Isolated Pulmonary Cryptococcosis Confused with Lung Tumor 5 Years After Kidney Transplantation: A Case Report.

BACKGROUND: In transplant recipients, due to the use of immunosuppressive therapy, it is occasionally difficult to distinguish between an infection and malignancy, especially in the case of a lung lesion. Here, we report a case of isolated pulmonary cryptococcosis after kidney transplantation that was difficult to distinguish from a lung tumor. CASE REPORT: A 52-year-old man underwent a kidney transplant from his mother when he was 44 years old. Immunosuppression was maintained with tacrolimus, methylprednisolone, and mycophenolate mofetil. His post-transplant course was uneventful and serum creatinine levels were maintained. Five years post-transplantation, a non-contrast computed tomography (CT) examination revealed a nodule measuring 3 mm in diameter in the middle lobe of the right lung. The nodule gradually increased to 12 mm in 2 years. Positron emission tomography/CT examination showed a maximum standardized uptake value of 0.5 for the nodule. Biochemical examination revealed no elevation in total leucocyte count and C-reactive protein levels. However, tumor markers were elevated: serum carcinoembryonic antigen, 5.9 ng/mL; pro-gastrin-releasing peptide, 84.6 pg/mL. Furthermore, the serum cryptococcus antigen was negative. Therefore, thoracoscopic partial lung resection was performed. Pathologically, a number of spherical fungi from the necrotic substance of the tumor were confirmed positive by periodic acid-Schiff and Grocott-Gomori staining. The patient was therefore diagnosed with pulmonary cryptococcosis. Two years later, the patient is alive and has shown no evidence of recurrence. CONCLUSIONS: In lung nodules after kidney transplantation, even if serum cryptococcus antigen is not identified, it is necessary to keep in mind the possibility of pulmonary cryptococcosis.

Complementary use of peritoneal and hemodialysis: therapeutic synergies in the treatment of end-stage renal failure patients.

The simultaneous use of peritoneal dialysis (PD) and hemodialysis therapy has been studied both in established PD patients who are experiencing problems with their dialysis treatment that might otherwise prompt a change in modality, and in patients new to dialysis. The application of combination therapy allows in incident patients a partial separation of solute clearance and ultrafiltration, optimizing each modality within that overall delivery. This article discusses the published experience of combination treatment, and considers the possible benefits of such an approach.

Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation.

The purpose of this study was to investigate the accumulation of genetic alterations during metachronous and/or synchronous development of multifocal low-grade superficial urothelial tumours in the same patient, by using array-based comparative genomic hybridisation (array-CGH) and FGFR mutation analysis. We analysed 24 tumours (pTa-1 G1-2) from five patients. We had previously identified a clonal relationship among the tumours of each patient by microsatellite analysis. This time, unsupervised hierarchical cluster analysis revealed that the tumours from each patient were clustered together independently of the tumours from the other patients. All of the tumours from a single patient showed a set of 2-7 identical regional or whole-arm chromosomal changes. In addition, several individual alterations were also found. Cladistic diagrams revealed that the accumulation of genetic alterations could not be explained by a linear model, and the existence of a hypothetical precursor cell was assumed in four patients. In some cases, FGFR mutation seemed to occur later during multifocal tumour development. Taken together, these findings suggest that low-grade superficial urothelial tumours accumulate minor genetic alterations during multifocal development, although these tumours are genetically stable.

Dicoumarol potentiates cisplatin-induced apoptosis mediated by c-Jun N-terminal kinase in p53 wild-type urogenital cancer cell lines.

3-3'-Methylene-bis [4-hydroxycoumarin] (dicoumarol), an inhibitor of NADPH:quinone oxidoreductase 1, has been reported to possess potential antineoplastic effects and the ability to abrogate p53 protein. In the present study, we investigated the cytotoxic effects of dicoumarol in combination with cisplatin (CDDP), using four bladder (RT112, 253J, J82 and UMUC3) and two prostate (LNCap and PC3) cancer cell lines. Single treatment with 100 microM dicoumarol suppressed cell proliferation but did not induce apoptosis at 24 h in all cell lines examined. On the other hand, pretreatment with dicoumarol enhanced cytotoxicity of CDDP in three cell lines with wild type of p53 (RT112, 253J and LNCap), but not in three other cell lines with mutant p53 or in RT112 stable transfectants with a dominant-negative mutant of p53. In RT112 and LNCap, CDDP induced p53 and p21 expression, while pretreatment of dicoumarol suppressed induction of p53/p21 and resulted in sequential activation of c-Jun N-terminal kinase (JNK) in a time-dependent manner. Furthermore, inhibition of JNK, using SP600125, completely suppressed activity of caspases and poly-(ADP-ribose) polymerase cleavage, leading to suppression of enhancement of CDDP-mediated apoptosis by dicoumarol. These results suggested that dicoumarol could enhance cytotoxicity of CDDP in urogenital cancer cells with wild-type p53 through the p53/p21/JNK pathways.

Effect of NOS inhibitor on cytokine and COX2 expression in rat pulpitis.

Various kinds of chemical mediators are synthesized in the course of pulpitis; thus, control of their production would assist in inducing a reduction in pulpal inflammation. We hypothesized that nitric oxide (NO) would be an important mediator of pulpal inflammation. Pulpal inflammation was induced by the application of LPS in rat incisor pulp, and inducible nitric oxide synthase (iNOS) expression was evaluated by reverse-transcription/polymerase chain-reaction and immunohistochemical staining. After LPS application, iNOS mRNA was first detected after 3 hrs, peaked at 6 hrs, and decreased thereafter. iNOS-positive cells were macrophages and neutrophils. An NOS inhibitor caused drastic decreases in the expression of pro-inflammatory cytokines and COX2 mRNA, which was highly induced in the LPS-induced pulpitis. These results indicate that NO synthesis is related to the initiation of mediator production, and that its down-regulation should contribute to the prevention of pro-inflammatory mediator synthesis.

The pathogenesis and therapeutic option of encapsulating peritoneal sclerosis.

Since the first peritoneal dialysis (PD) patients with encapsulating peritoneal sclerosis (EPS) were reported in 1980, EPS has been considered primarily a fatal complication. The incidence of EPS in PD patients has been reported to be from 0.7% to 7.3%, and the rate appears to be higher in patients receiving long-term treatment. Most data from Japan has shown an overall incidence of 2.5% with an evident negative effect of increasing duration of PD, which also augments mortality. Since EPS occurred after withdrawal from PD in more than half of the patients, strict monitoring is necessary when a long-term PD patient is withdrawn from PD. Maintaining patients on standard PD for more than 8 years using conventional solutions is associated with a substantial risk for development of EPS. Appropriate treatment according to the disease stage is most important in EPS treatment. Therefore, when examining a PD patient complaining of gastrointestinal symptoms, the possibility of EPS has to be kept in mind. Basic therapeutic tactics for EPS include an appropriate use of steroids. If the state of bowel obstruction persists, laparotomy and enterolysis should be performed to obtain complete cure. It is now recognized that EPS is not a fatal complication of PD.

Review of combination of peritoneal dialysis and hemodialysis as a modality of treatment for end-stage renal disease.

Because the contribution of residual renal function (RRF) to total solute clearance is often significant in continuous ambulatory peritoneal dialysis (CAPD), loss of RRF over time can lead to inadequate dialysis if appropriate prescription management strategies are not pursued. Additionally, declines in ultrafiltration caused by increases in peritoneal permeability may limit continuation of CAPD therapy. Peritoneal dialysis and hemodialysis (PD + HD) combination therapy (complementary dialysis therapy) is an alternative method. This therapy allows the patient to maintain daily activities, as with CAPD, while undergoing once-a-week HD supplements for the insufficient removal of solutes and water. This therapy allows for the continuation of PD without shifting to total HD in PD patients who continue to have uremic symptoms even after individualization of the PD prescription. This treatment option is psychologically more acceptable to patients and may be expected to provide such accompanying beneficial effects as peritoneal resting, improvement of QOL and reduction in medical cost.

Regioselectively substituted 6-O- and 2,3-di-O-acetyl-6-O-triphenylmethylcellulose: its chain dynamics and hydrophobic association in polar solvents.

Two kinds of regioselectively substituted cellulose derivatives, i.e., 6-O-triphenylmethylcellulose (6TC) and 2,3-di-O-acetyl-6-O-triphenylmethylcellulose (2,3Ac6TC), were prepared via cellulose. In these samples, C-6 position hydroxyls in the anhydroglucose units (AGU) along the cellulose chain were selectively substituted by the hydrophobic triphenylmethyl groups, but C-2 and -3 position hydroxyls remained in 6TC or were substituted completely by O-acetyls in 2,3Ac6TC. Their chain dynamics in polar solvents, dimethyl sulfoxide (DMSO) and N,N-dimethylacetamide (DMAc), in dilute solution were investigated by dynamic light scattering in the viewpoint of cluster formation. The results were compared with those of cellulose diacetates (CDA) in DMAc where three hydroxyls in the AGU were statistically substituted up to 2.44 by O-acetyls but hydroxyls at C-6 positions remained predominantly. It was found that 6TC and 2,3Ac6TC formed a dynamic structure about 10 times larger than single chains and that the structure would be a temporary and local association due to concentration fluctuations (dynamic structures) which were originated from the hydrophobic interactions between intermolecular triphenylmethyl groups. The dynamics and structures were in clear contrast to those of CDA where a solvent-mediated hydrogen bonding between intermolecular C-6 position hydroxyls was essential to cluster formation. The present structures were so weak as to dissipate easily under low shear field.

Potent and selective ET-A antagonists. 1. Syntheses and structure-activity relationships of N-(6-(2-(aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide derivatives.

Modifications to the ET(A/B) mixed type compounds 1 (Ro. 46-2005) and 2 (bosentan) were performed. Introduction of a pyrimidine group into 1 resulted in a dramatic increase in affinity for the ET(A) receptor, and the subsequent optimization of substituents on the pyrimidine ring led us to the discovery of N-(6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-5-(4-methylphenyl)-4-pyrimidinyl)-4-tert-butylbenzenesulfonamide (7k), which showed an extremely high affinity for the human cloned ET(A) receptor (K(i) = 0.0042 +/- 0.0038 nM) and an ET(A/B) receptor selectivity up to 29 000 (K(i) = 130 +/- 50 nM for the human cloned ET(B) receptor). The compound was designed on the hypothesis that the hydrogen atom of the hydroxyl group in 1 and 2 played a role not as a proton donor but as an acceptor in the possible hydrogen bonding with Tyr129. Since the incorporation of a pyrimidinyl group into the hydroxyethoxy side chain of the nonselective antagonist (1) dramatically enhanced both the ET(A) receptor affinity and selectivity, and since similar results were obtained from the benzene analogues, we put forward the hypothesis that a "pyrimidine binding pocket" might exist in the ET(A) receptor.

Potent and selective ET-A antagonists. 2. Discovery and evaluation of potent and water soluble N-(6-(2-(aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide derivatives.

In the preceding article,(1) we outlined the discovery and structure-activity relationship of a potent and selective ET(A) receptor antagonist 1 and its related compounds. Metabolites of 1 having potent selective ET(A) receptor antagonist activity were identified. This study suggested the metabolic pathways of 1 were considerably affected by species. Consequently, structural modification of 1 intended to improve the complexity of the metabolic pathway, and water solubility was performed. The subsequent introduction of a hydroxyl group into the tert-butyl moiety of 1 led to the discovery of our new clinical candidate, 6b, which showed a higher water solubility, a uniform metabolic pathway among species, and very high affinity and selectivity for the human ET(A) receptor (K(i) for ET(A) receptor: 0.015 +/- 0.004 nM; for ET(B) receptor: 41 +/- 21 nM).

Treatment options for encapsulating peritoneal sclerosis based on progressive stage.

Sclerosing encapsulating peritonitis (SEP) is recognized as a serious complication of peritoneal dialysis. However, recovery is possible if an appropriate diagnosis and treatment are made. The term SEP is used most often, but is inaccurate, particularly the reference to peritonitis. A more accurate description would be "encapsulating peritoneal sclerosis" (EPS). From the therapeutic perspective, the diagnosis should be established before EPS develops. Early diagnosis is important. Furthermore, it is also important to determine the therapeutic tactics for EPS according to the disease stage. Most cases of EPS develop with manifestations of fever, increased levels of C-reactive protein (CRP), and slight ileus symptoms, accompanied by increased ascites ("inflammatory stage"). Following precise identification of the inflammatory stage, steroid administration should be initiated immediately with the onset of EPS. Methylprednisolone pulse therapy is recommended during the early stage. If the EPS is not relieved, or if it recurs within 1 month, the steroid dose should be decreased and the patient should be managed by total parenteral nutrition (TPN) ("encapsulating stage"). If ileus symptoms remain despite the absence of inflammatory findings and decreased ascites, laparotomy and enterolysis should be considered within 6 months ("ileus stage"). However, it is important that the enterolysis be performed without damaging the capsule-covered intestine. To date, we have successfully treated EPS in 18 of 19 patients using these options. In 3 patients, EPS was relieved by steroid administration. In 15 patients, EPS was relieved by total intestinal enterolysis. Enterolysis patients had satisfactory operative outcomes and eventually returned to their previous social activities. One patient experienced perforation of the small intestine and pan-peritonitis, and died of sepsis. In summary, EPS is not an incurable disease. It can be completely overcome by active diagnosis and treatment.

Low serum albumin in elderly continuous ambulatory peritoneal dialysis patients is attributable to high permeability of peritoneum.

Our study was carried out to investigate changes in nutrition and individual peritoneal membrane transport characteristics in elderly patients on continuous ambulatory peritoneal dialysis (CAPD), expressed as the personal dialysis capacity (PDC). We performed 376 PDC tests in 229 non diabetic patients who were undergoing CAPD from May 1995 to May 1999 in a multicenter study in Japan. We divided the patients into three groups: elderly (age > or = 65 years, n = 56), middle-aged (age 50-65 years, n = 150), and young (age < 50, n = 170). No significant differences were seen in duration of CAPD and incidence of peritonitis between the groups. We then compared the peritoneal function calculated by PDC test in the groups. Serum levels of albumin in elderly patients were significantly lower than those in middle-aged and young patients (elderly: 3.2 +/- 0.1; middle-aged: 3.4 +/- 0.1, p = 0.0447 vs elderly; young: 3.4 +/- 0.1, p = 0.0272 vs elderly). Plasma protein loss from the peritoneum in elderly patients was significantly higher than in middle-aged and young patients (elderly: 0.11 +/- 0.01; middle-aged: 0.09 +/- 0.01, p = 0.0136 vs elderly; young: 0.09 +/- 0.01, p = 0.0161 vs elderly). No significant differences in ultrafiltration volume and water permeability were seen between the groups. Peritoneal area in the elderly group was significantly higher than in the middle-aged and young groups. Peritoneal creatinine clearance (CCr) and Kt/V in elderly patients were significantly higher than in middle-aged and young patients. However, no significant difference in protein nitrogen appearance (PNA) or protein catabolic rate (PCR) was seen between the groups. Urea and creatinine generation rates in elderly patients were significantly lower than in the middle-aged and young patients. These data show that elderly patients receiving CAPD are well maintained from the perspective of urea and water metabolism, indicating that CAPD therapy for the elderly is more acceptable than expected. However, caution should be exercised, owing to the lower serum albumin seen in elderly patients.

[Bladder carcinoma producing granulocyte colony-stimulating factor (G-CSF): a case report].

An 84-year-old male was admitted to our hospital with complaints of leg edema and general fatigue. He had undergone transurethral resection of transitional cell bladder cancer, grade 3, pT1b, one year previously. The computed tomographic scan revealed a hypoattenuating bladder tumor, protruding extravesically. Laboratory examination showed remarkable leukocytosis of 46,900/mm3 in the peripheral blood and high value of granulocyte colony-stimulating factor (G-CSF) 226 pg/ml (normal: less than 30 pg/ml). The resection of the tumor (partial cystectomy) was performed. The histological diagnosis was transitional cell carcinoma, grade 3. The production of G-CSF was confirmed by immunohistochemical examination in the recurrent tumor and the surgical sample from the transurethral resection. The leukocyte count in the peripheral blood decreased to the normal range after surgery. But leukocytosis recurred one month postoperatively and the computed tomographic scan revealed intrapelvic tumor recurrence. He died due to drastic progression of recurrent tumor at three months postoperatively.

Statistical analysis of diagnostic failure of fine needle aspiration cytology (FNAC) in breast cancer.

Fine-needle aspiration cytology (FNAC) was performed on 300 patients. Among those, 57 cases failed in accurate diagnosis of malignancy and 243 were successful. Fourteen clinicopathological factors altogether were analyzed to elucidate any correlation with FNAC failure using uni- and multivariate analysis. The univariate analysis in each clinicopathlogical factor showed that these error cases were vaguely palpable cancers, estrogen receptor (ER) positive cancers, small-sized of tumors, scattered type of cancer cell distribution in tumor tissues, with low tumor grade, with low Nottingham prognostic index (NPI), with benign-like ultrasound findings and with low TNM stage. The multivariate analysis revealed tumor grade was the strongest factor for all, followed by cellular distribution type of cancer cells and benign-like ultrasound findings. From these results, we speculated that diagnostic failure of FNAC at first clinic visit seemed to be caused by mainly two histocytological factors: extrinsic factor (structural factors of tissue-like tumor cells' distribution pattern, etc.); and intrinsic one (cellular factors of low atypism such as benign-like ultrasound finding, low tumor grade, and so on).

A utility of ductography and fiberoptic ductoscopy for patients with nipple discharge.

BACKGROUND: Breast carcinoma and precancer are thought to start in the lining of the milk duct or lobule. While ductography has been advocated as the main procedure in patients with nipple discharge, fiberoptic ductoscopy (FDS) is an emerging technique allowing direct visual access to the ductal system of the breast through nipple orifice exploration. METHODS: We applied ductography and FDS to 65 women who had nipple discharge, and compared their utility. RESULTS: Intraductal lesions occurred in the segmental duct and the first, second, third, fourth, fifth, and sixth branches in decreasing frequency with ductography and FDS screening. The detection rates of intraductal abnormal lesions by ductography and FDS and the their combination were 89.1 (37 patients), 97.4 (38 patients), and 97.5% (39 patients) respectively. Ductal washings performed during FDS were effective to obtain representative exfoliated ductal cells which could be evaluated (sensitivity 50%, specificity 94.3%, and diagnostic accuracy 89.7%). As a result, we diagnosed 35 cases of benign lesions and four cases of malignant lesions by cytological or/and histological examination. CONCLUSION: Ductography and fiberoptic ductoscopy are useful procedure in guiding subsequent breast surgery in the treatment of nipple discharge.

Encapsulating peritoneal sclerosis in Japan: prospective multicenter controlled study.

OBJECTIVE: Encapsulating peritoneal sclerosis (EPS) is recognized as a serious complication of peritoneal dialysis. The aim of this study was to determine the incidence, clinical features, and variation in mortality rates for EPS. DESIGN: A prospective multicenter design was used, in which peritoneal dialysis patients were pre-registered by facilities across Japan and the incidence of EPS was observed in the registrants. The registrants were followed for a total of 4 years to accurately observe the onset of EPS. RESULTS: As of April 1999, 2216 peritoneal dialysis patients from 64 facilities were registered. By the end of March 2001, 332 patients had dropped out, and 17 of the dropouts had developed SEP. The incidence was 0.77%. After excluding 110 patients who died, the incidence in 2106 patients was 0.81%. The incidence of EPS increased with the duration of peritoneal dialysis. Of the 17 patients with EPS, 12 developed the condition after discontinuing peritoneal dialysis and changing to hemodialysis. During the 2-year survey period, 6 of the 17 EPS patients died. The interval from onset to death was 10.8 +/- 5.8 months (range: 3-19.5 months). CONCLUSIONS: From this prospective multicenter study, the current incidence of EPS is 0.77% (0.81% when dropout owing to death is censored). After a follow-up of 2 years, we conjecture that the incidence of EPS will increase. The incidence, etiology, and prognosis of EPS will be further clarified by periodic observation of dropouts until the end of March 2003.

Encapsulating peritoneal sclerosis: definition, etiology, diagnosis, and treatment. International Society for Peritoneal Dialysis Ad Hoc Committee on Ultrafiltration Management in Peritoneal Dialysis.

Current definitions of encapsulating peritoneal sclerosis are practical and clinically relevant. It is important to adhere to a more uniform use of the proper terminology, and it is the recommendation of the authors that EPS be adopted as the more appropriate term. The best literal definition of EPS is based on clinical-pathologic criteria. Differentiation of EPS from the general category of ultrafiltration failure is required. Further, better appreciation of the diverse pathways that can lead to the same final common clinical-pathologic picture should not be overshadowed by the requirement of uniform terminology. Incidence and prevalence of the syndrome have been defined in some large populations and a few single-center experiences. The former show an incidence of less than 1%, while higher percentages are reported in the latter. The reported increased incidence with duration on therapy requires validation. The epidemiology of the syndrome offers limited insight into its pathogenesis. A list of factors, both dialysis-related and non dialysis-related. has been accumulated. Except in a few categories where agents are clearly related to the development of EPS, the majority of the listed factors for dialysis-related BPS remain, at best, associations and at worst, simple conjecture. The same limitations that plague the issue of etiology apply in the area of pathogenesis. More basic, focused work is required. The diagnosis of EPS remains based on clinical suspicion confirmed with, primarily, radiologic findings. Pathologic confirmation is obtained in cases that come to surgery for management or for catheter removal. Radiologic studies are precise enough for confirmation, but none have been evaluated for early diagnosis for possible early intervention or prevention. Studies based on transport characteristics or effluent dialysate constituents are not useful for EPS. At present, there are no reliable predictive tests for BPS that can be used in individual patients. Therapy of BPS is based on anecdotal evidence. The possible variable etiologies and probable distinct pathways leading to the syndrome may make a uniform therapeutic approach unlikely. Further, the limited number of cases and the sporadic pattern of occurrences make therapeutic trials not readily feasible. This is distinct from the case of ultrafiltration failure, where significant advances in mechanism elucidation and rationale-based interventions have been made.