Laparoscopic management for local recurrence of early gastric cancer after endoscopic mucosal resection.

Endoscopic mucosal resection (EMR) is a widely accepted technique for early gastric cancer because it is minimally invasive; however, incomplete resection with subsequent cancer recurrence in the remnant remains a difficult problem. Generally, the margins of the local recurrence lesions are unclear, and second EMR is difficult to perform because of scar formation after the first EMR. We performed a laparoscopic treatment on six patients with residual lesions after EMR and reviewed the safety and efficacy of this management. Laparoscopic management consisted of two techniques: laparoscopic wedge resection with a lesion-lifting method and laparoscopic-assisted distal gastrectomy with mini-laparotomy. Cancerous lesions were completely resected with sufficient surgical margins circumferentially. Mean operative time was 171 min, mean estimated blood loss was 16.5 g, time to first walking was 1 day, duration of epidural analgesia was 2.2 days, and mean length of hospital stay was 13.5 days. There were no intra- and postoperative complications, no conversion to open surgery, and no recurrence after surgery. No patients died of gastric cancer during a median follow-up of 60.3 months (range, 38-84). Laparoscopic management for residual lesions of early gastric cancer after EMR is a safe, effective, and minimally invasive procedure by which curative resection can be expected.

Aberrant dynamics of histone deacetylation at the thyrotropin-releasing hormone gene in resistance to thyroid hormone.

Histone acetylation status influences transcriptional activity, and the mechanism of negative gene regulation by thyroid hormone remains unclear, although its impairment by a mutant thyroid hormone receptor (TR) is critical for resistance to thyroid hormone (RTH). We found a novel RTH mutant, F455S, that exhibited impaired repression of the TRH gene and had a strong dominant-negative effect on the gene. F455S strongly interacted with nuclear receptor corepressor (NCoR) and was hard to dissociate from it. To analyze the dynamics of histone acetylation status in vivo, we established cell lines stably expressing the TRH promoter and wild-type or F455S TR. Treatment with a histone deacetylase (HDAC) inhibitor completely abolished the repression of the gene by T3. The histones H3 and H4 at the TRH promoter were acetylated, and addition of T3 caused recruitment of HDACs 2 and 3 within 15 min, resulting in a transient deacetylation of the histone tails. TR and NCoR were located on the promoter, and T3 caused NCoR dissociation and steroid receptor coactivator-1 recruitment. In the presence of F455S, the histones were hyperacetylated, and HDAC recruitment and histone deacetylation were significantly impaired. This is the first report demonstrating the direct involvement of aberrant dynamics of chromatin modification in RTH.

Hand-assisted laparoscopic splenectomy for solitary splenic metastasis from uterine corpus carcinoma.

Solitary splenic metastasis is a rare condition. We performed hand-assisted laparoscopic splenectomy (HALS) for a solitary splenic metastasis from a uterine corpus carcinoma that had directly invaded the wall of the stomach. HALS is a superior technique that offers the advantages of both open and laparoscopic splenectomy, and it may become one of the options for the management of primary and secondary cancer of the spleen.

Hand-assisted laparoscopic splenectomy for a huge splenic cyst: operative technique and case report.

We report the case of a huge splenic cyst that was successfully treated by hand-assisted laparoscopic splenectomy. A 17-year-old girl with a chief complaint of left-sided abdominal pain was admitted to our department for investigation of a splenic tumor. Ultrasonography, computed tomography, and magnetic resonance imaging revealed a huge cystic lesion in the spleen measuring approximately 10 cm in diameter. Hand-assisted laparoscopic splenectomy was safely performed to diagnose and treat the splenic tumor. The histologic diagnosis was an epithelial cyst of the spleen with no atypical cells in the cyst wall. Hand-assisted laparoscopic splenectomy may be a good method of managing a huge splenic cyst that becomes symptomatic and potentially life-threatening through enlargement, rupture, and secondary infection.

Excision of a urachal sinus with use of a voice-controlled laparoscope.

A 34-year-old man with an umbilical urachal sinus underwent a voice-controlled robot-assisted laparoscopic excision. In the operational procedure, three trocars were inserted into the peritoneal cavity. Exploration with a laparoscope revealed a cystic lesion at the middle part of the lower abdomen that extended about 4 cm in the major axis just from the umbilicus. The caudal stump of the urachus was ligated with an absorbable clip and divided. The cephalic side of the lesion was ligated just at the umbilicus with an Endo-Loop and divided. The lesion was then peeled from the peritoneum and taken from the peritoneal cavity. The robot allowed a safer and more secure movement of the scope. The postoperative course was uneventful, the surgical wound scars were very small, and the cosmetic results were satisfactory. There was no recurrence and no transformation of the navel. Our experience was encouraging enough to suggest that voice-controlled robot-assisted laparoscopic excision in patients with urachal disease is a beneficial therapeutic option that is easy, safe, and minimally invasive, with excellent cosmetic results.

The usefulness of laparoscopy-assisted distal gastrectomy in comparison with that of open distal gastrectomy for early gastric cancer.

BACKGROUND: The technique of laparoscopy-assisted distal gastrectomy (LADG) was developed for early gastric cancer, but its feasibility and the associated clinical outcome remain unclear. METHODS: We reviewed 24 patients who underwent LADG (LADG group) and 35 patients who underwent traditional open distal gastrectomy (ODG group) for early gastric cancer in our hospital, and compared the clinical data of the two groups. RESULTS: The clinical and pathological backgrounds of the patients in the two groups were similar. The duration of surgery was not significantly different between the two groups, but the blood loss in the LADG group was significantly less than that in the ODG group. The number of removed lymph nodes was not significantly different between the two groups. The times to the first passing of flatus, first walking, and the restarting of oral intake; the length of hospital stay; and the duration of epidural analgesia were significantly shorter in the LADG group. The morbidity rate in the LADG group was lower than that in the ODG group. CONCLUSIONS: LADG is a safe and minimally invasive surgical technique, after which we can expect a faster recovery.

[Evaluation of chemosensitivity testing by CD-DST, and TS and DPD activity in cases of colorectal liver].

We evaluated the usefulness of the following three in vitro assays in cases of resected colorectal liver metastases. Chemosensitivity by collagen gel droplet drug sensitivity test (CD-DST) was very low in all cases, suggesting this method is not predictive for this disease. In contrast, thymidylate synthetase (TS) activity and dihydropyrimidine dehydrogenase (DPD) activity in tumor tissue were high in many patients with recurrent disease. Thus, these enzyme activities are promising for assessment of clinical outcome following hepatic resection of colorectal liver metastases. Further analyses with large numbers of cases are needed to determine the significance of these in vitro studies.

[Significant role of cisplatin and 5-FU combination chemotherapy for first-line intensive treatment for advanced esophageal cancer].

We evaluated the efficacy of first-line chemotherapy consisting of cisplatin and 5-fluorouracil combination therapy (in the following, FP) in intensive treatment for esophageal cancer. This first-line chemotherapy was administered to 18 patients with squamous cell carcinoma. Three patients had T2 tumor, 10 had T3 and 5 had T4. Lymph node metastasis was detected in 10 patients and not detected in 8 patients. Five patients had distant metastasis. Ten patients showed a partial response and the response rate was 55.6%. Of these 10 patients, 5 were followed with surgery, 3 of whom survived without recurrence of the disease. Five patients were treated by FP, radiation therapy or combination of FP and radiation. Of these 5 patients, 2 showed a complete response. On the other hand, 8 nonresponders died from progressive disease, despite following intensive treatment. These results suggest that first-line chemotherapy by FP, which requires following intensive treatment, improves the overall long-term survival of advanced esophageal cancer patient.

[Usefulness of hepatic arterial infusion chemotherapy for liver metastasis in gastric cancer].

UNLABELLED: We have performed intra-hepatic arterial chemotherapy for 9 patients with liver metastasis arising from gastric cancer. We mainly used 5-FU and CDDP as antineoplastic drugs. RESULTS: The median survival after gastrectomy was 600 days. Of 9 cases, 2 showed CR, 4 PR, 2 NC, 1 PD. The response rate was 67%. The 9 cases were classified into 2 groups. One group, the short-term survival group, concised of 5 patients that had no more than 2 years survival and the other, the long-term survival group, consisted 4 patients that had more than 2 years survival. We compared these 2 groups and found no difference in the primary lesions between the 2 groups. The patients in the long-term survival group had fewer and smaller metastatic lesions in the liver than the patients of the short-term survival group. The patients in the long-term survival group had no unresectable lesions except liver metastasis when gastrectomy was performed. However, 2 patients in the short term survival group had unresectable lymphatic involvement at the time gastrectomy was performed. Of 9 patients, 6 died from the extrahepatic lesion. CONCLUSION: The intra-arterial chemotherapy was effective and useful for liver metastasis arising from gastric cancer. However, the majority of patients died from extrahepatic lesions. We should therefore consider the use of systemic chemotherapy with intra-arterial chemotherapy.

Human immunodeficiency virus type 1 Tat binding protein-1 is a transcriptional coactivator specific for TR.

The DNA-binding domain of nuclear hormone receptors functions as an interaction interface for other transcription factors. Using the DNA-binding domain of TRbeta1 as bait in the yeast two-hybrid system, we cloned the Tat binding protein-1 that was originally isolated as a protein binding to the human immunodeficiency virus type 1 Tat transactivator. Tat binding protein-1 has subsequently been identified as a member of the ATPase family and a component of the 26S proteasome. Tat binding protein-1 interacted with the DNA-binding domain but not with the ligand binding domain of TR in vivo and in vitro. TR bound to the amino-terminal portion of Tat binding protein-1 that contains a leucine zipper-like structure. In mammalian cells, Tat binding protein-1 potentiated the ligand-dependent transactivation by TRbeta1 and TRalpha1 via thyroid hormone response elements. Both the intact DNA-binding domain and activation function-2 of the TR were required for the transcriptional enhancement in the presence of Tat binding protein-1. Tat binding protein-1 did not augment the transactivation function of the RAR, RXR, PPARgamma, or ER. The intrinsic activation domain in Tat binding protein-1 resided within the carboxyl-terminal conserved ATPase domain, and a mutation of a putative ATP binding motif but not a helicase motif in the carboxyl-terminal conserved ATPase domain abolished the activation function. Tat binding protein-1 synergistically activated the TR-mediated transcription with the steroid receptor coactivator 1, p120, and cAMP response element-binding protein, although Tat binding protein-1 did not directly interact with these coactivators in vitro. In contrast, the N-terminal portion of Tat binding protein-1 directly interacted in vitro and in vivo with the TR-interacting protein 1 possessing an ATPase activity that interacts with the activation function-2 of liganded TR. Collectively, Tat binding protein-1 might function as a novel DNA-binding domain-binding transcriptional coactivator specific for the TR probably in cooperation with other activation function-2-interacting cofactors such as TR-interacting protein 1.

Isolation and characterization of the rat prolactin-releasing peptide gene: multiple TATA boxes in the promoter region.

The prolactin-releasing peptide (PrRP) gene is a novel bioactive peptide expressed in very restricted regions in the brain. To explore the molecular mechanism of PrRP gene expression, we cloned and characterized the gene and its promoter region. The gene spans approximately 2.4 kb and contains three exons and two introns. 3'RACE analysis showed that a polyadenylation signal 103 bp downstream from the stop codon was functional. Primer extension analysis indicated three transcriptional start sites (TSSs) 92, 199, and 325 bp upstream from the translational start site. Interestingly, in addition to the putative binding sites for SP1-1, AP-2, and Oct-2A, three characteristic TATA boxes were identified close to these TSSs. Transient transfection study using a series of deletion mutants revealed that the middle TATA box is important for the promoter activity. Furthermore, the cloned 1.6 kb promoter region was active only in neuron- and pituitary-derived cell lines, and the promoter region -1600 approximately -800 bp worked as a negative regulatory element. We demonstrated for the first time, the genomic organization and promoter function of the PrRP gene, and this knowledge will facilitate elucidation of transcriptional control of the PrRP gene.

[Evaluation of hepatic resection following hepatic arterial infusion chemotherapy for colorectal liver metastases].

We evaluated the significance of hepatectomy following hepatic arterial infusion (HAI) chemotherapy for colorectal liver metastases. The prognosis of 4 cases with initially resectable tumors was discouraging, indicating no benefit of preoperative HAI for resectable tumors. The 2- and 3-year survival of patients who underwent hepatectomy after downstaging by HAI of originally unresectable metastases were 100% and 67%, respectively, suggesting that hepatectomy combined with HAI is a promising modality for those patients. However, it seems that the control of extrahepatic disease and decision making for the timing for surgical therapy are issues requiring improvement.

[Malignant islet cell tumor of the pancreas with multiple liver metastases effectively treated by transcatheter arterial embolization with degradable starch microspheres--a case report].

A 57-year-old woman underwent distal pancreatectomy for malignant islet cell tumor of the pancreas in 1991. One year later, multiple liver metastases appeared. Although three transcatheter arterial embolizations (TAE) with spongel and nine ethanol injections were performed over seven years, the tumors were growing gradually. Therefore, TAE with degradable starch microspheres (DSM) was selected. Under angiography, TAE of the left hepatic artery was done using 900 mg of DSM following injection of Farumorubicin (20 mg), Lipiodol (3 ml) and cisplatin (90 mg). The tumors in the embolized hepatic area were remarkably decreased in size, and satisfactory local control was obtained. Thereafter, TAE with DSM was carried out twice, and she is still living with outpatient treatment. Thus, it is suggested that TAE with DSM could be a promising, alternative therapeutic modality for liver metastases from malignant islet cell tumor of the pancreas.

[The role of prophylactic hepatic arterial infusion chemotherapy after potentially curative resection of hepatic metastases from colorectal cancer].

Although hepatic arterial infusion (HAI) chemotherapy using fluoropyrimidines is pharmacologically regarded as an ideal therapy for colorectal liver metastases, clinical evaluation of prophylactic HAI following curative hepatectomy has not been carried out. In this report, we review the published literature on this treatment and discuss its efficacy and adverse effects. Fluorodeoxyuridine (FUDR) or 5-fluorouracil (5-FU) was used as the agent and a total dosage of 10-20 g was administered for 6-12 months in most studies. Despite adjuvant therapy, complications including hepatitis, cholangitis, peptic ulcer, and obstruction of the hepatic artery are often reported. Cessation of therapy was also necessary in some studies because of adverse effects or technical problems. In terms of therapeutic effect, significantly higher disease-free survival was achieved in most studies. However, it is still controversial whether this treatment has an ultimate survival benefit. Thus reasonable protocols that do not impair patients' quality of life should be adopted for prophylactic HAI. Furthermore, it is desirable to develop a new regimen combining HAI with systemic chemotherapy to achieve improved survival rates.

The usefulness, indications, and complications of laparoscopy-assisted colectomy in comparison with those of open colectomy for colorectal carcinoma.

The technique of laparoscopy-assisted colectomy (LAC) was developed for benign and malignant diseases of the colon and rectum; however, its feasibility and the associated clinical outcome remain unclear. We reviewed 45 patients who underwent LAC (LAC group) and 62 patients who underwent traditional open surgery (Open group) for colorectal carcinoma in our hospital, and compared the clinical data between the two groups in an effort to determine whether LAC is really minimally invasive and if it enhances the quality of life. So that the backgrounds of the patients in both groups were almost the same, we only compared data of patients with colorectal carcinoma of stages 0, I, and II. The duration of surgery in the Open group was significantly shorter for all procedures except sigmoid resection, but the blood loss was not significantly different between any of the procedures except for right colectomy. The time to the first passing of flatus and restarting oral intake, length of hospital stay, and duration of epidural analgesia were significantly shorter in the LAC group. The morbidity and mortality rates in the LAC group were almost the same as those in the Open group at 29.5% and 3.3% versus 22.6% and 1.6%, respectively. However, five major complications of LAC for advanced colorectal carcinomas might be prevented by performing an open procedure. In conclusion, LAC is a safe and minimally invasive surgical technique following which we can expect a faster recovery; however, patients with advanced colorectal carcinomas must be carefully selected for this operation.

Selective augmentations of intratumoral 5-fluorouracil concentration by local immunotherapy with OK-432 and fibrinogen.

PURPOSE: Pyrimidine nucleoside phosphorylase is an enzyme that converts 5'-deoxy-5-fluorouridine into its active metabolite, 5-fluorouracil. In colorectal cancer tissue pyrimidine nucleoside phosphorylase has been proven to be produced by macrophages in the cancer stroma despite presence of the cancer cells. We reported that local immunotherapy with OK-432 and fibrinogen induced aggregation of macrophages in the cancer stroma and enforced their pyrimidine nucleoside phosphorylase expression. Thus it was hypothesized that if colon cancer were treated with 5'-deoxy-5-fluorouridine, the 5-fluorouracil concentration in cancer tissues would be enhanced by local immunotherapy. The present study was conducted to investigate whether local immunotherapy for colon cancer could increase the intratumoral 5-fluorouracil concentration in patients given chemotherapy with 5'-deoxy-5-fluorouridine. METHODS: Twenty patients with resectable colorectal cancer were examined in this study. They were given 5'-deoxy-5-fluorouridine (600 mg/day) orally for seven days preoperatively. Nine randomly selected patients underwent intratumoral injection of OK-432 mixed with fibrinogen, which was performed on the third preoperative day (OK-432 and fibrinogen plus 5'-deoxy-5-fluorouridine group); eleven patients were given oral 5'-deoxy-5-fluorouridine only (5'deoxy-5-fluorouridine group). The 5-fluorouracil concentration in tumor tissue and normal colon mucosa tissue was measured, and the influence of the local immunotherapy was assessed. RESULTS: The 5-fluorouracil concentration in the cancer tissue was increased by the local immunotherapy, whereas that in the normal colon mucosa was not influenced. Thus, the influence of local immunotherapy was selective to the cancer tissue where the mixture of OK-432 and fibrinogen was injected. CONCLUSION: In patients with colorectal cancer, selective high 5-fluorouracil concentration in the cancer tissue could be achieved by a combination of 5'-deoxy-5-fluorouridine and local immunotherapy with a mixture of OK-432 and fibrinogen.

Expression of thyrotropin-releasing hormone (TRH) receptor subtype 1 in mouse pancreatic islets and HIT-T15, an insulin-secreting clonal beta cell line.

Thyrotropin-releasing hormone (TRH), originally isolated as a hypothalamic hormone, has been reported to be present and released from the pancreatic beta cells, affecting pancreatic functions. However, it still remains unclear whether TRH receptor is expressed in the pancreas. In the present study, we characterized TRH receptors (TRHR) in mouse pancreatic islets and HIT-T15 cells, a hamster clonal beta cell line. RT-PCR study showed significant expression of TRHR subtype 1 (TRHR1) mRNA in both mouse pancreatic islets and HIT-T15 (HIT) cells. In contrast, there was no expression of TRHR2 mRNA, a novel subtype of TRHR which is expressed predominantly in the central nervous system. Sequencing analysis demonstrated that TRHR1 of the islets was identical to that in the pituitary, and cloned hamster TRHR1 shared 93.3 % homology with that of the mouse at the nucleic acid level. Northern blot analysis of TRHR 1 mRNA in HIT-T15 cells showed a single strong hybridization signal approximately 3.7 kb in length. Furthermore, Scatchard plot analysis in HIT-T15 cells revealed that the Kd value for MeTRH was 0.63 nM. Significant elevation of intracellular calcium concentration was observed in response to as little as 10 nM TRH , and this was not affected by removal of extracellular calcium. This is the first description indicating the presence of functional TRH receptor subtype 1 in the pancreatic beta cells, and our observations suggested the regulation of pancreatic function by TRH through autocrine or paracrine mechanisms.

Expression of tumor suppressor gene p16(INK4) products in primary gastric cancer.

Recent studies have shown that the cyclin-dependent kinase (CDK) inhibitor p27(Kip1) represents an indicator for patients' outcome in several human malignancies including gastric cancer. However, the clinicopathologic value of another class of CDK inhibitor, p16(INK4), has not been determined. In a retrospective study, we examined the expression of p16(INK4) by immunohistochemical assay of 80 samples of primary gastric cancers and their adjacent nonneoplastic mucosas. Less than 10% of non-tumor gastric mucosal cells were p16(INK4) positive, whereas the expression of p16(INK4) in gastric cancer cells varied widely from 0 to 100% (mean, 24.5%). The expression of p16(INK4) was not seen in 11.3% (9/80) of the cancer cases, but in 65% (52/80) this protein was even overexpressed when compared with the nonneoplastic mucosa. A clinicopathologic survey indicated that a low or no expression of p16(INK4) was associated with poorly differentiated carcinoma (p = 0.0133), but the level of expression did not correlate with other parameters including patients' prognosis or with the expression of the pRb protein. In an effort to explore the underlying mechanism for the p16(INK4)-negative cases, a prospective study was also performed on 20 cases of gastric cancer to compare the level of the p16(INK4) protein with the methylation status of the p16(INK4) promoter. Gastric cancer tissues with methylation expressed significantly lower levels of the p16(INK4) protein (p = 0.0013) and two of them lacked p16(INK4) expression altogether, whereas all the cancer tissues without methylation expressed it. These findings suggest that the p16(INK4) protein may be associated with differentiation of gastric cancer tissues and that methylation of the p16(INK4) promoter may, in part, account for the loss of p16(INK4) expression.

Requirement of thyrotropin-releasing hormone for the postnatal functions of pituitary thyrotrophs: ontogeny study of congenital tertiary hypothyroidism in mice.

We recently reported that TRH-deficient mice showed characteristic tertiary hypothyroidism. In the present study, we investigated how this tertiary hypothyroidism occurred particularly in pre- and postnatal stages. Immunohistochemical analysis revealed a number of TSH-immunopositive cells in the TRH-/- pituitary on embryonic day 17.5 and at birth. The mutant pituitary at birth in pups born from TRH-deficient dams also showed no apparent morphological changes, indicating no requirement of either maternal or embryonic TRH for the development of pituitary thyrotrophs. In contrast, apparent decreases in number and level of staining of TSH-immunopositive cells were observed after postnatal day 10 in mutant pituitary. Similar decreases were observed in the 8-week-old mutant pituitary, while no apparent changes were observed in other pituitary hormone-producing cells, and prolonged TRH administration completely reversed this effect. Consistent with these morphological results, TRH-/- mice showed normal thyroid hormone levels at birth, but the subsequent postnatal increase was depressed, resulting in hypothyroidism. As expected, TSH content in the TRH-/- pituitary showed a marked reduction to only 40% of that in the wild type. Despite hypothyroidism in the mutant mice, both the pituitary TSHbeta and alpha mRNA levels were lower than those of the wild-type pituitary. These phenotypic changes were specific to the pituitary thyrotrophs. These findings indicated that 1) TRH is essential only for the postnatal maintenance of the normal function of pituitary thyrotrophs, including the normal feedback regulation of the TSH gene by thyroid hormone; 2) neither maternal nor embryonic TRH is required for normal development of the fetal pituitary thyrotroph; and 3) TRH-deficient mice do not exhibit hypothyroidism at birth. Moreover, reflecting its name, TRH has more critical effects on the pituitary thyrotrophs than on other pituitary hormone-producing cells.