Update on our investigation of malignant tumors associated with Peutz-Jeghers syndrome in Japan.

PURPOSE: To investigate the recent incidence of malignant tumors associated with Peutz-Jeghers syndrome (PJS) in Japan to clarify if there are any differences in malignant tumor risk and the spectrum of malignancies by reviewing the literature on this subject. METHODS: We reviewed PJS cases reported in 1115 papers in Japan between January, 1989 and December, 2014. RESULTS: Malignant tumors were identified in 186 of the total 583 PJS cases from 523 evaluable studies. The estimated cumulative risk of a malignant tumor was 83.0 % at 70 years of age. Compared with a previous study, on a collective 91 cases reported up until 1988 in Japan, the reported proportion of gastrointestinal malignancies decreased, from 82.4 to 48.3 %, whereas that of gynecological malignancies increased, from 8.8 to 34.3 % (P < 0.01). Moreover, breast cancers were occasionally reported (4.8 %), even though none were reported in the previous study. Adenocarcinoma of the uterine cervix was the most common malignant tumor (46.8 %) among women with PJS. CONCLUSIONS: The increased number of reports of cervical adenocarcinoma in women with PJS is the prominent trend in Japan, and a subject of concern among gynecologists. The risk of breast cancer seems to be increasing, but confirmation of this trend will require further investigation.

Oncologic outcome of stages II/III colon cancer treated via minilaparotomy.

We analyzed clinicopathologic, surgical, and survival data on consecutive series of patients with stages II/III colon cancer for whom curative resection via minilaparotomy (skin incision, < or = 7 cm) was attempted between September 2002 and March 2009 to clarify the oncologic safety of this type of surgery. There were 64 men and 55 women; the median age was 70 years (range, 25-91 years). The median body mass index was 21.7 kg/ m2 (range, 15.1-28.9 kg/m2). The minilaparotomy approach was successful in 115 cases (96.6%). The cumulative 5-year disease-free and overall survival rates were 89.7% and 82.4%, respectively, in patients with stage II disease (n = 62) and were 68.4% and 82.4%, respectively, in patients with stage III disease (n = 57), all of which were compatible with those of the historical control patients who underwent conventional open surgery. Minilaparotomy approach for stages II/III colon cancer seems to be oncologically equivalent to conventional open surgery.

The effect of meloxicam, a selective COX-2 inhibitor, on the microvasculature of small metastatic liver tumors in rats.

BACKGROUND: COX-2 is involved in tumor angiogenesis and modulation of the production of angiogenetic factors by colorectal carcinoma cells. It has been shown that COX-2 inhibitors have inhibitory activities against various types of tumor, including colorectal carcinoma. In this study, we investigated the tumor vessels of small metastatic liver tumors in rats and the effect of meloxicam, a selective COX-2 inhibitor, on their growth and microvasculature. METHODS: The metastatic liver tumors were produced by intraportal inoculation of RCN-H4 cells in male F344/DuCrj rats (n = 40). The microvasculature was examined by scanning electron microscopy and stereomicroscopy. Microvascular casts were produced by perfusion via the abdominal aorta 14 days after tumor inoculation. Four groups (control, groups 1-3) of rats were treated with meloxicam 0, 0.6, 1.0 and 3.0 mg/kg/day, respectively, by oral gavage 5 days/week for two weeks from the day of inoculation of RCN-H4 cells. RESULTS: The mean number of tumors was significantly decreased in groups 1-3 (5.6+/-0.8 standard deviation, SD; 3.6+/-1.1; and 5.5+/-1.1, respectively) compared with control (11.2+/-2.7; P = 0.0002, each). Meloxicam also significantly reduced the mean diameter of the tumor: 730+/-254, 685+/-212 and 644+/-139 in groups 1-3, respectively, in comparison with 870+/-276 in control (P = 0.0025, 0.0011 and <0.0001, respectively). CONCLUSIONS: Meloxicam's anti-angiogenic activity interferes with the growth of metastatic liver tumors. Meloxicam might have therapeutic potential for liver metastasis of colorectal carcinoma.

[Expression of mRNA levels of thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase and orotate phosphoribosyltransferase in diffusely infiltrating colorectal cancer].

Little is known about the expression levels of thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyltransferase (OPRT) in diffusely infiltrating colorectal cancer. We semiquantified the mRNA levels of these enzymes in colorectal cancer specimens from 10 patients with diffusely infiltrating type and 20 patients with other types (control) matched by the maximal diameter and pathological stage, using the Dannenberg tumor profiling method. The relative expression of these enzymes did not significantly differ between diffusely infiltrating and other types of tumors. There were no significant relationships among the relative expression of the four enzymes in the diffusely infiltrating tumors, while the following three combinations were found to be correlated with each other in the control tumors: TS versus TP,TS versus DPD, and TP versus DPD. In 5 patients who received 5-fluorouracil-based chemotherapy for evaluable lesions, there were no specific relationships between the expression of these enzymes and therapeutic response. In conclusion, diffusely infiltrating colorectal cancer does not appear to have any characteristics in terms of the expression of these enzymes, which may not alter the effect of 5-fluorouracil-based chemotherapy.

[Five cases of pseudomyxoma peritonei underwent abdominal lavage and administering CDDP].

We examined five cases of pseudomyxoma peritonei with treatments of cytoreduction surgery, abdominal lavage and intraperiotoneal administration of cisplatin (CDDP). These primary lesions contained one case of pancreas and four cases of appendix. Histological types contained one case of well differentiated adenocarcinoma and four cases of signet ring cell carcinoma. All cases underwent a resection of primary lesion and muconodule, abdominal lavage with saline and 5% glucose or low molecule dextran solution. CDDP was administered into the abdominal space during and after the surgery, a total amount of 100 to 400 mg/body. There were no cases of collected ascites within one year, except one case that we could not follow. There was a possibility that a short-term quality of life was improved by multidiciplinary therapy containing cytoreduction surgery and intraperiotoneal administration of CDDP.

[Squamous cell carcinoma of the anal canal in the elderly showing complete response following radiotherapy--a case report].

We reported an elderly case of squamous cell carcinoma of the anal canal which showed complete response following radiotherapy alone. An 86-year-old man complaining of anal bleeding and pain was admitted. Colonoscopy showed a type 1 tumor just above the dentate line. Biopsy revealed squamous cell carcinoma. Serum SCC Level before treatment was elevated (8.4 ng/mL). Magnetic resonance imaging did not show any metastatic lesions. Since the patient and his family members refused a surgical intervension and chemotherapy, he received an external radiotherapy (total dose: 60 Gy) to the pelvic space and showed complete response after radiotherapy. He is alive without evidence of recurrence about three years after the radiation, although serum SCC is slightly elevated.

[Relationship between the size and metastasis of hepatic lymph nodes in patients with synchronous liver metastasis of colorectal cancer].

BACKGROUND AND PURPOSE: This retrospective study was performed to examine the relationship between the size and metastasis of hepatic lymph node in patients with liver metastasis of colorectal cancer. PATIENTS AND METHODS: We analyzed a total of 163 hepatic lymph nodes that were removed during surgery from 55 patients with synchronous liver metastasis of colorectal cancer, who underwent resection of primary tumor without any residual lesions except for liver metastasi (e) s. The relationship between the size and metastasis was examined on paraffin-embedded specimens. RESULTS: The maximal and minimal diameters were significantly greater in positive lymph nodes (n=35) than in negative lymph nodes (n=128). The area under the curve of receiver operating curve for predicting metastasis by size was 0.69. The sensitivity, specificity, and accuracy were 62.9%, 60.9%, and 61.4%, respectively, when the cutoff value was set at 7 mm. CONCLUSION: These findings suggest that selecting patients with hepatic lymph node metastasis based on the size of lymph nodes would be difficult.

[A case of pseudomyxoma peritonei successfully treated with multidisciplinary treatment including modified FOLFOX6 regimen].

We report a case of pseudomyxoma peritonei caused by carcinoma of the appendix, which was successfully treated with multidisciplinary treatment including modified FOLFOX6 regimen. A 45-year-old man was diagnosed as having peritoneal dissemination associated with cancer of the cecum or appendix. Seven cycles of mFOLFOX6 treatment resulted in a marked decrease in ascites and serum levels of carcinoembryonic antigen and carbohydrate antigen 19-9. At laparotomy, a diagnosis of pseudomyxoma peritonei caused by cancer of the appendix was made. Intraperitoneal lavarge with 10,000 mL 5% glucose was performed after right hemicolectomy, omentectomy and removed of mucinous peritoneal nodules. Intraperitoneal chemotherapy comprised of 3000 mL low molecule dextran and 80 mg cisplatin was added on postoperative days 7 and 14. Modified FOLFOX6 regimen was started again two months postoperatively and reached 28 cycles. The patient does not show any sign of recurrence 12 months postoperatively.

[Squamous cell carcinoma of the anal canal showing complete response following chemoradiotherapy--a case report].

We report a case of squamous cell carcinoma of the anal canal which showed complete response following chemoradiotherapy. A 54-year-old woman was diagnosed as having squamous cell carcinoma of the anal canal (T2N0M0 stage II). Chemoradiotherapy comprising peroral tegafur/uracil and external radiotherapy (60 Gy) to the pelvic space resulted in complete response 4 months after the initiation of the treatment. PET-CT showed recurrence in paraortic lymph node, right sacral and left pubic bone 11 months after the initiation of treatment, although the primary lesion did not relapse. The patient is now given 5-fluorouracil/cisplatin in addition to external radiotherapy (57.5 Gy) to the metastatic lymph node. This case suggests that we should take measures to prevent distant metastases in the treatment of squamous cell carcinoma of the anal canal.

[Hepatic lymph node involvement in patients with synchronous multiple liver metastases of colorectal cancer].

BACKGROUND AND PURPOSE: Hepatic arterial infusion chemotherapy for unresectable liver metastases of colorectal cancer is generally indicated to patients without extra hepatic lesions. This study was performed to examine the status of hepatic lymph node metastasis as an extra hepatic lesion in patients with synchronous multiple liver metastases of colorectal cancer. PATIENTS AND METHODS: A total of 111 hepatic lymph nodes were removed from 33 patients with synchronous liver metastases of colorectal cancer during resection of the primary tumor at the D2- or D3- level. The frequency of hepatic lymph node metastases and factors predictive for hepatic lymph node metastasis were examined. RESULTS: Hepatic lymph node metastasis was detected in nine patients (27%): The sites were classified into three categories: (1) along the hepatic arteries in three, (2) in the hepato-duodenal ligament except the peri-hepatic arterial region in three, and (3) both in three. The serum level of CEA (p = 0.02), CA19-9 (p = 0.05), and the rate of lymph node metastasis of the primary lesion (p = 0.08) were higher or tended to be higher in patients with hepatic lymph node metastases than in those without. There was no significant relationship between the involvement of hepatic lymph nodes and the other clinicopathologic factors examined. CONCLUSION: We should note the frequency of hepatic lymph node metastasis in the treatment of unresectable liver metastases of colorectal cancer.

[The relationship between plasma level of VEGF or soluble Flt-1 and efficacy of hepatic arterial chemotherapy in patients with liver metastasis of colorectal cancer].

PURPOSE: To clarify the clinical significance of determining plasma levels of vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) in colorectal cancer, changes in plasma levels of VEGF and sFIt 1 during hepatic arterial chemotherapy were investigated in patients with liver metastases of colorectal cancer. PATIENTS AND METHODS: The relationship between plasma level of VEGF or sFlt-1 and serum level of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), or the efficacy of hepatic arterial chemotherapy was investigated in patients with liver metastases of colorectal cancer (n=19). Plasma levels of VEGF and sFlt-1 were determined by the enzyme linked immunosorbent assay. RESULTS: There was a positive relationship between plasma level of sFlt-1 and serum level of CEA (p = 0.13). The other combinations did not show any statistical correlations. Also, in terms of the doubling time (DT), there was a positive relationship between the sFlt1-DT and the CEA-DT (p = 0.04). The levels of VEGF tended to change in accordance with the efficacy of chemotherapy. In contrast, plasma levels of sFlt-1 increased in patients with the progressive disease, whereas the levels did not decrease in patients with the partial response. CONCLUSIONS: These results suggested that (1) VEGF may be a useful tumor marker during the chemotherapy in patients, whose CEA and CA19-9 are below the cutoff, and (2) the shrinkage of liver metastases may not cause a decrease in sFlt-1 or the half-life of sFlt-1 may be considerably long.

JTE-522, a selective COX-2 inhibitor, interferes with the growth of lung metastases from colorectal cancer in rats due to inhibition of neovascularization: a vascular cast model study.

The lung is a frequent site of metastasis from colorectal cancer, but angiogenesis of lung metastases has not been clarified. Some COX-2 inhibitors prevent tumor growth, although the inhibitory mechanism at the metastatic site is obscure. We investigated the microvascular structure of small lung metastases and the effect of JTE-522, a selective COX-2 inhibitor, on the angiogenesis of pulmonary metastases from colorectal cancer in rats. The tail veins of 25 male F344/DuCrj rats, aged 5 weeks, were injected with a tumor suspension containing 5 x 10(6) RCN-9, a rat colon cancer cell line. Three weeks later, pulmonary vascular resin corrosion casts were taken and the vascularity of metastases was studied using stereo and scanning electron microscopes. We investigated the effect of 0, 10 and 30 mg/kg/day of JTE-522 on the angiogenesis of pulmonary metastases in 3 groups of 5 male rats out of 25. JTE-522 reduced the diameter of tumor vessels as well as the number and size of metastatic tumors. The diameter of tumor vessels and the size of lung metastases significantly and positively correlated with neovascularization in the control group, but not in the JTE-522-treated groups. JTE-522 also affected type of vasculature of metastases, which differed depending on their size. JTE-522 interfered with the growth of hematogenous metastatic tumors by disrupting neovascularization. However, JTE-522 may have some important mechanisms other than inhibition of neovascularization. JTE-522 may be one of the therapeutic agents for the treatment of hematogenous metastasis of colorectal cancer.