Abundant expression of CXCL9 (MIG) by stromal cells that include dendritic cells and accumulation of CXCR3+ T cells in lymphocyte-rich gastric carcinoma.

The neoplastic environment is generally regarded as an immunosuppressive milieu. However, a group of cancers are characterized by the abundance of tumour-infiltrating lymphocytes (TILs). Here we examined the possible roles of chemokines in the formation of lymphoid stroma in lymphocyte-rich gastric carcinomas (GCs), including EBV(+) cases and conventional GCs. Regardless of EBV positivity, TILs in lymphocyte-rich GCs predominantly expressed CXCR3, while its ligand CXCL9 was abundantly expressed by stromal cells and a portion of cancer cells. CXCL9(+) stromal cells were judged to include dendritic cells, because they partly co-expressed fascin, DC-sign, CD83, DC-lamp or HLA-DR. T cells in close contact with CXCL9(+) cells showed frequent labelling of Ki-67 (approximately 10%), suggesting the immunostimulatory activity of CXCL9(+) stromal cells. The T-cell zone of the regional lymph nodes of lymphocyte-rich GCs also abounded with CXCR3(+) T cells and CXCL9(+) stromal cells. This indicated a close similarity between cancer stroma and regional lymph nodes of lymphocyte-rich GCs. Quantitative RT-PCR also confirmed the strong expression of CXCR3, CXCL9 and IFNgamma in lymphocyte-rich GCs. In contrast, conventional GCs contained less abundant CXCR3(+) T cells and few CXCL9(+) stromal cells. Collectively, the CXCL9-CXCR3 axis plays a pivotal role in the formation of lymphoid stroma in lymphocyte-rich GCs. Given similar findings in the regional lymph nodes, the lymphoid stroma of lymphocyte-rich GCs may represent a tertiary lymphoid tissue with predominantly Th1-shifted immune responses.

Activation of developmentally mutated human globin genes by cell fusion.

Human fetal globin genes are not expressed in hybrid cells produced by the fusion of normal human lymphocytes with mouse erythroleukemia cells. In contrast, when lymphocytes from persons with globin gene developmental mutations (hereditary persistence of fetal hemoglobin) are used for these fusions, fetal globin is expressed in the hybrid cells. Thus, mutations of developmental origin can be reconstituted in vitro by fusing mutant lymphoid cells with differentiated cell lines of the proper lineage. This system can readily be used for analyses, such as globin gene methylation, that normally require large numbers of pure nucleated erythroid cells, which are difficult to obtain.

Should total gastrectomy and total colectomy be considered for selected patients with severe tumor burden of pseudomyxoma peritonei in cytoreductive surgery?

BACKGROUND: This study aims to evaluate the safety and efficacy of cytoreductive surgery (CRS) including total gastrectomy and total colectomy in selected pseudomyxoma peritonei (PMP) patients with entire stomach and colon covered by mucinous tumor. METHODS: A total of 48 patients received this extensive treatment between January 2006 and January 2014. The main focus of this study was survival after CRS as well as perioperative morbidity and mortality. RESULTS: Twenty-eight patients were male, and median age was 52.5 years. Median peritoneal cancer index was 33. Complete cytoreduction was achieved in all 48 patients, and 26 patients received hyperthermic intraperitoneal chemotherapy (HIPEC). Until last follow-up, the estimated median survival after CRS was 54.0 months (95% CI 36.5-71.6 months). The 1-, 2-, 3-, and 5-year survival rates were 91.7%, 81.3%, 70.1%, and 48.6%, respectively. Histology was significantly associated with survival (P = 0.020). The median disease-free survival was 32.0 (95% CI 25.7-38.3) months. HIPEC (P = 0.048) and histology (P = 0.002) was significantly associated with disease-free survival after CRS. Overall Grade 3-5 complications occurred in 18 (37.5%) patients with mortality of 2.1%. For patients who received surgery over 6 months, they could gradually have an acceptable quality-of-life similar as other patients receiving ordinary CRS and HIPEC. CONCLUSION: CRS including total gastrectomy and total colectomy can be performed in experienced specialized institutions as a feasible option to achieve complete cytoreduction with acceptable safety in selected PMP patients with stomach and colon covered by mucinous tumor. Perioperative management should be carried out cautiously to decrease and avoid complications.

Radiofrequency capacitive hyperthermia for superficial malignant-tumors.

Eighteen patients with inoperable head, neck and upper chest wall cancers underwent radiofrequency hyperthermia in combination with chemotherapy and radiotherapy (HCR therapy). Of the eighteen patients, three showed complete response (CR); eight, partial response (PR); four, no change (NC); and three. progressive disease (PD). The overall efficacy (%CR+PR) was 61.1%. The efficacy tended to be higher in the patients treated with a maximal intratumoral temperature over or equal to 43-degrees-C (71%) than that in patients treated with under 43-degrees-C (25%). As the local control of the tumors was not related with their prognosis it is important that the patients should undergo not only regional hyperthermia but also systemic chemotherapy. Eight patients, who had suffered from heat burns, have all been cured by conservative therapy. These results suggested that HCR therapy might be useful in treating inoperable superficial malignant tumors, and be well tolerated under protection from skin bums.

Pancreaticoduodenectomy in combination with right hemicolectomy for surgical treatment of advanced gastric carcinoma located in the lower half of the stomach.

The results of surgical treatment of patients with gastric carcinoma infiltrating into the duodenum and the pancreas head and with N3 metastases are very poor. We have employed pancreaticoduodenectomy in combination with right hemicolectomy (PD + LH) with the aim of leaving no remnant of cancer cells in the vicinity of the primary lesion, in patients with carcinomas of the distal third of the stomach, associated with duodenal invasion, presence of fixity to the pancreas head or N3 metastases, in the last ten years. Twenty-six cases were treated with this technique (Group A). These cases were compared with 63 patients who underwent subtotal gastrectomy (Group B) in the same period. The operation time, amount of blood loss and numbers of operative complications were greater in Group A than in Group B. Operating mortality was found in 2 cases in Group B but was 0 for Group A. When the survival rates were compared, PD + LH can provide better long-term results than subtotal gastrectomy, especially in the patients with tumors infiltrating into the pancreas head or metastasizing to N3. The PD + LH is a rational and safe method for the treatment of gastric carcinoma infiltrating into the pancreas head or metastasizing to N3.

[Biliary metabolites of levonorgestrel in rats].

The metabolism of levonorgestrel (LNG) in the bile following oral administration of the drug was examined in female rat. 1) Within 48 h after administration of 14C-labelled LNG (LNG-14C), 67-82% of the radioactivity was excreted into the bile. 2) Almost all the metabolites in the bile were conjugated with glucuronic acid or sulfuric acid and only a small amount of the unchanged compound was found. 3) After treatment of these metabolites in the bile with beta-glucuronidase and arylsulfatase, more than ten aglycones were detected on TLC. Three main aglycones, M1, M2 and M3, were isolated. They accounted for 68.0, 0.8 and 11.5% of the radioactivity excreted into the bile, respectively. 4) The structures of M1 and M2 were assumed to be 13-ethyl-18,19-dinor-5 alpha,17 beta-pregn-20-yne-3 alpha,17- diol and 13-ethyl-18,19-dinor-5 beta,17 beta-pregn-20-yne-3 alpha,17-diol, respectively, by NMR and LC/MS analyses, and confirmed by direct comparison with respective authentic samples. M3 was assigned to be 13-ethyl-18,19-dinor-5 alpha,17 beta-pregn-20-yne-3 alpha,16 beta,17-triol by NMR, LC/MS and GC/MS analyses and acetonide derivation. 5) Isolation of the glucuronide metabolite, M4, from the bile, was achieved by column chromatography using Amberlite XAD-2 and Sephadex LH-20. Hydrolysis of this compound with beta-glucuronidase released M1 and glucuronic acid. After M4 was converted to an acetylated-methyl ester derivative, the definite structural assignment of M4 was established to be M1-3-O-yl glucuronic acid by NMR analysis. The NOE effect and the value of the corresponding coupling constant of the anomeric proton showed that the glucoside moiety was in the beta configuration. These findings suggested that LNG was predominantly converted to 5 alpha-reduced metabolites and that the 5 beta-metabolite accounted for less than 1% of the total metabolites in female rats. These metabolites were excreted as glucuronides into the bile.

[Adenoid cystic carcinoma of lower lobe of right lung: report of a case].

A 69-year-old male was admitted to the hospital for further examination of an abnormal shadow in the right lower lung fields. He was previously under medical treatment for right thoracic empyema. Chest computed tomography (CT) showed a solitary mass, 4.5 cm in diameter and broncofiberscopy evidenced a tumor in the right lower bronchus. The biopsy was performed and the tumor was diagnosed as a pleomorphic adenoma. Intraoperativefinding showed the tumor was 6 cm in gross, extended to the left atrium, and a daughter tumor was palpable in the middle lobe. The middle and lower lobe were resected. The tumor was located in S9, S10, 6 x 4 x 3.5 cm in size, 2 daughter tumor was found in the middle lobe, the pulmonary vein was thickened by tumor invasion. Pathohistologically, main tumor and daughter tumor showed malignant feature, were compatible with adenoid cystic cancer. Four years after operation, he is still now alive with home oxygen therapy.

[A case of 19th year pulmonary metastasis after radical mastectomy for breast cancer].

A 72-year-old woman was admitted to our hospital for further evaluation of a abnormal shadow in left middle lung field. The patient had undergone right mastectomy for infiltrating ductal carcinoma 19 years ago. She had no symptom, but had a time of mass X-ray screening this year. Chest CT finding showed a nodule 2 cm in diameter with slight irregular margin in S6 of left lung. We couldn't determine preoperatively that this tumor was a metastatic lesion or a primary lung cancer. And first, tumor was taken out for intraoperative frozen section diagnosis. Pathologist didn't diagnose whether this tumor was a metastatic or primary. So, we performed left lower lobectomy and mediastinal lymphadenectomy. On postoperative histopathologic finding lung cancer resembled well previous breast cancer. In immunohistochemical study cancer cells from lung and breast of the patient were respectively positive for anti Estrogen Receptor (ER) and anti Gross Cystic Disease Fluid Protein-15 (GCDFP-15). In conclusion lung cancer was diagnosed as a metastatic lesion from breast cancer 19 years ago. The patient has been well 2 years postoperatively without recurrence. In this case immunohistochemical examination was very useful for differentiation metastatic lesion and primary one.

[A case of so-called carcinosarcoma of peripheral lung].

A 67-year-old man was admitted to our hospital with blood sputum. Adenocarcinoma was diagnosed by sputum cytological examination. A chest X-ray film showed a tumor shadow in the lower field of the right lung. The middle and lower lobes were resected and lymph node dissection was performed. Tumor was composed of well differentiated adenocarcinoma and spindle cell sarcomatous element, and diagnosed as so-called carcinosarcoma. Pathological staging was IIIA by pT1N2M0. Postoperative chemotherapy was not performed for side effect, so radiotherapy only was done. He died of recurrence and metastasis after about 1 postoperative year.

[A case of pulmonary dirofilariasis].

A 58-year-old man was admitted to our hospital for detailed examination of continuous cough. On a chest X-ray film, abnormal shadow was detected in the right lower lung field. Preoperative examination findings didn't lead to a definitive diagnosis. Under thoracoscopy partial resection of the lung was performed to rule out a malignant lesion. Intraoperative pathologic finding revealed a granulomatous lesion. And, final pathological diagnosis showed to be a pulmonary dirofilariasis. His postoperative course was not eventful. On 20 th day he discharged postoperatively. Now, under the Pet-boom the disease has been reported increasingly. But it is difficult to find the disease preoperatively. So, it is real to be operated for differentiate from a malignant lesion. Recently in many cases open lung biopsy, has been undergone with less invasive procedure such as thoracoscopy and VATS. It will be mainstream in future.

[A case of lung carcinoid].

A 78-year-old female was pointed out an abnormal shadow in left lung field. For 4 years this shadow was followed up as benign tumor. Chest CT scan revealed growing tumor and new tumor in right lung. Tumor resection was performed. Until operation time carcinoid syndrome was not found. This case was diagnosed histopathologically typical carcinoid of peripheral lung.

[Intra-arterial infusion chemotherapy using an implantable reservoir in the treatment of hepatic metastases in colorectal cancer].

With colorectal cancer, the therapeutic outcome for multiple hepatic metastasis extending to the bilateral lobe, even when various chemotherapies are administered, is extremely poor. For multiple hepatic metastases at our clinic, from November, 1985, through February, 1991, we used an implantable reservoir to administer intra-arterial infusion chemotherapy and reviewed the results. We treated 16 patients with hepatic metastases of colorectal cancer, H2 in 3 cases and H3 in 13 cases. When we used the reduction rate of the tumor diameter as seen by CT scan as a criteria for antitumor effectiveness, 1 case was CR and 3 cases were PR, for an efficacy rate of 25.0%. Changes in the serum CEA level were related to antitumor effectiveness. Among the evaluable cases, the 1-year survival rate was 60.0%, which was significantly more favorable than the 20.0% obtained in the systemic chemotherapy group (p less than 0.05). Given the above, although there are a few problems such as the kind and dose of drugs, the use of intra-arterial infusion chemotherapy with an implantable reservoir to treat hepatic metastases of colorectal cancer permits a form of chemotherapy providing a better QOL out of hospital.

[The effect of continuous hyperthermic peritoneal perfusion using high-dose cis-diamminedichloroplatinum for peritoneal dissemination of gastric cancers].

A continuous hyperthermic peritoneal perfusion using high-dose cis-diamminedichloroplatinum (CDDP) and its antidote, sodium thiosulfate, was applied to eight patients with peritoneal metastasis from gastric cancers. Two of eight patients showed partial response and the rate of decrease of ascites was 38%. Renal failure and leukopenia were observed in one and two patients, respectively, but no severe or lethal dysfunction was observed and all were tolerated. These results showed that CDDP exerted anti-tumor effects on peritoneal metastasis from gastric cancers when used in high doses in combination with hyperthermia.

[Clinical experiences with hyperthermochemotherapy of hepatic metastasis from gastric cancer].

Thermochemotherapy was performed on gastric cancer cases of hepato-metastasis. The subjects were 12 gastric cancer cases having hepato-metastatic lesions (10 synchronous, 2 heterochronous). Using 8 or 13.58 MHz-dielectric heating apparatus, thermotherapy was carried out for 40-60 min (twice a week, 5-35 times, averaging 12.8 per case) at an intra-tumoral temperature greater than 42 degrees C. Chemotherapy consisted of hepato-arterial infusion of MMC 10 mg/BW, CDDP 75 mg/m2 once per 3-4 weeks and consecutive daily administration p.o. of UFT 800 mg/BW. Effect greater than PR was noted in 75% (9/12) on the whole and in 100% (5/5) and 57% (4/7) for H1-2 and H3, respectively. Mean and 50% survival periods were 9.3 and 7.2 months, respectively, with a one-year survival rate of 38%. Chemotherapy-induced side effects were nausea and vomiting in 83% and leukopenia and thrombopenia in 67%, while the only thermotherapy-induced side effect was subcutaneous fatty tissue necrosis in 3 cases. The above results suggested the effectiveness of the present thermochemotherapy in the treatment of hepato-metastasis of gastric cancer.

[A case of gastric cancer successfully treated with hyperthermo-chemo-radiotherapy].

A 56-year-old woman was diagnosed as having gastric cancer with lymph node metastasis and invasion to the pancreas head and was admitted to our hospital in September, 1984. She was treated with hyperthermo-chemo-radiotherapy, using radiofrequency-induced hyperthermia (8 MHz) with a daily dose of fractionations at 42-43 degrees C for 60 minutes, 5 fractions per week of irradiation at 180 cGy and systemic chemotherapy. After the total doses of hyperthermia and radiation had reached 11.8 hours and 2500 cGy, the primary tumor and lymph node metastasis measured by X-ray examination were reduced in size. On October 8th, laparotomy was done, and total gastrectomy combined with total pancreatectomy, left hepatic lobectomy and right hemicolectomy was performed. Histologically, almost all of the cancer cells in the primary tumor and lymph node metastasis had disappeared. These results show that this multimodal therapy is effective for local control of gastric cancer, when used preoperatively.

[A case of parotid tumor showing remarkable regression following hyperthermo-chemo-radiotherapy].

A 72-year-old woman developed adenocarcinoma of the left parotid gland. Because of the excessive size of her tumor and the fact that she suffered from severe liver dysfunction, she was treated by hyperthermo-chemo-radiotherapy (HCR therapy). After ten sessions of radiofrequency hyperthermia with HEH 500 (13.56 MHz radiofrequency wave), 50-Gy irradiation from a linac and administration of 33.0g of tegafur in suppository form, the tumor mass showed remarkable regression decreasing in size by as much as 84% on computed tomography. Histologically the tumor which was resected under local anesthesia, showed almost total necrosis. The multidisciplinary HCR therapy was well tolerated and effective as a therapy for cancer in this case.

[Multimodal therapy using hyperthermia for gastric cancer--with special reference to histological studies].

We carried out a combination preoperative therapy involving radiofrequency hyperthermia (8 MHz or 13.56 MHz) with radiation (10-MV X-ray) or chemotherapy (Mitomycin C, CDDP or UFT) for 24 advanced gastric cancers with the aim of preventing local recurrence and improving resectability. The tumor and histological effects were evaluated in each case. Furthermore, an agar phantom possessing a cavity, for simulating the stomach, was employed in an experiment to evaluate temperature distribution upon RF-heating. In the experiment using the agar phantom, the rising temperature around the cavity at 3 o'clock was higher than at 5' and 6 o'clock. This suggested that gastric juice and air must be aspirated when treating a patient by RF-heating. Of the 24 tumors, 4 (17%) showed partial response. Histological effects were observed in 67% of 21 primary tumors. The rate of histological effects in metastases of lymph nodes, liver and peritoneum were 29% (4/14), 100% (2/2) and 0% (0/4), respectively. Tumor response was closely correlated with irradiation and the temperature in the stomach cavity (over 42.5 degrees C). Almost all patients showed good tolerance of this combined therapy. These results show that combined treatment involving radiation, chemotherapy and hyperthermia appears to be a potentially useful from of preoperative therapy for patients with advanced gastric cancer.

[Evaluation of intraoperative intraperitoneal administration on anti-cancer drug for gastric cancer].

This study was undertaken in order to evaluate the effect of intraoperative intraperitoneal (IP) administration of cisplatin (CDDP) and/or mitomycin C (MMC) on patients who underwent an operation for gastric cancer, compared with an untreated group. There were no differences between the effect of CDDP and that of MMC. No differences were found between the survival rate of IP and untreated group in no liver and no peritoneal metastasis cases, nor in non-resection cases. However, the median survival time was longer at 377 days in IP group than at 213 days in the untreated group (p less than 0.1). The free CDDP levels in the serum after 50 mg IP injection remained effective for 15-30 min. On the other hand, the MMC levels in the serum after 20 mg IP proved in effective.

[Correlation of DNA index and BrdU labeling index with clinicopathological factors in colorectal carcinoma].

We studied the usefulness of the DNA index (DI) and bromodeoxyuridine (BrdU) labeling index (BLI) using fresh material from 71 patients with colorectal carcinoma. We compared the DI and BLI of the biopsy specimens with those of the resected specimens from 17 patients. These DI and BLI values were evaluated by flow cytometry. Neither DNA ploidy nor DI was correlated with other clinicopathologic factors. Intratumoral DI heterogeneity (DIH) was found in 33.8% (24/71) of tumors. Lymph node metastases were observed more often in cases with DIH than without DIH. The incidence of DIH was correlated with histologic stage. BLIs were higher in well-differentiated adenocarcinoma than in moderately and poorly differentiated adenocarcinoma. BLIs were not correlated with histologic stage. A significant correlation was observed between DI and BLI (r = 0.47, p less than 0.001). In cases without DIH, there was a good correlation between the DI values of the biopsy and resected specimens (r = 0.99, p less than 0.001). A significant correlation was also found between the BLI values of the two types of specimens (r = 0.69, p = 0.002). These results suggested that 4 biopsy specimens were adequate to estimate DI and BLI by FCM, and that DI and BLI values determined by FCM could facilitate the design of treatment regimens for preoperative patients.

[Metastasis and its relation to cell kinetics in human colorectal cancers].

The difference of the cell kinetics between primary tumor and its metastasis was studied on six cases of human colorectal cancers (four cases at synchronous liver metastases and two metachronous) with migration chase method using flow cytometry in vivo. The bromodeoxyuridine labeling indices (LI), DNA synthesis time (Ts), and generation time (Tg) were measured in normal colonic mucosae, primary tumors, lymph node metastases, and liver metastases. The LI, Ts, and Tg were 4.9 +/- 2.2%, 11.6 +/- 1.4 hours, and 11.3 +/- 3.7 days, respectively, in normal mucosa. In cancer, they were 13.9 +/- 7.1%, 16.9 +/- 4.8 hours, and 6.0 +/- 2.5 days, respectively. LI was higher and Ts was longer in cancer than in normal mucosa. Tg was shorter in cancer than in normal mucosa. In lymph node metastases, LI, Ts, and Tg were 12.0 +/- 4.5%, 14.4 +/- 6.0 hours and 5.0 +/- 0.5 days, respectively. Ts was faster in lymph node metastases than in primary tumors. In liver metastases, they were 30.1 +/- 18.1%, 28.0 +/- 10.2 hours, and 4.8 +/- 2.1 days, respectively. LI was higher and Ts was longer in liver metastases than in primary tumors. In both metastatic lesions, Tg was shorter than in primary tumors. The proliferation rate correlated with LI/DNA index significantly (r = 0.7868, p less than 0.00001). From the results, it was revealed that the proliferation rate was higher in metastatic lesions than primary tumors in vivo. The application of this method for clinical and experimental use would be expected.