Intrahepatic micrometastases around liver metastases from gastric cancer

Background/Purpose

We aimed to clarify the association between the presence of micrometastases around liver metastases from gastric cancer and the results of hepatic resection. In addition, we investigated the influence of E-cadherin and matrix metalloproteinase (MMP)-7 expression on the development of micrometastases.

Methods

Micrometastases around liver metastases were examined microscopically in 31 metastatic liver tumor specimens resected from 17 patients who had undergone hepatic resection for liver metastases from gastric cancer. E-cadherin and MMP-7 expression in the primary gastric tumor, the liver metastases, and the micrometastases were examined immunohistochemically.

Results

Hepatic micrometastases were present in around 48% of the liver metastases, accounting for 59% of the patients. The tumor recurrence rate in the remnant liver after hepatic resection was significantly higher, and survival significantly poorer, in patients with such micrometastases than in those without. Micrometastases tended to appear around the liver metastases that had reduced E-cadherin expression. Most of the micrometastases in the lymph ducts and sinusoids showed reduced E-cadherin expression. MMP-7 expression was not correlated with the presence of micrometastases.

Conclusions

About half of the hepatic metastases from gastric cancer had seeded off micrometastases, and the presence of these micrometastases was associated with a poorer result of hepatic resection. Reduced E-cadherin expression in metastatic liver tumors may be associated with the development of micrometastases.     

Transcatheter therapy of gastric cancer metastatic to the liver: preliminary results

Little is known about the effectiveness of transcatheter chemotherapy in liver metastases from gastric cancer. The aim of this study was to evaluate the initial results of hepatic artery infusion and oily chemoembolization in these liver secondaries. Courses of transcatheter arterial infusion with 5-fluorouracil/doxorubicin (12 patients) and oily chemoembolization with doxorubicin-in-iodized oil and gelatin sponge (12 patients) were performed in 24 patients with histologically proven unresectable gastric cancer liver metastases. A positive effect of treatment (partial response + stabilization) was seen in 92% of the patients after chemoinfusion and in 50% after chemoembolization. The 1- and 2-year actuarial survival rates were 92% and 53% for infusion vs 50% and 17% for chemoembolization, respectively (log-rank test, P = 0.0009). For patients who had already died, the mean survival was 19.2 months vs 9.5 months (Student's t-test, P < 0.05) with median survivals of 23 months vs 8 months, respectively. The results with arterial infusion were very close to those reported for liver resection. Transcatheter therapy appears to be useful for the palliation of unresectable liver metastases from gastric cancer. If regional chemotherapy is used, arterial infusion should be the first-choice treatment, with oily chemoembolization being reserved for patients who do not respond to infusion. Received: February 22, 2000 / Accepted: July 28, 2000     

New perspectives in the treatment of advanced or metastatic gastric cancer

Metastatic gastric cancer remains an incurable disease, with a relative 5-year survival rate of 7%-27%. Chemotherapy, which improves overall survival （OS） and quality of life, is the main treatment option. Metaanalysis has demonstrated that the best survival results obtained in earlier randomized studies were achieved with three-drug regimens containing a fluoropyrimidine, an anthracycline, and cisplatin （ECF）. Although there has been little progress in improving median OS times beyond the 9-mo plateau achievable with the standard regimens, the availability of newer agents has provided some measure of optimism. A number of new combinations incorporating docetaxel, oxaliplatin, capecitabine, and S-1 have been explored in randomized trials. Some combinations, such as epirubicin-oxaliplatincapecitabine, have been shown to be as effective as （or perhaps more effective than） ECF, and promising early data have been derived for S-1 in combination with cisplatin. One factor that might contribute to extending median OS is the advancement whenever possible to second-line cytotoxic treatments. However, the biggest hope for significant survival advances in the near future would be the combination of new targeted biological agents with existing chemotherapy first-line regimens.     

Feasibility of self-expandable metallic stent plus chemotherapy for metastatic gastric cancer with pyloric stenosis

Background and Aim:  Self-expandable metallic stent placement is accepted as palliative therapy for advanced gastric cancer with gastric outlet obstruction, but data are lacking for chemotherapy after self-expandable metallic stent insertion. This study retrospectively compared results between surgery plus chemotherapy and stenting plus chemotherapy for metastatic gastric cancer with pyloric stenosis.
Methods:  Subjects comprised 26 patients who received chemotherapy after surgery or endoscopic stenting for metastatic gastric cancer with pyloric stenosis between April 2000 and December 2007 in four Japanese hospitals. Patients were categorized into two groups: 15 patients who received chemotherapy after surgery for pyloric stenosis (Surgery group); and 11 patients who received chemotherapy after self-expandable metallic stent placement for pyloric stenosis (Stent group).
Results:  Median survival time and median time to treatment failure were 284 days and 226 days in the Surgery group and 337 days and 247 days in the Stent group, respectively. No significant differences were noted between survival and time to treatment failure. No significant differences were found in median oral intake rate (Surgery, 93.1%; Stent, 93.2%) or median hospital stay rate (Surgery, 24.6%; Stent, 23.7%) during survival. Response rate was 45.5% in the Surgery group and 50% in the Stent group, with no significant difference. Likewise, no significant differences were noted between groups for frequencies of toxicity or complications.
Conclusions:  The present results suggest that chemotherapy after stenting is as effective and safe as chemotherapy after surgery. Stents may replace surgery in combination therapy with chemotherapy for metastatic gastric cancer with gastric outlet obstruction.     

Role of cetuximab in first-line treatment of metastatic colorectal cancer

The treatment of metastatic colorectal cancer(mCRC)has evolved considerably in the last decade,currently allowing most mCRC patients to live more than two years.Monoclonal antibodies targeting the epidermal growth factor receptor(EGFR)and vascular endothelial growth factor play an important role in the current treatment of these patients.However,only antibodies directed against EGFR have a predictive marker of response,which is the mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog(KRAS).Cetuximab has been shown to be effective in patients with KRAS wild-type mCRC.The CRYSTAL study showed that adding cetuximab to FOLFIRI(regimen of irinotecan,infusional fluorouracil and leucovorin)significantly improved results in the first-line treatment of KRAS wildtype mCRC.However,results that evaluate the efficacy of cetuximab in combination with oxaliplatin-based chemotherapy in this setting are contradictory.On the other hand,recent advances in the management of colorectal liver metastases have improved survival in these patients.Adding cetuximab to standard chemotherapy increases the response rate in patients with wild-type KRAS and can thus increase the resectability rate of liver metastases in this group of patients.In this paper we review the different studies assessing the efficacy of cetuximab in the first-line treatment of mCRC.     

Chemotherapy for metastatic gastric cancer: past,present, and future

Despite the numerous efforts of randomized studies on advanced gastric cancer, no globally accepted standard regimen has yet been established. Two triplet regimens have already demonstrated significant survival prolongation in Western studies. However, the benefit seems to be marginal, and these regimens may be replaced by recently published newer generation regimens for which favorable survival is reported. At present, the combination of 5-fluorouracil (5-FU) and platinum analog is still the most widely accepted standard regimen worldwide: 5-FU can be replaced by S-1 or capecitabine, and cisplatin by oxaliplatin. In Japan, S-1 plus cisplatin is the most reasonable first-line standard, based on recent randomized studies. Some early clinical studies using molecular targeting agents have shown promising activity, particularly in combination with cytotoxic agents for gastric cancer. Several targeting agents such as trastuzumab, bevacizumab, and lapatinib are now under investigation in international randomized studies, including in Japan. These agents have shown a survival benefit in other tumor types. The next-generation targeting agents, including mammalian target of rapamycin inhibitor and a c-Met tyrosine kinase inhibitor, are also being evaluated in early clinical studies in association with biology research. Such agents can be advantageously used in gastric cancer studies, which, because of the ease with which tumor tissues can be obtained by endoscopy and the high incidence of gastric cancer in Japan, might advance the frontiers of biologic therapy. These efforts should result not only in further clinical advances but also in tailored medicine.     

Extensive resections for colorectal liver metastases

Journal of Hepato-Biliary-Pancreatic Sciences - Mortality and morbidity rates after liver resections have decreased with better surgical techniques and perioperative care. The aim of this study was...     

Early gastric cancer: A challenge in Western countries

Early gastric cancer(EGC)is an invasive carcinoma involving only the stomach mucosa or submucosa,independently of lymph node status.EGC represents over 50%of cases in Japan and in South Korea,whereas it accounts only for approximately 20%of all newly diagnosed gastric cancers in Western countries.The main classification systems of EGC are the Vienna histopathologic classification and the Paris endoscopic classification of polypoid and non-polypoid lesions.A careful endoscopic assessment is fundamental to establish the best treatment of EGC.Generally,EGCs are curable if the lesion is completely removed by endoscopic resection or surgery.Some types of EGC can be resected endoscopically;for others the most appropriate treatment is surgical resection and D2 lymphadenectomy,especially in Western countries.The favorable oncological prognosis,the extended lymphadenectomy and the reconstruction of the intestinal continuity that excludes the duodenum make the prophylactic cholecystectomy mandatory to avoid the onset of biliary complications.     

Treatment with Ramucirumab-paclitaxel in a metastatic gastric cancer patient undergoing hemodialysis: A case report

Rationale:Ramucirumab, a human Ig 1 monoclonal antibody against vascular endothelial growth factor receptor-2, in combination with paclitaxel is a second-line chemotherapy for patients with metastatic gastric cancer. Several reports have suggested that dose adjustments of cetuximab, an anti- epidermal growth factor receptor antibody, are not required in patients with renal impairment. However, the combination chemotherapy of ramucirumab and cytotoxic drug for hemodialysis (HD) patients has not been reported.Patient concerns:A 65-year-old man on HD was diagnosed with gastric cancer and underwent a subtotal gastrectomy with D2 lymphadenectomy. Abdominal computed tomography (CT) was examined after completion of 8 cycles of adjuvant chemotherapy with capecitabine combination oxaliplatin.Diagnosis:The patient was diagnosed with advanced gastric cancer at stage IIIb (pT3N2M0) 11 months ago. Unfortunately, 9 months after the start of adjuvant chemotherapy, multiple liver metastases from gastric cancer were found by abdominal CT.Interventions:He began receiving weekly paclitaxel(80 mg/m²) and every 15-day ramucirumab (8 mg/kg). HD was performed next day after administration of chemotherapy and repeated 3 times a week.Outcomes:He was treated with ramucirumab without dose adjustment. The metastatic liver mass had a partial response, after 2 and 4 cycles of chemotherapy and had a stable disease up to 12 cycles of chemotherapy. No obvious adverse effect was observed during treatment. However, after 14 cycles chemotherapy, follow-up abdominal CT revealed progression disease of multiple liver metastasis and lymph nodes invasion.Lessons:The paclitaxel chemotherapy with ramucirumab is effective and safe in HD patients with metastatic gastric cancer. As seen in patients with normal kidney function, ramucirumab can be safely administered without a dose reduction.     

Influence of resection margin on survival in hepatic resections for colorectal liver metastases

Background:

Traditionally a 1-cm margin has been accepted as the gold standard for resection of colorectal liver metastases. Evidence is emerging that a lesser margin may provide equally acceptable outcomes, but a critical margin, below which recurrence is higher and survival poorer, has not been universally agreed. In a recent publication, we reported peri-operative morbidity and clear margin as the two independent prognostic factors. The aim of the current study was to further analyse the effect of the width of the surgical margin on patient survival to determine whether a margin of 1 mm is adequate.

Methods:

Two hundred and sixty-one consecutive primary liver resections for colorectal metastases were analysed from 1992 to 2007. The resection margins were assessed by microscopic examination of paraffin sections. The initial analysis was performed on five groups according to the resection margins: involved margin, 0–1 mm, >1–<4 mm, 4–<10 mm and ≥ 10 mm. Subsequent analysis was based on two groups: margin <1 mm and >1 mm.

Results:

With a median follow-up of 4.7 years, the overall 5-year patient and disease-free survival were 38% and 22%, respectively. There was no significant difference in patient- or disease-free survival between the three groups with resection margins >1 mm. When a comparison was made between patients with resection margins ≤1 mm and patients with resection margins >1 mm, there was a significant 5-year patient survival difference of 25% versus 43% (P < 0.04). However, the disease-free survival difference did not reach statistical significance (P= 0.14).

Conclusions:

In this cohort of patients, we have demonstrated that a resection margin of greater than 1 mm is associated with significantly improved 5-year overall survival, compared with involved margins or margins less than or equal to 1 mm. The possible beneficial effect of greater margins beyond 1 mm could not be demonstrated.     

Esophageal and multiple gastric cancers treated by endoscopic mucosal resections

A case of successful endoscopic therapy of superficial esophageal and multiple gastric cancers in an 87‐year‐old man is reported. A slightly elevated superficial cancer 10 mm in diameter in the proximal stomach (type 0‐IIa) was detected by esophagogastroduodenoscopy (EGD) and treated by endoscopic mucosal resection (EMR) in September 1999. Four months later, in January 2000, a slightly depressed superficial cancer 10 mm in diameter in the proximal esophagus (type 0‐IIc) was found in follow‐up EGD and treated by EMR. Further, in August 2000, a slightly elevated superficial cancer 10 mm in diameter in the distal stomach (type 0‐IIa) was found in follow‐up EGD and treated by EMR. Microscopic examination of these resected specimens showed that invasion was limited to the mucosal layer, and confirmed that no lymphatic or vascular permeation had occurred. No endoscopic or histological recurrence was detected for 33 months after the most recent EMR for gastric cancer. As multiple primary cancers in the upper gastrointestinal tract are not rare in Japan, periodic endoscopic follow up is important for early detection of recurrence of new primary cancers.     

Long-term outcomes of patients with metastatic gastric cancer after initial S-1 monotherapy

Background S-1, an oral fluoropyrimidine, has been shown to have excellent activity against gastric cancer in two phase II studies and is widely used in Japan. However, the long-term outcomes of patients after S-1 monotherapy for metastatic gastric cancer are unclear. The aim of this study was to investigate the long-term outcomes in metastatic gastric cancer patients who had initially received S-1 monotherapy. Methods Ninety-two previously untreated patients with advanced gastric cancer received S-1 monotherapy as first-line chemotherapy at the National Cancer Center Hospital East, Kashiwa, Japan, and then the long-term outcomes and characteristics of long-term survivors were analyzed retrospectively. Multivariate analysis of prognostic factors was performed by the Cox proportional hazard method. Results With a median follow-up of 3.1 years, the median progression-free survival time was 4.6 months. The median survival time was 11.9 months, with 1-, 2- and 3-year survival rates of 49.1%, 22.8%, and 9.8%, respectively. Multivariate analysis showed that good performance status (P = 0.0004) and only one metastatic site (P = 0.0048) were significant independent prognostic factors. Among 48 patients with a single metastatic site, 22 with peritoneal metastasis had longer survival times (median survival, 24 months) than patients with metastasis at other sites. Among the nine 3-year survivors, six had peritoneal metastases alone. Conclusions The survival outcomes after S-1 monotherapy are promising, especially in patients with good performance status and a single metastatic site. Our findings suggest that, among patients with a single metastatic site, those with peritoneal metastases alone have a chance for long-term survival.     

The proteolysis-inducing factor: in search of its clinical relevance in patients with metastatic gastric/esophageal cancer

The proteolysis-inducing factor is a putative mediator of cancer-associated weight loss. The goal of this study was to examine for the first time: (i) its prevalence in patients with metastatic gastric/esophageal cancer; and (ii) whether it possibly correlated with weight loss and anorexia and whether it predicted tumor response and patient survival. This study recruited 41 patients as part of a phase II therapeutic, chemotherapy protocol for patients with metastatic gastric/esophageal cancer. Patient eligibility criteria were designed to select a group of patients who would tolerate treatment with the drugs capecitabine and oxaliplatin. Urine for assaying the proteolysis-inducing factor was obtained at registration and then 6 weeks later. Patients completed the FACT-E questionnaire every 6 weeks and had their weights checked at the same interval. Patients were followed prospectively for tumor response and patient survival. Twenty-three (56%) patients had the proteolysis-inducing factor in their urine at registration, and 18 (64%) had it at 6 weeks. There was no statistically significant correlation between the presence of the proteolysis-inducing factor and weight loss or between its presence and anorexia. Moreover, there was no evidence that the presence of the proteolysis-inducing factor in urine was able to predict tumor response or patient survival. The proteolysis-inducing factor in urine does not appear to be tied to weight loss, anorexia, tumor response, or patient survival in the clinical setting of metastatic gastric/esophageal cancer.     

Telomerase activity in gastric cancer

OBJECTIVE : To examine telomerase activity and its clinical significance in human gastric carcinoma and to evaluate the feasibility of non‐radioisotopic TRAP (telomeric repeat amplification protocol) assays to detect telomerase activity. METHODS : Telomerase activity in tissue samples from 58 gastric carcinomas (and their matched normal tissues), 12 gastric adenomas and nine gastric ulcers was examined by using a modified non‐ radioisotopic PCR (polymerase chain reaction)‐based TRAP assay. RESULTS : Forty‐nine of 58 gastric cancer specimens were positive for telomerase activity, with a positive rate of 84.5%. In contrast, none of the normal tissues exhibited telomerase activity (P < 0.001). One of each of the 12 gastric adenomas and nine gastric ulcers was also positive. The prevalence of telomerase activity in gastric carcinoma tissues was not correlated with age, tumor diameter, histological grade, tumor invasion depth, lymph node metastasis or tumor node metastasis (TNM) stage. CONCLUSIONS : Telomerase activity could be a good diagnostic marker for the detection of gastric carcinoma. The non‐radioisotopic TRAP assay is a feasible method for detecting telomerase activity.     

Early gastric stump cancer following distal gastrectomy

Background—Gastric stump cancer(GSC) is usually diagnosed at an advanced stage, and consequently theprognosis is poor.
Aims—To investigate theclinicopathological characteristics of GSC at an early stage to assistin its identification, and thereby improve its prognosis.
Methods—Forty three patients withresected early GSC were compared with 156 patients with resectedprimary early cancer in the upper third of the stomach.
Results—Sixty five per cent (28/43)of the early GSC patients showed the elevated type endoscopically,although the frequency of the depressed type in GSC has tended toincrease in the past five years. This occurred in less than 26%(40/156) of the primary early cancers. Half of the early GSCs werelocated on the lesser curvature (47%), and revealed differentiatedadenocarcinoma (81%) histologically. The male:female ratio of earlyGSC cases was about 6:1, which was much higher than that in patientswith primary early cancer. The five year survival rates of patientswith early GSCs and early primary cancers were 84% and 95%,respectively. GSC had a favourable prognosis, if it was detected at anearly stage.
Conclusion—To detect early GSC, ourresults suggest that special attention should be given to elevated aswell as depressed lesions on the lesser curvature of the stomach,particularly in men, during endoscopic examinations.

Keywords:gastric stump cancer; early gastric cancer; prognosis; endoscopy

     

Three pulmonary resections for metastatic lung cancer from hepatocellular carcinoma

We describe a patient who underwent pulmonary resection three times for metastatic lung cancer from hepatocellular carcinoma (HCC). A 56-year-old man, who had a past history of right hepatic lobectomy for HCC, was referred to our department with an abnormal finding on chest computed tomography (CT). Chest CT showed three abnormal shadows, in the right upper lobe (S3b), right middle lobe (S5), and right lower lobe (S10), respectively, and there was no evidence of intrahepatic recurrence. He underwent surgical resections (right upper lobectomy and partial resections) for the metastatic lung cancer from HCC. Subsequently, 12 and 16 months after the first pulmonary resection, metastatic lung cancer recurred, in right S6 and S9, respectively. Because there was no evidence of intrahepatic recurrence and because of the feasibility of curative resection, we performed partial pulmonary resections. He had no postoperative morbidity, and is alive with no evidence of disease 60 months after the first pulmonary resection. Twelve cases of repeat pulmonary resections for metastatic lung cancer from HCC have been reported in the literature, and the authors of these reports described that repeated pulmonary resections for metastatic lung cancer from HCC resulted in long-term survival. Repeat pulmonary resections for metastatic lung cancer from HCC can be an effective treatment for patients with such metastases.     

Second-line treatment of metastatic gastric cancer:Current options and future directions

Gastric cancer remains one among the leading causes of cancer-related deaths, regardless of its decreasing incidence and newly available treatment options. Most patients present at an advanced stage and are treated with upfront systemic chemotherapy. Those patients receiving first-line therapy may initially respond to treatment, but many of them relapse over time. In such condition, second-line treatment for disease progression remains the only available option. Although there exists no standard approach in the second-line setting, several phase Ⅲ trials have shown modest survival benefit in patients receiving irinotecan, taxane and ramucirumab over the best supportive care or active agents. This review analyzes the currently available treatment regimens and future directions of research in the second-line setting for metastatic gastric cancer with the best available evidence. Additionally, the prognostic factors that influence patient survival in those receiving second-line therapy are discussed.     

The role of gastric microbiota in gastric cancer

ABSTRACT

Gastric cancer represents one of the leading causes of cancer deaths worldwide. Helicobacter pylori (H. pylori) infection is the strongest risk factor associated with gastric cancer. Due to new molecular techniques allowing greater identification of stomach microbes, investigators are beginning to examine the role that bacteria other than H. pylori play in gastric cancer development. Recently, researchers have investigated how the composition of the gastric microbiota varies among individuals with various stages of gastric disease. Specific microbes residing in the stomach have been preferentially associated with gastric cancer patients compared to individuals with a healthy gastric mucosa. Studies conducted on the insulin-gastrin (INS-GAS) transgenic mouse model have provided additional insight into the association between the gastric microbiota and gastric cancer. The purpose of this article is to review the current state of literature on the relationship between the gastric microbiota and gastric cancer based on clinical studies performed to date.     

早期胃癌中凹陷型比率的临床分析

目的探索以凹陷型病灶为主的胃癌漏诊原因,统计早期胃癌中凹陷型的比率。方法 2007年1月～2010年12月的4年间,胃癌切除患者2 431例,统计经切除标本病理学证实的早期胃癌例数及凹陷型形态的早期胃癌的比率。结果 2 431例胃癌切除中,466例为早期胃癌(19.17%);其中Ⅱc型早期胃癌278例(59.66%),Ⅲ型早期胃癌83例(17.81%),复合凹陷型早期胃癌8例(1.72%),凹陷型早期胃癌总计369例,占早期胃癌总数的79.18%。结论早期胃癌的形态分型中以表浅凹陷及溃疡型居多,因而临床漏诊的几率亦增多。提高对凹陷型胃癌特别是早期胃癌病灶的识别能力至关重要。