efficacy in RCC, as single agents. Combining these two active agents could have potential additive or synergistic effects. We conducted a phase I study to evaluate the maximum tolerated dose (MTD) of this combination in patients with progressive mRCC. Methods: Patients predominantly had clear cell RCC, and progressive measurable diseases on prior treatments including immunotherapy, TKI and/or Everolimus. Patients were evaluated weekly for toxicities and every 8 weeks for radiological response, including at least both PET/CT and CT scans at baseline and 1st staging. Patients received daily Everolimus and twice daily sorafenib both orally at escalating dose levels of 2.5mg/400mg (dose level 0), 5mg/400mg (+1), and 10mg/400mg (+2). Results: 18 patients with mRCC were enrolled and 15 patients were evaluable. 6 patients were treated on dose level 0, dose- limited toxicity (DLT) was found in 2/6 patients, one with thrombocytopenia/leukopenia, the other with pneumonitis; 6 patients were treated on dose level +1, DLT of pulmonary embolism was found in 1/6 patient; and 3 patients were treated on dose level +2, without DLT. The most common side effect was grade 1/2 hand-foot syndrome (4/15, 27%). The MTD was dose level +2. Overall response by RECIST was 27% (4/15 patients): pathological complete response (CR) was 6% (1/15); radiographic CR was 6% (1/5); surgical CR after resection was 6% (1/15). 47% (7/15) of the patients had stable disease. Decreased FDG uptake was found in 67% (10/15) of the patients. The median PFS was 5.53 months (range, 1.4–14.7), and OS was 7.9 months (range, 2.3–23). Conclusions: The MTD of combining daily Everolimus 10mg and twice daily sorafenib 400mg are safe and effective for progressive metastatic RCC. The phase II trial is planned to start in early 2009.

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Oncological outcomes of radical cystectomy for bladder cancer: Laparoscopy versus open surgery
Authors: Guillotreau J. , Gamé X. , Mouzin M. , Doumerc N. , Malavaud B. , Rischmann P.
Published: August 2020

e16059

Background: To compare the oncological outcomes of laparoscopic versus open surgery in radical cystectomy for bladder cancer. Methods: A prospective non-randomized study was conducted between January 2003 and November 2008 in 52 patients, 2 women and 50 men, who underwent radical cystectomy for bladder cancer. Thirty seven cystectomies were carried out by laparoscopic surgery (LS) and 15 by open surgery (OS). Mean patient age was 67.3 ± 9.7 years. The median preoperative ASA score was 2 (1–3) in both groups. Kaplan-Meier curves were constructed to estimate the survival rate for the whole sample. Datas were compared by Log-rank test. Current followup, overall and specific deaths were used as endpoints. The survival time was defined as the time elapsed from the date of radical cystectomy to the endpoint. Results: All tumours were transitional cell carcinoma, high-grade and stage < pT3b pN0. One patient of OS group had a positive surgical margin. Eight patients (15.4%), 7 of LS group and 1 of OS group, completed 5 years of follow-up. At the last follow-up 40 patients (76.9%) were alive with no evidence of disease and 5 (9.6%) died, two patients (3.8%) from metastasis and 3 (5.7%) from different causes. No patient developed port- site metastasis. Overall survival was significantly better in LS group than in the OS group (p=0.039). No statistical difference was noted for Specific survival. Mean patient follow-up was 30.9 ± 20.3 months. Conclusions: The data suggest that LRC provides oncological outcomes comparable to contemporary series of open RC.

No significant financial relationships to disclose.
Bone markers in prostate cancer (PC) patients: Biologic criteria to identify patients at risk of developing distant metastases
Authors: Ayllon J. , Banu E. , Leviel F. , Houillier P. , Medioni J. , Barrascout E. , Oudard S. , Maruani G.
Published: August 2020

e16069

Background: Currently, there are no specific serum and/or urinary bone markers able to accurately identify PC patients with hormone-refractory disease and/or those with distant metastases. Methods: Four categories of PC patients were defined as follows: A. hormone-sensitive without distant metastases; B. hormone-sensitive with metastases; C. hormone-refractory without metastases; D. hormone-refractory with metastases. The serum bone markers investigated were osteogenesis-related [Osteocalcin (OC), procollagen type 1 amino-terminal propeptide (P1NP), bone alkaline phosphatase (BALP)], osteolysis-related [beta collagen 1 carboxyterminal peptide (βCTX), carboxyterminal telopeptide type 1 collagen (1CTP), tartrate resistant acid phosphatase (TRAP)] or osteoclastogenesis-related [osteoprotegerin (OPG)]. Receiver Operating Characteristic (ROC) curves and the Area Under these curves were used to estimate the overall accuracy of each marker in discriminating between the four categories (A vs. BCD; B vs. ACD; C vs. ABD and D vs. ABC) with no adjustment for multiplicity. Parametric (Student's t-test) and non-parametric (Kruskal- Wallis) tests were conducted too. All statistical analyses were performed by means of SPSS v 16 (SPSS Inc). Results: Data were from 40 consecutive PC patients treated at the Georges Pompidou European Hospital in Paris, France and who were equally distributed between categories. Hormone-refractory patients with distant metastases were accurately identified by P1NP, 1CTP and TRAP. The respective areas under the ROC values were 0.76, 0.84 and 0.79 (all Pvalues less than 0.01). None of the markers identified category B of patients. Conclusions: Some bone-related serum markers may be associated with the onset of hormone-refractory status and distant metastases. They should be prospectively validated in a larger cohort of patients.

No significant financial relationships to disclose.
The impact of docetaxel (D) in an older population of patients with advanced prostate cancer (PC): A simulation study using TAX327 and SEER Medicare data
Authors: Onukwugha E. , Mullins C. D. , Obeidat N. , Seal B. , Hussain A.
Published: August 2020

e16074

Background: The survival benefit of D in treatment of hormone refractory PC (HRPC) has been established in the TAX327 trial, but it is unclear how this benefit would translate in a heterogeneous population. This study sought to simulate the survival impact of D in a population of older pts with M1 PC on androgen deprivation therapy (ADT). Methods: A combination of TAX327 trial data and SEER-Medicare (SM) data were used. In pts age 69+ and randomized to D (every 3 weeks, D3P) or mitoxantrone (M), trial data showed a survival benefit for D. Accordingly, SM pts age 69+ diagnosed with M1 PC between 1994 and 2002 and receiving only ADT were selected. Graphical plots and statistical tests were used to find best-fitting parametric survival functions for D3P, M, and SM pts. The survival benefit for D was imposed on unadjusted and covariate-adjusted SM survival curves. The simulated benefit was assessed at 12 mos and 24 mos post-diagnosis of M1 PC in SM pts. Results: There were 326 TAX327 trial pts (D3P = 159, M = 167) used in the analysis. Median survival was 15.7 mos (12.6 - 19) in the M arm and 18.9 mos [17 - 21.8] in the D3P arm (p = 0.03). There were 3,515 SM pts, based on inclusion criteria. Median survival benefit of D was 3.2 mos based on Kaplan-Meier estimates and 2.4 mos using parametric curves in the TAX327 69+ group. Following covariate-adjustment in the SM sample, at 12 mos post-diagnosis, the median survival in mos was 61.7 (CI 36.3 - 87) in the ADT group and 62 (CI 37.6 - 87.1) in the simulated ADT+D group (i.e., 0.3 mos simulated benefit of D). A 0.8 mos simulated benefit was found if D was initiated 24 mos post diagnosis (in pts more likely to have HRPC). Conclusions: The survival benefit of docetaxel from the TAX327 trial is attenuated in a heterogeneous SEER-Medicare sample, and the simulated survival benefit is larger among patients who are more likely to have hormone refractory prostate cancer.

[Table: see text]
Phase II study of everolimus (E) with imatinib (IM) in patients with previously-treated renal carcinoma (RCC)
Authors: Ryan C. W. , Vuky J. , Chan J. S. , Beer T. M. , Rothkopf M.
Published: August 2020

e16075

Background: Inhibitors of mTOR improve progression-free survival (PFS) in advanced RCC. We hypothesized that co-administration of the mTOR inhibitor E with an upstream receptor tyrosine kinase inhibitor could augment activity in advanced RCC. We chose to study IM due to its inhibition of PDGFR, a relevant target for RCC with potential activity at both the tumor cell and the pericyte. Methods: Eligible patients had metastatic or unresectable clear cell renal carcinoma, at least one prior systemic therapy, no prior mTOR inhibitor therapy, performance status 0–2, and measurable disease. Treatment consisted of E 2.5 mg p.o. daily and IM 600 mg p.o. daily, a dose determined from a phase I study in GIST. A two-stage design was employed to test for a 3-month PFS of ≥ 70% vs. ≤ 50%. Results: 19 subjects were evaluable for toxicity and 18 for response. Median age 65; number of prior systemic therapies 1:2:3+ (47%:32%:21%); prior sorafenib and/or sunitinib 89%; MSKCC prognostic categories favorable:intermediate:poor (42%:47%:11%). There were no objective responses. Best response was stable disease (67%) and progressive disease (33%). The 3-month PFS rate was 49% (95% C.I. 23%, 72%). The median PFS was 2.9 months (95% C.I. 1.9, 6.2) and the median overall survival was 14.4 months (95% C.I. 11.3, N.R.). Toxicities and lab abnormalities affecting >50% of subjects were: nausea, elevated creatinine, edema, anemia, hypocalcemia, fatigue, diarrhea, vomiting, and dyspnea, and leucopenia. Most common grade 3+ events were: fatigue (16%), pleural effusion (16%), edema (11%), and renal failure (11%). The study was closed after the first stage as the 3-month PFS did not meet continuation criteria. Conclusions: The combination of E 2.5 mg with IM 600 mg in previously-treated patients with advanced RCC did not meet the study-defined level of activity to warrant further investigation. The natural history assumptions for this pretreated RCC population may have been overly optimistic. While the observed PFS is comparable to that reported with E 10mg monotherapy, there appears to be no advantage to combination IM therapy and the incidence of adverse events is high. Further development of this regimen for RCC is not recommended.

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High-grade proteinuria associated with bevacizumab in patients with renal cell cancer and non-renal cell cancer
Authors: Kim C. Y. , Chu D. , Baer L. , Wu S.
Published: August 2020

e16089

Background: Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor. It is a widely used angiogenesis inhibitor in the treatment of renal cell cancer (RCC) and other solid tumors. Proteinuria is associated with significant morbidity and treatment interruptions. The overall risk for proteinuria is unclear. This study was conducted to determine the risk of developing proteinuria among RCC and non-RCC patients receiving bevacizumab. Methods: Databases from PUBMED and Web Science from January 1966 until July 2008 and abstracts presented at ASCO from January 2000 to July 2008 were searched to identify relevant studies. Studies included randomized controlled clinical trials in which standard anti-neoplastic therapy was administered with and without bevacizumab with available data for proteinuria. Summary incidence rate, relative risk (RR), and 95% confidence interval (CI) were calculated employing fixed or random effect models based upon the heterogeneity of included studies. Results: A total of 6,702 patients from 14 randomized controlled studies were included for analysis. The incidence of all-grade proteinuria in patients receiving bevacizumab was 19.3% (95% CI: 11.9–29.6%) with 2.3% (95% CI: 1.2–4.1%) being high-grade (grade 3 or 4). Patients treated with bevacizumab had an increased risk of developing high-grade proteinuria with RR of 6.3 (95% CI: 4.0–9.9) compared with controls. Risk may vary with dose of bevacizumab; significant difference may exist in patients receiving bevacizumab at 5 mg/kg/week (RR 9.1, 95% CI: 4.3–19.6, p < 0.001) and 2.5 mg/kg/week (RR = 5.1, 95%CI: 3.0–8.8, p < 0.001). The risk of high-grade proteinuria may also depend on tumor type; the incidence of high-grade proteinuria was 10.0% (95% CI: 4.3–22.4%) with a RR 48.7 (95% CI: 9.7–244.3) among 703 RCC patients compared with an incidence of 1.7% (95% CI: 0.09–3.2%) and RR of 5.2 (95% CI: 3.3–8.4) among 5,999 non-RCC patients. Conclusions: There is a significant risk for high-grade proteinuria in patients receiving bevacizumab. The risk may vary with bevacizumab dose and tumor type. RCC patients may have higher risk than non-RCC patients. Close monitoring and management are recommended for patients at high risk.

No significant financial relationships to disclose.