Sentinel node mapping for gastric cancer: a prospective multicenter trial in Japan.

PURPOSE: Complicated gastric lymphatic drainage potentially undermines the utility of sentinel node (SN) biopsy in patients with gastric cancer. Encouraged by several favorable single-institution reports, we conducted a multicenter, single-arm, phase II study of SN mapping that used a standardized dual tracer endoscopic injection technique. PATIENTS AND METHODS: Patients with previously untreated cT1 or cT2 gastric adenocarcinomas < 4 cm in gross diameter were eligible for inclusion in this study. SN mapping was performed by using a standardized dual tracer endoscopic injection technique. Following biopsy of the identified SNs, mandatory comprehensive D2 or modified D2 gastrectomy was performed according to current Japanese Gastric Cancer Association guidelines. RESULTS: Among 433 patients who gave preoperative consent, 397 were deemed eligible on the basis of surgical findings. SN biopsy was performed in all patients, and the SN detection rate was 97.5% (387 of 397). Of 57 patients with lymph node metastasis by conventional hematoxylin and eosin staining, 93% (53 of 57) had positive SNs, and the accuracy of nodal evaluation for metastasis was 99% (383 of 387). Only four false-negative SN biopsies were observed, and pathologic analysis revealed that three of those biopsies were pT2 or tumors > 4 cm. We observed no serious adverse effects related to endoscopic tracer injection or the SN mapping procedure. CONCLUSION: The endoscopic dual tracer method for SN biopsy was confirmed as safe and effective when applied to the superficial, relatively small gastric adenocarcinomas included in this study.

[The efficacy of neoadjuvant chemotherapy with S-1/CDDP (SP) to the patients with large type 3 and type 4 gastric cancer].

Here, I examined the efficacy of neoadjuvant chemotherapy( NAC) with S-1/CDDP( SP) in my hospital. The subjects were 8 patients with advanced gastric cancer who had undergone NAC since 2007 (7 men and 1 woman; median age, 70 years). The staging before the treatment was Stage II A: 1 patient, II B: 2 patients, III B: 3 patients, III C: 1 patient, and IV: 1 patient. The macroscopic type of 3 and 5 patients was large type 3 and type 4, respectively. Gastrectomy was performed following the NAC with SP. The NAC response rate was 62.5%. In the histological response criteria, 1 patient was grade 0, 2 patients were grade 1a, 2 patients were grade 1b, and 3 patients were grade 2. Adverse events following the NAC were in the acceptable range. We noted that the presence of Stage IV or grade 0 histological response criteria to NAC indicated poor prognosis. Thus, I believe that preoperative surgery after NAC in Stage III gastric cancer should be considered to be curative.

[A case that showed an improved quality of life for rectal gastrointestinal stromal tumor patient treated with cytoreductive surgery].

A 49-year-old man was admitted to another hospital with the complaint of difficulty in defecating. He underwent laparotomy, and investigation of the biopsy revealed a huge intraperitoneal tumor. He began to take imatinib in April 2008 following a diagnosis of gastrointestinal stromal tumor (GIST), but the tumor increased in size. He was referred to our hospital for oral administration of sunitinib to reduce the tumor size. The tumor was 30 cm in diameter, and there were several peritoneal metastases around the liver. He began to take sunitinib in February 2009. The tumor increased in size from August 2010 but a partial remission was noted. We performed cytoreductive surgery in April 2011 as palliative care, but the tumor size increased again in October. We performed cytoreductive surgery again, but he died in December 2011. Although cytoreductive surgery for GIST is a potential treatment option, we suggest supportive care.

Narrow-band imaging on screening of esophageal lesions using an ultrathin transnasal endoscopy.

BACKGROUND AND AIM: Ultrathin transnasal endoscopy, used extensively in Japan, is considered to have inferior image quality and suction performance, and questionable diagnostic performance. So the aim of the present study was to compare the diagnostic performance of white light (WL) examination and non-magnified narrow-band imaging (NBI) examination in screening for esophageal disorders with ultrathin transnasal endoscopy. METHODS: A prospective case study of 105 consecutive patients screened for upper gastrointestinal disorders at a single clinic in Tokyo Medical University Hospital. All subjects were diagnosed using WL, NBI and Lugol-staining examinations. Areas ≥ 5 mm clearly not a Lugol-staining lesion were defined as esophageal disorders and the rates of detection of the two examination methods (WL vs NBI) were compared. RESULTS: For WL examination, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy (concordance rate) for esophageal disorders were 19.6%, 98.1%, 90.9%, 55.4%, and 59.2%, respectively, versus 60.8% 96.2%, 93.9%, 71.4%, and 78.6% for NBI. CONCLUSION: A useful level of diagnostic performance for esophageal disorders can be achieved with non-magnified narrow-band NBI ultrathin transnasal endoscopy.

[A case of liver metastases from gastric cancer treated with stereotactic body radiation therapy].

A 69-year-old man underwent distal gastrectomy in September 2007 for type 2 gastric cancer with liver metastasis (S5) in LM area (p-T2N3aM1, Stage IV). After the operation, we performed chemotherapy. But the liver metastasis was enlarged, so we performed a partial hepatectomy in July 2008. After hepatectomy, liver metastases appeared on S6 and S7 in February 2009. So we performed the fifth-line chemotherapy with paclitaxel. The effect of paclitaxel was not so good. Therefore, SBRT was performed for the liver metastases (S6/7 and S7) in December 2009 and February 2010. After SBRT, he had no recurrent tumor. SBRT was one of the effective treatments for liver metastases from gastric cancer.

Phase II study of combined chemotherapy with docetaxel, CDDP and 5-FU for highly advanced esophageal cancer.

Advanced esophageal cancer with widespread metastasis to lymph nodes or other organs is difficult to treat and has an extremely poor prognosis. A new combined chemotherapy of docetaxel with cisplatin (CDDP) and 5-fluorouracil (5-FU) (DPF therapy) was performed and its efficacy and safety were examined. Among those hospitalized between May 2003 and October 2009, 30 patients with stage III or stage IV unresectable, untreated advanced esophageal squamous cell carcinoma which had invaded other organs were enrolled in this study. The regimen of DPF therapy was as follows: a set of intravenous drips of 60 mg/m(2) of docetaxel (day 1), 60 mg/m(2) of CDDP (day 1) and 800 mg/m(2) of 5-FU (days 1-5) was administered twice at an interval of 3 to 4 weeks. Antitumor effects, adverse reactions and treatment outcomes were then examined. The patients included 26 men and 4 women aged 40 to 73 years (average age, 58.1 years), and the performance status (PS) was 1 in 18 cases and 2 in 12 cases. The main location of the esophageal cancer was the upper/middle/lower thoracic esophagus in 7/14/9 cases, respectively. Clinical stage was III in 5 cases and IV in 25. The effective rate of DPF therapy was 83.3% for the primary lesion (complete response, CR: 4 cases, partial response, PR: 21 cases), 72.4% for lymph node metastasis (CR: 3 cases, PR: 18 cases) and 72.0% for distant organ metastasis (CR: 3 cases, PR: 15 cases). The observed adverse reactions of grade 2 or higher of National Cancer Institute-Common Toxicity Criteria (NCI-CTC) included anemia (16.7%), leukopenia (73.3%), liver dysfunction (20.0%), anorexia (16.7%), stomatitis (33.3%), esophagitis (16.7%), alopecia (16.7%) and diarrhea (26.7%). The therapy completion rate was 96.7% and the therapy-related death rate was 3.3%. Treatments given after the completion of the DPF therapy were surgery in 6 cases, chemotherapy such as additional DPF in 12, chemoradiation in 4, esophageal stent placement in 1, and no treatment in 7. The patients' median survival time was 271 days, the 1-year survival rate was 41.9% and the 5-year survival rate was 13.3%. DPF therapy can be used as a standard chemotherapy for advanced esophageal cancer in view of its strong antitumor effect and relatively safe outcome.

Helicobacter pylori infection and reflux esophagitis in young and middle-aged Japanese subjects.

BACKGROUND AND AIMS: Helicobacter pylori infection rates are reported to be high in people over the age of 40 years, but are decreasing in younger age groups. A negative correlation has been reported between H. pylori infection and reflux esophagitis (RE). METHODS: The subjects were 418 patients who underwent esophagogastroduodenoscopy and measurement of serum immunoglobulin G H. pylori antibodies examined as part of their routine health checks. Their mean age was 39.2 +/- 8.3 years (range 22-58). We analyzed the RE findings (Los Angeles classification: A, B, C, D). RESULTS: The total H. pylori infection rate was 33.7% (141/418). By age group, infection rates were 15.7% in the 20-29 years group, 28.0% in the 30-39 group, 34.3% in the 40-49 group and 69.1% in the 50-59 group. The proportion of H. pylori-negative subjects with RE was 23.5% (20-29, 22.9%; 30-39, 31.7%; 40-49, 32.4%; 50-59, 41.7%), significantly higher than that (12.1%) in H. pylori-positive subjects (20-29, 0%; 30-39, 16.7%; 40-49, 12.2%; 50-59, 10.5%). The severity of RE increased with advancing age in H. pylori-positive subjects, but not in H. pylori-negative subjects. CONCLUSION: In this study, higher rates of RE were seen in H. pylori-negative subjects. It may be, however, that the presence of H. pylori infection influences the progression of RE.

[A long-term survival case of hepatic metastases after curative gastrectomy by combined therapies].

A 74-year-old female was performed distal gastrectomy (f-T3N0H0P0CY0M0, Stage II) for gastric cancer in 2003. After 14 months, CT scan showed a metastasis in S7 segment of the liver. We performed chemotherapies until seventh-line and radio-frequency ablation (RFA). It finally got a long-term survival of 36 months postoperatively. RFA may be one of the useful therapies of liver metastasis from gastric cancer.

[A case report of long-term survival of advanced gastric cancer (P1CY1) after gastrectomy].

A-57-year-old male was performed a total gastrectomy (f-T3N2H0P1CY1M0, Stage IV) for gastric cancer in 2004. We kept performing chemotherapies until the seventh-line, and the patient at last had a long-term survival of 46 months after surgery. If we recognized a tumor that had a tendency to be progressive, the long-term survival may be obtained by changing a regimen as early as possible.

[A case of stenosis of the reconstructed jejunum due to recurrent cancer after total gastrectomy in which stent-in-stent placement was effective].

OBJECTIVES: We report one case of stenosis of the reconstructed jejunum due to recurrent cancer after total gastrectomy in which stenting was effective and good QOL was achieved. CASE: The patient was a 70-year-old woman. In July 2000, the patient underwent total gastrectomy.Roux-en Y reconstruction with a diagnosis of gastric cancer. The pathological diagnosis was U-Post, Type 3, por 1, T3, N1, H0, P0, CY0, M0, and Stage IIIA. From 9 months after the operation, aphagia occurred and stenosis of the reconstructed jejunum was noted. Based on a biopsy of the stenosis, a diagnosis of post-operative recurrent gastric cancer was made. Although the patient received two cycles of low-dose FP therapy, complete response was not obtained, and the patient stayed at home under the IVH control for about 4 months. In June 2001, the patient was hospitalized for a stent placement due to the patient's request. METHOD: After a guide wire was endoscopically inserted and a good passage on the anal side of the stenosis was confirmed, a stent was placed. Self Expandable Metallic Stent (SEMS) was used. CLINICAL COURSE: Following the stent placement, the patient was able to ingest orally, but 6.5 months later, stenotic symptoms developed and another stent was deployed (stent in stent). CONCLUSION: Stenting is relatively simple and less invasive, which is useful for the improvement of QOL and in recurrent cases as well.

Impact of transnasal ultrathin esophagogastroduodenoscopy (UT-EGD) in the evaluation of esophageal peristaltic function.

BACKGROUND: We used transnasal ultrathin esophagogastroduodenoscopy (UT-EGD) to simultaneously perform realtime esophageal manometry and observe esophageal peristalsis. METHODS: The subjects were 22 healthy volunteers and 10 patients with proton-pump inhibitor (PPI) dependent gastroesophageal reflux disease (GERD). We induced the primary peristaltic wave associated with swallowing and observed it endoscopically in the lower esophagus, at the same time measuring the intraesophageal pressure using a manometry catheter. RESULTS: The mean primary peristaltic amplitude associated with swallowing was 65.6+/-47.4 mmHg in the volunteer group, and 28.0+/-25.6 mmHg in the GERD group. Although peristalsis was observed endoscopically in the GERD group, in some cases incomplete peristalsis left a small but definite lumen and in these subjects, the primary peristaltic wave was almost flat. CONCLUSIONS: The use of an ultrathin transnasal endoscope makes possible simultaneous manometry and endoscopic observation of the esophagus. This combination should prove useful in the evaluation of esophageal peristaltic function, such as in the diagnosing of GERD.

Usefulness of serum protein profiling for prediction of preoperative chemoradiosensitivity of esophageal cancer.

We examined whether serum protein profiling is a reliable index for prediction of therapeutic efficacy of preoperative chemoradiotherapy (PCRT) in advanced esophageal cancer compared with evaluation of the efficacy of conventional clinical examination. We entered 42 patients who received PCRT and surgery between 1998 and 2002 into this study. Serum protein profiling was performed using the preoperative serum of the patient to select the marker set that enabled the efficacy of PCRT to be evaluated accurately. The efficacy of PCRT was predicted with the marker set, and the sensitivity, specificity and accuracy of the method were calculated based on evaluation of the efficacy by pathological examination. Similarly, therapeutic efficacy was also predicted based on evaluation of the efficacy of conventional clinical examination, and the results were compared with those of prediction by serum protein profiling. The correlation between each predictive examination and outcome was evaluated. The sensitivity, specificity and accuracy of prediction of therapeutic efficacy of PCRT by serum protein profiling were 90.9, 100 and 93.3%, respectively. In clinical examination, prediction of the efficacy of PCRT by three methods was as follows: by esophagography, sensitivity 76.0%, specificity 17.6%, accuracy 52.4%; by endoscopy, sensitivity 80.0%, specificity 11.8%, accuracy 52.4%; by computed tomography, sensitivity 60.0%, specificity 47.1%, accuracy 54.8%, respectively. These results demonstrated the superiority of serum protein profiling in predicting the therapeutic efficacy of PCRT compared with conventional clinical examination. Moreover, serum protein profiling was the only significant prognostic factor as regards the correlation with outcome by multivariate analysis.

[Long survival and effective treatment of unresectable gastric cancer by TS-1 based chemotherapy with a sequential combination].

We report a case of peritoneal cancer dissemination and cytological appearance of cancer cells with Type 4 gastric cancer. Treatment with unichemotherapy and combination chemotherapy with TS-1 proved successful. The patient was a 58-year-old female,who complained of abdominal pain. She was diagnosed as unresectable Type 4 gastric cancer, T 3 NxH 0 P 1 CY 1 M 0, Stage IV (cytology: Class V). Thirteen days after surgery, chemotherapy with TS-1 (80 mg/body/day, 4 weeks) at 2-week intervals in 1 course was performed. However, due to side effects with marrow restraint of grade 1, we changed to the following chemotherapy regimen: TS-1 (80 mg/body/day, 2 weeks) at 4-week intervals as 1 course (23 courses in total). After 16 courses, a partial response (PR) was noted. As additional therapy to recover tumor marker (CA19-9) after 21 courses, combination chemotherapy with TS-1 (80 mg/body/day, 2 weeks) and CDDP (25 mg/body/day, day 1, 8, 15 drip infusion) was performed as one course. This chemotherapy was then performed in 3 courses and tumor markers did not deteriorate, so we changed docetaxel (DOC) (50 mg/body/day(day 1)) to CDDP, and tumor markers returned to the normal value. No recurrence and no side effects appeared (hematological or non-hematological) during this combination chemotherapy.

[A long-term survival case of metachronous liver metastasis from gastric cancer].

A 62-year-old man was admitted for gastric cancer. He was performed a distal gastrectomy with Billroth I reconstruction in August 1999. Then he had remnant gastric cancer and metachronous liver cancer in November 2002. He was performed a total gastrectomy and partial hepatic resection. The histological findings of remnant stomach and liver cancer showed a same pattern of the primary gastric cancer. Another metachronous liver cancer appeared in March 2006. He was treated with chemotherapy using S-1 (day 1-21) and CDDP 20 mg/m2 (day 1, 8 and 15) q5w. The size of liver metastasis was kept the same for 16 months.

[Bone metastasis of gastric cancer].

We evaluated 19 patients with bone metastasis after surgery for gastric cancer. In a number of cases, the located in the tumor was U and M region, of macroscopic 3, and the histological type was poorly-differentiated adenocarcinoma with high-grade of lymphatic invasion. The major symptom was lumbago and back pain. The serum AFP level was high in 73.7% of the cases, and LDH was high in 47.7%. The metastatic lesion was predominantly seen in the bone with red pulp such as lumbar and thoracic vertebra and rib. The median survival time was 189 days (range: 24-509) with a poor prognosis. However, newly developed anticancer drugs were very effective for some cases, indicating that such chemotherapy should be tried for cases with bone metastasis.

Vitamin K2-induced antitumor effects via cell-cycle arrest and apoptosis in gastric cancer cell lines.

Vitamin K2 (VK2) has a growth inhibitory effect on various types of cancer cells in vitro, and its efficacy has been demonstrated in clinical applications in a number of patients with leukemia and hepatocellular carcinoma. In this study, the effect of cell growth inhibition and apoptosis induction and the concomitant use of an anticancer agent by VK2 (menaquinone: MK4), on gastric cancer cell lines were examined. When 4 kinds of gastric cancer cells (KATO III, MKN7, MKN74 and FU97) were exposed to MK4, the cell growth was inhibited in an MK4 dose-dependent manner. Morphologically, apoptosis induced by MK4 was recognized in FU97, but only a slight number of apoptotic images was recognized in other cell lines. On the contrary, in all the cell lines, the percentage of APO2.7 positive cells increased significantly in the MK4-treated group as compared to the controls. Caspase-3 activity increased significantly in KATO III and FU97 as compared to the controls, while no significant differences were noted in MKN7 or MKN74. Moreover, in all the cell lines, the percentage of G0/G1-phase cells ( approximately 70% in KATO III and FU97, and > or =80% in MKN7 and MKN74) increased in comparison to the controls, suggesting that cell-cycle arrest had occurred. All of the gastric cancer cell lines were given MK4 in different concentrations and two kinds of anticancer agent, with the result that cell growth was inhibited by the anticancer agent in a dose-dependent manner when it was given with MK4 in concentrations of up to 10 microM. In conclusion, our results demonstrate that the effect of MK4 on apoptosis and cell-cycle arrest differs in differentiated (MKN7, MKN74) and undifferentiated (KATO III, FU97) gastric cancer cell lines, and that MK4 alone or with anticancer agents has an antitumor effect on gastric cancer cell lines.

[The efficacy of gastrojejunostomy for patients with unresectable gastric cancer].

We evaluated the efficacy of gastrojejunostomy for patients with unresectable gastric cancer. Thirteen patients had undergone gastrojejunostomy (GJ group) and 14 patients who couldn't receive gastrojejunostomy, but had only been observed into their abdomen in the operation (S group). Between two groups, there were no significant differences in the effective rate, median survival time and the number of dates the patient stayed home after the operation. Gastrojejunostomy was useful for patients with a strong case of stenosis in the stomach, and may improve the quality of life as one of the multimodal therapy.

[The efficacy of intra-peritoneal chemotherapy for the patients with cytology positive gastric cancer].

In this study, we assessed efficacy of repeated intra-peritoneal chemotherapy with CDDP for patients with cytology positive gastric cancer. The median survival time was 338 days, 1-year survival was 60% and 2-year survival was 45% of the patients. The POCY1 patients with repeated intra-peritoneal chemotherapy yielded a tendency to extend the survival rate than the patients without repeated intra-peritoneal chemotherapy (p = 0.06). But, no differences were found between the survival rate of P1CY1 patients with or without repeated intra-peritoneal chemotherapy. The patients using more than 3 anti-cancer drugs yielded a tendency to have a better prognosis than the patients using 2 or less anti-cancer drugs (p = 0.09). There was a possibility to which the multidiscipline treatment was effective for the POCY1 gastric cancer patients.

Overexpression of protein kinase Cdelta enhances cisplatin-induced cytotoxicity correlated with p53 in gastric cancer cell line.

OBJECTIVE: An important issue in cancer therapy is to investigate the mechanism for cellular sensitivity to anticancer agents such as cisplatin. Cisplatin is one of the DNA-damaging agents and several factors including p53 are related to the sensitivity to cisplatin in cancer. Protein kinase C (PKC) delta is known as a positive regulator for cisplatin-induced cell death. In our present study, we examined whether overexpression of PKCdelta and p53 increases the sensitivity of the human gastric cancer cell line, MKN28, which has a mutation of p53 gene, to cisplatin. METHODS: Cell viability and DNA content were measured in MKN28 with adenovirus-mediated expression of PKCdelta and p53 after exposure to cisplatin. In addition, the active form of caspase-3 was detected by Western blotting. RESULTS: Overexpression of exogenous PKCdelta did not induce cell death in MKN28 but inhibited cell growth at 1 microg/ml cisplatin as compared to that by cisplatin alone. Moreover, overexpression of both wild-type p53 and exogenous PKCdelta in MKN28 increased cisplatin-induced cell death in MKN28. CONCLUSION: These results suggest that PKCdelta, in cooperation with p53, possibly regulates cisplatin-induced caspase-3-mediated cell death in gastric cancer.

Concurrent preoperative chemoradiotherapy for stage III or IV esophageal squamous carcinoma.

The poor progress of advanced esophageal carcinoma cannot be expected to be improved by surgical treatment alone. We retrospectively examined the results of surgery alone (SA: 39 cases) and of concurrent preoperative chemoradiation therapy (PCRT: 51 cases) for stage III or IV esophageal squamous carcinoma. In the PCRT group, the rate of pathological complete response was 31.4% for the primary lesion and 31.1% for metastatic lymph nodes, which viable cancer cells were not recognized in either region in 25.5% of all cases. In the PCRT group, grade 2 or more toxicity was found in 39 cases of leukopenia, 10 cases of anemia, 7 cases of thrombocytopenia, 11 cases of esophagitis, 4 cases of stomatitis, 2 cases of nausea, 2 cases of diarrhea, 2 cases of liver disfunction and 2 cases of infection. In 2 cases, PCRT was terminated for about 3 weeks because of thrombocytopenia. In the remaining 49 cases, PCRT was administered as scheduled. No statistically significant differences were noted between the PCRT group and the SA group in postoperative complications. There was postoperative recurrence in 16 cases (31.4%) in the PCRT group and 26 cases (66.7%) in the SA group (p=0.008). In stage III, the 5-year survival rate was 58.6% for the PCRT group and 17.2% for the SA group (p=0.022). In stage IV, the survival rate was 0% for the SA group and 16.7% for the PCRT group, showing better results in the latter, although there was no statistically significant difference. Multivariate analysis of prognostic variables revealed that therapeutic method (presence or absence of PCRT) contributed the greatest to the prognosis. These results indicate that PCRT is an effective adjuvant therapy for squamous cell carcinoma.