bluuebunny/crossref_metadata_2025_split 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.