bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety, efficacy, and time to clinical response with bevacizumab plus FOLFIRI regimen in metastatic colorectal cancer
Authors: Tomao S. , Spinelli G. , Rossi L. , Pasciuti G. , Arcangeli G. , D’Aprile M. , Veltri E. , Baiano G.
Published: August 2020

e15138

Background: Bevacizumab (BEV) has shown clinical activity in metastatic colorectal cancer patients (mCRC)and randomised phase III trials have demonstrated that this agent significantly improves overall and/or progression-free survival when added to first-line irinotecan based chemotherapy (CT) regimens. We evaluated the efficacy and safety of BEV plus FOLFIRI (irinotecan, 5- fluorouracil, and leucovorin) as first line treatment in 27 consecutive metastatic colorectal cancer cases, with the primary end point to calculate the median time to clinical response with this chemotherapeutic schedule. Methods: Between October 2007 and January 2008 we collected the data on 27 patients with mCRC treated with first line chemotherapy with BEV plus FOLFIRI. Elegibility criteria had to be: mCRC; no prior CT for metastatic disease; ECOG PS 0/1, adequate organ function; no CNS metastases. The treatment consisted of a minimum of six cycles of irinotecan plus infusional 5-FU/LV according to the classical FOLFIRI schedule; BEV (5mg/kg) was given on day 1 with CT and then every 2 weeks until disease progression. Safety and response were assessed at the time of first CT and every 4 weeks thereafter. Results: 27 pts were evaluable (male 18; median age 61 years (range 45–77), ECOG PS 0: 52%, PS 1: 48%. The sites of metastases were: liver (15 pts), lung (5 pts), liver and lung (5 pts), peritoneal wall (2 pts).Median follow-up was 18 weeks. Two patients had complete response(CR) and 13 pts partial response (PR), with an overall response rate of 57.7%. Five patients had stable disease and 6 patients showed progressive disease. A clinical benefit was demonstrated in 77 % of pts. We observed a median time to clinical response of 11 weeks, evaluated with tumor markers and with CT/NMR/US examinations. A grade 3 or 4 neutropenia was detected in 39% of pts and grade 2 or 3 hypertension in 9%. We did’nt observe cases of thrombosis, bleeding and gastrointestinal perforation, sometimes related to the use of BEV. Conclusions: In this little experience the efficacy and safety of BEV associated with FOLFIRI schedule, a first line therapy in mCRC,is consistent with results from other previous studies, showing moreover a short time to clinical response with this association.

No significant financial relationships to disclose.
Expression of EGFR, VEGF, and K-ras mutation as predictors for response of cetuximab in colorectal cancer patients
Authors: Hwang D. , Jung E. , Cho S.
Published: August 2020

e15147

Background: Cetuximab has been effective in metastatic colorectal cancer (CRC) patients. EGFR is involved in CRC through its downstream signaling pathways, including RAS and MAKP pathway and angiogenesis. We evaluated the predictive value of EGFR and VEGF expressions and K-ras mutation status in colorectal cancer patients treated with cetuximab in combination with chemotherapy Methods: Our study included 29 CRC patients treated with cetuximab in combination with chemotherapy (20 patients with FOLFIRI and 5 patients with FOLFOX, and 4 patients with monotherapy). Paraffin blocked tumor tissues were analyzed for EGFR and VEGF expression using quantitative real time PCR and K-ras mutation status (codons 12 and 13) using direct sequencing. Results: 12 patients (43%) had a partial response (PR) and 6 patients (21%) with stable disease (SD) and 11 patients (38%) with progressive disease (PD). EGFR expression was not correlated with the response of cetuximab (p=0.60) The median EGFR expression level was 0.30 x 10-3 in PR and 0.25 x 10-3 in SD and 0.26 x 10-3 in PD. High VEGF expression was associated with the response of cetuximab (p=0.03). The mean VEGF expression level was 4.3 x 10-3 in PR and 1.64 x 10-3 in SD and 1.72 x 10-3 in PD. A K-ras mutation was present in 45 % (13/29) and did not significantly correlated with non-response of cetuximab (p=0.05). A K-ras mutation was detected 33% (4/12) in PR and 33% (2/6) in SD and 70 % (7/10) in PD. Conclusions: VEGF expression in tumor may be a potential predictor for the response of cetuximab. But EGFR expression and K-ras mutation status is not significantly correlated with clinical outcome of cetuximab. And a K-ras mutation is found in the response group.

[Table: see text]
Preliminary results of a multicenter phase II study of imatinib and fluorourcail/leucovorin (FU/LV) in patients with unresectable or metastatic gallbladder or biliary tract cancer
Authors: Sprenger K. , Moehler M. , Kettner E. , El-Batran S. , Hegewisch-Becker S. , Steffens C. , Pustowka A. , Goekkurt E. , Ehninger G. , Stoehlmacher J.
Published: August 2020

e15502

Background: There are no standard chemotherapeutic regimens for incurable biliary adenocarcinomas. Monotherapies with gemcitabine or FU/LV achieve occasional responses and a median overall survival of about 6 months. By blocking PDGFR a decreased intrastromal pressure may increase therapy effects of chemotherapy. The combination of imatinib and FU/LV has been shown to be safe and feasible in a previous Phase I trial. This multicenter phase II trial was designed to investigate the disease control rate (DCR) of FU/LV and imatinib. Methods: Eligibility criteria included unresectable or metastatic measurable biliary tract cancer (BTC)/gallbladder cancer (GBC), performance status < 2, adequate organ function and no clinically significant cardiovascular disease. Enrolment of 44 chemonaive patients (pts.) was planned. Pts. received LV 200 mg/m2 followed by FU 2000 mg/m2 as a 24-hour infusion on days 1 and 2 combined with 600mg imatinib on days -4 to 4 (8 days). Cycles were repeated every 2 weeks up to 12 cycles. Radiological assessments were performed every 4 cycles. Results: 41 pts (19 GBC; 22 BTC) were enrolled in this phase II study since May 2007. Median age was 62 years (range 33–77), male/female=24/17, ECOG 0/1/2=13/23/5. 35 pts. showed metastatic disease at baseline. Treatment was well tolerated. Treatment related grade 3/4 toxicities included (number of pts): diarrhea (2), edema (1), neutropenia (2), nausea (2), transient SGPT elevation (4). The DCR of 26 pts. available for response assessment at time of analysis 1 was 58% (15 pts) (1 CR, 1 PR,13 SD of at least 4 cycles). 11 pts. showed progressive disease (PD) per RECIST criteria. 3 pts. had disease stabilization after 12 cycles and continue on treatment. We present these preliminary data as they represent a large patient number in this entity and response data are promising. Conclusions: This preliminary analysis suggests that the combination of FU/LV and imatinib can be safely administrated in pts. with GBC/BTC. Early evidence of antitumor activity was seen with some pts. achieving long term stabilization of the disease.

[Table: see text]
Weekly cetuximab (CET) plus oxaliplatin (OX), infusional 5-fluorouracil (5-FU) and radiation therapy (RT) as neoadjuvant treatment for esophageal squamous cell carcinoma (ESCC): A phase I study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)
Authors: Lordick F. , Meyer zum Büschenfelde C. , Thuss-Patience P. , Röthling N. , Geinitz H. , Budach V. , Schumacher G. , Friess H. , Siewert J. R. , Peschel C.
Published: August 2020

e15507

Background: CET, a chimeric monoclonal IgG1 antibody that targets the epidermal growth factor receptor (EGFR), has proven activity in a variety of SCC models in vitro and in vivo and has also been shown to enhance the activity of both chemo- and radiotherapy. Methods: Patients (pts) with locally advanced ESCC received CET for 2 weeks at an initial dose of 400mg/m2 (d - 15) i.v. followed by 250mg/m2(d -8) before they started a neoadjuvant dose escalation regimen. Pts received weekly CET 250mg/m2 plus RT 25 x 1.8 Gy (cumulative dose 45 Gy) d1–33. Cohort 1–3 received escalating doses of OX 45–50 mg/m2 d1,8,22,29 plus 5-FU 180–200–225 mg/m2/d; d1–5,8–12,15–19,22–26,29–33). Surgery was scheduled 4–6 weeks after RT. Toxicity was assessed according to NCI-CTC. Response was categorized according to the histopathologic score. Results: 15 pts were enrolled (2 female, 13 male; mean age 62 years, ECOG-PS 0 or 1). All pts had locally advanced SCC (uT2–4, cNx, cM0–1a) of the cervical (n=1), the upper (n=5) or the distal (n=7) esophagus. 6 pts were treated in cohort 1 and 3 pts in cohort 2 without any dose limiting toxicity (DLT). Of 6 pts treated in cohort 3, 1 pt developed grade 3 diarrhea and mucositis. All other observed toxicities were mild or moderate: anemia n=12, neutropenia n=2, thrombocytopenia n=3, nausea/vomiting n=8, mucositis n=6, diarrhea n=4, neuropathy n=4, hand-foot-syndrome n=8, skin rash n=14, no infection and no infusion-related reactions were observed. 12 pts underwent abdomino-thoracic esophagectomy with no postop. mortality; 3 pts were not resected. 8/12 resected pts had an R0 resection (67%) and 4 pts (33%) achieved a histopathological complete response (score 1a). Conclusions: 2 weeks of CET (400mg/m2 and 250mg/m2) followed by weekly CET (250mg/m2) plus OX 50mg/m2 d1,8,22,29, 5-FU 225 mg/m2/d d1–5,8–12,15–19,22–26,29–33 and RT 45 Gy (1.8Gy/f) was shown to be safe as neoadjuvant treatment for locally advanced ESCC. The anti-tumor activity of this regimen is promising and is being further investigated in an ongoing phase II study.

[Table: see text]
Multicenter phase II study of gemcitabine (GEM) plus S-1 in patients (pts) with advanced biliary tract cancer (BTC)
Authors: Sasaki T. , Isayama H. , Nakai Y. , Ito Y. , Togawa O. , Yagioka H. , Kogure H. , Yasuda I. , Hasebe O. , Maetani I.
Published: August 2020

e15516

Background: Pts with advanced BTC have a poor prognosis and no standard palliative chemotherapy has been defined. The purpose of this prospective multicenter phase II study was to evaluate the efficacy and safety of GEM plus S-1 combination therapy in pts with advanced BTC. Methods: Pts with advanced BTC, with at least one measurable lesion were eligible for this study. Other eligibility criteria included: no previous palliative chemotherapy, ECOG performance status ≤ 2, and adequate organ function. S-1 was given orally at a dose of 80mg/m2 daily from day 1 to day 14. GEM was given intravenously at a dose of 1,000mg/m2 over 30 min on day 1 and day 15, repeated every 4 weeks. Tumor response was the primary endpoint and was assessed according to RECIST every 8 weeks. Planned sample size was 35 according to Simon's two stage method. Results: 35pts were enrolled: median age 67; M/F (22/13); ECOG performance status 0/1/2 (16/18/1). The primary tumor site was; 14 pts in gallbladders, 14 pts in intrahepatic bile ducts, 6 pts in extrahepatic bile ducts, and 1 pt in Vater of papilla. Seven pts had previous surgical resection. Complete and partial responses were achieved in 2 and 9 pts, respectively. Eighteen pts had stable disease. Overall response rate was 31.4% and overall disease control rate was 82.9%. The median TTP was 6.1 months (95%CI, 4.0–8.1 months) and the overall survival was 11.7 months (95%CI, 7.3- months). The grade 3/4 toxicities were: neutropenia (31.4%), anemia (17.1%), thrombocytopenia (2.9%), anorexia (2.9%). No treatment-related deaths occurred during the study. Conclusions: GEM plus S- 1 combination therapy showed promising efficacy and good tolerability in pts with advanced BTC.

No significant financial relationships to disclose.
Evaluation of response in the multimodality treatment of esophageal cancer by [18F]-fluorodeoxyglucose-positron emission tomography: A systematic review and meta-analysis
Authors: Vallbohmer D. , Holscher A. H. , Brabender J. , Metzger R. , Mönig S. , Schmidt M. , Dietlein M. , Bollschweiler E.
Published: August 2020

e15520

Background: Neoadjuvant therapy followed by surgery is frequently applied to improve the prognosis of patients with esophageal cancer. However, only a major histopathological response will provide a survival benefit. On the other hand, evidence suggests that patients with response to chemoradiation have no additional benefit from surgery compared with definitive chemoradiation. Consequently, effective methods for early and late response assessment are required in order to perform these different individualised, response-guided treatment concepts. The value of [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) for this diagnostic purpose is still under debate. This systematic review and meta-analysis aims to evaluate the potential of FDG-PETfor the assessment of response in the multimodality treatment of patients with esophageal cancer. Methods: A systematic literature search of studies published between 1990 and September 2008 was performed. The meta-analysis estimated the pooled sensitivity and specificity of histopathological response assessment by FDG-PET using a random effect model. Results: Thirty relevant studies with 1151 patients (865 adenocarcinoma, 493 squamous cell cancer) were identified and included in the systematic review. Mainly neoadjuvant chemoradiation (22 studies) was performed. FDG-PET was conducted mostly before and after neoadjuvant therapy (21 studies) and second most (6 studies) the subsequent FDG-PET was scheduled 7–14 days after the initiation of preoperative therapy. Sixteen studies were included in the meta-analysis. For metabolic response assessment 7–14 days after the initiation of therapy, including 254 patients (with 5 studies from one center), the pooled sensitivity was 85.5% (95% CI: 75.5%-92.8%) and specificity 76.1% (95% CI: 69.3%-82.0%). For late response assessment, including 446 patients, the pooled sensitivity was 77.1% (95% CI: 72.8%- 81.0%) and specificity 59.0% (95% CI: 55.3%-62.7%). Conclusions: For early response assessment FDP-PET seems to be useful in the multimodality treatment of esophageal cancer. In contrast, this study suggests FDG-PET invaluable for late response assessment.

No significant financial relationships to disclose.
Standardized treatment and follow-up protocol of hepatocellular carcinoma with transcatheter arterial chemoembolization: Survival, clinical, and tumor control outcome over 12 years at a U.S. center
Authors: Liapi E. , Hong K. , Georgiades C. S. , Wahlin T. , Reyes D. , Kamel I. R. , Geschwind J. H.
Published: August 2020

e15522

Background: To report the outcome of the care of patients with hepatocellular carcinoma (HCC) treated with standardized transcatheter arterial chemomembolization (TACE), with a focus on tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST), progression of underlying cirrhosis [Child-Pugh (CP) score], time to progression (TTP) and survival from 1996 to 2008. Methods: TACE was performed on 365 patients in 1,035 sessions. According to a standardized protocol, all patients received imaging (MRI and/or CT) at baseline and at 4–6 weeks after each session and were clinically, biochemically and radiologically evaluated before each session. Liver disease status was evaluated before and at the end of the treatment period with the CP class system and tumor size measurements according to the RECIST. The Barcelona Clinic Liver Cancer (BCLC) classification was employed to stage patients. Three chemotherapeutic agents and lipiodol, followed by non-occlusive embolization were utilized during TACE. Complete vessel occlusion was avoided at all times. Overall survival and TTP were calculated according to the Kaplan-Meier method. The log-rank test was used to calculate differences between groups in the subgroup analysis. Results: All patients (78% male, mean age: 63.5 years) received an average of 3 TACE sessions (range: 1–10 and average interval between sessions: 75 days). Sixty six percent of patients had 3 or more tumors, with a mean tumor size at presentation of 6.9 cm. Partial response was achieved in 32 % of patients, while 65% remained stable over the course of 3 TACEs. CP class remained unchanged for 75% of patients over the above course of treatment. Median survival for the entire cohort was 20 months and TTP was 14 months. Interestingly, advanced BCLC patients achieved similar tumor response (PR:33%), TTP of 13.4 months and median survival of 13.7 months. Conclusions: Patients with HCC treated with the aforementioned standardized TACE and follow-up protocol showed durable survival, stable liver disease and effective tumor control.

[Table: see text]
Macrophage migration inhibitory factor and long-term survival in gastric cancer
Authors: Mohri Y. , Kageyama S. , Mohri T. , Tanaka K. , Ohi M. , Yokoe T. , Kusunoki M.
Published: August 2020

e15525

Background: Our study aimed to evaluate whether pretherapeutic serum macrophage migration inhibitory factor (MIF) is an independent factor predicting long-term survival in gastric cancer. Gastric cancer is the second leading cause of cancer-related deaths worldwide, but no satisfactory tumor marker exists. We recently found serum MIF expression was progressively increased in gastric cancer. Methods: One hundred five patients, 73 men and 32 women, mean (±SD) age 63±14 years, with histologically proven gastric adenocarcinoma were included in the study. Pretherapeutic serum was collected and MIF assayed using a commercially available enzyme-linked immunosorbent assay kit. Results: Ninety-three percent of patients received curative surgery. Mean follow up was 53.5±28.3 months, and five-year survival was 65.3 percent. The mean pretherapeutic level of MIF was 72.9ng/ml (range, 2.6 to 852.1). There were no significant correlations between serum MIF level and histopathological findings (Wilcoxon test). Mean pretherapeutic levels of carcinoembryonic antigen, C-reactive protein, and albumin were 27.5ng/ml (range, 0.1 to 778 ng/ml), 0.67mg/dl (range, 0.2 to 7.82mg/dl), and 3.6g/dl (range, 2.4 to 4.4g/dl), respectively. By multivariate analysis, serum MIF was found to be an independent factor predicting long-term survival (Odds ratio, 2.84; 95% C.I. 1.27–6.68). The five-year survival rate for patients with an MIF serum level greater than 23ng/ml was 55 percent, and that for patients with an MIF serum level less than 23ng/ml was 75 percent (p=0.03; log rank test). Conclusions: The serum level of MIF is a potentially valuable pretherapeutic prognostic factor in patients with gastric cancer.

No significant financial relationships to disclose.
Induction chemotherapy followed by concurrent chemoradiotherapy with/without esophagectomy for locally advanced esophageal squamous cell carcinoma
Authors: Lin C. , Hsu C. , Cheng J. C. , Lee J. , Tsai Y. , Luo J. , Hsu F. , Wang H. , Lee Y. , Cheng A.
Published: August 2020

e15526

Background: To assess the feasibility of preoperative induction chemotherapy in addition to concurrent chemoradiotherapy (CCRT) followed by esophagectomy if possible for locally advanced esophageal squamous cell carcinoma (ESCC) with a special emphasis on M1a or nodal M1b disease. Methods: Patients who had histologic proof of T3N1M0, M1a, or nodal M1b ESCC first received up to 3 courses of induction chemotherapy (paclitaxel 70 mg/m2 or docetaxel 40 mg/m2 IV 1-hr D 1, 8; cisplatin 35 mg/m2 IV 2-hr D 1, 8; 5-fluorouracil 2000 and leucovorin 300 mg/m2 IV 24-hr D 1, 8; repeated every 28 days). This was followed by CCRT (paclitaxel 35 mg/m2 1-hr D 1, 4 /wk, cisplatin 15 mg/m2 1-hr D 2, 5/wk, and radiotherapy 2 Gy D 1–5 /wk) (Lin CC et al. Ann Oncol 18:93–8,2007). When the accumulated radiation dose reached 40 Gy, the feasibility of esophagectomy was evaluated in all patients. In patients for whom esophagectomy was not feasible, CCRT was continued to a dose of 60 Gy. Results: Fifty-six patients (M:F = 51:5, median age 58, range 41–78) with locally advanced (T3N1M0:M1a:M1b[nodal] = 30:7:19) ESCC (upper:mid:lower = 15:25:16) were enrolled from June 22, 2006 to December 17, 2008. By December 31, 2008, 10 patients are still under protocol treatment. Eighteen (T3N1:M1a:M1b[nodal] = 14:3:1) (40%) and 20 of 46 patients underwent surgery and continued CCRT up to 60 Gy, respectively. Nine (T3N1:M1a:M1b[nodal] = 7:2:0) (20%) and 5 patients had pathologic complete response and microscopic residual disease, respectively. With a median follow-up of 8.4 months (range 0.5–30.8), 17 (T3N1:M1a:M1b[nodal] = 9:2:6) patients had relapse. Four and 13 patients had local recurrence and distant metastasis, respectively. The median progression-free survival was 20.3 months. The median overall survival had not reached yet with 1- and 2-year overall survival being 76 and 57%, respectively. There was no difference in progression- free or overall survival among patients with T3N1M0, M1a, or nodal M1b disease. Conclusions: Three-step strategy of preoperative taxane-based induction chemotherapy then CCRT followed by esosphagectomy if possible appears quite active in locally advanced ESCC patients with 46% having M1a or nodal M1b disease.

No significant financial relationships to disclose.
HOGG1 polymorphism and gastric cancer/atrophic gastritis
Authors: Cheng J. , Sun L.
Published: August 2020

e15535

Objective: 8-Hydroxydeoxyguanine (8-OHdG) formation is one of the most common types of oxidative DNA damage leading to gastric cancer development and human oxoguanine glycosylase 1(hOGG1) is responsible for repairing 8-OHdG lesions. Among several hOGG1 gene polymorphisms, the Ser→Cys polymorphism at position 326 is related to decreased repair function. We aimed to investigate the association between Ser326Cys hOGG1 polymorphism and gastric cancer/atrophic gastritis. Methods: 488 subjects (73 with gastric cancer, 160 with atrophic gastritis and 255 controls) were prospectively enrolled from 2005 to 2008 in Sir Run Run Shaw Hospital. Genomic DNA was obtained from peripheral blood and PCR-RFLP analysis was performed to distinguish the genotyping of hOGG1 Ser326Cys polymorphism. Statistical analysis was conducted by two-sample t-test or generalized regression models for continuous variables and the Pearson χ2 test for categorical variables. Logistic regression models were fitted to find the risk factors for gastric cancer and atrophic gastritis. For all analyses, significance was determined at the P < 0.05 level (two-tailed). Results: Patients with gastric cancer were significantly older than the control group (59.6±11.2yrs vs 43.6±10.3 yrs, P<0.0001) and atrophic gastritis group (59.6±11.2yrs vs 51.4±10.6 yrs, P<0.0001). Gastric cancer group had significantly higher rate of male than atrophic gastritis group (65.8% vs 48.7% in atrophic gastritis, p=0.02). Neither the hOGG1 Ser/Cys nor the Cys/Cys genotype was associated with gastric cancer, compared with the Ser/Ser genotype (OR: 0.96, 95% CI (0.51–1.84) and OR: 1.1, 95% CI: (0.48–2.1)). Ser/Cys and Cys/Cys were significantly associated with atrophic gastritis (OR: 1.76, 95% CI: 1.03–3.0) and OR: 2.38, 95%CI: 1.34–4.23)). After controlling for age, gender, smoking and alcohol, these significant associations still held with OR: 2.05, 95% CI: (1.14–3.68) for Ser/Cys and OR: 2.76, 95% CI: (1.47–5.18) for Cys/Cys. Conclusions: Our study supported that hOGG1 polymorphisms (genotype Ser/Cys and Cys/Cys) are associated with atrophic gastritis. These associations still exist after controlling for age, gender, smoking and alcohol. No significant association was detected between hOGG1 polymorphisms (genotype Cys/Cys or Ser/Cys) and gastric cancer.

No significant financial relationships to disclose.
Correlation of Cks1 and p27kip1 with tumor biologic aggressiveness and survival in gastrointestinal stromal tumor
Authors: Horvath J. W. , Frankel W. , Bellizzi A. , Guenterberg K. , Iwenofu O. H.
Published: August 2020

e15549

Background: The biologic behavior of gastrointestinal stromal tumors (GIST) based upon morphologic parameters is unpredictable. Cyclin dependent kinase-1 (Cks1) plays an important role in the ubiquitination and proteolysis of p27kip1, a negative regulator of protein kinase Cdk2/cyclin E and Cdk2/cyclin A. This study was to ascertain whether Cks1 overexpression and p27kip1 downregulation were predictive of biologic aggressiveness and overall survival in GIST. Methods: Tissue microarray was built from 61 patients with GIST. Pathology reports as well as clinical follow-up were retrieved. Sections were stained with antibodies to p27kip1 and Cks1. Staining was scored for quantity of tumor cells (%) and intensity (0, 1+ weak staining, 2+ strong staining), and a score was calculated from the product of intensity and %. Tumors were evaluated for correlation of p27kip1 and Cks1 expression level with overall survival time and tumor risk stratification. Tumor risk stratification was classified into very low risk, low risk, intermediate risk, and high risk, and is reflective of intrinsic biologic aggressiveness. Actuarial survival curves were estimated using Kaplan Meier method. Results: The tumors show a high frequency of Cks1 expression (92%; 1+, n=39; 2+, n=17). The % expression ranged from 0–90% (mean 37%). The p27kip1 positive rate is 85% (1+, n=20; 2+, n=32). The % expression ranged from 0–90% (mean 48%). Overall survival ranged from 0.1–10.7 years. By univariate analysis of overall survival using Cox regression model, increased p27kip1 expression (continuous variable) is significantly correlated with overall survival (p=0.04), but Cks1 expression does not (p=0.84). In a univariate analysis of p27kip1 and Cks1 (continuous variables) with risk stratification of the tumor using F-test, higher tumor grade has significantly higher Cks1 expression values (p=0.0045). Conclusions: Our study shows that with univariate analysis high expression of Cks1 expression is significantly associated with increased intrinsic biologic aggressiveness, while high expression of p27kip1 is associated with increased overall survival. The lack of correlation of Cks1 and p27kip1 suggests additional p27kip1 independent mechanisms might play a role in the oncogenesis of GIST.

No significant financial relationships to disclose.
Prognostic impact of response to second-line chemotherapy on overall survival of patients with advanced gastric cancer
Authors: Kim S. , Hwang M. , Park Y. , Park S. , Kim Y. , Ryu K. , Lee J. , Park Y. , Kim N. , Park S.
Published: August 2020

e15551

Background: It has been debated on whether tumor response to first-line chemotherapy (CT) would be reliable predictor for overall survival (OS) of cancer patients (pts). In case of advanced gastric cancer (AGC), many pts receive 2nd line CT after failure to 1st line treatment, so response to 2nd line CT as well as 1st line could affect OS. Methods: We retrieved clinical data of a total of 1,335 pts with AGC treated with palliative CT from January 2000 to December 2006 in National Cancer Center, Korea, including 757 pts who also received 2nd line CT. Responses to 1st and 2nd line CT were evaluable in 504 pts. Retrospective analysis was done to find correlation between objective tumor response to 1st and 2nd line CT and OS of the 504 pts, whom we divided into 4 groups: responders to both 1st and 2nd line CT (RR group); responders to 1st but not to 2nd line CT (RN group); responders to 2nd but not to 1st line CT (NR group); and nonresponders to both 1st and 2nd line CT (NN group). Results: Objective response rate of 1st and 2nd line CT was 41.7% and 12.3%, respectively. Responders to 1st line CT had a trend to respond to 2nd line CT (ORR of 2nd line CT in responders vs nonresponders to 1st line CT: 15.7% vs 9.9%, p = 0.049). 33/177/29/265 pts were assigned to each of RR/RN/NR/NN group, respectively. With median follow-up of 48.7 mo (range 23.2 - 93.7), median OS was 12.7 mo (95% CI 11.8–13.6). Baseline characteristics were balanced between 4 groups except higher hemoglobin and serum albumin level in RR group, younger median age in NN group, and fewer pts with poor performance status or poorly differentiated histology in NR group. Overall survival of RR, RN, NR, and NN group was 31.8 mo, 15.5 mo, 18.9 mo, and 9.2 mo, respectively (p<0.001). Multivariate analysis revealed relapsed disease after curative surgery, well-differentiated histology, absence of pulmonary metastasis, higher serum albumin level, lower serum bilirubin and alkaline phosphatase level, response to both of 1st line and 2nd line CT were reliable factors for favorable survival. Conclusions: Among the patients who received 2nd line chemotherapy for AGC, response to 2nd line CT was strongly associated with OS regardless of previous response to 1st line CT.

No significant financial relationships to disclose.
Effect of hospitals on survival and postoperative mortality of stomach cancer: A population-based study on type, referral, and volume-effect in the northeast Netherlands
Authors: Siemerink E. , Schaapveld M. , Hospers G. A. , Mulder N. H. , Plukker J. T.
Published: August 2020

e15564

Background: To optimize treatment results of patients with stomach cancer some institutions prompt referral to high volume hospitals with experienced surgeon's analogue to esophageal cancer. We analyzed if evidence can be found for superior treatment outcome depending on hospital type, referral pattern or hospital volume. Methods: Data from all patients diagnosed with primary invasive stomach cancer from 1994–2006 were obtained from the nationwide Netherlands Cancer Registry of the north-east part of the Netherlands. This area is served by one university hospital (U), 4 teaching hospitals (T), and 18 non-teaching hospitals (N-T). Results: In the study period, 5243 patients were diagnosed with stomach cancer (65.6% men, 34.4% female), 44.5% underwent surgery. Older age, advanced stage and proximal tumor location resulted in a lower probability of tumor resection. The 5 year relative survival (5yrsurv) was similar in the three hospital types. However, patients with proximal tumors were more often referred for surgery to U (18%), especially by N-T hospitals. In the non-proximal tumors the 5yrsurv was significantly better in U versus T and N-T hospitals, also after multivariate analysis. The significantly better 5yrsurv of low referral centers disappeared after excluding hospital U. No volume effect could be observed. Postoperative mortality registered in the period from 2004–2006 showed no differences between the hospitals. Conclusions: We found highly superior survival for non-proximal tumors but not for proximal cancer in an university hospital. In this study no evidence was found for a referral or volume effect.

[Table: see text]

No significant financial relationships to disclose.
Clinical outcome of endoscopic mucosal resection (EMR) in clinical stage I (cSt I ) esophageal cancer
Authors: Yoshii T. , Tamai S. , Aoyama N. , Minamide J. , Takagi S. , Motohashi O. , Nakayama N. , Nishimura K. , Takata K. , Kameda Y.
Published: August 2020

e15569

Background: When a tumor invades to the muscularis mucosa or submucosal layer (T1a-MM or T1b, in Japan), cSt I esophageal cancer(EC) has 10–50%. risk of lymph node metastasis (LNM). Surgery, though very invasive, is the standard radical therapy for the patients(pts.) with such stage EC. Endoscopic mucosal resection (EMR), which conserves the esophagus, is a minimally invasive and attractive therapeutic modality for such pts. However, the clinical outcomes of EMR for these pts. have been not fully elucidated. Methods: We conducted retrospective analysis of the clinical courses of 44 pts. who underwent EMR for newly diagnosed T1a-MM or T1bcN0M0 EC between 1994 and 2007at our hospital, and who could be followed up for at least 1 year. Statistical analysis was performed by the Kaplan-Meier methods and the Cox proportional hazard model. Results: Patients decided on the following treatments immediately after EMR based on informed consent and their general condition; 2 underwent surgery, one underwent prophylactic chemotherapy(CHT) and 41 selected follow-up without any additional therapy. Of the 41, 20 selected this course by choice, 12 because of severe concurrent disease; 2 because of poor performance status and 7 because of other multiple primary cancers (MPCs). Twelve pts. died; 2 were cause specific; (4.5%), 8 from MPCs and, 2 from unknown causes. Median age was 67 years old (range 53–80), and 5 were female. No critical comlications were noted. Median follow-up time was 1542days (375–3786). 5 developed LNM. One with prophylactic CHT, was followed by surgery, and another was followed by CHT, who showed cause specific deaths later. Other 3 pts. followed by chemoradiotherapy, did not show cause specific death. Overall and cause specific survival rates at 5 years were 67.3% and 91.8%, respectively. Multivariate analysis revealed that either severe concurrent disease or MPCs significanctly influenced survival (p=0.041, HR 5.437(95%CI 1.073–25.542)). 8 and 6 pts. developed metachronous EC and local recurrence, respectively. Apart from one, they could be retreated endoscopicaly. Conclusions: EMR is a very useful therapeutic modality for cSt I EC, not only for local control but also as a clinically sufficient treatment; especially in pts. with severe concurrent disease.

No significant financial relationships to disclose.
Safety and efficacy of single-day GemOx (S-GemOx) regimen in pts with pancreatobiliary cancer (PBC)
Authors: Merl M. Y. , Li J. , Lee M. X. , Saif M. W.
Published: August 2020

e15577

Background: GemOx (G 1000 mg/m2 over 100 mins on d1 and Oxaliplatin (Ox) 100 mg/m2 on d2 q2 wks) achieved a RR of 26.8%, improved PFS but failed to demonstrate a benefit in OS vs G in PBC. This regimen has regained attention after recent pooled- and meta-analysis suggesting a survival benefit of G-platinum doublets over G. However, GemOx is associated with inconvenience to pts, early cumulative dose to develop neuropathy and thrombocytopenia. In addition, prolonged infusion of G showed no benefit over 30 mins in ECOG 6201study. Pharmacokinetic profile of both drugs did not show statistically significant differences regardless the order of administration. We modified GemOx as S-GemOx (G 1000 mg/m2 over 30 mins and Ox 85–100 mg/m2over 2 hrs on d1 q2 wks) given on same day to create a more convenient and equally effective regimen for these pts. Methods: A retrospective study was conducted to evaluate PBC pts who received S-GemOx from Sep 06 to Dec 08. Adverse events were graded according to NCI-CTC v3.0. Response was assessed with RECIST by a CT scan q 8 wks. Results: 34 pts (median age 60y, M/F: 17/17) who received S-GemOx were evaluated: PC (26), BC (7) and ampullary ca (1). 7 pts received S-GemOx plus a biological agent (3 bevacizumab, 3 cetuximab and 1 panitumumab). Median duration of therapy was 12 wks (r: 2–56). Median cumulative dose of Ox was 510mg/m2(r: 85–2380). 27 pts were evaluated for efficacy after initial staging: 1 (3.7%) CR, 4 (14.8%) PR, 18 (66.7%) SD and 4 (14.8%) PD. ORR (CR+PR) and ODC (CR+PR+SD) were 18.5% and 85.2% respectively. Median EFS, PFS and OS were 12, 16.7 and 37.6 wks respectively. 13 (38%) pts required Ox dose reduction due to toxicities (cytopenia, HSR, elevated LFTs and diarrhea). G3/4 hematological toxicities include anemia (8%), neutropenia (11%), thrombocytopenia (5%), N/V (3%), diarrhea (3%), HSR (14%) and neuropathy (3%). No deaths occurred due to therapy. 1 pt received a total of 1,025 mg/m2 of Ox on OPTIMOX approach. 9 pts discontinued therapy due to PD and 19 due to toxicities. Currently 4 pts are still receiving therapy. Conclusions: S-GemOx regimen provides convenient schedule, appears to be less toxic (G3/4 neuropathy: 3% vs 19.1%; thrombocytopenia 5% vs 14 %) and has comparable efficacy vs GemOx. Prospective studies of S-GemOx in a large pt population are warranted.

[Table: see text]
Impact of first-line and second-line PFS definitions within a randomized phase III trial in patients (pts) with metastatic pancreatic adenocarcinoma (MPA)
Authors: Dahan L. , Methy N. , Seitz J. , Mitry E. , Ychou M. , Gasmi M. , Raoul J. , Mariette C. , Bedenne L. , Bonnetain F.
Published: August 2020

e15583

Background: The FFCD phase III trial in pts with MPA comparing LV5FU2-P followed by gemcitabine (arm A) versus the opposite sequence (arm B) had failed to demonstrate a significant difference in median OS and PFS. The aim of this ancillary study was to investigate definitions of 1st and 2nd line PFS and their impacts on results. Methods: From 08/2003 to 05/2006, 202 pts with measurable MPA, PS 0–2, non prior CT were included in 33 centers, 102 in arm A and 100 in arm B. PFS1 in 1st line was defined as time interval between randomization and progression (P) or death (D) during the 1st line. Alive patients without P have been censored at the beginning of 2nd line or at the last FU. PFS2 in 2nd line was defined as time interval between randomization and P or D during the 2nd line. Alive patients without P during 2nd line have been censored at the last FU. For patients receiving only one line, PFS2 was defined as time interval between randomization and first P or D. Survival curves has been estimated using Kaplan Meier and compared using log-rank Tests. Strict ITT and modified ITT (ie pts receiving 2 lines) analyses were performed Results: Amongst the 202 pts after a median follow-up of 44 months, 69 pts (45 pts due to P) in Arm A and 55 pts (48 pts due to P) in Arm B have received a 2nd line. Median PFS was respectively equal to 3.4 months in Arm A and 3.5 months in Arm B (Stratified Log-Rank p = 0.78). For PFS1 we observed 77 and 93 events respectively in Arm A and B. Median PFS1 was equal to 4.0 months in Arm A and 3.5 months in Arm B (Stratified Log-Rank p = 0.57). For PFS2 we observed 99 and 100 events respectively in Arm A and B. Median PFS2 was equal to 5.0 months in Arm A and 5.8 months in Arm B (Stratified Log-Rank p = 0.68). Restraining PFS2 amongst patients receiving 2 lines (N = 124 pts), we observed 67 and 55 events respectively in Arm A and B, median PFS2 was equal to 6.3 months in Arm A and 8.8 months in Arm B (Stratified Log-Rank p = 0.03) Conclusions: Our results suggest that PFS2 for patients receiving 2 lines was longer when pts received Gemcitabine in 1st line. To be clinically meaningful definition of PFS1 and PFS2 should be optimized regarding censoring rules. New definitions should be proposed and assessed.

No significant financial relationships to disclose.
Safety and tolerability of combined gemcitabine (G) and erlotinib (E) plus sorafenib (S) in the first-line treatment of metastatic pancreatic cancer
Authors: Cohen D. J. , Ryan T. , Moskovits T. , Cazeau N. , Newman E. , Pachter H. L. , Hochster H. S.
Published: August 2020

e15594

Background: The addition of E to G results in improved survival for patients(pts) with locally advanced and metastatic pancreatic cancer. Many pancreatic tumors have constitutively activated ras/raf pathways and overexpress VEGF. Sorafenib, a multitargeted tyrosine kinase inhibitor which targets VEGR 1–3, PDGFR-α and β and the RAF/MEK/ERK pathway, when combined with G and E may synergize with these agents resulting in a more complete blockade of the signal transduction cascade in pancreatic cancer growth and progression and therefore improve outcome. Methods: Pts with previously untreated, histologically confirmed, unresectable pancreatic adenocarcinoma, ECOG PS 0–1, and adequate organ function were eligible and received G 1,000 mg/m2 over 30 min weekly × 3 every 4 weeks. E 150 mg PO daily and S 400 mg PO bid were given continuously. CT scans were performed every 2 cycles (8 weeks). Endpoints included safety and tolerability of the novel combination, PFS at 4 months, response rate, and OS. Results: Between 9/07–12/08 19 pts were enrolled with a median age 59 (range 45- 75), M/F 13/6, PS (0/1) 14/5. All 19 had metastatic disease. 17 pts are evaluable for toxicity and efficacy. The median number of cycles on treatment was 2 (range 1–10). The most common grade (gr) 3 toxicities were thrombocytopenia (24%), venous thrombosis (12%), and hyperbilirubinemia (12%). The most common gr 4 toxicity was infection (12%). 1 pt each experienced gr 3 HFSR, gr 3 diarrhea, gr 3 bleeding (epistaxis) and 1 had a non-fatal bowel perforation. There was 1 PR and 6 SD for an overall RR of 6% and a DCR of 41%. Conclusions: The combination of G and E plus S in the treatment of advanced pancreatic cancer is a well tolerated regimen without significant increased toxicity as compared to gemcitabine alone, except for very manageable cutaneous reactions. Further follow up is required to determine the combination's efficacy, though some patients have achieved prolonged disease stabilization. Supported in part by grants from Bayer Healthcare Pharmaceuticals/Onyx and OSI.

[Table: see text]
Identification of chromosomal regions that harbor novel genes important for pancreatic cancer pathogenesis by genome-wide screening methods
Authors: Thieltges S. , Kalinina T. , Krohn A. , Simon R. , Moeller-Krull M. , Dierlamm J. , Izbicki J. , Yekebas E.
Published: August 2020

e15609

Background: Pancreatic adenocarcinoma is a genetically highly complex and heterogenous tumor type with strong genetic instability which makes it resistant to therapy. Known amplifications of oncogenes such as KRAS or MYC and deletions of tumor suppresor genes such as CDKN2A and SMAD4 have demonstrated the importance of genetic alteration in this tumor type. Methods: We report the use of an Affymetrix Genome-Wide Human single nucleotide polymorphism (SNP) Array 6.0 (906,600 SNPs) to screen for gene copy number changes and allelic imbalances in 8 microdissected primary pancreatic tumors and 7 established pancreatic cancer cell lines. Gene Chip Human Genome U133 2.0 Array was used to make an RNA expression profile. Mutation analysis of KRAS and M-FISH analysis of cell lines was performed. Results: SNP arrays confirmed the presence of previously reported cytogenetic abnormalities in the cell lines and primary tumor probes, including MYC amplifikation at 8q24, gain of 17q12 (ERBB2/HER2), 7p12 (EGFR) and 12p12.1 (KRAS). KRAS mutation was seen in 71% of cell lines (5/7). We identified several alterations in signaling pathways such as Wnt/Notch Signaling and KRAS signaling. A sizeable subset ( 7 of 15 cases; 47%) showed an amplikon at 19q13.1–13.2 in which the serine/threonine kinase Mirk/Dyrk1B is localized, a downstream effector of oncogenic k-ras. There was also strong concordance between primary tumors and cell lines with respect to gains on 8q, 12p and 18q. Analysis of gene expression was used to localize potential target genes. M-FISH analysis showed complex karyotypes with chromosomal deletions in 9p and 18q, regions that are known to harbor tumor suppressor genes (CDKN2A, SMAD4 and TP53). Conclusions: Several signaling pathways mediate tumor cell survival. Analysis of gene amplification and RNA expression profile provide molecular biological characteristics and an individual gene signature of the tumor which allow us to choose more efficient drugs to an individualized treatment. Pathways activated by KRAS such as DYRK1B may offer new therapeutic targets. Further functional characterization is needed to provide evidence for the actual role of any putative target gene.

No significant financial relationships to disclose.
Concomitant chemoradiation using gemcitabine in locally advanced hepatocellular carcinoma
Authors: Masood A. I. , Javed A. A. , Mateen A. , Gurchani S. A.
Published: August 2020

e15611

Background: Hepatocellular carcinoma (HCC) is among the most common malignancies in Pakistan. There is currently no standard management for advanced HCC. Non-surgical modalities have demonstrated minimal improvements in survival. The aim of present study is to assess response rate and toxicity of concomitant gemcitabine and external radiation therapy (ERT) in locally advanced HCC. Methods: Thirty three biopsy proven advanced HCC patients having Okuda stage I and II disease were enrolled. 70 mg/m2 gemcitabine was given once weekly for three weeks during ERT. Partial liver ERT was delivered with 60Co upto 30 gray (Gy), 1.8 Gy/fraction and five fractions in a week. Tumor response was assessed by computed tomography (CT) eight weeks after completion of treatment. Response Evaluation Criteria in Solid Tumors (RECIST) was used to assess complete and partial response (CR, PR); progressive and stable disease (PD, SD). Hematological [neutropenia and thrombocytopenia], gastrointestinal (vomiting and diarrhea) and liver [encephalopathy, bilirubin, alanine and aspartate transferases (ALT and AST), and alkaline phosphatase (ALP)] toxicities were assessed weekly during treatment and then fortnightly upto 2 months according to Common Toxicity Criteria for Adverse Events version (3.0). Primary end point was to assess response rate at eight weeks after completion of treatment and Grade 3 or 4 toxicity during this period. Results: 28/33 patients were evaluable. No CR was seen. PR, SD and PD (%) were seen in 36, 39 and 25 of patients respectively. No grade 3 or 4 neutropenia was observed. 7/28 (25%) of patients developed grade 3 thrombocytopenia during treatment and needed a delay of one week for gemcitabine administration. Grade 3/4 toxicity (%) related to vomiting, diarrhea, encephalopathy, bilirubin, ALT, AST and ALP was seen in 18, 29, 21, 18, 14, 29 and 32 of the patients. Conclusions: The study showed that concomitant chemoradiation using 70mg/m2 gemcitabine is a feasible option with acceptable toxicity in locally advanced HCC. A larger study will be appropriate to define its definite role.

No significant financial relationships to disclose.
Compare the diagnostic value of FLT and FDG PET/CT in assessment of regional lymph nodes in thoracic esophageal squamous cell carcinoma
Authors: Yu D. HanJ. , Zhong X. , Mu D. , Fu Z. , Zhang B. , Zhang L. , Zhang W.
Published: August 2020

e15620

Background: To determine whether FLT PET/CT can detect regional lymph nodes metastases in untreated thoracic esophageal squamous cell carcinoma. In view of the reported high sensitivity of FDG PET/CT for the evaluation of thoracic nodules of esophageal carcinoma, we additionally performed FDG PET/CT for direct comparison with that of FLT. Methods: From March 2008 to December 2008, 18 patients with thoracic esophageal squamous cell carcinoma underwent dual-tracer PET/CT examinations before surgery. The results of reviewing side-by-side FDG PET/CT and FLT PET/CT images for the diagnosis of locoregional lymph node metastases were compared prospectively in relation to pathologic findings. The PET images were visually inspected with the maximum standardized uptake value (SUVmax) determined from a circular region of interest (ROI) over the entire lesion. The differential threshold for malignancy was set as SUVFDG≥2.5, and SUVFLT≥1.4, respectively. Results: All patients underwent esophagectomy and lymphadenectomy, and pathologic examination confirmed nodes positive for metastasis in 14 patients and 42 of 344 excised nodes. The uptake of FDG (median SUVmax, 5.59; range, 2.5–10.6) in locoregional lymph nodes metastasis was significantly higher than that of FLT (median SUVmax, 2.93; range, 1.6–4.6). There were 14 false positive nodes in FDG PET and only 3 in FLT PET, 7 false negative nodes in FDG PET, while 11 false negative nodes in FLT PET. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of FLT PET/CT were 73.81%, 99.01%, 95.93%, 91.18% and 96.45%, respectively, whereas those of FDG PET/CT were 83.33%, 95.36%, 93.90%, 71.43% and 95.36%, respectively. P values were 0.425, 0.014, 0.298, 0.055, and 0.541, respectively. Conclusions: FLT uptake in regional lymph node of esophageal carcinoma is significantly lower compared with FDG uptake.FLT PET has fewer false-positive findings compared with FDG PET. The specificity of FLT PET/CT is higher than that of FDG. We suggest that esophageal carcinoma N-staging need to combine FLT with FDG PET/CT images.

No significant financial relationships to disclose.