Putao Cen

Eradication of gastric cancer is now both possible and practical

In 1994, Helicobacter pylori was declared a human carcinogen. Evidence has now accumulated to show that at least 95% of gastric cancers are etiologically related to H. pylori. An extensive literature regarding atrophic gastritis and its effects on acid secretion, gastric microflora, and its tight association with gastric cancer has been rediscovered, confirmed, and expanded. Methods to stratify cancer risk based on endoscopic and histologic findings or serologic testing of pepsinogen levels and H. pylori testing have been developed producing practical primary and secondary gastric cancer prevention strategies. H. pylori eradication halts progressive mucosal damage. Cure of the infection in those with non-atrophic gastritis will essentially prevent subsequent development of gastric cancer. For all, the age-related progression in cancer risk is halted and likely reduced as eradication reduces or eliminates mucosal inflammation and reverses or reduces H. pylori-associated molecular events such aberrant activation-induced cytidine deaminase expression, double strand DNA breaks, impaired DNA mismatch repair and aberrant DNA methylation. Those who have developed atrophic gastritis/gastric atrophy however retain some residual risk for gastric cancer which is proportional to the extent and severity of atrophic gastritis. Primary and secondary cancer prevention starts with H. pylori eradication and cancer risk stratification to identify those at higher risk who should also be considered for secondary cancer prevention programs. Japan has embarked on population-wide H. pylori eradication coupled with surveillance targeted to those with significant remaining risk. We anticipate that countries with high gastric cancer burdens will follow their lead. We provide specific recommendations on instituting practical primary and secondary gastric cancer prevention programs as well identifying research needed to make elimination of gastric cancer both efficient and cost effective.

Lymphovascular invasion as a tool to further subclassify T1b esophageal adenocarcinoma.

Lymphovascular invasion (LVI) and/or lymph node metastases (LNM) adversely influence the overall survival (OS) of patients with T1 esophageal adenocarcinoma. Although endoscopic therapy may be adequate for patients with T1a cancer, patients with T1b cancer require esophagectomy/lymphadenectomy. The authors hypothesized that LVI status would subclassify T1b cancers and facilitate new therapeutic strategies.

The Role of CD44 in the Pathogenesis, Diagnosis, and Therapy of Gastric Cancer.

CD44 is a transmembrane glycoprotein and surface receptor for hyaluronan that is involved in the response of cells to their microenvironment. CD44 splice variants play roles in carcinogenesis, differentiation, and lymph node metastasis and are predictive of the prognosis for various carcinomas, including gastric cancer. Current data suggest that gastric tissue stem cells and gastric cancer stem cells both express the splice variant, CD44v9. Overall, the data regarding the alterations that occur in CD44 and its splice variants in response to acute and chronic infection with Helicobacter pylori are scant and poorly elucidated in terms of possible changes in expression that occur in gastric cancer precursor lesions, such as chronic atrophic gastritis, pyloric metaplasia and intestinal metaplasia. In this study, we discuss the available data and suggest which new data would likely be useful in clinical practice. We also discuss the potential for CD44-targeted therapeutic strategies in gastric cancer. CD44 and its splice variants are positively associated with the initiation and progression of gastric cancer and may also play important roles in diagnosis, therapy and prognosis. CD44 research has been active but fragmented, and it may offer new therapeutic approaches to gastric cancer.

A preoperative serum signature of CEA+/CA125+/CA19-9 ≥ 1000 U/mL indicates poor outcome to pancreatectomy for pancreatic cancer

Pancreatectomy is associated with significant morbidity and unpredictable outcome, with few diagnostic tools to determine, which patients gain the most benefit from this treatment, especially before the operation. This study aimed to define a preoperative signature panel of serum markers to indicate response to pancreatectomy for pancreatic cancer. Over 1000 patients with pancreatic cancer treated at two independent high‐volume institutions were included in this study and were divided into three groups, including resected, locally advanced and metastatic. Eight serum tumor markers most commonly used in gastrointestinal cancers were analyzed for patient outcome. Preoperative CA19‐9 independently indicated surgical response in pancreatic cancer. Patients with CA19‐9 ≥1000 U/mL generally had a poor surgical benefit. However, a subset of these patients still achieved a survival advantage when CA19‐9 levels decreased postoperatively. CEA and CA125 in the presence of CA19‐9 ≥1000 U/mL could independently predict the non‐decrease of CA19‐9 postoperatively. The combination of the three markers was useful for predicting a worse surgical outcome with a median survival of 5.1 months vs. 23.0 months (p < 0.001) for the training cohort and 7.0 months vs. 18.2 months (p < 0.001) for the validation cohort and also suggested a higher prevalence of early distant metastasis after surgery. Resected patients with this proposed signature showed no survival advantage over patients in the locally advanced group who did not receive pancreatectomy. Therefore, a preoperative serum signature of CEA+/CA125+/CA19‐9 ≥1000 U/mL is associated with poor surgical outcome and can be used to select appropriate patients with pancreatic cancer for pancreatectomy.

Gene Profile Identifies Zinc Transporters Differentially Expressed in Normal Human Organs and Human Pancreatic Cancer

Deregulated expression of zinc transporters was linked to several cancers. However, the detailed expression profile of all human zinc transporters in normal human organs and in human cancer, especially in pancreatic cancer is not available. The objectives of this study are to investigate the complete expression patterns of 14 ZIP and 10 ZnT transporters in a large number of normal human organs and in human pancreatic cancer tissues and cell lines. We examined the expression patterns of ZIP and ZnT transporters in 22 different human organs and tissues, 11 pairs of clinical human pancreatic cancer specimens and surrounding normal/benign tissues, as well as 10 established human pancreatic cancer cell lines plus normal human pancreatic ductal epithelium (HPDE) cells, using real time RT-PCR and immunohistochemistry. The results indicate that human zinc transporters have tissue specific expression patterns, and may play different roles in different organs or tissues. Almost all the ZIPs except for ZIP4, and most ZnTs were down-regulated in human pancreatic cancer tissues compared to the surrounding benign tissues. The expression patterns of individual ZIPs and ZnTs are similar among different pancreatic cancer lines. Those results and our previous studies suggest that ZIP4 is the only zinc transporter that is significantly up-regulated in human pancreatic cancer and might be the major zinc transporter that plays an important role in pancreatic cancer growth. ZIP4 might serve as a novel molecular target for pancreatic cancer diagnosis and therapy.

Comparison of toxicity profiles of fluorouracil versus oxaliplatin regimens in a large population-based cohort of elderly patients with colorectal cancer

BACKGROUND Population-based studies of adverse events are scarce. Our objective was to evaluate chemotherapy-associated adverse events among elderly colorectal cancer (CRC) patients treated in the community. PATIENTS AND METHODS Data on elderly patients aged ≥65 years diagnosed with CRC at any stage between 2003 and 2005 were obtained from the Surveillance, Epidemiology, and End Results (SEER)-Medicare Database. RESULTS Of 46 692 patients assessed, 36 137 (77.4%) received no i.v. chemotherapy, 5472 (11.7%) received fluorouracil (5-FU) alone, 2284 (4.9%) received oxaliplatin-containing regimens, 1306 (2.8%) received bevacizumab-containing regimens but without oxaliplatin, and 1493 (3.2%) received other chemotherapy. Symptoms and laboratory test abnormalities were commonly found in elderly, even in those who had not received any i.v. chemotherapy. The addition of i.v. chemotherapy was associated with higher incidences of adverse events. Oxaliplatin-based regimens led to higher incidences in nausea, neutropenia, and neuropathy compared with 5-FU alone. Patients aged ≥70 years (n = 37 601, 80.5%) tended to experience higher rates of certain adverse events, including infection, anemia, delirium, and heart disease than patients aged 65-69 years (n = 9091, 19.5%). CONCLUSIONS Among community-dwelling elderly with CRC, the addition of i.v. chemotherapy and advanced age were associated with increasing adverse events. Appropriate selection of patients and assessment of social support may be important.

Emerging drugs in the treatment of advanced gastric cancer

Background: Gastroesopheal cancer is one of the most common cancers worldwide. If detected early, curative treatment is possible. Often, gastroesophageal cancer is detected at an advanced stage when therapy is palliative. Objectives: To provide a critical evaluation of historic and recently developed chemotherapy regimens for the treatment of advanced gastroesophageal cancer (AGC). Methods: Published clinical trials in AGC as well as selected abstracts presented at international oncology meetings were selected. Results/conclusion: Chemotherapy has demonstrated a benefit over best supportive care alone by improving the quality and quantity of life for patients with advanced disease. Recent Phase III trials investigating cytotoxic chemotherapy and Phase II trials incorporating biotherapy for the treatment of AGC show promise for the future.

Value of endoscopic ultrasound staging in conjunction with the evaluation of lymphovascular invasion in identifying low-risk esophageal carcinoma

With increasing emphasis on endoscopic therapy (ET) for T1 esophageal carcinoma, the identification of low‐risk patients is critical. It was hypothesized that endoscopic ultrasonography (EUS) in concert with detailed histopathologic evaluation would identify low‐risk cancers for an appropriate but organ‐preserving strategy.

Medical treatment for advanced gastroesophageal adenocarcinoma.

Purpose of review Gastroesophageal cancers continue to pose a significant health burden around the world. Advanced gastroesophageal cancer is an incurable condition and more research is desirable. Considerable new and important information, however, has become available. Recent findings The number of phase III trials for patients with advanced gastroesophageal cancer is increasing and that is welcome news. Current results suggest that capecitabine can be substituted for 5-fluorouracil and oxaliplatin for cisplatin. Docetaxel, when combined with 5-fluorouracil and cisplatin, prolongs overall survival as well as improves safety, quality of life, and efficacy. S-1, a fourth generation oral fluoropyridine, is especially effective in combination with cisplatin. Dosing of S-1 is different between Western and Asian populations due to differences in metabolism by CYP2A6. Irinotecan should not be used as frontline therapy for advanced gastroesophageal cancer. Biologic agents are currently under investigation. Summary Safer, more convenient, and more effective chemotherapy combinations are being developed for patients with advanced gastroesophageal cancer; however, considerable challenges exist to select the optimal therapy for an individual patient.

Pancreatic cancer tumour initiating cells: the molecular regulation and therapeutic values.

•  Introduction •  Surface markers of pancreatic TICs •  Signalling pathways in pancreatic TICs •  Function of microRNAs in TICs regulation, self‐renewal and differentiation •  New therapies targeting the deregulated pathways and miRNAs to treat TICs in pancreatic cancer •  Conclusion