bluuebunny/crossref_metadata_2025 huggingface dataset:
Bridging sunitinib exposure to time-to-tumor progression in hepatocellular carcinoma patients with mathematical modeling of an angiogenic biomarker.
Authors: Ait-Oudhia Sihem , Mager Donald E. , Tomaszewski Garin , Groman Adrienne E. , Zagst Patricia D. , Fetterly Gerald J. , Iyer Renuka V.
Published: March 2020

e14690

Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with 250,000 new annual cases in the US. Sunitinib (SU), an oral tyrosine kinase inhibitor, inhibits tumor cell proliferation, selectively binds to the angiogenesis biomarker (VEGFR2), and is metabolized to an equipotent metabolite (SU12662). The objective of this study is to utilize mathematical modeling to bridge drug exposure and VEGFR2 dynamics to tumor growth inhibition (TGI) and time-to-tumor progression (TTP). Methods: Plasma concentrations of SU, SU12662, and VEGFR2, and tumor growth and TTP measurements were obtained from a phase-II study in 16 patients with unresectable HCC. SU was administered at 37.5 mg daily 7-days prior to chemoembolization, then on days 15-35. A MAP Bayesian approach was utilized to model SU and SU12662 pharmacokinetics (PK), both captured with a two-compartment model including linear clearances. Inhibition of VEGFR2 production was mediated by predicted active unbound concentrations (ACub) of SU and SU12662. VEGFR2 concentrations were the driver for TGI. The TTP probability was modeled with exponential hazard function dependent on a time varying covariate -the difference in VEGFR2 concentration from its baseline (ΔVEGFR2). Results: Drug and metabolite clearances (CLd, CLm) were estimated at 30.3 (19, %RSE) and 19.7L/h (14). Their volumes of distribution (Vd, Vm) were 1,780 (39) and 1840L (25). SU exposure was within target range for VEGFR2 inhibition. VEGFR2 half-life in plasma was calculated at 4h. The slope (α) for ACub effect on VEGFR2 production was 0.77(µg/mL)-1 (14). The ΔVEGFR2 effect on TGI was assumed maximal, whereas its potency (ΔIC50) was estimated at 1.83x10-2µg/mL (41). The between-subjects variabilities were 37.4, 51, 44.7, 64.8, 21, and 36% for CLd, CLm, Vd, Vm, α, and ΔIC50. The median observed tumor size baseline was 91 mm3. The simulated mean TTP was 7 months. Conclusions: The time-course of SU, SU12662, and VEGFR2 were captured well with final PK/pharmacodynamic models. VEGFR2 profiles successfully linked drug exposure to TGI and TTP. This model may serve as a general platform for the dynamics of anti-angiogenic drugs.
Conditional survival probability of patients with pancreatic cancer.
Authors: Muzaffar Mahvish
Published: March 2020

e14693

Background: Conditional survival gives more accurate estimate of survival probability for patients who have survived one or more years since initial diagnosis. The aim of this study was to analyze conditional survival probability for pancreatic cancer patients and impact of gender, age and extent of disease on conditional survival. Methods: Using the Surveillance, Epidemiology, and End Results database we analyzed 57,409 patients with pancreatic cancer diagnosed between 1990 and 2008. SEER*Stat: Version7.0.5 software was used to calculate conditional survival, defined as the calculated probability of survival having already survived a specified number of years from diagnosis, with sub-stratification by age(less than 65 yrs and above/equal 65yrs ), gender and stage summary (localized, regional and distant). Results: Conditional survival probability for patients with pancreatic cancer increased from 8.3% to 47.1% having survived one year after diagnosis. Conditional survival per gender increased from 8.5% to 49.8% in women and for men from 8.1% to 44.3%. Conditional survival probability per summary stage increased most for patients with localized disease (from 25.5% to 70.2%) as opposed to distant disease (3.2% to 37.0%). Age may have a slight impact on conditional survival probability, with increase from 12.5% to 50.7% in patient younger than 65 years, as opposed to from 5.7% to 42.3% in age group more than or equal to 65yrs. Conclusions: The expected 5-year conditional survival increases for pancreatic cancer patients who survive a number of years post diagnosis. The increase in conditional survival probability may be to a lesser extent than other cancers, but provides more useful longer term prognostic information.
Diagnostic and therapeutic outcomes in goblet cell appendiceal neuroendocrine tumors.
Authors: Toumpanakis Christos , Baneke Alex , Pericleous Marinos , Meyer Tim , Caplin Martyn E
Published: March 2020

e14696

Background: Goblet cell appendiceal neuroendocrine tumours (GCA-NETs), comprise approximately 6% of appendiceal neuroendocrine tumours (NETs) and share histologic features of both adenocarcinomas and NETs. We are presenting our data from 37 patients, focusing on diagnostic features, prognostic markers, treatment and survival. Methods: A retrospective analysis included 18 male and 19 female patients (mean age: 48.8; range: 19-73 years). Follow-up was complete (mean follow-up: 4.1 years). Results: Although majority of patients (69%) presented with appendicitis, 15.5% had bowel obstruction and 15.5% atypical abdominal pain. 27% had metastases at presentation (1 in lungs). Chromogranin-A, CEA and CA-125 were not significantly raised in these patients. Initial treatment was appendicectomy (26 patients) and 24/26 had a subsequent prophylactic right hemicolectomy. Additional hysterectomy and bilateral oophorectomy was performed in 6 patients and 4 patients just underwent either single or bilateral oophorectomy . 12% had recurrence and all had Ki67 proliferation index ≥ 20%. Octreoscan was negative, but FDG-PET was positive in all these patients, and in patients with distal metastases at presentation. FOLFOX chemotherapy was given prophylactically in 2 patients with local lymph nodes resulting in no evidence of recurrence (Median=8 months) and in 2 patients with distal metastases resulting in only temporary disease stabilization. 19% have died with disease and again all had Ki67 ≥ 20%. Conclusions: GCA-NETs may metastasize to the lungs (first report in literature). Ki67≥ 20% seems to be related with a worse prognosis. FDG-PET is the molecular imaging of choice. No optimal biomarkers or chemotherapy regimens are available to date.
The relationship between patient experience with service quality and survival in pancreatic cancer.
Authors: Lis Christopher G. , Markman Maurie , Rodeghier Mark , Gupta Digant
Published: March 2020

e14697

Background: Despite the recognized relevance of symptom burden in pancreatic cancer, there has been limited exploration of whether an individual patient’s assessment of the overall quality-of-care received might influence outcome. To assess this issue we evaluated the relationship between patient-reported experience with service quality and overall survival. Methods: We evaluated 496 returning pancreatic cancer patients treated at Cancer Treatment Centers of America between July 2007 and December 2010. Overall patient experience “considering everything, how satisfied are you with your overall experience with CTCA?” was measured on a 7-point Likert scale ranging from “completely dissatisfied” to “completely satisfied.” It was dichotomized into 2 categories: top box response (7) versus all others (1-6). Patient survival was the primary end point. Cox regression was used to evaluate the association between patient experience and survival. Results: 317 patients were newly diagnosed while 179 were previously treated. 16, 93, 81 and 306 patients had stage I, II, III and IV disease respectively. 292 were males and 204 females. Mean age was 57.3 years. 387 (78%) patients had expired at the time of this analysis. 345 patients were “completely satisfied” while 151 were not. Median overall survival was 7.9 months (95% CI: 7.3-8.6 months). On univariate analysis, “completely satisfied” patients had a significantly lower risk of mortality compared to those not “completely satisfied” (HR=0.62; 95% CI: 0.50-0.78; p<0.001). On multivariate analysis controlling for stage at diagnosis, treatment history, age and gender, “completely satisfied” patients demonstrated significantly lower mortality (HR=0.61; 95% CI: 0.49-0.76; p<0.001) compared to those not “completely satisfied”. Conclusions: Patient experience with service quality was an independent predictor of survival in pancreatic cancer. This finding underscores the importance of psychosocial factors in patient prognosis. Patients who evaluate their quality of care more favorably may in turn have more positive attitudes toward their treatment outcomes, and may engage in other health behaviors that could potentially increase survival.
Multistage phase II design for mixed tumor response and time-to-event endpoints: An application for screening new drugs in hepatocellular carcinoma (HCC).
Authors: Zee Benny C. Y. , Lai Xin , Lee Ann Sing , Lai Maria , Chong Marc , Kwok Chloe , Jolivet Jacques
Published: March 2020

e14706

Background: Phase II trials aim to assess the anti-tumor activity of investigational therapies, and consider if they warrant further study. In some instances such as a study treatment added to standard therapy in HCC, tumor response alone may not provide a clear picture on its effectiveness (e.g. biologics and targeted therarpy). Other endpoints such as progression-free survival (PFS) in addition to conventional tumor response would increase the chance of detecting useful treatment and also be able to terminate a study earlier if the treatment was deemed ineffective. Methods: Following a similar rationale for multinomial endpoints in phase II trials by Zee (1999), we have developed a multi-stage phase II stopping rule for "mixed tumor response and time-to-event endpoints". We used a study entitled, “Randomized Phase II study of the x-linked inhibitor of apoptosis (XIAP) antisense AEG35156 in combination with sorafenib in patients with advanced HCC” as an illustration. We applied this multi-stage stopping rule for mixed endpoints in a randomized phase II setting, where the control arm was being used here as a way to set up the null hypothesis. We defined the null hypothesis by a mixture of response rate of 5% and PFS of 2.6 months versus an alternative hypothesis of response rate of 20% and PFS of 5.2 months. Results: The stopping rule was such that the null hypothesis would be rejected at a correlation of 0.5 for the mixed endpoints and conclude that the treatment is effective if we have 0-1 responders and a PFS>=4.0 months, or 2 responders and PFS>=3.8 months, or 3 responders and a PFS>=3.6 months, or 4 responders and a PFS>=3.0 months, or 5 responders with any PFS. Conclusions: In the AEG35156 study, we had 3 responders (based on Choi’s criteria), and 1 responder even if we used RECIST criteria. A PFS of 4.0 months. Therefore, we concluded that the study treatment in combination with sorafenib has a positive effect and warrants further investigation. This methodology would greatly improve the efficiency for phase II screening especially on new biologics on top of a standard or for diseases where tumor response alone does not reflect the full effectiveness of the new treatment.
Sorafenib (S) for hepatocellular carcinoma (HCC) treatment: Russian experience in cirrhotic (C) and non-cirrhotic (non-C) patients.
Authors: Breder Valeriy Vladimirovich , Bisovskaya Yulia , Khokhlova Svetlana Victorovna , Gorbunova Vera
Published: March 2020

e14723

Background: S is the standard for HCC treatment in advanced stage. There is no date about an etiology of HCC and S efficacy/toxicity in Russian pts. Methods: 69 patients (19 f/ 50 m, average age 54 years) with advanced HCC BCLC A/B/C/D 1/30/38/0 were treated with sorafenib as a I-st line. S treatment: 400 mg bid until progression, uncontrolled toxicity, or death. S dose reduced when toxicity (NCI CTC, ver 3.0) ≥Gr 2 occured. We evaluate influences of BCLC and Child-Pugh stage, presence of C and/or viral hepatitis on S efficacy and toxicity. Results: 33 (48%) out of 69 patients had C and 36 (52%) were non-C. No hepatitis - 36 pts (C/non-C - 5/31 pts), 16 pts had HBV (C/non-C – 15/1), 17 pts had HCV (C/non-C – 15/2), 1 pt had hepatitis B+/C without C. Clinically significant toxicity (Gr 2/3) occurred in 20 (C/non-C – 9/12) pts: HFS 1/6, skin rash 3/3, diarrhea 3/2, arterial hypertension (AG) 2/0, asthenia 1/1, fever 1/0. S interrupted in 12 (C/non-C – 5/7) pts: HFS- 0/4, skin rash -1/3 diarrhea - 2/1 and AG - 2/0. Efficacy evaluated in 68 pts: PR - 5 (7,4%) pts, stable – 46 (67,6%) and disease progressed in 17 (25%) pts. All PR (OR=13,9%) observed in non-C pts: 6, 9,3, 10, 10,2 and 13+ mo). Median PFS and OS on S treatment was 5,4 and 9,3 mo respectively. No significant difference were in PFS and OS for C and non-C pts, irrespectively for HCV/HBV status and Child-Pugh stage A/B (Table). Conclusions: More than 50% of HCC pts in Russia are non-C and don’t have HBV/HCV. Clinically significant toxicity of S differs in C/non-C pts, with prevalence of skin side effects in non-C pts, AG and diarrhea in C group. Non-C HCC pts have better chance to respond to S treatment. However we didn’t find any significant difference of S treatment in terms of survival and side effects between C and non-C pts. [Table: see text]
Gastric signet ring cell in a Moroccan medical oncology unit.
Authors: Brahmi Sami Aziz , Bouyahia Nezar , Chad Amine Mohammed , Daoudi Khaoula , Hijri Fatima Zahra , Arifi Samia , Nawfel Mellas , El Mesbahi Omar
Published: March 2020

e14725

Background: Signet ring cell carcinoma (SRC) of the stomach is a histological type based on microscopic characteristics, and its clinicopathologic characteristics and treatment are still controversial. Methods: In this retrospective study, we reviewed the records of 68 patients diagnosed with gastric SRC treated between January 2007 and July 2011. The aim of this study is to identify the epidemiological, clinical and therapeutic features of this type cancer in a Moroccan population Results: In our study, SRC of the stomach represents 39 % of the gastric cancer and 11 % of all the digestif tract cancer. The mean age at the diagnosis was 46 years ranged from 25 to 80 years, 68 % were female. The clinical symptoms were vomiting (72%), epigastric pain (70%) and deterioration of Performans Status (93%). 73% of the patients were metastatic at the diagnosis, sites of metastasis were: peritoneum (85 %), lymphatic nodes (43 %), liver (35%), lung (28 %), ovaries (7 %), adrenal glands (7 %), bone (4 %) and the kidney (2 %). 23% of the patients had a localized disease and locally advanced 8%. Among the 64 patients, 27% were treated with curative intent by total gastrectomy followed by adjuvant concomittant chemoradiotherapy (n=6), adjuvant chemotherapy (n = 4) or perioperative chemotherapy (n=7). For the metastatic patients, chemotherapy regimens were distributed as following: ECC (Epirubicine 50 mg/m2, Cisplatine 60 mg/m2, Capecitabine 625 mg/m2/12h) was administred to 45 % of the cases, cisplatine-5FU to 18 % of the cases, capecitabine as monotherapy for 16 %; FUFOL Mayo clinic regimen for 9 % and EOX (Epirubicine 50 mg/m2, oxaliplatine 130 mg/m2, capecitabine 625 mg/m2/12h) for 5%. 7% of the patients were oriented to supportive care. A second line of chemotherapy was administed to 4 patients based on XELIRI (irinotecan 250 mg/m2 and capecitabine 2000mg/d for 14 days) in 3 patients and XELOX (oxaliplatine 85 mg/m2 and capecitabine 2,000mg/d for 14 days) in one patient (n = 1). Conclusions: The gastric Signet ring cell carcinoma represents an entity with specific characteristics, which tends more toward tumor invasion depth, with nodal and peritoneal metastases. Our results are consistent with those of the literature concerning the epidemiological finding and diagnosis aspects.
Metastatic and unresectable biliary tract tumors: A single-center retrospective review.
Authors: Vieito Maria , Martinez Lago Nieves , Aguin Losada Santiago , Lopez Rafael , Candamio Sonia , Brozos Vazquez Elena Maria , Gallardo Elena , Varela Ponte Rafael , Anido Urbano , Vazquez Francisca , Vidal Yolanda , Cueva Banuelos Juan Fernando , Campos Marta Carmona , Rodriguez Lopez Carmela
Published: March 2020

e14733

Background: Biliary tract tumours are rare and often poor prognosis cancers that comprise cholangiocarcinomas, ampullary tumours and gallbladder cancers. Methods: Medical Electronic Records for patients diagnosed between January 2008 and December 2010 and treated at a medical oncology unit were reviewed, and clinical and epidemiological data for patients were retrieved. Results: We have found 28 patients with a distribution with a clear majority of men (60%), with a median age of 66 years (range 45-80).Patients were mostly metastatic (85%) at diagnosis and the majority of patients had intrahepatic cholangiocarcinoma (60%) as diagnosis and debuted with large intrahepatic masses and metastatic disease.Those with tumours arising outside the liver (40%) had obstructive jaundice (28%) or cholangitis (26%) at diagnosis and needed in most cases biliary stenting (33%).Six patients had PS2 at diagnosis and received gemcitabine monotherapy. Only one patient remaining progression free at 6 months and none of them received treatment at progression, the mean PFS was of 5.3 months and the OS was of 8.3 months.Of 22 patients with good performance status, 12 of them with a mean age of 60 years received polychemotherapy with GEMOX or CDDP-gem with PFS of 7. 3 months and OS of 12. 3 months.The other 10 patients (with a mean age of 65 years) received gemcitabine as monotherapy with a PFS of 7. 9 months and a OS of 11. 4 months.Eight patients were treated with second line therapy with no responses and a mean of PFS of 2 months, OS was not superior to patients who did not receive second line treatment. Conclusion: Our patients with biliary tract tumours had a mean progression free survival of 8.2 months and a mean overall survival of 12.3 months with 5 patients remaining progression free more than 20 months after beginning treatment. This survival data are compatible with those reported in recent clinical trials although we did not find improvements in survival with polychemotherapy and second line therapies. Conclusions: Taken as a whole our patients with biliary tract tumours had a mean progression free survival of 8.2 months and a mean overall survival of 12.3 months with 5 patients remaining progression free more than 20 months after beginning treatment.
Prognostic significance of second mitochondria-derived activator of caspase expression in bladder cancer and target for therapy.
Authors: Mizutani Yoichi , Azuma Haruhito
Published: March 2020

e15000

Background: Although the expression of second mitochondria-derived activator of caspase (Smac/DIABLO) has been reported in various cancers, little is known about its clinical significance in bladder cancer. The present study was designed to evaluate the relationship between progression of disease and Smac/DIABLO expression by clinical pathological analysis of patients with bladder cancer. Methods: The level of Smac/DIABLO expression was quantified by western blot analysis using non-fixed fresh frozen tissues derived from patients with bladder cancer. Results: All normal bladders expressed Smac/DIABLO. However, 64/84 ( 76% ) of bladder cancers expressed Smac/DIABLO and 24% were negative. In Ta and T1 superficial bladder cancers, 98% expressed Smac/DIABLO, whereas only 41% expressed Smac/DIABLO in muscle-invasive bladder cancers. Smac/DIABLO expression inversely correlated with the grade of bladder cancer. Patients with Ta and T1 superficial bladder cancer with higher Smac/DIABLO expression had a longer postoperative recurrence-free period than those with lower Smac/DIABLO expression after transurethral resection in the 5-year follow-up. Patients with invasive bladder cancer expressing Smac/DIABLO had a longer postoperative disease-specific survival than those without Smac/DIABLO expression after radical cystectomy in the 5-year follow-up. The cisplatin-resistant T24 bladder cancer line ( T24/CDDP ) and the adriamycin-resistant T24 line ( T24/ADR ) showed lower level of Smac/DIABLO expression, compared with the T24 parental line. Conclusions: The present study demonstrates for the first time that Smac/DIABLO expression was downregulated in bladder cancer, especially in high grade muscle-invasive bladder cancer, and that lower Smac/DIABLO expression in bladder cancer predicted a worse prognosis. In addition, the cisplatin-resistant T24/CDDP line and the adriamycin-resistant T24/ADR line expressed lower level of Smac/DIABLO expression. These results suggest that Smac/DIABLO expression in bladder cancer may be used as a prognostic parameter, and that low Smac/DIABLO expression in bladder cancer may be associated with resistance to chemotherapy.
Phase II clinical and pharmacokinetic (PK) trial of zalypsis (Z) in patients with urothelial carcinoma (UC) progressing after a first-line platinum-based regimen.
Authors: Ghanem Ismael , Carles Joan , Molins Joaquim Bellmunt , Coronado Cinthya , Maroto José Pablo , Font Pous Albert , Morales Rafael , Suarez Cristina , Etxaniz Olatz , Capdevila Laia , Martin Lorente Cristina , Rodriguez Cleofe , Kahatt Carmen Maria , Luque Manuel , Castellano Daniel E.
Published: March 2020

e15001

Background: Platinum-based chemotherapy (CT) is beneficial as first-line treatment of advanced UC. However, the majority of patients develop recurrent disease with poor long-term survival rates. Attempts to improve second-line treatments have evaluated single agents and multi-drug combinations, neither of which has managed to improve survival or achieve durable responses. Z is a cytotoxic agent that induces apoptosis by acting at cell cycle level, has DNA-binding properties and inhibits transcriptional responses. Z has shown anti-tumor activity in vitro and in vivo in xenograft models. Based on the activity observed in a phase I study (1PR and 2 SD) in advanced bladder cancer, we have designed a phase II study to explore the efficacy of Z in this setting. Methods: Patients with histologically-confirmed advanced or metastatic UC, who had failed one prior line of platinum-based CT, with proven progression or relapse before study entry, were included. Patients were treated with a Z intravenous infusion of 3 mg/m2 over 1-hour and every 3 weeks. A two-stage design was chosen; at least four (of 17) evaluable patients had to reach the primary endpoint during the first stage in order to progress into a second stage of up to 37 patients. The primary endpoint was tumor control rate (TCR): percentage of patients with objective response (OR) of any duration or patients alive and progression-free (PFS) at three months. Results: Twenty patients of a median age of 71 years (r: 54-83) were enrolled after a median of one prior treatment line (r:1-2). One patient was considered non-evaluable. No ORs were observed and only one patient had PFS ≥ 3 months. The median time on treatment was 1.68 months (r: 0.76-4.21). Toxicity consisted mostly of grade 1-2 fatigue, anorexia and nausea. Five patients had isolated troponin I increases (with no ECG or LVEF findings). Hematological toxicity was mild, one patient had grade 3 neutropenia and one patient had grade 3 thrombocytopenia. Conclusions: Only one patient reached the primary endpoint (TCR) during the first stage; consequently, the study was closed and no further development was considered.
Early outcome results of a phase I/II study for an IL-2/T-cell receptor fusion protein in combination with gemcitabine and cisplatin (GC) in patients with locally advanced or metastatic urothelial cancer.
Authors: Hajdenberg Julio , Landau Danny , Vaena Daniel A. , Fishman Mayer N. , Rosser Charles Joel , Milhem Mohammed M. , Weber Jeffrey S. , Rizzo Virginia , Zehr Pamela , Williams-Elson Irene , Rhode Peter , Schutt Tessa , Hernandez Liza , Huang Bee-Yau , Wong Hing C.
Published: March 2020

e15010

Background: ALT-801 is a human IL-2/single-chain T-cell receptor fusion protein previously tested in a phase 1 in patients with advanced malignancy (Fishman 2011 CCR 17:7765) (CA097550). In various murine models, ALT-801 demonstrated potent activity against syngeneic and xenograft UC, suggesting sensitivity of this disease to IL-2 based immunotherapy (Wong, unpubl. data.). Although UC are sensitive to platinum-based chemotherapy, combinations such as gemcitabine (G) + cisplatin (C) are associated with CR rates of around 15%, and limited durability of responses with limited effects of retreatment. Methods: We report here initial efficacy results of co-administration of G (1000 mg/m2/dose, d 1 & 8), C (70 mg/m2/dose, d 1) and ALT-801 (escalating doses, d 3, 5, 8, 10) on a 21 day schedule, for 3 cycles, in patients with UC that was locally advanced, or metastatic, for whom GC chemotherapy would be considered. ALT-801 planned doses are 0.04 to 0.12 mg/kg/dose in 5 dose cohorts with a 3+3 escalation design. Subjects with at least stable disease after 3 courses may receive 4 additional weekly doses of ALT-801 alone. Results: To date, three Stage IV UC patients (1F, 2M; 59-63 yrs; 2 patients had predominantly nodal metastases and one patient liver metastases) completed treatment with 0.04 mg/kg ALT-801+GC. Two had previously undergone radical cystectomy and had then later failed following GC treatment. Grade 3/4 toxicities observed include neutropenia (2), thrombocytopenia (2), leukopenia (1), lymphopenia (1) and anemia (1), consistent with GC and ALT-801 known pharmacodynamic effects. All 3 had radiological CRs by week 13. One patient underwent radical cystectomy had a pCR. The next (0.06 mg/kg/dose) cohort has started treatment. A phase II expansion cohort is planned at the MTD. Conclusions: The early response pattern is encouraging in that ALT-801 may be a novel, active immunotherapy for UC. NCT01326871
Outcomes of small call carcinoma of bladder in elderly.
Authors: Thota Swapna , Kistangari Gaurav , Garje Rohan , Daw Hamed
Published: March 2020

e15023

Background: Small cell carcinoma (SCCB) is an aggressive tumor and presents in an advanced stage. In this retrospective study we analyze the patterns of treatment and survival among elderly patients (age>75 years). Methods: We identified 38 patients who were diagnosed with primary SCCB at our institution and its affiliated hospitals between 1995-2010. Out of which 15 patients were above the age of 75 years. For each patient histological, demographic and clinical data were obtained by chart review. Deaths of all patients were confirmed by social security death index (SSDI). Staging of all patients were categorized as limited (T1-4N0-1M0) or extensive stage (TxNxM1 or TxN2-3M0). Results: 15 patients were identified with pure small cell carcinoma of bladder. Mean age of patients was 80 years ( ranged from 76 years to 90 years). Male to female ratio was 5:1. 86% were caucasians. Among patients with available clinical information, 5 out of 15 patients (33.3%) had extensive stage and remaining 10 had limited stage SCCB. Around 73% (11/15) of the patients underwent transurethral resection of bladder tumor (TURBT). One patient had partial cystectomy and three patients had radical cystectomy. All three pateints who underwent radical cystectomy had limited disease and had an overall median survival (OMS) of 27 months. Patients with TURBT had a OMS of 6 months. Conclusions: Prognosis for patients with SCCB remains poor. Careful selection of patients for radical cystectomy with limited disease may improve overall median survival among elderly population with SCCB.
Compliance with follow-up (f.-up) program and outcome of patients (pts) with stage I nonseminomatous germ cell tumors (NSGCT).
Authors: Fedyanin Mikhail , Tryakin Alexey , Denisova Elena , Bulanov Anatoly , Zakharova Tatiana , Matveev Vsevolod B. , Figurin Konstantin , Garin Avgust , Tjulandin Sergei
Published: March 2020

e15025

Background: There are limited data about f.-up quality of pts with stage I NSGCT after orchiectomy (OE) management and their survival. A retrospective analysis was performed to find the impact of compliance with schedule of f.-up on outcome of relapsed pts with stage I NSGCT. Methods: We analyzed data of 261 pts with stage I GCT treated in our department from 1994 to 2010. NSGCT was revealed in 128 (49%) pts. Therapeutic options following OE comprised retroperitoneal lymph node dissection (RPLND) – in 4/128 (3%), adjuvant cisplatin-based chemotherapy (CT) - in 75/128 (58%) and surveillance - in 49/128 (39%). The following procedures were performed in our center during the f.-up: ultrasound of the abdomen and pelvis, serum AFP, HCG and LDH – bimonthly in the 1st year, quarterly in the 2nd year, biannually in the 3rd-4th years and then annually; X-Ray of the chest – thrice-yearly in the 1st year, biannually on the 2nd year and then annually. Median f.-up time was 75 (range 16 - 176) months. Results: No pts had relapse after RPLND, 4/75 (5,3%) pts had relapses after CT, 16/49 (32%) pts – in surveillance group. 17/20 (85%) relapses were revealed in the first 2 years of f.-up. During relapses, 17/20 (85%) pts had good, 2/20 (10%) - intermediate and 1 patient - poor IGCCCG prognosis. The mean number of visits in the 1st year after OE was 3, on the 2nd year -1,4, in the 3rd- 4th years - 1 per year. All relapsed pts received induction CT (EP or BEP regimen). 11/20 (55%) pts were compliant to visits, 9/20 (45%) pts were not. The 5-years overall survival was 90% and 68% (p=0,3); the median size of metastases in RPLN was 2,2 and 5,5 cm (p=0,001), respectively. All pts in intermediate and poor prognosis were in the noncompliant group, whereas all pts, who were compliant were in good prognosis (3/9 (33%) vs 0/11 (0%), p=0,07). Moreover, surgical removal of residual tumor after induction CT was more often performed in the noncompliant group (5/11 (33%) vs 5/9 (71%), р=0.6). Conclusions: Poor compliance with f.-up program in stage I NSGCT results to non significant worse long-term outcome. Also pts, who were compliant had significantly smaller size of metastases in retroperitoneal lymph nodes at relapse and had good IGCCCG prognosis in all case.
Role of an extended pathology exam in risk classification of testicular germ cell tumors (GCTs).
Authors: Marinca Mihai Vasile , Caruntu Irina Draga , Liliac Ludmila , Giusca Simona Eliza , Marinca Andreea , Miron Lucian
Published: March 2020

e15032

Background: The 1997 IGCCCG Consensus classification provides clinicians with enough information to efficiently choose between treatment options for most GCT patients. Nevertheless, therapy is ineffective in 5-10% of cases (even more in less developed countries), and about the same numbers experience severe side effects. This exploratory study aims to assess the impact of more rigorous and detailed pathology examination on improving the assignation of these patients to prognostic groups and, consequently, making optimal therapeutic decisions. Methods: Predefined features were reviewed on histology slides from 39 GCT patients followed-up for a median of 48.28 months. We designed a uniform pathology protocol, focused on identifying potential new prognostic factors. Categorical and continuous variables were quantified using light microscopy and computer-aided morphometry and, due to the small sample size, their statistical correlation was analyzed by exact tests and Spearman’s rho, respectively. Significant (2-sided p-value <0.05, under sample size reserve) coefficient values were entered in hierarchical cluster analysis (HCA). Results: Favorable IGCCCG group, presence of seminoma, glandular tissue pattern, presence and histoarchitecture of lymphocytic infiltrate associated better survival rates and lower risk of progression. Invasion of the epididymis and spermatic cord, presence of teratoma, choriocarcinoma and yolk-sac elements, papillary pattern and cell pleomorphism predicted poorer outcomes. HCA yielded 2 significantly distinct patient groups in terms of overall survival (p=0.018) and time to progression (p=0.080), but not disease-free survival (p=0.614). Conclusions: Quantification of tumor subtypes and other histology features of GCTs (e.g. necrosis, tissue patterns, inflammation) is feasible and, if standardized, may prove useful in optimal selection of risk groups, when performed by an experienced pathologist.
Retrospective analysis of 132 patients with stage I seminoma: Observation versus adjuvant radiation or chemotherapy in a single institution.
Authors: Vega Estela , Cascales Almudena , De Velasco Guillermo , Cabeza Rodriguez Maria Angeles , Parrilla Lucia , Colmenero Maria , Manneh Ray , D'Ambrosi Rafael , Pascual Tomas , Rodriguez Garcia Sofia , Valdiviezo Natalia , Gomez Ordonez Silvia , Dorta Miriam , Guardado Sandra , Bartolome Adela , Lechuga Carmen , Perez Regadera Jose Fermin , Lanzos Gonzalez Eduardo , Cortes-Funes Hernan
Published: March 2020

e15033

Background: Classically, radiotherapy (RT) has been the standard adjuvant treatment for stage I seminoma patients. Improvements in early relapse diagnosis have led high cure rates. Two cycles of adjuvant carboplatin present similar efficacy to radiotherapy with less toxicity have led to re-examination of the standard treatment approach. Methods: Retrospective study of 132 patients diagnosed with stage I seminoma from 1980-2010 who received whether treatment with RT, chemotherapy (Cht) or active surveillance (AS) after orchiectomy at one Universitary Hospital. The objective was to determine the relapse-free survival (RFS), overall survival (OS), and disease -specific survival (DSS). Results: Of the 132 patients, 68 were treated with prophylactic irradiation (paraaortic ± pelvic nodes, the median total dose radiation 26 Gy at 2 Gy per fraction), 33 with adjuvant chemotherapy (31 had carboplatin x 2, 2 had BEP x 2), and 31 underwent surveillance. Among the RT patients (median follow-up 121months), mean age was 40 years (range: 20-70) with mean tumor size of 5.5 cm (range: 1-14). 6% of them had rete testis involvement and 15% vascular invasion. There was 1 relapse with a median disease-free survival (DFS) of 103 months and no deaths from seminoma. RFS was 98% at 10 years. OS and DSS were 100% at 10years. Among the chemotherapy patients mean age was 30 years (range: 18-66) with mean tumor size of 6,18cm (range: 1,5-10). 9% of them had rete testis involvement and 60 % vascular invasion. With a median follow-up of 66 months, there was 1 relapse. Five-year RFS was 97%, OS and DSS were 100%. Among the observation patients (median follow-up 148 months), mean age was 35 years (range: 20-78) with mean tumor size of 3,7cm (range: 1,3-7). 6% of them had rete testis involvement and 6 % vascular invasion. There were 6 relapses with no deaths from seminoma. RFS was 80%, specific OS and DSS was 100% at 10 years. Of the patients who relapsed, all were rendered disease-free with chemotherapy; with non evidence disease at last follow-up. Conclusions: Consistent with published trials both radiotherapy, chemotherapy or active surveillance are safe and effective treatments with similar oncologic results.
Survival and prognostic factors after complete response to first-line cisplatin-based chemotherapy in patients with advanced testicular seminoma: The Instituto Nacional de Enfermedades Neoplásicas experience.
Authors: Neciosup Silvia P. , Callacondo David , Rua Oliver , Rojas Jose Ernesto , Quesada Jose , Schwarz Luis Jesus , Aguilar Marin Ivan Carlos , Más Luís , Gomez Henry , Vallejos Carlos S.
Published: March 2020

e15036

Background: The IGCCCG classification, used to guide the management of metastatic seminomas may underestimate the predictive value of other prognostic factors. We aimed to identify prognostic factors for long term survival in patients with advanced testicular seminoma who achieved a complete response to first line cisplatin based chemotherapy. Methods: A retrospective analysis was carried out on 101 patients with advanced testicular seminoma who received induction cisplatin based chemotherapy between 1990 and 2010.Data regarding clinical and laboratory parameters that may influence the overall survival (OS) or progression free survival (PFS) were collected from clinical records. Univariate analysis was performed using the Kaplan-Meier method, while Cox regression modeling was used for multivariate analysis. Results: The mean follow up time was 8.4 years. 9 (9%) patients died and 16 (16%) developed relapse. The 10 year OS and PFS rates were 91% and 84%. In univariate analysis, a testicular tumor ≥5.5cm and a retroperitoneal metastases ≥16 cm were associated with poor OS and PFS. The prechemotherapy LDH levels ≥2.4xUNL and age ≤36 years showed a trend to shorter PFS. Multivariate analysis showed that only the retroperitoneal metastases ≥16 cm was significant independent prognostic factor for OS (p=0.04, HR 3.86; 95% CI, 1.03-14.41) and PFS (p=0.05, HR 3.17; 95% CI, 0.99-10.15). Age ≤36 years (p=0.03, HR 4.29; 95% CI, 1.12-16.34) was also an independent prognostic factor for PFS. Conclusions: The presence of a retroperitoneal metastases ≥16 cm, a testicular tumor ≥5.5cm and age ≤36 years are associated with decreased OS and/or PFS in patients who achieved a complete response to first line cisplatin based chemotherapy. The use of these factors may assist the elaboration and implementation of new prognostic models that can guide the follow-up and management of patients with advanced testicular seminomas.
Development and validation of prognostic models in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib: A Greek-French collaboration.
Authors: Karavasilis Vasilios , Tzanis Kimon , Bamia Christina , Elaidi Reza-Thierry , Kostouros Efthimios , Visvikis Antonios , Skarlos Dimosthenis-Vasilios , Linardou Helena , Razis Evangelia , Chrisofos Michael , Stravodimos Kostas , Lazaridis George , Timotheadou Eleni , Hatzimouratidis Constantinos , Oudard Stephane , Fountzilas George , Dimopoulos Meletios A. , Bamias Aristotelis
Published: March 2020

e15040

Background: The use of tyrosine kinase inhibitors (TKIs) in mRCC has improved prognosis but the individual outcome remains largely unpredictable. The MSKCC model, used to identify risk groups, was developed in cytokine-treated patients and has not been externally validated in the TKI era. It contains 3 laboratory factors (total 5), making its application to retrospective series somewhat problematic. Subsequently, a more complicated model, using 4 laboratory factors (total 6) has been described. The Hellenic Cooperative Oncology Group recently described a simpler model with only 3 clinical factors. We are describing the application and external validation of this model. Methods: 128 Greek patients with mRCC treated with 1st line sunitinib were included. All had had nephrectomy. Previous interferon was allowed. Cox regression was used to develop a predictive model for overall survival (OS). Our model was compared to that of MSKCC and Heng’s using ROC curves and Harrell’s Concordance Index. Risk groups were defined by the calculated prognostic index and by clinical factors. External validation was done using a sample of 226 French patients. The Royston and Sauerbrei D statistic was used as a measure of discrimination of the survival model. Results: Time from diagnosis of RCC to start of sunitinib (<12), PS (>1) and number of metastatic sites (>1) were independent adverse prognostic factors in the Greek dataset. The co-efficients for each factor were: 0.51, 0.97, 0.61, respectively. The 3 risk groups were defined by the 25th and 75th percentiles of the prognostic index values (Table 1). The model was of equal prognostic value to the MSKCC (p=.272) and Heng’s (p=.075). French had better survival than Greek patients especially in the high risk group (for all models). Validation of our model in the French data showed that it was applicable (R2 D: 0.14, SE: 0.09), especially for the low/medium risk groups. Conclusions: Our model is the only one externally validated in TKI-treated patients. It may be considered as a simpler alternative to those currently applied. [Table: see text]
Partial versus radical nephrectomy in the elderly: A surgical conundrum.
Authors: Narayanan Ramkishen , O'Malley Rebecca Leigh , Brewer Katherine , Hayn Matthew H. , Mehedint Diana , Safwat Mohab W. , Kim Hyung Lae , Underwood Willie , Schwaab Thomas
Published: March 2020

e15046

Background: Whether increased risk of complication (Cx) is balanced by the renal preserving benefits of partial nephrectomy (PN) in those with shortened lifespan is unclear. We compared Cx and renal function outcomes of PN and radical nephrectomy (RN) in the elderly. Methods: From a prospectively maintained renal tumor database, we retrospectively identified patients ≥ 75 years old who had RN or PN for a solitary, localized tumor ≤ 7cm and a normal contralateral kidney. CKD-EPI formula estimated glomerular filtration rate (eGFR). Propensity analysis was used to account for population selection bias: probability of RN was calculated by multivariate logistic regression, including variables thought to influence selection for nephrectomy type, yielding a propensity score based on quintile of RN probability. Odds ratios for any Cx, high grade Cx and postoperative stage ≥ 4 chronic kidney disease [CKD4] by nephrectomy type were recalculated using logistic regression adjusting for propensity score. Other statistical tests used were Student′s t, Wilcoxon rank-sum and Fisher′s exact. Results: 57 patients met inclusion criteria: 47% and 53% had PN and RN, respectively. Age, gender, baseline Cr, BMI and Charlson index were similar between the PN and RN groups. In both groups, surgical approach was minimally invasive in 93%. Mean tumor size with RN was larger than with PN (4.6 v. 3.6 cm, p<0.01). EBL was higher with PN (360 v. 122 mL, p=0.02), although intraoperative transfusion rate was similar (p=0.13). With similar preoperative eGFR between groups, mean postoperative eGFR was lower in the RN group (36 v. 50 ml/min/1.73m2, p<0.01). Propensity analysis showed likelihood of CKD4 was significantly higher with RN (OR 5.5, p=0.04). Cx rate was similar between PN and RN (30% v.37%, p=0.39), but most high grade Cxs were seen with PN (56% v. 23%, p=0.01). Propensity analysis supported these data in that risk of total Cxs was not increased with PN (p=0.46) but risk of high grade Cxs was significantly higher with PN (OR 9.2, p<0.01). Conclusions: Risk of significant renal dysfunction following RN was 5-fold that of PN, but risk of high grade complications with PN is 9-fold that of RN. Evaluating the clinical impact of these risks should be done on an individual patient basis.
International, expanded access program of everolimus in patients with metastatic renal cell carcinoma (mRCC) who progressed after previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy (VEGFr-TKI): Subanalysis from emerging growth market (EGM) countries.
Authors: Lee Se-Hoon , Buyukberber Suleyman , Ou Yen-Chuan , Shapiro Jeremy David , Panneerselvam Ashok , Ocak Arikan Ozlem , Xue Hong-Ling , Rusakov Igor
Published: March 2020

e15047

Background: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor shown to benefit patients with mRCC after failure of initial VEGFr-TKI therapy. In the phase 3 RECORD-1 trial, median progression-free survival was 4.9 months with everolimus and 1.9 months with placebo (hazard ratio, 0.33; P < .001). REACT (RAD001 Expanded Access Clinical Trial in RCC; NCT00655252) was an open-label, expanded access program that provided everolimus before commercial availability to 1367 patients with VEGFr-TKI refractory mRCC in 34 countries. Final results of REACT were recently published (Eur J Cancer. 2012;48:324-332). Methods: The primary objective of REACT was to evaluate the long-term safety of everolimus 10 mg/day as determined by the overall incidence of grades 3 and 4 adverse events (AEs). Best overall tumor response was assessed according to RECIST 1.0. This subanalysis was conducted to assess primary and secondary end points in a subgroup of patients from 11 EGM countries: Turkey, Australia, Russia, Israel, Lebanon, Jordan, Saudi Arabia, South Korea, Singapore, Taiwan, and Thailand. Results: Baseline characteristics of the EGM population (n = 243) were similar to the overall REACT population: median age, 60.0 years; clear cell histology, 95.1%; and progression on/intolerance to previous VEGFr-TKI therapy, 89.7%/16.9%. Median duration (range) of everolimus exposure was 20.4 (0.3-83.7) weeks. Clinical benefit was observed in 60.1%/53.3% of EGM patients/all patients (stable disease, 55.6%/51.6%; partial response, 4.5%/1.7%). Common grade ≥3 AEs in EGM patients/all patients included anemia (19.8%/13.4%), pneumonia (7.4%/4.2%), hyperglycemia (7.0%/5.5%), stomatitis (5.8%/5.4%), and pneumonitis (2.9%/2.7%); 13.2%/16.6% of EGM patients/all patients discontinued because of AEs. Conclusions: In patients from EGM countries, safety findings and tumor responses were consistent with the overall REACT population and with RECORD-1. Everolimus was well tolerated, with no new safety issues identified.
Association of single nucleotide polymorphisms in AGT, VEGF, and APOE genes with clinical outcome of target therapy in advanced renal cell carcinoma.
Authors: Mao Li Li , Si Lu , Chi Zhi Hong , Cui Chuan Liang , Sheng Xi Nan , Guo Jun , Tang Bi Xia , Li Si Ming
Published: March 2020

e15051

Background: Recent evidences have indicated that hypertension and obesity predict longer PFS of targeted therapy in metastatic renal cell carcinoma (mRCC) patients, thus we suppose polymorphisms in hypertension associated genes(angiotensinogen, AGT; vascular endothelial growth factor, VEGF) and obesity associated gene (apolipoprotein E, APOE) may have an effect on treatment outcome in patients treated with targeted therapy for mRCC. Methods: A cohort of consecutive patients (pts) treated with sunitinib or sorafenib were studied. Baseline clinical characters such as age, gender, blood pressure and BMI (body mass index) were recorded. All patients were genotyped for genetic polymorphisms in rs2493137 of AGT, rs699947 of VEGF and rs8106922, rs405509 of APOE from peripheral blood. All the patients were followed up for progression free survival(PFS),overall survival (OS),objective response rate (RR). Results: We studied a cohort of 77 cases, 58 (24.7%) pts were male, 18 (23.4%) pts were ≥65 years and 47 (61%) pts received sunitinib. The distribution of all the tested SNP genotypes were in Hardy-Weinberg equilibrium (p>0·05). With a median follow-up time of 24 months (range: 1.5-36.2 months), 60 pts developed progression and 34 pts died. The rs2493137 TT genotype in the AGT gene showed a trend of prolonging PFS when compared with the CC+CT genotypes, but without statistically significance (p=0.08). No correlations were found among other genotype subgroups (rs699947, rs8106922 and rs405509) on either clinical characters or survival endpoints in this study. Conclusions: Polymorphism in the promoter of AGT gene (rs2493137) might be associated with better clinical outcome in patients treated with targeted therapy for mRCC. Further studies with a larger sample size are needed on the function of this polymorphism.