bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized phase II trial of two different four-drug combinations in advanced pancreatic adenocarcinoma: Cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel
Authors: Cereda S. , Rognone A. , Ghidini M. , Rezzonico S. , Passoni P. , Mazza E. , Nicoletti R. , Zerbi A. , Villa E. , Reni M. 
Published: August 2020

4614 Background: The combination of cisplatin (P), epirubicin (E), 5-fluorouracil (F) and gemcitabine (G) (PEFG regimen) yielded a progression-free survival at 6 months from treatment start (PFS6) of about 50% and a 1-year overall survival (OS) around 40% in patients with advanced pancreatic adenocarcinoma (PA). The current trial was aimed to assess whether the replacement of E with docetaxel (D) may improve PFS6. Methods: Chemo-naive patients with stage III or metastatic PA, age 18–75y, Karnofsky performance status (PS) >50 received P (30 mg/m2 day 1), G (800 mg/m2 day 1) and capecitabine (1250 mg/m2/day days 1 to 14) and were randomized to receive either D at 25–30 mg/m2 day 1 (arm A: PDXG regimen) or E at 30 mg/m2 day 1 (arm B: PEXG regimen). Cycles were repeated every 14 days for a maximum of 6 months. Tumor was assessed by CT scan every 8 weeks. The Fleming design was used to calculate the sample size on the probability of being PFS6 (primary endpoint). Assuming P0=40% and P1=60%, α .05 and β.10, the study was to enroll 52 patients per arm. The regimen had to be considered of interest with > 26 patients being PFS6. Results: Between July 2005 and September 2008, 105 patients were enrolled at a single institution, stratified by stage and randomized (53 arm A). Patients’ characteristics were (A/B): median age 61/59, PS > 70 92/88%, metastatic disease 66/65%; CA19.9 > upper limit of laboratory normal (ULN) 87/90%, median CA19.9 820/755 UI/mL. To date, 46 patients per arm are assessable for the primary endpoint: PFS6 was 58/54%. One- year OS was 41% in both arms. A partial response was observed in 61/37% of patients. Among assessable patients with basal CA19.9 value > ULN (37 per arm), a major biochemical response (reduction >89%) was observed in 46/35% and a minor biochemical response (reduction between 50 and 89%) in 43/35% of patients. Main per cycle G3–4 toxicity was: neutropenia 4/13%, thrombocytopenia 3/2%, anemia 4/3%, fatigue 6/4%. Conclusions: PEXG yielded similar results when compared to prior series treated by PEFG, suggesting that capecitabine may replace F. The inclusion of D instead of E seems to be promising. The present trial confirms the relevant impact on outcome of advanced PA of four-drug regimens. No significant financial relationships to disclose.
Identification of prognostic factors for patients with advanced pancreatic cancer by proteomics
Authors: Matsubara J. , Ono M. , Ueno H. , Okusaka T. , Furuse J. , Furuta K. , Sawada J. , Saijo N. , Hirohashi S. , Yamada T. 
Published: August 2020

4615 Background: Gemcitabine monotherapy is the current standard for patients with advanced pancreatic cancer (PC). Its efficacy, however, varies significantly depending on individuals. This study was aimed at discovering a new diagnostic biomarker that can estimate the outcome of patients after receiving the therapy. Methods: All patients included in this study (304 patients) had metastatic PC and received at least two cycles of gemcitabine monotherapy. We compared the baseline plasma proteome between representative 29 short-term survivors (survived for less than 100 days) and 31 long-term survivors (survived for more than 400 days) using quantitative mass spectrometry (MS). Results: Among a total of 45,277 peptide peaks, we identified 637 peaks whose intensities were significantly different (p<0.001, Welch's t-test). The 2 MS peaks with the highest statistical significance (p=2.57×10-4 and 5.03×10-4) were revealed to be derived from α1-antitrypsin (AT) and α1-antichymotrypsin (ACT), respectively, by tandem MS. The levels of AT and ACT, WBC count, platelet count, alkaline phosphatase, and ECOG performance status were selected using a forward stepwise procedure by Akaike's information criterion, and a scoring system (nomogram) was constructed to estimate the prognosis of individual patients. Among the selected parameters the AT level was found to be the second most significant contributor to the nomogram (p=0.0003; Table ). This survival prediction model was internally validated using a bootstrap approach with 200 resamples. Conclusions: Our survival prediction model including values of AT and ACT seems to have high practical utility and may lead to tailoring the treatment of patients with advanced PC. Modification of therapeutics may need to be taken into consideration for patients with increased AT and ACT. [Table: see text] [Table: see text]
A randomized phase II study of FOLFOX or FOLFIRI.3 as second-line therapy in patients with advanced pancreatic cancer previously treated with gemcitabine-based chemotherapy
Authors: Hwang J. Y. , Yoo C. , Kim T. , Lee J. , Park D. , Seo D. , Lee S. , Kim M. , Han D. , Kim S. , Lee J. 
Published: August 2020

4618 Background: Only few clinical trials have been conducted in patients with advanced pancreatic cancer after failure of first-line gemcitabine-based chemotherapy. We conducted a randomized phase II trial of modified FOLFOX vs. modified FOLFIRI.3 as second-line regimen for the patients with gemcitabine refractory pancreatic cancer ( NCT00786006 ). Methods: Patients with advanced pancreatic adenocarcinoma previously treated with gemcitabine were randomly assigned to FOLFOX or FOLFIRI.3 stratifying by age (≤ 65 vs. >65), performance status (0–1 vs. 2) and prior response to gemcitabine (PR/SD vs. PD). FOlFIRI.3 regimen consisted of Irinotecan 70 mg/m2 (over 60 min) D1, leucovorin 400 mg/m2 (over 2h) D1, 5-FU 2000 mg/m2 (over 46 hours) from D1, then irinotecan 70 mg/m2 (over 60 min) at the end of the 5-FU infusion every two week. FOLFOX regimen is composed of oxaliplatin 85 mg/m2 (over 120 min) D1, LV 400 mg/m2 D1, 5-FU 2,000 mg/m2 (over 46 hours) every two week. The primary end-point was 6-month overall survival (P0=20%) and Simon-Wittes-Ellenberg design was used to calculate the sample size (29 evaluable patients for each treatment arm). Results: From January 2007 to December 2008, sixty patients were enrolled and randomized to FOLFOX (N=30) or FOLFIRI.3 (N=30). Baseline characteristics were well balanced between each arm; median age 56 (35–60) vs. 56 yo (37–73); ECOG PS 0/1/2, 5/24/1 vs. 5/25/0; prior response to gemcitabine-based chemotherapy PR/SD/PD 10/13/7 vs. 10/11/9. With a median follow-up period of 6.0 months (95% CI, 4.7–7.3) the median overall survival was 4.0 months in both group (HR=0.95, 95% CI 0.52–1.75) with 6-month survival rates of 25% and 20%, respectively. The median PFS was 1.4 months for FOLFOX and 1.9 months for FOLFIRI.3 (HR=1.11, 95% CI, 0.64–1.92). Disease control (PR+SD) was achieved in 20% (5/25 in FOLFOX) and 28% (7/25 in FOLFIRI.3) of patients with measurable disease. The incidences of grade 3/4 toxicities were similar in both groups. Conclusions: Both FOLFOX and FOLFIRI.3 were tolerated with manageable toxicity, offering modest activity as second-line treatment of patients with advanced or metastatic pancreatic cancer, previously treated with gemcitabine. No significant financial relationships to disclose.
Interim results of the phase I/II study of trabedersen (AP 12009) in patients with pancreatic carcinoma, malignant melanoma, or colorectal carcinoma
Authors: Oettle H. , Hilbig A. , Seufferlein T. , Schmid R. M. , Luger T. , von Wichert G. , Schmaus S. , Heinrichs H. , Schlingensiepen K. 
Published: August 2020

4619 Background: TGF-beta 2 is one of the most potent immunosuppressors and mediates escape from immunosurveillance. It also plays a crucial role in tumor progression by regulating metastasis, angiogenesis, and proliferation. Trabedersen, a TGF-beta 2-specific inhibitor has already shown a clear survival benefit in a randomized active-controlled phase II study in high-grade glioma patients, compared to standard chemotherapy. Methods: 33 patients with advanced pancreatic carcinoma (stage IVA/IVB) (N=23), malignant melanoma (stage III/IV) (N=5) or colorectal carcinoma (stage III/IV) (N=5) were treated with trabedersen as 2nd-4th-line treatment. Two treatment schedules (1st schedule:7d on, 7d off; 2nd schedule: 4d on, 10d off; up to 10 cycles) were evaluated in a cohort dose-escalation design. Primary study objective: maximum tolerated dose (MTD); secondary objectives: safety and tolerability, pharmacokinetics and antitumor activity. Results: Patient recruitment for both schedules is completed. Very good safety and tolerability of trabedersen was observed, with moderate thrombocytopenia as main adverse event. Max. grade 3 dose-limiting toxicities (2 thrombocytopenias, 1 exanthema) occurring with 240 mg/m2/d in the 1st schedule established the MTD at 160 mg/m2/d. MTD has not been reached in the 2nd schedule. Of the 5 melanoma patients one from the 1st schedule showed stable disease and lived for 13.8 months; 3 patients from the 2nd schedule are still alive. Median overall survival (mOS) for pancreatic carcinoma patients in the 1st schedule was 6.8 months. One pancreatic carcinoma patient showed a complete response and is alive 38 months after trabedersen therapy. Current mOS for pancreatic carcinoma patients in cohort 1 (N=5) of the 2nd schedule is 13.2 months; 2 of these patients are alive, one with stable disease 14.8 months after begin of trabedersen treatment. Conclusions: Trabedersen has a very good safety and tolerability profile. The survival data are very encouraging. The study will continue with one dose in at least 12 patients. A randomized, active-controlled phase II study compared to standard therapy in patients with pancreatic carcinoma is in preparation; another one in malignant melanoma is being planned. [Table: see text]
Inhibition of mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: The results of two prospective phase II studies
Authors: Javle M. M. , Xiong H. , Reddy S. , Bhosale P. , Davis D. , Varadhachary G. , Fogelman D. , Kaseb A. , Wolff R. A. , Abbruzzese J. L. 
Published: August 2020

4621 Background: PI3-kinase/ Akt pathway is constitutively activated in pancreatic cancer and is mediated by mTOR kinase. Our in vitro studies suggest that prolonged exposure to mTOR inhibitors can promote insulin receptor substrate-PI3-kinase interactions and paradoxically increase Akt phosphorylation and cyclin D1 expression in pancreatic cancer cells (negative feedback loop). The addition of erlotinib to rapamycin down-regulates rapamycin-stimulated Akt in preclinical models. Methods: Study A: CCI-779 (Temsirolimus), Study B: RAD001 (Everolimus) + Erlotinib. Inclusions: Adult patients with gemcitabine-refractory pancreatic cancer, ECOG PS 0–1, adequate laboratories and measurable disease. Dose and schedule: CCI-779 25 mg IV weekly; RAD001 30 mg weekly + erlotinib 150 mg daily. Primary endpoint: overall survival at 6 months. Secondary endpoints: time-to-progression, response and toxicity. Tumor biopsies analyzed by immunofluorescence and laser scanning cytometry analysis for expression of pmTOR/mTOR, pAkt/Akt, pErk/Erk, pS6, p4EBP-1, PTEN and for k-ras mutations. Results: Study A: 5 patients enrolled, 4 patients received 2–4 doses. 2 patients died within a month; one from rapid progression other from hemorrhagic stroke. 2 developed SAEs: dehydration and asthenia. Study B: 16 patients enrolled; 12 males, all ECOG PS=1. Median cycles=1 (range 1–2). Grade 4 toxicity: hyponatremia (n=1), Grade 3: diarrhea (n=1), cholangitis (n=3), hyperglycemia (n=1), fatigue (n=1). Grade 2: pneumonia (n=2), dehydration (n=2), neutropenia (n=1), mucositis (n=2) & rash (n=2); hospitalizations=4. Progressive disease occurred in 15 and 1 was non-evaluable. Pretreatment biopsies revealed increased pAkt/ Akt ratio in tumor specimens as compared with non malignant pancreatic tissue. No such trends occurred for pErk/Erk or pmTOR/ mTOR. K-ras mutations occurred in 2/7 patient samples. Conclusions: Neither study with mTOR inhibitors demonstrated objective responses or disease stability. Negative feedback loop seen preclinically may account for the rapid progression noted with mTOR inhibitors in pancreatic cancer. The addition of erlotinib may not counter this effect in the clinical setting. [Table: see text]
Effects of adjuvant intra-operative radiation therapy after curative resection in pancreatic cancer patients : Results of a randomized study by 11 institutions in Japan
Authors: Kinoshita T. , Uesaka K. , Shimizu Y. , Sakamoto H. , Kimura W. , Sunada S. , Sunada S. , Imaizumi T. , Ozawa I. , Okamoto A. , Oda T. 
Published: August 2020

4622 Background: To evaluate the benefits of adjuvant intra-operative radiation therapy after curative resection in advanced pancreatic cancer (APC) patients, a multi-center phase III trial was conducted by 11 participating institutions in Japan. Methods: Eligibility included pts with potentially resectable APC (duct cell origin) by image diagnosis. Patients were randomized in a 1:1 ratio to adjuvant IORT or surgery alone less than a week before surgery. Stratification factors were tumor size (TS1/TS2,3,4), location (head/body and tail), and institution. Patients who were assigned to adjuvant IORT arm received IORT after curative resection before reconstruction. IORT consisted of 25Gy with electron beam energies of more than 6MeV and was delivered by the round shaped acrylic cylinder of 6–8cm diameter. The radiation field included the tumor bed and in most cases included the celiac axis, superior mesenteric artery, and the portal vein. The primary endpoint was overall survival. The secondary endpoint was local control rate at 2 years after surgery. Assuming 65 eligible pts in each arm, the study had 0,8 power to detect 20% difference in 2-year survival rate. Results: Between 05/2002 to 12/2006 198 pts were randomized and 153 pts underwent curative resection with assigned treatment. Among the 153 pts with curative resection, seven pts revealed ineligible by the histological examination. Finally full analysis sets were 144 pts. Seventy three pts were in the IORT arm and 71 pts in the surgery alone arm. There was only one hospital death in the IORT arm. Cause of the death was intraabdominal arterial bleeding due to pancreatic fistula. Conclusions: We now are collecting the final follow up data. The final analyses will be presented at the meeting. No significant financial relationships to disclose.
Phase II trial of GTX chemotherapy in metastatic pancreatic cancer
Authors: Fine R. , Moorer G. , Sherman W. , Chu K. , Maurer M. , Chabot J. , Postolov I. , Prowda J. , Schreibman S. , Levitz J. 
Published: August 2020

4623 Background: Preclinical studies suggest synergy between gemcitabine (G), docetaxel (T) and capecitabine (X). This GTX regimen was designed to inhibit MEK-ERK phosphorylation and increase BAX and BAK and also decrease BCL-2 in pancreatic cancer cell lines. Based on these findings, we pursued a prospective clinical trial evaluating the activity of GTX in previously untreated patients with metastatic pancreatic cancer. Methods: Patients with histologically confirmed metastatic adenocarcinoma of the pancreas, median age 60, 63% male, ECOG PS 0–2, received capecitabine 1500mg/m2/day total orally in divided doses, days 1 thru 14, gemcitabine 750mg/m2 IV over 75 minutes followed by docetaxel 30mg/m2 IV on days 4 and 11 on a 21 day cycle. Scans were completed every 9 to 10 weeks to assess for tumor response by RECIST criteria. Treatment was continued until evidence of disease progression, intolerable toxicity, surgery or a delay in treatment greater than 6 weeks. The primary endpoint was response rate. Secondary endpoints were overall survival (OS) measured as time from start of GTX to death, time to treatment failure (TTF) measured as time from start of GTX to disease progression or other reason for a halt in therapy. Results: Forty-three patients were enrolled at two centers between May 2004 and January 2007. Forty-one patients were eligible for assessment by intent to treat analysis. 35 patients (85%) had liver metastases. 9 patients (21.9%) had partial responses and 17 patients (41.5%) had stable disease. The one year survival rate was 56%. Two year survival rate was 14.6%. The median OS was 14.5 months. The median TTF was 6.9 months. Grade 3 and 4 toxicities included leukopenia (31.6%), neutropenia (29.2%), thrombocytopenia (12.2%), infection (12.5%), and mucositis (7.5%). Conclusions: The combination of gemcitabine, docetaxel, and capecitabine has activity in metastatic pancreatic cancer with a median survival over 1 year. A randomized phase III trial is in planning. [Table: see text]
Salivary biomarkers for pancreatic cancer detection
Authors: Wong D. T. , Zhang L. , Farrell J. , Zhou H. , Elashoff D. , Gao K. , Paster B. 
Published: August 2020

4630 Pancreatic cancer is the 4th leading cause of cancer death. Lack of early detection technology for pancreatic cancer invariably leads to a typical clinical presentation of incurable disease at initial diagnosis. We evaluated the performance and translational utilities of the salivary transcriptomic and microbial biomarkers for pancreatic cancer detection. Biomarker discovery strategies were used to profile transcriptome in saliva supernatant and microflora in saliva pellet. The Affymetrix Human Genome U133+2.0 array was used to discover altered gene expression in saliva supernatant. The Human Oral Microbe Identification Microarray (HOMIM) was used to investigate microflora shift in saliva pellet. Biomarkers selected from both studies were subjected to an independent clinical validation using a cohort of 30 pancreatic cancer, 30 chronic pancreatitis and 30 healthy matched-control saliva samples. Two panels of salivary biomarkers, including eleven mRNA biomarkers and two microbial biomarkers were discovered and validated for pancreatic cancer detection. The logistic regression model with the combination of three mRNA biomarkers (ACRV1, DMXL2 and DPM1) yielded a ROC-plot AUC value of 0.974 (95% CI, 0.896 to 0.997; P < 0.0001) with 93.3% sensitivity and 90% specificity in distinguishing pancreatic cancer patients from healthy subjects. The logistic regression model with the combination of two bacterial biomarkers (Neisseria elongata and Streptococcus mitis) yielded a ROC-plot AUC value of 0.895 (95% CI, 0.784 to 0.961; P < 0.0001) with 96.4% sensitivity and 82.1% specificity in distinguishing pancreatic cancer patients from healthy subjects. More importantly, the logistic regression model with the combination of four biomarkers (mRNA biomarkers, ACRV1, DMXL2 and DPM1; bacterial biomarker, S. mitis) could differentiate pancreatic cancer patients from all non-cancer subjects (chronic pancreatitis and healthy control), yielding a ROC-plot AUC value of 0.949 (95% CI, 0.877 to 0.985; P < 0.0001) with 92.9% sensitivity and 85.5% specificity. This is the first report demonstrating the value of multiplex salivary biomarkers for the non-invasive detection of a high impact systemic cancer. No significant financial relationships to disclose.
Met160Val TMPRSS2 gene polymorphism and early onset prostate cancer in high-risk men
Authors: Giri V. N. , Hughes L. , Ruth K. 
Published: August 2020

5000 Background: The TMPRSS2-ERG gene fusion has been found in over 50% of prostate tumors and its role is being characterized in various clinical settings. The T-allele of the Met160Val single nucleotide polymorphism (SNP) has been found to be associated with translocation and multiple copies of the TMPRSS2-ERG fusion. This SNP needs clinical characterization in men at high risk for prostate cancer (PCA) (men with a family history [FH] of PCA and African American [AA] men) to determine the role in personalizing PCA early detection. The Prostate Cancer Risk Assessment Program (PRAP) is a prospective screening program for high risk men. PRAP has > 700 participants, and 60% are AA. Here we evaluated the Met160Val SNP (rs12329760) in the TMPRSS2 gene with respect to race, FH of PCA, and time to PCA diagnosis. Methods: Eligibility for PRAP includes men ages 35–69 years with one first degree relative with PCA, two second degree relatives with PCA on the same side of the family, any AA man regardless of FH of PCA, and men with BRCA1/2 mutations. Criteria for biopsy and biopsy approach have been reported previously. Genotyping of the Met160Val SNP was performed using the Taqman SNP Genotyping Assay (Applied Biosystems). Standard statistical methods were used to determine risk-genotype distributions. Cox models were used for time to PCA diagnosis by risk genotype. Results: Out of 700 men in PRAP, 631 were able to be genotyped for the Met160Val SNP. There was no difference in distribution of genotypes (CT/TT vs. CC) among 231 White men with familial PCA and 400 AA men in PRAP. Among 183 White men with familial PCA with > one follow-up visit, those with the CT/TT genotypes were found to have a significantly earlier time to PCA diagnosis vs. the CC genotype (p = 0.0058). In addition, the hazard ratio for PCA among high-risk White men of the CT/TT genotypes vs CC genotype was 2.55 (p = 0.022) after controlling for age and PSA. No trends were seen among AA men for time to PCA diagnosis for any of the Met160Val SNP genotypes. Conclusions: The T-allele of the Met160Val variant in the TMPRSS2 gene may be informative of time to PCA diagnosis among White men who have a FH of PCA. This genetic variant warrants further study in high-risk men with familial PCA for its role in personalizing PCA early detection. No significant financial relationships to disclose.
Use of CA9 gene single nucleotide polymorphisms to predict prognosis and treatment response of metastatic renal cell carcinoma
Authors: de Martino M. , Klatte T. , Seligson D. B. , LaRochelle J. , Shuch B. , Caliliw R. R. , Li Z. , Kabbinavar F. F. , Pantuck A. J. , Belldegrun A. S. 
Published: August 2020

5003 Background: Carbonic anhydrase 9 gene (CA9) is located in a prognostically relevant chromosomal area on chromosome 9p and is encoding for one of the most significant protein markers in metastatic renal cell carcinoma (MRCC), CAIX. In contrast to CAIX protein, however, no efforts have been made to date to study CA9 gene in metastatic RCC. Here, we test the hypotheses that single nucleotide polymorphisms (SNPs) and mutations of the CA9 gene are associated with CAIX expression, response to immunotherapy and survival. Methods: Genomic DNA was extracted from frozen tumor samples of 54 patients with clear cell MRCC. All exons of the CA9 gene were PCR-amplified and sequenced. The antibody M75 was used to evaluate CAIX protein expression immunohistochemically. Statistical associations of CA9 gene status and CAIX protein expression with response to IL-2 based immunotherapy and overall survival were assessed with chi-square tests, t-tests, Kaplan-Meier survival estimates and Cox proportional hazards regression models. Results: CA9 reference SNP (rs) 2071676 was found in 59%, rs12553173 in 15%, rs3829078 in 11% and rs1048638 in 33% of the patients. The deletion c.376del393 was observed in two patients. CAIX expression was high (>85%) in 65% of the patients. None of the SNPs was significantly associated with CAIX expression. Patients with the C allele variant of rs12553173 had improved median survival (27.3 vs. 13.6 months, p = 0.0431) and a greater likelihood of response to IL-2 (57% vs. 22%, p = 0.081) Likewise, high CAIX expression was associated with longer median survival (25.5 vs. 8.5 months, p < 0.0001) and a greater IL-2 response rate (37% vs. 8%, p = 0.070). In a multivariate Cox model, both C allele variant of CA9 SNP rs12553173 and CAIX expression were retained as independent prognostic factors. Conclusions: CA9 SNPs are frequently found in patients with MRCC. The C allele variant of rs12553173 is associated with improved overall survival and a greater likelihood of response to IL-2. CA9 rs12553173 and CAIX are both independent prognostic factors of overall survival and complementary in predicting prognosis of MRCC. No significant financial relationships to disclose.