bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of PTEN/AKT/PI3K signal pathway on the chemotherapy for gastric cancer
Authors: Oki E. , Kakeji Y. , Tokunaga E. , Nishida K. , Koga T. , Egashira A. , Morita M. , Maehara Y. 
Published: March 2020

4034 Background: Growth factor receptor-mediated signal transduction has been recently implicated in conferring resistance to conventional chemotherapy on cancer cells. We have described a pathway that involves AKT/PI3K to mediate chemoresistance in gastric cancer patients. The phosphatase activity of PTEN is crucial in controlling the phosphatidylinositol-3 (PI-3) kinase signal transduction pathway and in the activation of the protein kinase B(PKB/Akt) proto-oncogene. This indicates that PTEN exerts its tumor-suppressor function by negatively regulating the anitapoptotic PI3-kinase/AKT signaling pathway. Methods: Primary gastric carcinoma tissues and corresponding normal mucosa were obtained from 119 gastric cancer patients who underwent surgery in the Department of Surgery II in Kyushu University Hospital from the years 1996 to 2000. Methylation of PTEN was studied with methylation-specific PCR and LOH (loss of heterozygosity) of PTEN was studied using a DNA sequencer with D10S796 and D10S1173 microsatellite marker in the same samples. AKT activation was investigated by immunostaining with a phosphorylation-specific antibody. The chemotherapeutic sensibilities of these patients were investigated using an MTT assay. Results: We found that methylation of PTEN was rarely recognized, However, the gastric cancer patients who had a higher AKT phosphorylation (activated AKT) appeared to have LOH of PTEN (p < 0.0008), and the prognosis of the patient who has LOH of PTEN was significantly poor. When the chemotherapeutic sensibilities of these patients were studied in an MTT assay, it was found that the activated AKT was associated with increased resistance to multiple chemotherapeutic agents, which included those currently used on gastric cancer patients (5-fluorouracil, adriamycin, mitomycin C, and cis-platinum). Conclusions: The results of this study indicate that AKT activation and LOH of PTEN plays an important role in conferring a broad-spectrum chemoresistance in gastric cancer patients. It also indicates that clinical trials for an appropriate chemotherapy combination with conventional drugs and a new generation of signal transduction inhibitors that inhibit the PTEN/AKT pathway should be considered in treating gastric cancer in the near future. No significant financial relationships to disclose.
A phase II trial of gefitinib in patients (pts) with progressive metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study
Authors: Hobday T. J. , Holen K. , Donehower R. , Camoriano J. , Kim G. , Picus J. , Philip P. , Lloyd R. , Mahoney M. , Erlichman C. 
Published: March 2020

4043 Background: Systemic treatment options for progressive metastatic NET, including islet cell carcinoma (ICC) and carcinoid tumor (CT), are limited. These tumors frequently express the epidermal growth factor receptor (EGFR). Gefitinib, a small-molecule inhibitor of the EGFR tyrosine kinase, has been shown to inhibit the growth of NET cell lines. Methods: Eligibility criteria included: radiographic progression by RECIST criteria, ECOG PS ≤ 2, ≤ 1 prior chemotherapy, and good organ function. Prior interferon and prior or concurrent octreotide (if disease progression documented on stable dose) were allowed. Pts received gefitinib 250 mg po daily. We evaluated 6 month (mos) progression-free survival (PFS) in two cohorts (ie, CT and ICC) using separate 2-stage phase II designs. 6 mos PFS rates of 30% (CT) and 10% (ICC) were considered promising. Results: 96 pts were enrolled: (57 CT, 39 ICC). For pts evaluable for the primary endpoint, 23 of 38 (61%) CT pts and 9 of 29 (31%) pts with ICC were progression-free at 6 mos. 1 PR and one minor response (MR = 20–29% decrease in sum of target lesion diameters) were observed in 40 CT pts; 2 PR and 1 MR in 31 ICC pts. In addition, 32% (12/38) of CT and 14% (4/29) of ICC pts had stable disease on study for a duration that exceeded by at least 4 months the time to progression documented prior to study entry. Grade 3–4 toxicity was infrequent with fatigue (6%), diarrhea (5%) and rash (3%) most common. Evaluation of markers of the EGFR pathway on tumor tissue will be presented. Conclusions: Gefitinib is well-tolerated and results in prolonged disease stabilization in pts with prior documented objective progression of CT and ICC, with rare objective responses. Supported by NOI CM17104. No significant financial relationships to disclose.
Improving the quality of surgery for gastric cancer—Are surgeons aware of the relevant quality indicators?
Authors: Helyer L. K. , O Brien C. , Coburn N. G. , Swallow C. J. 
Published: March 2020

4048 Background: Gastric cancer survival in the West is inferior to that achieved in Asian centers. While differences in tumor biology may play a role, poor quality surgery contributes to understaging. In our evaluation, adequate lymph node (LN) assessment (≥15) was achieved in only one third of patients and independently predicted survival across Surveillance, Epidemiology and End Results (SEER) regions (ASCO 2005, Abstract # 4004). The standard proximal margin of resection is recommended to be ≥5 cm; revision based on intraoperative frozen section is of benefit. We hypothesize that the majority of surgeons performing gastric cancer surgery in a North American setting are unaware of the recommended standards. Methods: Using the Ontario College of Physicians and Surgeons registry, surgeons who potentially include gastric cancer surgery in their scope of practice were identified. A questionnaire was mailed to 559, 55% responded. 203surgeons reported managing gastric cancer. Results were evaluated by chi-square and logistic regression; p<0.05 was considered significant. Results: 86% of respondents were male; 59% in urban non-academic practice, and 30% in academic. 42% of surgeons operate on 2–5 cases/yr and 18 % on >5. One third of surgeons identified ≤ 4 cm to be the desired proximal margin. Frozen section is used by 52% to evaluate proximal margin status. 20% were unsure of the number of LN needed to accuratly stage, the median number reported by the remainder was 10 (range 0 - 30). 99% refer for adjuvant therapy. This was less likely for patients in poor medical condition, poor nutritional status, or age >70 years. Young patients, those with bulky LN or positive margins were more likely to be referred. Overall, only 16 of 203identified the need for both a ≥5 cm proximal margin and ≥15LN; this was too small a group to analyze for demographic associations. Surgeons who do >5 gastric resections/yr were more likely to report performing a D2 resection (p = 0.008). Conclusions: The majority of surgeons operating on gastric cancer in Ontario did not identify standard quality indicators of gastric cancer surgery. A continuing medical education program should be designed to address the knowledge gap, aiming to improve the quality of surgery and outcome of multidisciplinary management. No significant financial relationships to disclose.
A phase II study of oral S-1 with pharmacokinetics and pharmacogenomic investigation in advanced or recurrent gastric cancer
Authors: Rha S. Y. , Jeung H. C. , Kim H. K. , Kim S. Y. , Kim S. Y. , Lim H. Y. , Kong S. J. , Chung H. C. 
Published: March 2020

4072 Background: Present study describes the first phase II study of S-1 including pharmacokinetic and pharmacogenomic evaluation for extra-Japanese Asian population with advanced gastric cancer. Methods: Chemo-naive advanced gastric cancer with measurable disease was enrolled. Initial dose of S-1 was b.i.d. at 35, then 40 mg/m2 according to devised dosing method (range, 90–160 mg/day) for 28 days every 6 weeks. Pharmacokinetic study was performed after 28-day administration at cycle 1 and 3. Microarray based CGH was performed with genomic DNA from peripheral mononuclear cells to detect the toxicity-related genetic changes. Results: When first 31 patients were enrolled, protocol was amended to conduct the study by two steps for additional patients at 40 mg/m2 without dose escalation in initial 31 patients of 35 mg/m2, because these patients showed neither significant nor cumulative toxicity. Of 62 patients enrolled, median relative dose intensity was 0.99. Overall response rate was 19.3% (95% CI, 9.2–29.5). With 558-day follow-up duration, median TTP and OS were 126 and 264 days, respectively. One-year survival rate was 33.9%. Toxicity increased with dose escalation, but there was no grade 4 toxicity. The most common significant toxicity was anemia. Pharmacokinetics parameters were similar to those of Japanese population. In microarray-CGH, we selected 18 genes with different copy numbers of 13 amplified and 5 deleted genes in patients with anemia. Conclusions: Our phase II study showed the feasibility of S-1 in gastric cancer at the dose of 35 mg/m2, and we suggested that selected 18 genes might be candidate markers for predicting anemia with S-1 treatment. No significant financial relationships to disclose.
HtrA1 expression as a predictive factor of response to cisplatin-based regimen in patients with advanced gastric cancer
Authors: Catalano V. , Baldi A. , Shridhar V. , Staccioli M. P. , Chien J. , Giordani P. , Rossi D. , Baldelli A. M. , Alessandroni P. , Muretto P. , Catalano G. 
Published: March 2020

4077 Background: Human HtrA1 is a member of the HtrA (High temperature requirement) family of serine proteases. Recent reports suggest that htrA1 plays a protective role in varous malignancies due to its tumour suppressive properties. This study was performed to estimate HtrA1 expression as a predictor of the response to chemotherapy of patients with gastric cancer. Methods: HtrA1 was measured immunohistochemically on archival specimens of primary gastric cancer from 51 patients treated consecutively at our institution with a weekly chemotherapy including cisplatin 40 mg/m2, epirubicin 35 mg/m2, 6S-leucovorin 100 mg/m2, 5-fluorouracil 500 mg/m2, with the support of filgrastim 5 μg/Kg from the day 2 to 7 (PELF regimen), or cisplatin 40 mg/m2, epirubicin 35 mg/m2, 6S-leucovorin 100 mg/m2, 5-fluorouracil 500 mg/m2 (PLF regimen). Response to chemotherapy was assessed after 8 weekly treatments according to the WHO criteria. Results: our population consisted of M/F 32/19; median age 64 years (range, 46–79). The prevalent metastatic sites were liver (17 pts), peritoneum (13 pts), lymph nodes (21 pts), locoregional disease (16 pts); 31/16/4 pts had 1/2/3 or more sites of disease. 23 pts had a low expression of HtrA1 (0/1+) versus 28 patients with higher expression (2+). Of the total 51 patients, there were 28 responders: 8 showing complete response (CR) and 20, partial response (PR). Of the 28 responders, 20 were in the higher HtrA1 staining group (2+), while of the 23 non-responders, 15 were in the higher HtrA1 staining group (0/1+). A statistically significant correlation between HtrA1 expression (HtrA1 2+ versus HtrA1 0/1+) and the clinical response was observed (response rate in patients with 2+ and 0/1+: 71.4% versus 34.8%, P < 0.01, respectively). Interestingly, among 16 pts with locoregional disease (stomach, gastric bed, anastomosis), 1/6 pts had HtrA1 1+ expression compared to 8/10 pts with HtrA1 2+ (17% versus 80%, respectively; p = 0.025). Conclusions: The immunohistochemical identification of HtrA1 on the primary gastric cancer prior to chemotherapy may be a useful predictor for choice of potentially responders to a cisplatin-based chemotherapy. No significant financial relationships to disclose.
A phase II study of DJ-927 as second-line therapy in patients (pts) with advanced gastric cancer (GC) who have failed a 5-FU non taxane based regimen
Authors: Evans T. , Dobrila R. , Berardi R. , Sumpter K. A. , Wall L. R. , Oyama R. , Anthoney D. A. 
Published: March 2020

4081 Background: Most 1st-line combination chemotherapy regimens in pts with advanced GC include 5-FU. Taxanes are also active agents in GC, either alone or in combination. However, there is no recognized 2nd-line regimen for use in pts with advanced GC. DJ-927 is a semi-synthetic novel taxane with in vitro activity against GC cells lines. It is administered orally, with hematologic dose-limiting toxicity (DLT) in Phase I studies. The primary objective of this study was to determine the objective response rate of DJ-927 as 2nd-line therapy in pts with advanced GC. Methods: Eligible pts had confirmed advanced GC with no more than 1 prior systemic 5-FU-containing regimen for advanced disease, with adequate hematologic, renal and liver function, and with measurable disease. The starting dose in the 1st cohort of 6 pts was 27 mg/m2 orally, every 3 weeks. If < 2 DLTs occurred at this dose, the next cohort of 6 pts would start at a dose of 35 mg/m2, every 3 weeks, and all subsequent pts would be treated at the optimal dose level. Measurable disease was assessed after every 2 courses. Pharmacokinetic sampling was performed during course 1 only. Sample size based on a 3-outcome 1-stage design was calculated to be 27 pts evaluable for response, with ≥ 4 responses of 27 pts indicating that DJ-927 has activity in advanced GC. Results: 36 pts (male=25; female = 11), KPS ≥ 60%, with GC (n = 23) or OG junction cancer (n = 13), received 104 courses (median = 2; range 1–9) of DJ-927. 2 DLTs (febrile neutropenia; Grade 4 neutropenia > 5 days) occurred at 35 mg/m2, and the optimal starting dose was confirmed as 27 mg/m2. 6 of 36 pts were not evaluable for response (< 1 complete treatment course) due to early disease progression (3), toxicity (2), and drug not given (1). Response data is available for 26 of 30 evaluable pts with confirmed PR (n = 5), SD (15), and PD (6). Toxicity, ≥ grade 3, in evaluable pts (n = 33) included neutropenia (17), anemia (5), thrombocytopenia (4), diarrhoea (7), fatigue (5), lethargy (4), neutropenic sepsis (5). Conclusions: DJ-927 has modest activity in pts with GC who have failed a 5-FU non-taxane based regimen. Toxicities include neutropenia ± sepsis, diarrhoea and lethargy. Further studies of DJ-927 in combination with other active agents are warranted in pts with GC. [Table: see text]
The prognostic significance of IL-1-B and GST T1/M1 polymorphisms in non-metastatic gastric cancer
Authors: Al-Moundhri M. S. , Al-Bahrani B. , Al-Nabhani M. , Burney I. , Al-Kindy M. , Ganguly S. S. , Tanira M. 
Published: March 2020

4084 Background: Gastric cancer is the most common malignancy in Oman. The proinflammatory cytokine IL-1-B polymorphisms have been associated with increased gastric cancer risk and shown to be of a prognostic value in advanced gastric cancer. Our aim is to study the prognostic significance of IL-1B- 31, -3954, IL-1RN- and GST T1/M1 polymorphisms in non-metastatic gastric cancer and correlate it with clinicopthological features. Methods: Genomic DNA was extracted from peripheral blood of 40 gastric cancer patients treated with adjuvant chemotherapy or chemoradiotherapy. The DNA samples were analyzed using TaqMan real-time polymerase chain reaction and 5’ nuclease assay. The deletion of GST T1/M1 genes was assessed by PCR. Results: The pathological stages were stage I = 1, stage II = 13, stage III = 22, stage IV = 3. The median follow up was 17 months. There was no prognostic significance for all the above polymorphisms in isolation. However, IL-1RN 2/2 IL-31 C/C genotypes (n = 13) were associated with worst outcome compared with IL-1RN L/L or 2/L and IL-31 T/T and T/C genotypes (n = 27). The median survival of IL-1RN 2/2 IL-31 C/C genotype was 16 months versus 63 months for IL-1RN L/L or 2/L and IL-31 T/T and T/C genotypes (p = 0.035). The IL-1RN 2/2 IL-31 C/C genotype correlated with signet ring pathology (p = 0.01) and non-distal gastric cancer location (p = 0.01). There was no significant association with T, N, or overall stage. Conclusion: These preliminary results suggest a prognostic value for IL-1-B polymorphisms in non-metastatic gastric cancer. No significant financial relationships to disclose.
Correlation between HER2/neu overexpression/amplification and clinicopathologic parameters in advanced gastric cancer (AGC) patients (pts): A prospective study
Authors: Gravalos C. , Marquez A. , Colomer R. , Garcia-Carbonero R. , Sastre J. , Rivera F. , Saenz-Cusi A. , Velasco A. , Guzman C. , Jimeno A. 
Published: March 2020

4089 Background: Trastuzumab is widely used in the treatment of HER2/neu overexpressing breast cancer pts and also exhibits activity in human gastric cancer cells that overexpress HER2/neu. We are conducting a phase II trial to assess the efficacy and tolerance of trastuzumab in combination with cisplatin as first line chemotherapy (CT) in HER2/neu positive AGC. Objectives: To determinate prospectively the frequency of HER2/neu expression and to evaluate the relationship with clinicopathologic characteristics in advanced gastric adenocarcinoma pts. Methods: Pts were screening for HER2/neu expression/amplification. Immunohistochemistry (IHQ) was performed using herceptest. A fluorescence in situ hybridization (FISH) assay was done when IHQ was = 2. HER2/neu expression was considered negative if IHQ = 0, 1 or IHQ = 2 and FISH negative; and positive if IHQ = 2 and FISH positive or IHQ = 3. Results: A hundred and twenty six pts were tested for HER2/neu status between 2/2004 and 12/2005. 96 (76%) males, median age 61 years (range 29–84). Histological characteristics: all were adenocarcinomas and 47% type intestinal, 33% diffuse, 20% unknown. Primary tumor localization was 101 (80%) gastric and 25 (20%) gastroesophageal junction (GEJ). 115 (91%) pts had metastases (47% liver; 45% lymph nodes; 27% peritoneum; 10% lung; 27% others) and 11 (9%) locoregional advanced disease. Prior therapies: 67 pts surgery, 18 adjuvant/neoadjuvant CT and 14 adjuvant irradiation. HER2/neu expression was negative in 109 (86.5%) cases. The positive cases were: type intestinal (15.5%); type diffuse (10%) (p = 0.54); 9% gastric localization and 29% GEJ tumors were HER2/neu positive too (p = 0.01). Conclusions: HER2/neu overexpression/amplification was found in 13.5% of AGC and is more common in gastroesophageal junction cancers. The study is ongoing. [Table: see text]
Association of VEGF expression with poor prognosis among patients with low-grade neuroendocrine carcinoma
Authors: Phan A. T. , Wang L. , Xie K. , Zhang J. , Rashid A. , Evans D. , Vauthey J. , Abdalla E. , Abbruzzese J. L. , Yao J. C. 
Published: March 2020

4091 Background: Low-grade neuroendocrine carcinomas (LGNET) can arise from neuroendocrine cells throughout the body and have a wide range of aggressiveness. Reliable predictive and prognostic markers of outcome are lacking. Angiogenesis is critical for metastasis and tumor growth beyond a small tumor size and VEGF is a powerful mediator of tumor angiogenesis. Methods: LGNET tissue from 50 patients (24 with local-regional disease, 26 with metastasis) who underwent tumor resection at the University of Texas M.D. Anderson Cancer Center was evaluated for expression VEGF by immunohistochemistry. Chi-square and Fisher’s exact test were used to test the association between study parameters. Kaplan-Meier analysis was used to assess the affect of study parameters on progression free survival (PFS). Results: Strong, weak, and negative VEGF expression was observed in 32%, 54%, and 14% of cases respectively. Larger tumor size was observed among patients with strong VEGF expression. Mean tumor sizes in patients with strong, weak and negative VEGF were 4.8, 2.8, and 2.9 cm. Compared to the group with negative VEGF expression, VEGF (weak/strong) expression was associated with metastasis (14% v 58%; P = .045). The median PFS durations of patients with strong and weak VEGF expression were 29 months and 81 months respectively. With a median follow-up duration of 50 months, the median PFS duration for the group with negative VEGF expression has not been reached. Compared by log rank test VEGF expression was associated with poor PFS (P = .022). Conclusions: This study suggests that tissue VEGF expression is associated with aggressive tumor growth and metastasis among patients with LGNET. VEGF expression may serve as a useful prognostic marker following tumor resection. No significant financial relationships to disclose.
Survival of resectable pancreatic cancer patients with diabetes
Authors: Busaidy N. L. , Yazbeck C. F. , Shah P. , Evans D. B. , Li D. , Geraci J. M. , Weiser M. A. 
Published: March 2020

4098 Background: Pancreatic cancer is the fourth leading cause of cancer mortality in the United States. Determining modifiable prognostic factors may be a key step in improving outcomes of these patients with overall poor survival. Pancreatic adenocarcinoma is often associated with diabetes. Our aim is to determine whether diabetes worsens disease specific mortality in resectable pancreatic cancer patients. Methods: In this study, we reviewed 298 patients with resected pancreatic adenocarcinoma in our surgical database at MD Anderson Cancer Center between August 1992 and July 2003. Patients were classified into diabetics (N = 87) (defined as those carrying the diagnosis of diabetes (DM) at time of presentation or on long term therapy for DM) and nondiabetics (N = 211). Univariate (log-rank) and Multivariate (Cox Regression) analyses were performed. Results: Compared to nondiabetics, patients with DM had a poorer overall survival with a median survival of 19.8 vs 29.2 months (p = 0.01). On multivariate analysis, correcting for known poor prognosticators in resectable patients: staging, histologic tumor differentiation and retroperitoneal margin status, diabetes was a significant independent risk factor for increased overall mortality (OR 1.55, 95% CI 1.15–2.07, p = 0.004). Disease-specific mortality was also higher in diabetics vs. non-diabetics with a median survival of 29.87 vs. 21.47 months (OR 1.37 95% CI 1.00–1.89 p = 0.048). Stage specific mortality was also higher among diabetics. Potential etiologies will be discussed. Conclusions: Diabetes worsens disease specific and overall mortality in patients with pancreatic cancer. Diabetes may be a modifiable risk factor and should be considered while prognosticating patients with resectable pancreatic cancer. Further studies are needed to determine whether treatment of diabetes improves outcomes. No significant financial relationships to disclose.