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PubMed1995

Eyelid involvement in multicentric reticulohistiocytosis.

CASE REPORT: The authors report the first biopsy-confirmed ocular adnexal involvement by multicentric reticulohistiocytosis. The patient was a 28-year-old black woman with a 15-year history of well-documented multicentric reticulohistiocytosis who had multiple dermal nodules and severe mutilating arthritis that had produced a characteristic telescoping deformity of the digits. Eyelid nodules were excised to relieve pseudoptosis and for cosmesis. MATERIALS: The eyelid nodules were studied by routine light microscopy and a battery of immunohistochemical stains, including S-100 protein and several macrophage markers. RESULTS: Microscopy disclosed an infiltrate of histiocytes and giant cells with glassy eosinophilic cytoplasm and large round or oval vesicular nuclei with prominent nucleoli set in a densely fibrotic stroma consistent with multicentric reticulohistiocytosis. The histiocytes showed positive immunoreactivity for lysozyme, but were negative for alpha-1 antichymotrypsin, S-100 protein, and neuron-specific enolase. CONCLUSION: Multicentric reticulohistiocytosis should be included in the differential diagnosis of multiple eyelid nodules.

Adult↗
PubMed2002

Multicentricity in renal cell carcinoma: can primary tumor location serve as a co-determinant of surgical treatment?

OBJECTIVE: To assess the incidence of multicentricity in our series of renal cell carcinoma (RCC) patients and to investigate whether certain clinicopathological parameters could assist the selection of the appropriate surgical modality. METHODS: We performed a retrospective analysis of 235 RCC specimens that had been resected by radical nephrectomy at our institution from June 1995 to 2001. RESULTS: Twenty-six (11%) kidneys contained at least one small accompanying nodule. Fourteen (6%) kidneys exhibited satellite tumors that were histologically consistent with the adenomas, while "true" multicentricity was detected in 12 (5%) specimens. In the latter, the number of concomitant foci was independent of the size of the primary tumor. No correlation was observed between histological pattern and multifocality. In five out of seven (71%) specimens that contained the main tumor mass within the upper or middle portion of the kidney, satellite lesions were found to be located at the mid-kidney, whereas specimens with lower-pole RCC demonstrated no restriction in the distribution of accompanying nodules. All patients had been screened pre-operatively by ultrasonography and CT scanning. CONCLUSIONS: Our findings may be suggestive of a putative link between primary tumor location and multicentricity, although this relation could not be statistically confirmed. The 5% incidence of multicentricity renders the biological significance of satellite adenomas and/or adenocarcinomas unclear.

Carcinoma, Renal Cell↗
PubMed2000

Clinicopathologic features and postoperative prognosis of multicentric small hepatocellular carcinoma.

BACKGROUND: Assessment of clinicopathologic characteristics and postoperative prognoses for patients with multicentric hepatocellular carcinoma (HCC) is important to determine not only a need to operate, but also an appropriate treatment after hepatic resection. STUDY DESIGN: Between May 1990 and April 1998, among 116 patients with an initial hepatectomy for HCC measuring 3 cm or less in maximum diameter, 34 patients had multicentric HCC (MC group), and 82 patients had single nodular HCC (SN group). To clarify the clinicopathologic features of patients in the MC group versus the SN group, we compared both the clinicopathologic parameters and the postoperative prognosis after curative hepatectomy between the two groups. RESULTS: The percentages of patients positive for hepatitis B surface antigen and hepatitis C virus antibody were not significantly different between the two groups. No differences were noted in pathologic characteristics of the main tumor or tumor markers. On the other hand, in the MC group, the percentage of patients evaluated in a Child's classification as either B or C was significantly higher (p < 0.05) than that of patients in the SN group, indicating that patients with multicentric HCC have a poor hepatic functional reserve. Both survival and disease-free survival of patients in the MC group who underwent a curative hepatectomy did not differ statistically from those in the SN group. CONCLUSIONS: Our results indicate that hepatic resection is useful, even for patients with multicentric HCC, if a curative hepatectomy can be performed and liver function can be saved, despite their poor hepatic functional reserve.

Aged↗
PubMed2003

Multicentric occurrence of hepatocellular carcinoma in patients with a somatic mutation of mitochondorial DNA and hepatitis C virus.

The relationship between the multicentric occurrence of hepatocellular carcinoma (HCC) and the frequency of mutation of mitochondrial DNA (mtDNA) in the noncancerous hepatic tissue in patients infected with hepatitis C virus was investigated. Of the 48 patients, multicentric occurrence of HCC was found in ten of 33 patients with three or more mutations in the mtDNA, whereas no patients had multicentric HCCs in 15 patients with two or fewer mutations in the mtDNA (P=0.0201). A high rate of mtDNA mutation in noncancerous hepatic tissue may be related to multicentric hepatocarcinogenesis and the hypercarcinogenic state in such patients.

Journal Article↗
PubMed1996

Comparison of the characteristics of hepatocellular carcinoma between hepatitis B and C viral infection: tumor multicentricity in cirrhotic liver with hepatitis C.

Clinicopathological and prognostic features in patients who had undergone hepatectomy for hepatocellular carcinoma (HCC) were examined in relation to viral infection. Among 175 patients, cirrhosis was diagnosed histologically in 134, while 41 had noncirrhotic livers. One hundred twenty-four patients were positive for antibody to hepatitis C virus (anti-HCV) (HC group), 32 for hepatitis B virus surface antigen (HBsAg) (HB group), and 19 negative for both anti-HCV and HBsAg (non-B, non-C group). In the HB group, the mean patient age was significantly younger, and liver function in terms of the plasma retention rate of indocyanine green at 15 minutes and the serum total bilirubin level was significantly better than in either the HC or the non-B, non-C group. Seventeen patients had synchronous multicentric HCCs: the HC group showing a significantly higher incidence than the HB group (P < .05). In the HC group, the proportion of cirrhotic liver in patients with multicentric HCCs was significantly larger than in patients with unicentric HCC (P < .05). No significant differences in disease-free survival rate after hepatectomy were observed between the three groups. The present retrospective study of surgically treated patients showed that anti-HCV-positive HCCs tended to occur in older individuals who showed worse liver function and a higher incidence of cancer multicentricity compared with HBsAg-positive HCCs. The prognosis of anti-HCV-positive HCCs, which had the disadvantageous characteristic of multicentricity, did not differ from that of HBsAg-positive HCCs.

Adult↗
PubMed1995

Renal thrombotic microangiopathy associated with multicentric Castleman's disease. Report of two cases.

Castleman's disease (also called giant lymph node hyperplasia or angiofollicular lymph node hyperplasia) is a clinicopathological entity of unknown etiology. Two histologic patterns of lymph nodes are classically recognized: the hyaline-vascular and plasma-cell variants. Recently, multicentric Castleman's disease has emerged as a separate clinical entity manifested primarily by generalized lymphadenopathy and systemic manifestations, such as thrombocytopenia, hemolytic anemia, hepatosplenomegaly, altered liver function tests, central nervous system alterations, and autoimmune manifestations. A number of renal alterations have been described in association with the two pathological variants of Castleman's disease, but thrombotic microangiopathy has been previously reported only once in a patient with Castleman's disease. No renal biopsy was performed in that patient, although there was evidence of renal dysfunction. We report two cases of biopsy-proven renal thrombotic microangiopathy associated with multicentric Castleman's disease. In addition to having lymph node pathology characteristic of Castleman's disease, both patients presented with generalized lymphadenopathy and systemic manifestations, including acute renal failure, hypergammaglobulinemia, anemia, thrombocytopenia, and hypoalbuminemia. Autoantibodies were present in both patients, including antiphospholipid antibodies in one patient. The renal biopsies, examined by light, immunofluorescence, and electron microscopy, were diagnostic for renal thrombotic microangiopathy. The simultaneous development of two rather uncommon syndromes, multicentric Castleman's disease and renal thrombotic microangiopathy, suggests a possible link between Castleman's disease and renal thrombotic microangiopathy. Furthermore, we propose that the production of autoantibodies, in particular antiphospholipid antibodies, may lead to the development of thrombotic microangiopathy in some patients with multicentric Castleman's disease.

Adult↗
PubMed2003

Bilateral corneal opacities associated with idiopathic multicentric osteolysis.

PURPOSE: To report unusual bilateral corneal opacity and inferior corneal thinning in a patient with idiopathic multicentric osteolysis. METHODS: A 17-year-old girl with a history of idiopathic multicentric osteolysis was evaluated for corneal opacities. RESULTS: She was found to have bilateral, linear, posterior corneal opacity and inferior corneal thinning. Her vision did not appear to be affected. No progression of the corneal findings was noted over a period of 2 years. CONCLUSION: Posterior corneal opacity and inferior corneal thinning may be associated with idiopathic multicentric osteolysis, a rare disorder of unknown etiology characterized by bony abnormalities and nephropathy. Patients with idiopathic multicentric osteolysis should be evaluated by an ophthalmologist for the presence of corneal opacities.

Adolescent↗
PubMed2004

Trust and confidence: towards mutual acceptance of ethics committee approval of multicentre studies.

AIMS: To compare issues raised by Human Research Ethics Committees (HREC) during the ethics review process and to determine the length of time taken to gain HREC approval for multicentre research studies. METHODS: Review and analysis of HREC documentation and correspondence for all multicentre research studies were conducted through three HREC under the auspices of Cancer Trials Australia, Melbourne, Victoria, Australia, between November 1997 and March 2001 to determine the variance of documentation, correspondence and recommendations across the three HREC and the time taken for study approval. RESULTS: Thirty-one projects were submitted to any two of the HREC (16 studies) or all three HREC (15 studies). The median time for study approval at an individual HREC was 75 days, but it was 111 days for approval at all participating sites. There were 554 clarifications or comments made by the reviewing HREC, the majority of which had no significant bearing on the ethical or scientific calibre of the study. There was only one study in which a significant protocol change was requested by a HREC. CONCLUSIONS: Multicentre study approvals are delayed when submitted to multiple HREC. The three HREC raised similar issues without substantive differences in their recommendations. A process for the mutual acceptance of HREC recommendations could facilitate multicentre research.

Australia↗
PubMed1992

Multicentric reticulohistiocytosis with arthritis and cardiac infiltration: regression following treatment for underlying malignancy.

The case is reported of a 63 year old man presenting with a rapidly destructive symmetrical polyarthritis and widespread papular nodular skin lesions, confirmed by a biopsy to be due to multicentric reticulohistiocytosis. Biventricular cardiac failure developed secondary to extensive myocardial infiltration with multicentric reticulohistiocytosis, a complication of this disease which has not previously been reported. The joint, skin, and cardiac manifestations of multicentric reticulohistiocytosis substantially regressed following resection of an associated squamous cell carcinoma. This report adds to the small amount of published work which suggests that multicentric reticulohistiocytosis can be a paraneoplastic disease that may respond to treatment directed at the underlying tumour.

Arthritis↗
PubMed2002

Proportional hazards models with random effects to examine centre effects in multicentre cancer clinical trials.

In randomized clinical trials comparing treatment effects on diseases such as cancer, a multicentre trial is usually conducted to accrue the required number of patients within a reasonable period of time. The fundamental point of conducting a multicentre trial is that all participating investigators must agree to follow the common study protocol. However, even with every attempt having been made to standardize the methods for diagnosing severity of disease and evaluating response to treatment, for example, they might be applied differently at different centres, and these may vary from comprehensive cancer centres to university hospitals to community hospitals. Therefore, in multicentre trials there is likely to be some degree of variation (heterogeneity) among centres in both the baseline risks and the treatment effects. While we estimate the overall treatment effect using a summary measure such as hazard ratio and usually interpret it as an average treatment effect over the centre, it is necessary to examine the homogeneity of the observed treatment effects across centres, that is, treatment-by-centre interaction. If the data are reasonably consistent with homogeneity of the observed treatment effects across centres, a single summary measure is adequate to describe the trial results and those results will contribute to the scientific generalization, the process of synthesizing knowledge from observations. On the other hand, if heterogeneity of treatment effects is found, we should carefully interpret the trial results and investigate the reason why the variation is seen. In the analyses of multicentre trials, a random effects approach is often used to model the centre effects. In this article, we focus on the proportional hazards models with random effects to examine centre variation in the treatment effects as well as the baseline risks, and review the parameter estimation procedures, frequentist approach-penalized maximum likelihood method--and Bayesian approach--Gibbs sampling method. We also briefly review the models for bivariate responses. We present a few real data examples from the biometrical literature to highlight the issues.

Bias↗
PubMed2005

Bayesian analysis of multicentre trial outcomes.

Bayesian methods provide flexibility in the analysis of data from multicentre trials that would be difficult to achieve by other means. This paper illustrates some useful applications of Bayesian methods to the analysis of multicentre trials, with emphasis on insights that would be difficult to obtain using conventional frequentist methods. Two trials provide data for illustration: a large multicentre trial comparing two doses of a drug with placebo with respect to an essentially continuous measurement for which the original analysis revealed a significant treatment by centre effect, and a large multicentre trial with intraclass correlation induced by a categorical outcome of up to four episodes of heartburn reported by individual patients. The data from both trials had been analysed previously using conventional frequentist methods. Both sets of data were reanalysed using Bayesian and empirical Bayesian methods; all of the analyses provided the same conclusions for the key questions regarding treatment differences. The Bayesian methods provided some insights useful for model checking and also provided a way to explore some important quantitative aspects about the magnitude of treatment effects.

Antacids↗
PubMed2006

Multicentric breast cancer: a new indication for sentinel node biopsy--a multi-institutional validation study.

PURPOSE: Multicentric breast cancer has been considered to be a contraindication for sentinel node (SN) biopsy (SNB). In this prospective multi-institutional trial, SNB-feasibility and accuracy was evaluated in 142 patients with multicentric cancer from the Austrian Sentinel Node Study Group (ASNSG) and compared with data from 3,216 patients with unicentric cancer. PATIENTS AND METHODS: Between 1996 and 2004, 3,730 patients underwent SNB at 15 ASNSG-affiliated hospitals. Patient data were entered in a multicenter database. One hundred forty-two patients presented with multicentric invasive breast cancer and underwent SNB. RESULTS: Intraoperatively, a mean number of 1.67 SNs were excised (identification-rate, 91.5%). The incidence of SN metastases was 60.8% (79 of 130). This was confirmed by axillary lymph node dissection (ALND) in 125 patients. Of patients with positive SNs, 60.8% (48 of 79) showed involvement of nonsentinel nodes (NSNs), as did three patients with negative SNs (false-negative rate, 4.0). Sensitivity, negative predictive value, and overall accuracy were 96.0%, 93.3%, and 97.3%, respectively. Ninety-one percent of the patients underwent mastectomy, and 9% were treated with breast conserving surgery. None of the patients have shown axillary recurrence so far (mean follow-up, 28.8 months). Compared with 3,216 patients with unicentric cancer, there was a significantly higher rate of SN metastases as well as in NSNs, whereas there was no difference in detection and false-negative rates. CONCLUSION: Multicentric breast cancer is a new indication for SNB without routine ALND in controlled trials. Given adequate quality control and an interdisciplinary teamwork of surgical, nuclear medicine, and pathology units, SNB is both feasible and accurate in this disease entity.

Adult↗
PubMed2000

Telemedicine techniques can be used to facilitate the conduct of multicentre trials.

A multicentre randomized controlled trial was established in Pretoria, Bloemfontein and Edendale in South Africa, and coordinated from London. The purpose of the trial was to determine the efficacy of low-dose beta irradiation of glaucoma. Five communication modalities (telephone, fax, e-mail, videoconferencing and face-to-face meetings) were examined in terms of their benefits in a multicentre trial. The eight stages of the multicentre trial examined were: set-up and training, recruitment, standardization, patient management, data transmission, update and data dissemination, clinical follow-up and monitoring, and publication. On four-point Likert scales for rating the usefulness of the communication modalities at each of the eight stages of the trial (from 0 = not useful to 3 = very useful; maximum score 24) the telephone was given a total score of 10, fax 9, e-mail 13, videoconferencing 15 and face-to-face meetings 9. Telemedicine techniques offer considerable benefits in the coordination of multicentre trials by improving data collection, maintaining the efficacy and monitoring of trials, while potentially offering reduced costs in terms of travel and time. The realtime scrutiny of patient records helps to ensure data uniformity and completeness of data collection. Videoconferencing was most useful when considered as one of several communication tools that can be used to improve the effectiveness of a service or process.

Glaucoma↗
PubMed2026

Inhibition of MAFB and PI3K/AKT Signaling for Hereditary FSGS with Multicentric Carpotarsal Osteolysis.

KEY POINTS: Multicentric carpotarsal osteolysis, a rare disorder, causes progressive osteolysis and kidney failure because of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene mutations. A genome-edited mouse model carrying the multicentric carpotarsal osteolysis mutation was used to obtain a deeper understanding of this rare disease. Targeting MAFB/IGF-1/PI3K/AKT signaling may provide new treatments for multicentric carpotarsal osteolysis-related nephropathy. BACKGROUND: Multicentric carpotarsal osteolysis (MCTO) is a rare condition characterized by progressive osteolysis and often kidney failure. It is caused by autosomal dominant mutations in the transcription factor v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B ( MAFB ). METHODS: Given the absence of efficacious therapeutic interventions for MCTO and the obscurity of its pathophysiologic mechanisms, we used mice with the MCTO mutation ( MafbMCTO/MCTO mice) to explore the role of MAFB. RESULTS: MafbMCTO/MCTO mice displayed FSGS, mirroring the manifestations seen in patients with MCTO. These mice showed that the MCTO mutation leads to the accumulation of MAFB protein. Heterozygous MafbMCTO/- mice, generated by crossbreeding to reduce MAFB levels, neither exhibited albuminuria nor showed any histologic abnormalities in the kidney, suggesting that excess MAFB was detrimental. We subsequently conducted RNA-seq on the glomeruli from MafbMCTO/MCTO mice and detected pronounced upregulation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway through IGF-1. Given that receptor tyrosine kinases activate PI3K/AKT, we treated MafbMCTO/MCTO mice with the inhibitor imatinib. This led to a significant decline in urinary albumin levels compared with the control group. CONCLUSIONS: Our findings demonstrate that the MCTO mutation resulted in MAFB protein accumulation and led to the development of FSGS in mice.

Animals↗
PubMed2001

Multicentricity in papillary thyroid carcinoma: analysis of predictive factors.

OBJECTIVES: Multicentricity has been cited as a rationale for total thyroidectomy in patients with papillary thyroid carcinoma (PTC) confined to one lobe. The purpose of this study was to examine the incidence of multicentricity of PTC in a cohort of 165 patients with PTC confined to one lobe and to examine clinical and pathologic features that may help predict for the presence of contralateral disease. DESIGN: Retrospective review. SETTING: Tertiary care hospital. METHOD: A retrospective review of 165 patients with PTC confined to one lobe treated at the Toronto General Hospital from 1992 to 1997 was performed. MAIN OUTCOME MEASURE: The predictive factors affecting the presence of multicentricity of PTC were analyzed. RESULTS: The incidence of PTC present in the contralateral lobe was 56.3%. We were unable to find any correlation of multicentricity with age, sex, tumour size, extrathyroidal spread, thyroiditis, or tall cell variant of PTC. There were trends toward higher incidence of contralateral disease in those patients with a prior history of irradiation and those with lymphatic metastases, but these trends did not reach statistical significance. CONCLUSIONS: The incidence of contralateral disease in papillary thyroid cancer treated at the Toronto Hospital was 56.3%. There was a higher incidence of contralaterality in those patients with a previous history of irradiation and in those with lymphatogenous metastases, but this did not reach statistical significance.

Adult↗
PubMed2006

Multicentric peripheral ossifying fibroma.

Peripheral ossifying fibroma (POF) is a common solitary gingival growth thought to arise from the periodontal ligament. Though the etiology of POF remains unknown, some investigators consider it an inflammatory or reactive process, while others suggest it is a neoplastic process. In this report, we present and discuss a unique case of multicentric POF, affecting the maxillary and mandibular gingiva of a 49-year-old Caucasian female with meticulous oral hygiene and routine dental care. Though biopsy samples from multiple sites revealed similar histopathologic features, consistent with POF, the fact that there was a multicentric presentation is a unique phenomenon for this lesion. Multicentric lesions presenting in the oral and maxillofacial region are not typical, but have been observed in conditions associated with known genetic mutations, such as nevoid basal cell carcinoma syndrome (multiple odontogenic keratocysts), multiple endocrine neoplasia type II (multiple neuromas), neurofibromatosis (multiple neurofibromas) and Gardner syndrome (multiple neoplasms). This case is the first one to demonstrate that there may be a multicentric variant of POF that has not been previously recognized, and given the clinical presentation and multifocal nature of disease, the lesions in this patient are likely the result of genetic mutation(s) that predisposes to gingival soft tissue overgrowths containing mineralized product.

Female↗
PubMed2005

Pathological study on multicentric occurrence of hepatocellular carcinoma.

Recently, it has been suggested that many of hepatocellular carcinoma (HCC) are of multicentric origin based on the clinicopathologic studies on small HCCs of the early stage and clinical follow-up studies after successful treatments of small HCCs. The author studied the multicentric occurrence of HCC from the point of view of pathomorphology in 168 HCCs less than 3 cm in diameter consecutively resected from 1999 to 2004 and 8 autopsy of liver cirrhosis of micronodular type from 1990 to 2004 at Kurume University Hospital from 1999 to 2004. The association of well-differentiated HCC ranging from 9 mm to 1.2 cm in diameter was found in the non-cancerous tissue of 9 cases (9.5%) among 94 cirrhotic livers. Adenomatous hyperplasia (AH) was found in 7 cases (7.4%). Accordingly, prevalence of synchronous and metachronous multicentric hepatocarcinogenesis was highly suggested in 9.5% and 7.4%, respectively. In 4 (50%) of the 8 autopsy cases of micronodular cirrhosis, however, the coexistence of 2 well-differentiated HCCs around 1.5 cm were found in the different segment. The prevalence of multicentric occurrence in the resected cases is the lowest estimation and true prevalence should be much more higher because HCC cases with multiple nodules are not sent to surgery and the observation is limited in a small area of the subsegmentectomized liver. Indeed, the result of autopsy cases reflects a true prevalence (50%) of synchronous occurrence of HCC.

Autopsy↗
PubMed1989

Multicentric reticulohistiocytosis: response to alkylating agents in six patients.

STUDY OBJECTIVE: To determine the efficacy of alkylating agents in multicentric reticulohistiocytosis. DESIGN: Open consecutive case series. SETTING: Tertiary-care referral clinic. PATIENTS: Six patients with skin-biopsy-proven multicentric reticulohistiocytosis. All had skin nodules and polyarthritis. INTERVENTION: Five patients received cyclophosphamide (dose range, 1.25 to 2.2 mg/kg body weight) and one patient received chlorambucil (0.1 mg/kg). Therapy was administered from 6 to 24 months. MEASUREMENTS AND MAIN RESULTS: In five patients treated with cyclophosphamide a response was seen within 4 months. Four patients eventually had a complete remission and one had almost a complete remission. The four patients in complete remission had cyclophosphamide therapy discontinued after 6, 12, 16, and 18 months. Three of the four patients remained in complete remission off therapy at 6, 6, and 22 months, whereas one had a recurrence after 6 months. The one patient given chlorambucil went into a complete remission and stopped treatment after 12 months. He remained in complete remission 32 months after stopping medication. CONCLUSION: Our experience with patients with aggressive multicentric reticulohistiocytosis shows that alkylation therapy is warranted. We conclude that a response to an alkylating agent may be expected. Whether after treatment for 6 to 18 months most patients may be able to discontinue the drug and remain in remission has yet to be shown. The rarity of multicentric reticulohistiocytosis precludes the possibility of a double-blind study.

Adult↗