Masahito Tanimizu

Circulating vascular endothelial growth factor (VEGF) is a possible tumor marker for metastasis in human hepatocellular carcinoma

Abstract: Vascular endothelial growth factor (VEGF) is closely related to angiogenesis in various human cancers. However, little is known of its circulating levels in hepatocellular carcinoma (HCC). We examined circulating VEGF levels in chronic liver disease to assess their clinical significance. Plasma VEGF concentrations were determined, by enzyme immunoassay, in patients with chronic hepatitis (CH; n = 36), liver cirrhosis (LC; n = 77), and HCC (n = 86) for a cross-sectional study. Plasma VEGF levels in healthy controls (n = 20) and CH, LC, and HCC patients were 17.7 ± 5.4 (mean ± SD), 30.6 ± 22.8, 34.4 ± 27.0, and 51.1 ± 71.9 pg/ml, respectively. The levels were significantly elevated in the HCC group, compared with the control, CH, and LC groups. Plasma VEGF levels in stage I, II, III, IVA, and IVB HCC patients were 27.6 ± 16.1, 26.5 ± 13.7, 35.8 ± 15.3, 45.4 ± 39.4, and 103.1 ± 123.2 pg/ml, respectively. The stage IVB patients with remote metastasis showed significantly marked elevation compared with the patients at the other stages. Platelet numbers were weakly correlated with plasma VEGF levels in the HCC group. Plasma VEGF level was highly elevated in patients with HCC, particularly those with metastatic disease. We consider that plasma VEGF is a possible tumor marker for metastasis of HCC. Circulating VEGF may be derived mainly from the large burden of tumor cells, and partly from platelets activated by the vascular invasion of HCC cells.

Perceptions and attitudes of clinical oncologists on complementary and alternative medicine: a nationwide survey in Japan.

The prevalence of complementary and alternative medicine (CAM) is increasing worldwide because of the growing public interest in natural or holistic therapies and because of the flow of information through the Internet. However, there is a lack of communication between cancer patients and their physicians on topics relating to CAM. The authors performed a cross‐sectional survey to evaluate the perceptions and attitudes of Japanese clinical oncologists toward cancer CAM.

Plasma level of basic fibroblast growth factor increases with progression of chronic liver disease

Basic fibroblast growth factor (FGF) is thought to be involved in carcinogenesis and, to clarify its clinical significance, the study of its blood level in cancer patients is important. Plasma levels of basic FGF are reported to be elevated in some cancers. However, little is known of basic FGF levels in plasma in hepatocellular carcinoma (HCC). In this study, we measured basic FGF plasma levels in patients with chronic liver disease and compared the levels in chronic hepatitis (CH), liver cirrhosis (LC), and HCC. We also examined whether these levels were related to serum levels of asparate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, alkaline phosphatase, leucine aminopeptidase, total bilirubin, total protein, and albumin, and to the indocyanine green test (i.e., liver function tests) and to type III procollagen, 7S domain of IV type collagen, and hyaluronic acid (i.e., markers of liver fibrosis). Levels of basic FGF. determined by a quantitative “sandwich” enzyme immunoassay, were significantly elevated with the progression of liver disease; being 3.67 ± 2.37 (mean ± SD), 7.78 ± 6.61, and 12.37 ± 7.67pg/ml in the CH, LC, and HCC groups, respectively. FGF levels were elevated to a greater extent in the HCC patients than in the CH (P<0.0001) and LC patients (P=0.0117). Levels were higher in LC than in CH (P=0.0204). None of the liver function test findings or levels of markers of liver fibrosis were correlated with levels of basic FGF. These results suggest that circulating basic FGF could serve as a new indicator of the progression of chronic liver disease. The extremely elevated plasma of level basic FGF in the HCC group suggests that basic FGF may be related to the development of HCC.

Multicenter Prospective Study on Efficacy and Safety of Octreotide for Inoperable Malignant Bowel Obstruction

OBJECTIVE The aim of this study was to evaluate the efficacy and safety of octreotide for malignant bowel obstruction in a multicenter study. METHODS Terminally ill patients diagnosed with inoperable malignant bowel obstruction were treated with octreotide 300 microg/day. The primary endpoint was the overall improvement rate of subjective abdominal symptoms. The degrees of nausea, vomiting, abdominal pain, distension, anorexia, fatigue, thirst and overall quality of life were evaluated by the self-rating scores selected from the MD Anderson Symptoms Inventory and Kuriharas Face Scale. RESULTS Forty-nine patients were enrolled in the study, and 46 patients received study treatment, including 17 gastric, 13 colorectal, 7 ovarian and other cancers. The median survival time was 25 days. The number of vomiting episodes significantly correlated with the MD Anderson Symptoms Inventory nausea and vomiting scores (P< 0.001) before octreotide treatment. Of 43 patients evaluable for efficacy, the scores of all the MD Anderson Symptoms Inventory items except abdominal pain and the number of vomiting episodes improved during the first 4 days of octreotide treatment (P< 0.0062). The MD Anderson Symptoms Inventory scores were decreased in 59-72% of patients, and overall quality-of-life scores improved in 56% of patients. No serious adverse events were observed. CONCLUSIONS The high improvement rate in abdominal symptoms suggested the efficacy of octreotide in terminally ill patients with malignant bowel obstruction.

Granular cell tumor occurring in the sigmoid colon treated by endoscopic mucosal resection using a transparent cap (EMR-C)

A case of granular cell tumor occurring in the sigmoid colon is reported. The patient, a 56-year-old man, visited our hospital for further evaluation of occult blood in his stool. Endoscopic examination revealed a yellowish, hemispheric submucosal tumor (SMT) with redness, about 6 mm in diameter, in the sigmoid colon. Endoscopic mucosal resection using a transparent cap (EMR-C) was performed, and histological examination revealed that the tumor consisted of a nested growth of large tumor cells with ample granular cytoplasm and small round nuclei. The tumor cells expressed S-100 protein and were stained with neuron-specific enolase (NSE) and periodic acid-Schiff, but were negative for desmin, vimentin, and cytokeratin. The resected tumor was diagnosed as a granular cell tumor. This may be the first report of a colorectal granular cell tumor successfully treated with EMR-C.

Evaluation of endoscopic injection sclerotherapy with and without simultaneous ligation for the treatment of esophageal varices.

Abstract: For more effective and simple endoscopic injection sclerotherapy (EIS) for esophageal varices, we developed an EIS procedure with ligation (EISL) that is non-invasive, in which EIS and endoscopic variceal ligation (EVL) are performed simultaneously. In this study, we compared EISL and EIS in a randomlized sample of patients (n = 14 for each procedure). For EISL, EVL was performed, including the injection site, after the injection of 5% ethanolamine oleate with iopamidol (EOI) into a varix. The mean number of treatment sessions required for eradication of esophageal varices was 2.3 ± 0.5 for EISL and 3.9 ± 0.8 for EIS (P < 0.001); the mean number of treatment sites was 6.2 ± 2.2 for EISL and 14.0 ± 5.0 for EIS (P < 0.001); the mean total amount of EOI used was 13.8 ± 5.2 ml for EISL and 26.3 ± 9.8 ml for EIS (P < 0.001). There were no significant differences in rates of recurrence of varices or in bleeding between the two groups. For EISL, fewer treatment sessions and less sclerosant were sufficient, probably because the sclerosants were more effective due to the blockage of variceal blood flow by the ligation. This method should provide a novel modification of EIS.

Extensive liver metastasis of gastric cancer effectively treated by hepatic arterial infusion of 5-fluorouracil/cisplatin

Most gastric cancer patients with jaundice caused by extensive liver metastasis show no tumor shrinkage response to systemic chemotherapy, while often showing severe adverse reactions. Their prognosis is very poor. We experienced two patients for whom hepatic arterial infusion (HAI) of 5-fluorouracil (5-FU) and cisplatin through an implantable port was effective for treating extensive liver metastasis. One patient had jaundice (serum bilirubin level before HAI therapy, 12.4 mg/dl) caused by metachronous liver metastasis, and prior systemic chemotherapy with 5-FU and irinotecan had not been effective. The other patient had gastric cancer with synchronous liver metastasis and also exhibited jaundice (serum bilirubin level before HAI therapy, 11.8 mg/dl). Both patients were treated with HAI of cisplatin, 20 mg/m2 for 30 min on day 1, and continuous intraarterial infusion of 5-FU, 300 mg/m2, from day 1 to day 4 every week. Their metastatic liver tumors were significantly reduced in volume and the jaundice disappeared. They survived for 30 and 27 weeks, respectively. A pharmacokinetic study conducted during the period of partial remission revealed that the extraction ratios of 5-FU and cisplatin in the liver were 0.89 and 0.024, respectively, suggesting a favorable first-pass effect of 5-FU. Although our findings here suggest that the successful local control of liver metastasis could improve the deteriorated condition and prolong the survival in some patients with far advanced cancer, it is essential to pay much attention to possible adverse effects during the treatment.

A case of small undifferentiated intramucosal gastric cancer with lymph node metastasis

Early gastric cancer (EGC) has a favorable prognosis after surgical gastrectomy. For intramucosal EGC with little risk of lymph node metastasis, endoscopic mucosal resection (EMR) is an accepted treatment method. Herein we document a noteworthy case of small undifferentiated gastric cancer with nodal metastasis. A 60-year-old Japanese woman underwent gastrectomy with D2 lymph node dissection for the treatment of EGC in the lower gastric body. Histological examination revealed that signet-ring cell carcinoma was located in approximately one-third of the superficial portion of the mucosal layer, with a tumor size of 13 mm. No lymphatic invasion, venous invasion, or fibrosis was observed in the submucosal layer. This case had nodal metastasis and was finally diagnosed as stage IB (T1N1M0) according to the Japanese Classification of Gastric Carcinoma (JCGC). The patient is alive without recurrence 6 years after treatment.

Validation analysis of Japanese histological classification of breast cancer using the National Summary of Hospital Cancer Registry 2007, Japan

Using the National Summary of Hospital Cancer Registry 2007, Japan, (HCRJ) from 219 local core cancer hospitals (LCCH) that had registered more than 29 breast cancers, we validated the Japanese classification of breast cancer (JCBC). In JCBC, most invasive ductal carcinomas (IDC) are subclassified as papillotubular carcinoma (coded as 850031 in the HCRJ) or scirrhous carcinoma (850033). Because of the confusing criterion that IDC with substantial ductal carcinoma in situ (DCIS) is papillotubular carcinoma, pathological T (pT)1 might be overestimated as pT2–3 by measuring the tumor size to include DCIS at LCCH where papillotubular carcinoma is diagnosed correctly. The LCCH were divided based on the difference between the proportion of papillotubular carcinoma to scirrhous carcinoma (PPS), that is, the proportion of 850031 cases to the sum of 850031 and 850033 cases at each LCCH (mean: 45.6%), and the PPS of the LCCH whose in‐house histological classification was the origin of JCBC (standard PPS [StPPS]: 42.3%), into G5 (PPS within StPPS ± 5%), L5 (PPS < StPPS–5%), HL (StPPS + 15% ≥ PPS > StPPS + 5%), and HH (PPS > StPPS + 15%). On pT2–3, the proportion of N1–3 cases to N0 in G5 and HL was significantly lower than that in L5. The averages of the proportion at each LCCH of G5 and HL were also significantly lower than that of L5. Meanwhile, on pT1, the proportions and averages were not significantly different among the groups. The frequent overestimation of pT in G5 and HL explains their lower frequency of lymph nodal metastasis on pT2–3, leaving the frequency on pT1 unchanged. The JCBC has spoiled the accuracy of pTNM. (Cancer Sci 2011; 102: 1597–1601)

Present situation of pTNM classification in Japan: Questionnaire survey of the pathologists of Gan‐shinryo‐renkei‐kyoten Byoin (local core cancer hospitals) on pTNM classification

pTNM classification is the most important element of surgical pathology. Internationally, the International Union against Cancer (UICC)‐TNM is the standard TNM classification. In the present study questionnaires about the pTNM were sent to the pathology divisions of 288 institutions designated as Gan‐shinryo‐renkei‐kyoten Byoin (local core cancer hospitals) on the basis of the Cancer Control Act. The questionnaire consisted mainly of questions about the TNM. There were 78 respondents, including 70 qualified pathology specialists, with a mean of 18.4 years of experience. The recognition rate of the important basic rules of the UICC‐TNM were as follows: ‘When in doubt, select the lower’: 63.6% (49/77); ‘Direct invasion to a lymph node is an N component’: 61.0% (47/77); ‘Only the extension of an invasive cancer is a T component’: 45.5% (35/77). Few respondents knew the UICC criteria for judging whether multiple pulmonary lesions represent metastatic or multiple primary lesions. Only 26 (36.4%) of 77 pathologists were informed about cTNM routinely, suggesting that neither pathologists nor clinicians possess adequate knowledge about pTNM classification in many institutions. It is recommended that pathologists be informed about the rules and importance of pTNM through education, the revised Japanese classification of cancers, and self‐assessment of their own institutes.