Second Hepatic Resection for Recurrent Hepatocellular Carcinoma in Patients with Chronic Hepatitis C

Background Although a second hepatic resection (SHR) for recurrent hepatocellular carcinoma (HCC) is widely accepted, the indications for SHR have not been established. The risk factors for HCC recurrence after SHR were evaluated to investigate the indications for SHR. Methods Subjects included 51 patients who underwent a second hepatic resection for recurrence of HCV-related HCC. Sixteen patients received interferon therapy before or after the first operation. Six patients attained a sustained viral response (SVR) that was defined as return of the alanine aminotransferase (ALT) activity to within the reference range and no detectable serum HCV RNA for at least 1 year after interferon therapy. A biochemical response (BR), defined as a normalized ALT activity for at least 1 year after interferon therapy with or without the transient disappearance of serum HCV RNA, was attained in three patients. The other seven patients were defined as the nonresponse (NR) group. Results By univariate analysis, NR and lack of interferon therapy, high indocyanine green retention rate at 15 min (ICGR15), high aspartate aminotransferase activity, high ALT activity, large tumor, and multiple tumors were risk factors for HCC recurrence after SHR. By multivariate analysis, NR and lack of interferon therapy, high ICGR15, large tumor, and multiple tumors were independent risk factors. Conclusions Patients in whom active hepatitis has been controlled by interferon therapy are the best candidates for SHR. Interferon therapy should be recommended in patients undergoing resection of an HCV-related HCC because SHR can prolong life in SVR and BR patients.     

Demonstration of both primary and secondary reninism in renal tumors in children

Two infants with renal tumors and associated hypertension are presented. By using an antibody to purified human renal renin, the sites of renin production were localized immunohistochemically in each tumor. The first case was a 9-month-old girl with Beckwith-Wiedemann syndrome. She presented with bilateral renal masses and hypertension (140/90 mm Hg). Following a left nephrectomy and chemotherapy and radiotherapy, her BP returned to normal. Her tumor was a Wilms' tumor of favorable histology, composed predominantly of glomeruloid structures. Renin was localized within a part of these neoplastic glomeruloid bodies. We therefore designated this as a Wilms' tumor with glomeruloid differentiation having primary reninism. The second case was a 24-day-old girl with hypertension (140/70 mm Hg). A renal tumor was found and successfully removed. Her BP returned to normal. The tumor was histologically confirmed as a congenital mesoblastic nephroma. By indirect immunoperoxidase staining, renin was localized only in the hypertrophied juxtaglomerular cells adjacent to the residual glomeruli entrapped by the tumor. None was seen in the tumor cells. We concluded that this was a case of secondary reninism--a case of hypertension secondary to the local ischemia at the entrapped glomeruli.     

Prognostic Significance of Immunohistochemically Detected Blood and Lymphatic Vessel Invasion in Colorectal Carcinoma: Its Impact on Prognosis

Background The prognostic significance of blood vessel invasion (BVI) and lymphatic vessel invasion (LVI) is unclear. Because of the absence of specific markers for venous and lymphatic vessels, earlier studies could not reliably distinguish between BVI and LVI. Methods By immunostaining for podoplanin and CD34 antigen, we retrospectively investigated LVI and BVI in 419 tissue specimens of colorectal carcinoma. We performed univariate and multivariate analysis of the clinicopathologic features, frequency of recurrence, and outcome of patients with or without LVI and BVI. Results The use of hematoxylin and eosin (H&E) staining to identify BVI and LVI yielded a false positive rate of 9.1% and false negative rate of 12.6%. The incidence of BVI was significantly higher among tumors with LVI than tumors without LVI (P <.001). In logistic multivariate analysis, only LVI (P < .001) was associated with lymph node metastasis and BVI (P = .015) was associated with distant recurrence. Calculating the prognostic relevance, both two invasion types correlated with decreased survival in univariate analysis (both P <.001). In multivariate analysis, BVI (P =.024), lymph node status (P =.003) and tumor stage (P <.001) remained statistically significant factors for survival. Conclusions Our results suggest that immunohistologic evaluation of BVI and LVI could be useful in colorectal carcinoma indicating the risk of lymph node metastasis and recurrence, thereby contributing to prognostic evaluation.     

Plasma islet amyloid polypeptide levels in obesity, impaired glucose tolerance and non-insulin-dependent diabetes mellitus.

We examined the response of plasma islet amyloid polypeptide (IAPP) to an oral glucose load in non-obese and obese subjects with normal glucose tolerance or impaired glucose tolerance (IGT), and in non-obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Plasma IAPP response to intravenous glucagon injection in NIDDM patients was also studied. Plasma IAPP concentration was determined by a sensitive and specific radioimmunoassay. Basal levels of plasma IAPP in non-obese subjects with normal glucose tolerance, IGT and NIDDM were not significantly different from each other. Non-obese subjects with IGT showed delayed and higher plasma IAPP response to oral glucose load compared to normal non-obese subjects. In NIDDM patients, IAPP response to glucose was delayed and lower when compared to normal non-obese subjects. Basal levels of plasma IAPP in normal obese subjects and obese subjects with IGT were significantly higher than those in normal non-obese subjects. Plasma IAPP response to glucose load in these obese subjects was higher than that in normal non-obese subjects. Plasma IAPP response was decreased in diabetic patients treated with diet, oral hypoglycemic agents and insulin in that order. We conclude that the secretion of IAPP is reduced with progression of NIDDM, although it appears to be rather augmented in IGT compared to normal non-obese subjects.     

Serum concentration of L‐kynurenine predicts the clinical outcome of patients with diffuse large B‐cell lymphoma treated with R‐CHOP

Purpose: Introduction of rituximab has largely improved the prognosis of patients with diffuse large B‐cell lymphoma(DLBCL). Such change in therapeutic outcome necessitates the identification of additional prognostic factors to conventional indexes that have been validated for CHOP without rituximab. Indoleamine 2,3‐dioxygenase (IDO) exerts intense immunomodulatory effects because of enzymatic activities that catalyze the breakdown of the essential amino acid L‐tryptophan. The activity of IDO can be estimated by measuring the serum concentration of L ‐kynurenine. Here, we investigated the role of L ‐kynurenine as a prognostic marker in R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) therapy. Experimental design: Data from 73 consecutive patients treated with eight cycles of R‐CHOP or R‐THP (tetrahydropyranyl adriamycin)‐COP between December 2002 and March 2007 were analyzed. L ‐kynurenine concentrations in serum samples obtained at admission were measured by high‐performance liquid chromatography. Results: The median serum L ‐kynurenine level was 1.575 μm (range 0.537–9.588). The complete response (CR) rates of patients with L ‐kynurenine <1.5 and ≥1.5 μm were 83% and 61%, respectively (P < 0.05). The three‐yr overall survival (OS) rates for patients with L ‐kynurenine <1.5 and ≥1.5 μm were 89% and 58%, respectively (P < 0.005). In addition, higher age, poor performance status, elevated serum lactate dehydrogenase, and unfavorable as well as revised International Prognosis Index were significantly worse factors for CR rate and OS. Multivariate analyses revealed only L ‐kynurenine as an independent prognostic factor for OS. Conclusions: Serum L ‐kynurenine might be a novel prognostic factor to determine the treatment outcome of DLBCL with the R‐CHOP regimen.     

Effect of Hammerhead Ribozyme against Human Thymidylate Synthase on the Cytotoxicity of Thymidylate Synthase Inhibitors

One of the resistance mechanisms to folate-based thymidylate synthase (TS) inhibitors is the increase in TS activity in tumor cells. Human B lymphoblastoid cell line (W1L2) was made resistant to a lipophilic non-polyglutamatable TS inhibitor (ZM249148), and the subline (W1L2:R179) showed a 20-fold increase in TS enzyme activity with concomitant overexpression of TS mRNA. To overcome the resistance, we designed a ribozyme that can cleave the CUC sequences in a triple tandemly repeated sequence of TS mRNA. Expression of this ribozyme in W1L2:R179 cells transfected with Epstein Barr virus-based expression vector resulted in sensitization to TS inhibitors concomitantly with a decrease of TS expression. The ribozyme expressed in transfectants was shown to be functional in cleaving artificial TS RNA in vitro.     

Accumulation of photosensitizer ATX-S10 (Na) in experimental corneal neovascularization

PURPOSE: To determine the most appropriate time for laser irradiation to produce selective occlusion of new corneal vessels by photodynamic therapy (PDT) with a new photosensitizer, ATX-S10(Na). METHODS: The time course of the plasma levels of ATX-S10(Na) and the degree of dye accumulation in the corneal neovascularization after intravenous administration was determined in rabbit eyes. Plasma concentration of ATX-S10(Na) was analyzed by a spectrophotometer. The amount of ATX-S10(Na) in the new corneal vessels was measured by nitrogen-pulsed laser spectrofluorometry. Frozen sections of neovascularized cornea and iris were observed by fluorescence microscopy. RESULTS: Plasma ATX-S10(Na) concentration was highest 5 minutes after dye injection and rapidly decreased and reached almost zero at 24 hours, indicating its prompt excretion from the body. The amount of ATX-S10(Na) in the new corneal vessels as measured by nitrogen-pulsed laser spectrofluorometry increased and reached maximal level at 2 to 4 hours. Under fluorescence microscopy, the dye was more abundantly localized in the wall of new corneal vessels than in the normal tissue at 2 to 4 hours. CONCLUSION: These results indicate that laser irradiation between 2 and 4 hours after dye injection is appropriate for selective PDT with ATX-S10(Na) for the occlusion of new corneal vessels.     

Successful treatment of a huge meningeal hemangiopericytoma using Preoperative Autologous Transfusion and Hemodilutional Autologous Transfusion: case report

We report successful operations for a meningeal hemangiopericytoma using sufficient amounts of Preoperative Autologous Transfusion (PAT) and Hemodilutional Autologous Transfusion (HAT). A 23-year-old woman with amenorrhea and bilateral visual field disturbance was found to have a huge intracranial tumor. MRI showed a well-enhanced cystic mass in the left middle fossa, suprasellar, intrasellar, sphenoidal sinus, and cavernous sinus. Preoperatively, the tumor was thought to be a cystic pituitary tumor or meningioma. Surgical removal was planned in three steps. The first operation was carried out via the transsphenoidal approach. Total blood loss was 1348 ml and 2 MAP infusion were required to control bleeding. Histopathological diagnosis was hemangiopericytoma. After preparation of PAT 400 ml and HAT 800 ml, we carried out the second partial removal operation mainly via the interhemispheric approach. Total blood loss was 1829 ml and required autologous transfusion only. After preparation of PAT 1200 ml and HAT 400 ml, the last total removal operation was carried out mainly via the pterional and subtemporal approach. Total blood loss was 1813 ml and required autologous transfusion only. We needed 2 MAP infusion in the first operation, but were able to perform total removal successfully without homologous blood transfusion because a sufficient amount of PAT and HAT had been prepared preoperatively. Hemangiopericytoma required postoperative radiation therapy to avoid local recurrence. After successful removal of the tumor surgically, postoperative radiation therapy was able to be carried out efficiently.     

Usefulness of self-expandable metallic stent with an antireflux mechanism as a palliation for malignant strictures at the gastroesophageal junction

BACKGROUND: Patients with unresectable malignant gastroesophageal strictures often are troubled with reflux esophagitis after stent placement. METHODS: A self-expandable metallic stent (SEMS) without an antireflux mechanism was placed in seven patients with unresectable malignant gastroesophageal strictures (group A), and SEMS with an antireflux mechanism was placed in five patients (group B). After we obtained monitoring systems, two patients in group A and all the patients in group B underwent measurement of bilirubin and pH in the esophagus using a 24-h bilirubin and pH monitor. RESULTS: The mean percentage of total time less than 0.14 for use of the bilirubin absorbance unit was 12.4% in group B and 64.0% in group A. The mean percentage of total time for a pH less than 4 was 2.9% in group B and 37.8% in group A. CONCLUSION: The placement of SEMS with the antireflux mechanism can be effective not only for palliation of gastroesophageal stricture, but also for prevention of reflux.     

A selective plasmin inhibitor, trans-aminomethylcyclohexanecarbonyl-L-(O-picolyl)tyrosine-octylamide (YO-2), induces thymocyte apoptosis

The treatment of rat thymocytes with YO-2, a novel inhibitor of plasmin, resulted in an increase in DNA fragmentation. DNA fragmentation was also induced by another YO compounds such as YO-0, -3, -4 and -5. These YO compounds are the inhibitor of plasmin activity. On the other hand, YO-1, -6 and -8 that hardly inhibit plasmin activity had no effect on DNA fragmentation. Analysis of fragmented DNA from thymocytes treated with YO-2 by agarose gel electrophoresis revealed that the compound caused internucleosomal DNA fragmentation. In addition, judging from a laser scanning microscopy, annexin V-positive and propidium iodide-negative cells were increased by the treatment of the cells with the compound. Moreover, chromatin condensation was observed in thymocytes treated with the compound. These results demonstrated that YO-2 induces thymocyte apoptosis. There seemed to be some correlation between the apoptosis induced by YO compounds and their plasmin inhibitory effect. However, because the other protease inhibitors including pepstatin A, leupeptin, AEBSF, DFP and E-64-d did not affect DNA fragmentation, YO compounds are likely to have unique mechanism on plasmin or to show the effect on the other plasmin-like proteases. The plasmin inhibitory activity may have an important role in YO-2-induced apoptosis. Furthermore, the stimulations of caspase-8, -9 and -3-like activities were observed in thymocytes treated with YO-2. These results suggest that YO-2 induces thymocyte apoptosis via activation of caspase cascade.