Sequential dose-dense Doxorubicin and Ifosfamide in advanced soft-tissue sarcoma patients in an out-patient-basis schedule.

Aims. This phase II study explored activity/safety of front-line dose-dense chemotherapy in high-grade STS (soft tissue sarcoma) patients and tested ezrin as prognostic factor. Patients and Methods. The protocol consisted of three cycles of doxorubicin (DOXO) 30 mg/m(2) on days 1-3 every 2 weeks, followed by three cycles of ifosfamide (IFO) 2.5 g/m(2) two hours a day on days 1-5 every 3 weeks, with GCSF support. Ezrin was assessed immunohistochemically. Results. Twenty patients, 13 metastatic and 7 locally advanced, were enrolled. Median age was 39 years (25-60). Median dose intensities were 42 mg/m(2)/week and 3.6 g/m(2)/week for DOXO and IFO, respectively. Grade 3/4 toxicities occurred in 18 patients. Response rate was 15% (3 of 20) by RECIST. Patients younger than 45 years with locally advanced disease and synovial histology presented longer survival. A trend towards longer survival was observed among ezrin-positive patients. Conclusions. This dose-dense schedule should not be routinely used due to its high frequency of toxic events; however, a sequential strategy with DOXO and IFO may benefit selected patients and should be further explored with lower doses. The role of ezrin as a prognostic marker should be confirmed in a larger group of patients.

Synchronous collision malignant melanoma and adenocarcinoma of the rectum.

"Collision tumors" consist of two independent but coexisting tumors. This uncommon situation might be easily mistaken for a composite tumor where one histogenetic event originates from two apparently distinct neoplasms. Colorectal collisions are particularly unusual; here, we report the exceedingly rare case of a 61-year-old man with malignant melanoma and adenocarcinoma colliding in the rectum. Collision tumors have an idiopathic pathophysiology and in fact "accidental meeting" is accepted by many authors. This article discusses the concepts about cancer development, which are overlooked by this hypothesis, another theory to explain that this rare occurrence involves microenvironment changes.

p63 protein expression in high risk diffuse large B-cell lymphoma.

BACKGROUND: p63 gene is a p53 homologue that encodes proteins with transactivation, DNA-binding and tetramerisation domains. The isoforms TAp63 and TAp73 transactivate p53 target genes and induce apoptosis, whereas the isoforms DeltaNp63 and DeltaNp73 lack transactivation and might have dominant-negative effects in p53 family members. p63 is expressed in germinal centre lymphocytes and can be related to the development of the lymphoma, but the prognostic significance of its expression in the survival of patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. AIMS: To determine whether quantitative immunohistochemical (IHC) analysis of p63 protein expression correlates with CD10 antigen, Bcl-6 antigen and IRF4 antigen expression and to determine whether p63 is a surrogate predictor of overall survival in high-intermediate and high risk DLBCL populations. METHODS: CD10, Bcl-6 and IRF4 expression were retrospectively evaluated by IHC in 73 samples of high-intermediate and high risk DLBCL and were used to divide the lymphomas into subgroups of germinal centre B-cell-like (GCB) and activate B-cell-like (ABC) DLBCL. Similarly, p63 expression was evaluated by IHC and the results were compared with subgroups of DLBCL origin and with the survival rates for these patients. RESULTS: p63 was expressed in more than 50% of malignant cells in 11 patients and did not show correlation with subgroups of GCB-like DLBCL or ABC-like DLBCL, but p63(+) patients had better disease-free survival (DFS) than those who were negative (p = 0.01). CONCLUSIONS: p63(+) high-intermediate and high risk DLBCL patients have a better DFS than negative cases.

Prognostic impact of diffuse large B-cell lymphoma subgroups in patients undergoing autologous SCT.

A total of 53 patients aged 18-60 years with high-intermediate or high-risk diffuse large B-cell lymphoma (DLBCL) were evaluated to analyze the impact of the cell of origin. Of 53 patients, 16 underwent autologous SCT (ASCT) in first remission and the rest received conventional chemotherapy. Immunohistochemistry was evaluated in 47 cases: 17 were of germinal center (GC) origin and 30 were of non-GC origin. There was no survival difference between the two groups. Overall survival (OS) and disease-free survival (DFS) at 3 years were 93 and 83%, respectively, for the 14 patients who underwent ASCT. Their DFS was significantly better than that of patients who achieved CR but did not undergo ASCT. We conclude that ASCT is safe and improves the DFS of high-intermediate and high-risk DLBCL, regardless of the cell of origin. This observation should be confirmed in a larger study.

Multiple endocrine neoplasia type 1 in Brazil: MEN1 founding mutation, clinical features, and bone mineral density profile.

OBJECTIVE: Only few large families with multiple endocrine neoplasia type 1 (MEN1) have been documented. Here, we aimed to investigate the clinical features of a seven-generation Brazilian pedigree, which included 715 at-risk family members. DESIGN: Genealogical and geographic analysis was used to identify the MEN1 pedigree. Clinical and genetic approach was applied to characterize the phenotypic and genotypic features of the family members. RESULTS: Our genetic data indicated that a founding mutation in the MEN1 gene has occurred in this extended Brazilian family. Fifty family members were diagnosed with MEN1. Very high frequencies of functioning and non-functioning MEN1-related tumors were documented and the prevalence of prolactinoma (29.6%) was similar to that previously described in prolactinoma-variant Burin (32%). In addition, bone mineral density analysis revealed severe osteoporosis (T, -2.87+/-0.32) of compact bone (distal radius) in hyperparathyroidism (HPT)/MEN1 patients, while marked bone mineral loss in the lumbar spine (T, -1.95+/-0.39), with most cancellous bone, and femoral neck (mixed composition; T, -1.48+/-0.27) were also present. CONCLUSIONS: In this study, we described clinically and genetically the fifth largest MEN1 family in the literature. Our data confirm previous findings suggesting that prevalence of MEN1-related tumors in large families may differ from reports combining cumulative data of small families. Furthermore, we were able to evaluate the bone status in HPT/MEN1 cases, a subject that has been incompletely approached in the literature. We discussed the bone loss pattern found in our MEN1 patients comparing with that of patients with sporadic primary HPT.

Mucinous ovarian tumors associated with pseudomyxoma peritonei of adenomucinosis type: immunohistochemical evidence that they are secondary tumors.

Pseudomyxoma peritonei (PMP) is a clinical condition initially thought to be related to ovarian mucinous tumors; however, immunohistochemistry and molecular biology techniques have convincingly made the link to appendiceal mucinous neoplasms, resulting in changes in histologic and clinical approaches. The objective of this study was to compare the immunohistochemical profile of ovarian tumors associated with PMP and intestinal mucinous ovarian neoplasms without PMP. The study was retrospective and included 28 intestinal ovarian mucinous tumors selected from the files of the Division of Surgical Pathology of the University of Sao Paulo Medical School, from 1996 to 2005. Seven cases were associated with PMP of disseminated peritoneal adenomucinosis-type and all presented borderline histology. Immunohistochemical staining for mucin genes products (MUC1, MUC2, MUC5AC, and MUC6), CK7, CK20, CA19.9, and CA125 were performed in tissue microarrays. Of note, we detected differences in the expression of MUC2 and CK20 between cases with and without PMP. Comparisons of borderline histology with that of benign/malignant tumors also revealed differences in MUC2 and CK20. Our results confirm that there is a distinct profile of intestinal ovarian tumors associated with pseudomyxoma, particularly with respect to the expression of the gel-forming mucin MUC2. The profile of borderline tumors, even in cases without PMP, was distinct from that of other primary mucinous tumors of the intestinal type, suggesting that borderline histology may represent a secondary tumor or a less aggressive variant of PMP. An appendiceal origin seems the most probable for this group of neoplasias.

Solitary fibrous tumour of the mouth: report of two cases involving the tongue and cheek.

We describe two additional cases of solitary fibrous tumour (SFT) affecting the mouth. SFT is very uncommon in the oral cavity and we found only 14 cases reported in the literature. Our two cases were well circumscribed, slow growing tumours that, after surgical removal, did not recur. Case 1 was a 3 cm nodule on the right cheek. Hypo and hypercellular adjacent areas were mainly patternless, and the stroma was formed by thin collagen fibrils. Case 2 was a 4.8 cm mass in the anterior portion of the tongue. Microscopically it was formed by spindle cells embedded in a vascularized sclerotic collagen matrix. Some areas were hypercellular with scarce collagen fibrils. The immunohistochemical findings were similar in both cases, with strong immunoreactivity for vimentin, CD34, bcl-2, focal positivity for Ki-67 and negativity for other immunomarkers. Based on these clinical, microscopical and immunohistochemical features the final diagnosis of these two cases was SFT. Diagnosis of SFT is difficult and, although uncommon, it should be considered in the differential diagnosis of oral soft tissue tumours.

Morphological diagnosis of HPV lesions and cervical intraepithelial neoplasia (CIN) is highly reproducible.

PURPOSE: to assess the value of individual histological criteria in the diagnosis of cervical HPV lesions. METHODS: 138 women referred for colposcopic evaluation (due to abnormal PAP smears) were subjected to cervical punch biopsy. The biopsies were classified as no HPV lesion, CIN 1, or CIN 2-3 by two observers independently. Kappa tests were used for interobserver agreement of the diagnosis. The presence of binucleation, multinucleation, abnormal mitosis. koilocytosis, spindle koilocytosis and dyskeratosis was similarly assessed. RESULTS: the Kappa statistic was 0.638 (CI 95% 0.533-0.743), showing substantial inter-observer agreement. Abnormal mitosis and multi-nucleation were the two most powerful discriminators between CIN 2-3 and CIN 1. Koilocytosis proved to be the single most powerful discriminator between CIN 1 lesions and non-HPV lesions. CONCLUSION: the results advocate the use of histology as the gold standard in diagnosing cervical precancerous lesions. The classical criteria can be also used to differentiate low-grade lesions, which has practical implications by avoiding the unnecessary treatment of minor abnormalities.

Cigarette smoking and high-risk HPV DNA as predisposing factors for high-grade cervical intraepithelial neoplasia (CIN) in young Brazilian women.

BACKGROUND: This cross-sectional study was designed to evaluate the role of cigarette smoking and high-risk HPV types as risk factors of CIN 2 and 3 in young, sexually active Brazilian women. MATERIALS AND METHOD: A series of 100 consecutive women with abnormal Pap smears were recruited, subjected to colposcopy, punch biopsy, and questionnaire for their social, sexual and reproductive factors. Of these, 77 women between 20 and 35 years of age (median 26.5 years) with biopsy-confirmed CIN 1 or CIN 2 and 3, were enrolled in this study. Representative samples from the exocervix and endocervix were obtained for HPV testing with the Hybrid Capture HPV-DNA assay, including the probes for the oncogenic HPV types (16, 18, 31, 33, 35, 45, 51, 52 and 56). RESULTS: The overall rate of CIN 2 and 3 was 23/77 (29.8%). The women with CIN 1, 2 and 3 did not differ from each other with regard to their age, race, schooling, marital status, lifetime number of sexual partners, age at first intercourse, use of oral contraceptives, or parity. However, current cigarette smoking was strongly associated with CIN 2 and 3 (p<0.001), and among smokers, the risk of high-grade CIN increased in parallel with the time of exposure (years of smoking) (p=0.07). HPV-DNA of the oncogenic types was detected in 43 (56%) women, the risk of being HPV DNA-positive was significantly higher in CIN 2 and 3 as compared with CIN 1 (p=0.037). Importantly, the prevalence of high-risk HPV types was significantly higher in cigarette smokers than in non-smokers (p=0.046). CONCLUSIONS: The results indicate that the severity of CIN lesions was clearly related to two fundamental risk factors: 1) high-risk HPV types, and 2) current cigarette smoking. These two risk factors were closely interrelated in that the high-risk HPV types were significantly more frequent in current smokers than in non-smokers, suggesting the possibility of a synergistic action between these two risk factors in cervical carcinogenesis.

Abdominal mycobacterial infection in acquired immunodeficiency syndrome patients.

The authors studied 12 patients with AIDS and abdominal mycobacteriosis hospitalized in the Hospital Ipiranga (São Paulo, Brazil), from June 1989 to January 1992. Diagnosis was confirmed by the histopathological examination of organ specimens collected during laparotomy, which, in most cases, was carried out due to an emergency situation. Observations included perforation of the ileum, seropurulent fluid involved and bloked by viscera, epiploon, and fibrin. Hepatoesplenomegaly was present in all patients and generalized granulomatous peritonitis was observed in more than 50%. A patient died in the immediate post-op period, four after an average period of 55 days in the hospital. A patient evolved with stercoral fistula and asked to be discharged. Six patients were discharged after an average hospitalization period of 27 days. The authors stress that in developing regions where tuberculosis incidence is high, a patient with AIDS and a painful and irritative abdominal picture should always lead to the hypothesis of mycobacteriosis.

[An alternative model for schistosomiasis control: the present status of the project in the State of Espírito Santo, Brazil]. / Modelo alternativo para o controle da esquistossomose: estado atual do projeto no Estado do Espírito Santo, Brasil.

An intervention study for schistosomiasis control is being carried out in the county of Afonso Cláudio, state of Espírito Santo, Brazil, having begun in February 1992. This study is an alternative response to classical control methods. The project is being developed using an interdisciplinary approach and involves both research and service institutions. The organization of health services at the primary care level is part of the project. Participant observation is seen as the methodological point of departure for guiding data collection and analysis and the intervention process in local reality. Control methods are restricted to the medical treatment given to all infected individuals and to improvements in the sanitation facilities available in the area. These methods are obviously integrated with the above-mentioned social actions. Consisting of three phases - pre-control, control (intervention), and final evaluation - the project is now in its intervention phase, lasting approximately three years.

Human fatal yellow fever. Immunohistochemical detection of viral antigens in the liver, kidney and heart.

An immunohistochemical method to detect yellow fever antigen was developed using immune sera from rabbits and hamsters and hyperimmune ascitic fluid from mice. A search for the antigen was carried out in liver, kidney and heart in three fatal cases of yellow fever. In the liver it was present in the cytoplasm of hepatocytes, Councilman bodies and Kupffer cells. Yellow fever antigen was also detected in renal tubular epithelium and in groups of myocardial fibers. These findings suggest that viral replication occurs at sites other than the liver. Since yellow fever shares many features with other haemorrhagic fevers the use of immunohistochemistry can impart a significant improvement in the accuracy of its histopathological diagnosis.

[The importance of fixation in immunohistochemistry: distribution of vimentin and cytokeratins in samples fixed in alcohol and formol]. / A importância da fixação em imuno-histoquímica: a distribuição de vimentina e citoqueratinas em amostras fixadas em alcool e formol.

The fixation in ethanol or formalin for trypsin digestion in immunohistochemical detection of cytokeratins and vimentin was assessed in a case of ovarian cystadenofibrocarcinoma. Superior reactivity for both markers was achieved in ethanol-fixed sections, even in samples stocked up to 60 days. Cytokeratin reaction in formalin-fixed sections was better when trypsin was used. However, this digestion was deleterious to vimentin detection. These data are presented to alert surgeons and oncologists on the relevance of fixation of specimens suspicious for neoplasia, since different epitopes may require different fixatives and the inadequate choice in the operative room may impart difficulties when immunohistochemistry is necessary.

[Ileal loop perforation caused by tuberculosis in patients with the acquired immunodeficiency syndrome]. / Perfuração de alça ileal por tuberculose em portadores da síndrome da imunodeficiência adquirida.

UNLABELLED: This clinical and surgical study was performed in a Public Government Hospital with the purpose of investigating the etiology and treatment of acute perforative abdomen in AIDS patients, particularly in the case of intestinal tuberculosis. The authors describe the cases of two young male AIDS patients with acute abdomen in which surgery revealed intestinal ileal perforation due to tuberculosis. One of the patients did not survive due to his poor post-operative condition. The other case had a better evolution and was submitted to outpatient care. The immediate surgery with occlusion of the perforation and biopsy of the lesion permitted to arrive at the etiology and contributed to the good evolution of the second patient. CONCLUSION: Literature indicates cytomegalovirus as the main cause of intestinal perforation in AIDS patients. In this study, etiology was tuberculous and this is probably an important cause of acute perforative abdomen in our AIDS patients due to the general prevalence of tuberculosis in AIDS patients in Brazil and in other developing countries.