Bastadin 6, a spongean brominated tyrosine derivative, inhibits tumor angiogenesis by inducing selective apoptosis to endothelial cells

Bastadin 6, a macrocyclic tetramer of a brominated tyrosine derivative, was isolated from a marine sponge and its anti-angiogenic activity was evaluated. Bastadin 6 was found to inhibit vascular endothelial growth factor (VEGF)- or basic fibroblast growth factor (bFGF)-dependent proliferation (IC50=0.052 micromol/l) of human umbilical vein endothelial cells (HUVECs) 20- to 100-fold selectively in comparison with normal fibroblast (3Y1) or several tumor cells (KB3-1, K562 and Neuro2A). Bastadin 6 also inhibited VEGF- or bFGF-induced tubular formation (0.1 micromol/l, 6 h treatment) and VEGF-induced migration (1 micromol/l, 4 h treatment) of HUVECs. Moreover, bastadin 6 almost completely blocked VEGF- or bFGF-induced in vivo neovascularization in the mice corneal assay and suppressed growth of s.c. inoculated A431 solid tumor in nude mice (100 mg/kg, i.p.). Bastadin 6 induced cell death of HUVECs with an apoptotic phenotype, whereas it showed no effect on the VEGF-induced auto-phosphorylation of VEGF receptors Flt-1 and KDR/Flk-1. These results suggest that the anti-angiogenic effect of bastadin 6 is closely related to selective induction activity of apoptosis against endothelial cells.     

A case of complete remission of carcinomatous ascites refractory for TS-1 monotherapy treated with TS-1 plus paclitaxel combined therapy for gastric cancer

A 38-year-old female patient with gastric cancer, of which histological type was a poorly differenciated adenocarcinoma and a clinical finding was T3N1MO (Stage IIIA), underwent total gastrectomy with D2 lymphadenectomy as the surgical treatment. However, CY1 was detected during the operation and the final finding was T3N1MOHOPOCY1 (Stage IV). Because this surgical treatment ended in curative C, we administered 80 mg/m2/day of TS-1 for four weeks followed by two weeks rest per one course for CY1 after the surgical treatment. After two courses of TS-1 monotherapy, extensive carcinomatous ascites appeared and blood concentration level of CA19-9 increased. We next treated this patient with TS-1+paclitaxel as a second line chemotherapy, because both of them have been reported to migrate to peritoneal very well and to be effective for peritoneal dissemination. The regimen of this combined therapy consisted of four weeks administration of TS-1 (80 mg/m2/day) followed by two weeks rest and injections of paclitaxel (50 mg/m2) at day 1 and 8 for 21 days as one course. When this patient underwent TS-1+paclitaxel combined treatment, the amount of carcinomatous ascites and blood concentration level of CA19-9 were gradually reduced and the former completely disappeared, and the latter fell to a normal range after five courses. Through all treatment courses, a performance status of this patient was kept 0 without a severe adverse event under ambulatory treatment. After 29 courses, the blood concentration level of CA19-9 rose again and local recurrence was detected at the lesion of esophagoenterostomy, though carcinomatous ascites had been kept in complete remission. We treated surgically for this local recurrence because of CY0 at the operation. At the present, 3 years and 8 months have passed since the first treatment started. This patient is still alive without cancer in ambulatory.     

Study of analgestic efficacy of ropivacaine-fentanyl patient-controlled epidural analgesia after upper abdominal gynecological surgery

BACKGROUND: Most of the patients who undergo radical or subradical hysterectomy with paraaortic lymphadenectomy suffer from postoperative pain for upper abdominal incision. They also complain of postoperative nausea and vomiting (PONV) frequently, which are increased by opioids. METHODS: Reducing total fentanyl dose to 0.6 mg, frequency of moving pain complaints increased gradually. Therefore, we introduced patient-controlled epidural analgesia (PCEA) for suppressing pain on moving. We investigated analgestic efficacy of 0.2% ropivacaine-fentanyl PCEA in twelve patients undergoing upper abdominal gynecological surgery. Postoperative analgesic effects were evaluated by visual analogue scale (VAS) at rest and on moving, times of bolus infusion, side effects, and degrees of satisfication by patient's self-assessments. Continuous epidural infusion of 0.6 mg fentanyl in 288 ml 0.2% ropivacaine was started at a rate of 4 ml x hr(-1) with a bolus dose of 2 ml. RESULTS: VAS was maintained below 20 mm at rest but was elevated to the maximum of 45 mm on moving with few bolus requests. Ninty-two percents of the patients answered satisfied but fifty percents of them had PONV. CONCLUSIONS: We conclude that ropivacaine-fentanyl PCEA is effective after upper abdominal gynecological surgery, and we can decrease the dose of fentanyl by explaining PCEA system more effectively to the patients for suppressing the pain on moving and PONV.     

Prophylactic strategies for perioperative pulmonary embolism: the second report; reevaluation of usefulness of combination of elastic stockings and intermittent pneumatic compression

BACKGROUND: The incidence of perioperative pulmonary thromboembolism (PTE) has increased in Japan. As the mortality rate of PE is very high, its prophylaxis is important. METHODS: From January 1998 to December 1999 no prophylactic strategies were employed. From May 2000 to December 2004, elastic stockings (ES) for prevention of perioperative deep vein thrombosis were worn from the morning of the operation until the beginning of ambulation. Intermittent pneumatic compression (IPC) apparatuses were used in combination with ES right after the induction of anesthesia until leaving ICU. Sixty percent of patients stayed in ICU until the next morning after the operation and the other patients for a few hours after the end of surgery. RESULTS: We managed 4,511 patients without any preventing method and 11,688 patients with the combination of ES and IPC. Seven patients developed PTE without any prophylaxis and one with preventative methods. The incidence of PTE was significantly decreased from 15.51 persons/10,000 cases to 0.86 person/10,000 cases. Symptomatic deep vein thrombosis occurred in 3 cases in spite of preventative methods. CONCLUSIONS: Our preventive strategies with the combination of ES and IPC seem to be useful to decrease the incidence and severity of perioperative PTE.     

Motility of the pouch correlates with quality of life after total gastrectomy

BACKGROUND: Jejunal pouch reconstruction is used to provide reservoir function after total gastrectomy, but controversy remains regarding pouch functions and quality of life (QOL). In this study, pouch motility was studied in conjunction with postoperative QOL. METHODS: Pouch motility of 23 patients with jejunal pouch interposition after total gastrectomy was examined by manometry under fasting conditions and by an emptying test using dual-scintigraphy under postprandial conditions. Residual food was graded by endoscopic examinations. QOL was evaluated using the Gastrointestinal Quality of Life Index, and a stasis- or dumping-related symptom score. RESULTS: The pouch showed interdigestive contractile activity. Bursts of contractile activity occurred frequently and were long-lasting compared with the migrating motor complex phase III of the control jejunum. The percentage of time of contractile bursts correlated with postprandial pouch emptying (liquid: R(2) = 0.229, P < .03; solid: R(2) = 0.243, P < .02). Patients with little or no residual food had more percentage of time of contractile bursts than those with moderate residual food (P < .01). The percentage of time of contractile bursts was correlated with the Gastrointestinal Quality of Life Index score (R(2) = 0.262, P < .02), stasis-related symptoms (R(2) = 0.279, P < .01), and dumping-related symptoms (R(2) = 0.218, P < .03). CONCLUSIONS: An interposed jejunum pouch showed bursts of contractile activity that affected postoperative gastrointestinal function and patient QOL.     

Loss of protein expression of hMLH1 and hMSH2 with double primary carcinomas of the stomach and colorectum

The frequency of synchronous or metachronous multiple primary carcinomas in patients with gastrointestinal carcinoma or colorectal carcinoma (CRC) has been reported to be approximately 10%. We determined the role of hMSH2 and hMLH1 in double carcinomas with both GC and CRC. Fifty-six patients with synchronous or metachronous colorectal carcinoma with gastric carcinoma (CRC with GC), and 69 patients with CRC alone was included in our study. We investigated their clinicopathological characteristics, family history and immunohistochemical stains of hMSH2 and hMLH1 were compared between the patients with CRC alone and those with both CRC with GC. The defective protein expression of hMSH1 and/or hMLH1 in colorectal carcinomas was significantly higher in patients with both CRC with GC than in those with CRC alone (p < 0.0001). The survival rate in patients with both CRC with GC was significantly lower than that in those with CRC alone (p < 0.01), in addition, the survival rate in patients with defective protein expression of hMSH2 and/or hMLH1 was higher than in those with a positive protein expression of hMSH2 and/or hMLH1 in CRC with GC (p < 0.05). The incidence of defective protein expression of hMSH2 and/or hMLH1 in CRC with GC patients suggests that abnormalities in the function of hMSH2 and hMLH1 may play an important role in carcinogenesis. Our findings indicate that the CRC patients who demonstrate a defective protein expression of hMSH2 and/or hMLH1 have a higher risk of developing secondary carcinoma in the gastrointestinal tract.     

Development of MPS IVA mouse (Galnstm(hC79S.mC76S)slu) tolerant to human N-acetylgalactosamine-6-sulfate sulfatase

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disease caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency. In recent studies of enzyme replacement therapy for animal models with lysosomal storage diseases, cellular and humoral immune responses to the injected enzymes have been recognized as major impediments to effective treatment. To study the long-term effectiveness and side effects of therapies in the absence of immune responses, we have developed an MPS IVA mouse model, which has many similarities to human MPS IVA and is tolerant to human GALNS protein. We used a construct containing both a transgene (cDNA) expressing inactive human GALNS in intron 1 and an active site mutation (C76S) in adjacent exon 2 and thereby introduced both the inactive cDNA and the C76S mutation into the murine Galns by targeted mutagenesis. Affected homozygous mice have no detectable GALNS enzyme activity and accumulate glycosaminoglycans in multiple tissues including visceral organs, brain, cornea, bone, ligament and bone marrow. At 3 months, lysosomal storage is marked within hepatocytes, reticuloendothelial Kupffer cells, and cells of the sinusoidal lining of the spleen, neurons and meningeal cells. The bone storage is also obvious, with lysosomal distention in osteoblasts and osteocytes lining the cortical bone, in chondrocytes and in the sinus lining cells in bone marrow. Ubiquitous expression of the inactive human GALNS was also confirmed by western blot using the anti-GALNS monoclonal antibodies newly produced, which resulted in tolerance to immune challenge with human enzyme. The newly generated MPS IVA mouse model should provide a good model to evaluate long-term administration of enzyme replacement.     

Differences in tumor core distribution between palpable and nonpalpable prostate tumors in patients diagnosed using extensive transperineal ultrasound-guided template prostate biopsy

BACKGROUND: The authors performed extensive transperineal ultrasound-guided template prostate biopsies to investigate carcinoma core distribution. METHODS: Between August 2000 and May 2004, 371 men underwent template biopsies. Three hundred twelve patients had not undergone a previous biopsy (first group) and 59 had undergone previous transrectal sextant biopsies (repeat group). Of the 312 patients in the first group, 236 had normal digital rectal examination (DRE) findings (DRE- first group) and 76 patients had an abnormal DRE (DRE+ first group). A mean of 20.1 biopsy cores (range, 9-38 cores) was taken from the entire prostate. The region > 2.0 cm from the rectal face of the prostate was defined as the anterior region and the remaining area was defined as the posterior region. RESULTS: In the DRE- first group, the carcinoma core rate (number of tumor cores/number of biopsy cores) in the anterior region (7.2%) did not differ from that of the posterior region (7.3%) (P = 0.9635). However, in the DRE+ first group, the carcinoma core rate in the posterior region (22.0%) was found to be higher than in the anterior region (13.2%) (P < 0.0001). In the repeat group, the carcinoma core rate in the posterior region (3.1%) was significantly (P = 0.0008) lower than that exhibited in the anterior region (7.2%). CONCLUSIONS: The results of the current study suggest that nonpalpable prostate carcinoma is distributed equally within the entire prostate, although palpable carcinoma is distributed mainly in the posterior region and many of the tumor foci in the anterior region may be missed by a transrectal sextant biopsy. The examination of radical prostatectomy specimens is required to prove these results.