Proposal for a new therapeutic high dosage of Pidotimod in children with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome: a randomized controlled study.

BACKGROUND: Despite to PFAPA syndrome is considered a benign and self-limited condition in childhood its impact on patients and families can be remarkable in many cases. Currently, the therapeutic options for managing are non-specific and no consensus exists about the best treatment to use. Pidotimod has been suggested as a new potential treatment in PFAPA syndrome for its immunodulatory effects. We conducted a preliminary, prospective, controlled, open, cross-over trial to assess the efficacy and the safety of Pidotimod in the treatment of children with PFAPA syndrome. METHODS: 22 children with PFAPA syndrome were randomly allocated to treatment with pidotimod (with 2 vials of 400 mg daily) in combination with betamethasone 0.5-1 mg on need, based on parents/caregivers' decision (group A) or betamethasone 0.5-1 mg on need, based on parents/caregivers' decision (group B). Each treatment period was for 3 months (Phase 1), after that patients were switched to the other arm for other 3 months (Phase 2). Efficacy was expressed in terms of number of episodes of fever, pharyngitis, or aphthous stomatitis, as well as the additional use of betamethasone on need. Safety and tolerability of the Pidotimod were evaluated on the basis of the number and type of adverse events (AEs) recorded during the treatment. RESULTS: Patients receiving Pidotimod and use betametasone showed a significant decrease in frequency of fevers (p = 0.002); number of episodes of pharyngitis (p = 0.049); aphthous stomatitis (p = 0.036) as well as the betamethasone use on need (p = 0.007). Overall, 19/22 (86.4%) showed benefits from Pidotimod administration. The safety profile of Pidotimod was excellent as no serious adverse events have been reported in the treated groups. CONCLUSIONS: We firstly showed that high dosage of Pidotimod could be an effective and safe to reduce the PFAPA attacks in children.

Eosinophil-Specific Granules in Tumor Cell Cytoplasm: Unusual Ultrastructural Findings in a Case of Diffuse-Type Gastric Carcinoma.

A case of desmoplastic variant of diffuse-type gastric carcinoma in a 72-year-old woman is reported. Microscopic findings included poorly cohesive tumor cells, resembling mononuclear inflammatory cells, prominent diffuse desmoplasia, and tumor-associated tissue eosinophilia. Electron microscopy confirmed the undifferentiated phenotype of tumor cells and disclosed activated eosinophils in the tumor stroma. Eosinophil-specific granules were found either free in the tumor stroma or within the cytoplasm of some tumor cells. Electron microscopy provided also circumstantial evidence of phagocytosis of apoptotic eosinophils by tumor cells. Extracellular, membrane-bound, eosinophil-specific granules have been long recognized in tissues associated with eosinophilia, including allergic diseases, inflammatory responses to helminths, and in stroma of some neoplasms. Our ultrastructural study now extends these findings and provides additional morphological evidence of eosinophil-specific granules within the cytoplasm of gastric carcinoma cells.

Mechanisms of coagulative necrosis in malignant epithelial tumors (Review).

Histological tumor necrosis (TN) has been reported to indicate a poor prognosis for different human cancers. It is generally accepted that TN results from chronic ischemic injury due to rapid tumor growth. However, whether insufficient tumor vascularization and inadequate tumor cell oxygenation are the only factors causing TN remains controversial. Mitotic catastrophe is considered to occur as a result of dysregulated/failed mitosis, leading to cell death. We hypothesize that mitotic catastrophe, induced by hypoxic stress, may lead to the TN which is observed in high grade carcinomas. The current review describes the morphological features of TN in malignant epithelial tumors. In addition, evidence regarding the involvement of mitotic catastrophe in the induction of TN in human carcinomas is discussed.

Gastric adenocarcinoma incidence in the province of Messina (Insular Italy): A cancer registry study.

The incidence of cancer by age, gender and tumor type at a population-based level is infrequently investigated. The aim of the present study was to describe the burden and outcome of gastric carcinomas (excluding cancers of the esophagogastric junction) experienced by the elderly, particularly for patients aged ≥81 years. A population-based series of 322 patients exhibiting gastric cancer, diagnosed between 2003 and 2005 and from the province of Messina (insular Italy; population, 662,450) was used. The median age of patients at the time of diagnosis was 72 years. The patients were categorized into three age groups according to interquartile range values, <64, 65-80 and >81 years. The cancer-specific survival rate at five years was lowest in the very elderly (P<0.001). Patients aged ≥81 years were less likely to receive surgery than younger patients (44 vs. 55 vs. 22% for the <64, 65-80 and >81 years age groups, respectively; P<0.01). In the resected cases, very elderly patients (age, >81 years) were more likely than younger patients to exhibit advanced stage pathological tumor-node-metastasis (P<0.05). It was concluded that patients aged ≥81 years accounted for 25% of total gastric carcinomas, were less likely to receive surgery and experienced worse outcomes when compared with younger patients.

Apoptotic-like tumor cells and apoptotic neutrophils in mitochondrion-rich gastric adenocarcinomas: a comparative study with light and electron microscopy between these two forms of cell death.

Mitochondrion-rich adenocarcinomas represent a rare variant of gastric adenocarcinomas composed predominantly of columnar adenocarcinoma cells with eosinophilic cytoplasm, a strong supranuclear immunoreactivity for antimitochondrial antibody, and a marked neutrophil infiltration associated to tumor cell death. The purpose of this work is to investigate, using correlated light and electron microscopy, mitochondrion-rich gastric adenocarcinomas focusing on the nature of the death in neoplastic cells and in infiltrating neutrophils. Adenocarcinoma cells, single or in small clusters, showed convoluted nuclei, irregularly condensed chromatin, loss of microvilli, and nuclear envelope dilatation. No nuclear fragmentation was observed in these dying cells and the plasma membrane did not show signs of disruption. These ultrastructural findings represent intermediate aspects between apoptosis and necrosis and are compatible with apoptosis-like programmed cell death. By contrast, some infiltrating neutrophils showed ultrastructural signs of classic apoptosis such as chromatin condensation into compact geometric (globular, crescentshaped) figures, tightly packed cytoplasmic granules and intact cell membrane. Our study provides ultrastructural evidence of apoptosislike tumour cell death in mitochondrion-rich gastric carcinomas and confirms that stereotyped outcome either as apoptosis or necrosis of tumor cells cannot always be expected in human neoplasms.

Chronic allergic-like inflammation in the tumor stroma of human gastric carcinomas: an ultrastructural study.

Inflammatory cell infiltration around the sites of carcinoma invasion is believed to play important roles in tumor biological behavior. The status of inflammatory cell infiltration at the sites of frank invasion in 92 cases of gastric carcinomas was examined, with special emphasis on tumor-associated tissue eosinophilia (TATE). TATE was found in 7 out of 92 (7.6%) gastric carcinomas (6 of intestinal-type and 1 of diffuse-type). Electron microscopy, selectively performed in the 7 cases of gastric carcinomas with TATE, showed that eosinophils participated in the stromal reaction by interacting with tumor cells, mast cells, and each other. Most of the tumor-infiltrating mast cells exhibited anaphylactic or piecemeal degranulation, indicating that the mast cells had been activated in situ. Some mast cells were noted in close contact to viable tumor cells, suggesting the existence of direct cell-to-cell interactions. There was also extracellular deposition of free eosinophil granules and Charcot-Leyden crystals. These morphologic findings are similar to that described in late/chronic-phase allergic reaction in both human and experimental animals, where angiogenesis and fibrosis/tissue repair are also present. In conclusion, TATE may indicate a chronic allergic-like Th2 host-tumor reaction, and understanding these pathways should create tools to enhance defence and contrast neoplastic disease.

Ultrastructural observations on inflammatory angiogenesis in gastric carcinomas with massive neutrophil infiltration.

Neutrophils are traditionally thought of as terminal effectors of inflammatory reaction, but experimental studies suggest that they play a direct role in the inflammatory angiogenesis of tumors. Thus, further evidence in humans is required regarding the mechanisms by which neutrophils induce tumor angiogenesis. In this study, 4 cases of human gastric carcinomas with massive neutrophil infiltration were studied by light and electron microscopy, focusing on the inflammatory angiogenesis in the tumor stroma. At light microscopy, the tumors were advanced gastric carcinomas in which various degrees of tubular differentiation were present. Under an electron microscope, pericytes exhibited two major differentiated states with distinct ultrastructural features: a contractile phenotype and a synthetic phenotype. The contractile phenotype was characterized by abundant microfilaments. Synthetic pericytes contained abundant rough endoplasmic reticulum, lipid bodies, and numerous membrane-bound vesicles. These ultrastructural findings extend concept of contractile/synthetic phenotype modulation, originally described in smooth muscle cells, to tumor microvascular pericytes. Tumor microvasculature was also characterized by abortive or slit-like lumina, endothelial cell mitoses, and replicating basement membranes. These qualitative and observational transmission electron microscopy findings provide additional morphological evidence of active inflammatory angiogenesis in gastric carcinomas with massive neutrophil infiltration.

Microvascular changes in human gastric carcinomas with coagulative necrosis: an ultrastructural study.

Ultrastructural findings in three cases of gastric carcinoma with coagulative necrosis are reviewed with special emphasis on microvascular changes. Intratumoral microvasculature revealed more or less stabilized vessels. Some were characterized by a close association between pericytes and endothelial cells, whereas others showed laminated basement membrane, with a loose association between pericytes and endothelial cells. Some mural cells exhibited ultrastructural signs of regressive changes, including lipofuscin granules, swollen mitochondria, and cytoplasmic lucency. These findings are discussed in relationship to a number of recent studies of the microvascular injury caused by hypoxia and reoxygenation, in humans and animals.

Micropapillary carcinoma of the breast with necrosis-like cell death: a case report.

A primary invasive micropapillary carcinoma of the breast in a 46-year-old woman is reported. Histologically, it was composed predominantly of papillary tumor cell clusters without fibrovascular cores, surrounded by a clear space. Tumor cells were positive for cytokeratin (CK) 7, estrogen receptor (ER), and progesterone receptor (PR), but negative for p53, CK 20, CD34, c-Erb-B2, CK5, epidermal growth factor receptor (EGFR), vimentin, and c-kit. MUC1 expression was found at the reversed apical membrane of neoplastic cell clusters. Accordingly, electron microscopy showed the lack of basement membrane and presence of microvilli at the basal surface of the tumor cells. Moreover, ultrastructural examination revealed single tumor cell death characterized by patchy condensations of chromatin throughout the nucleus. These nuclear alterations were associated with the occurrence of empty cytoplasmic vacuoles, conferring a necrosis-like phenotype to this cell death. Alternative programmed cell deaths are reviewed and their morphologic distinction is discussed.

Uteroglobin-related protein 1 gene -112G/a polymorphism and atopic asthma in Sicilian children.

The secretory protein, uteroglobin-related protein 1 (UGRP1), is expressed mainly in the lung and trachea and recently has been implicated in asthma. The -112G to A transition in the promoter was reported to be associated with asthma in the Japanese population. However, this has not been replicated in other studies. The aim of this study was to find the association of the UGRP1 gene polymorphism with atopic asthma in the Sicilian population. We conducted a transmission disequilibrium test (TDT) in 73 trios identified through 113 pediatric patients being treated for asthma. A case-control study also was performed by comparing the 113 unrelated asthmatic children and 230 unrelated healthy Italian subjects (121 children and 109 adults). The -112 G/A polymorphism was genotyped by the polymerase chain reaction-restriction fragment length polymorphism method and direct sequencing. The TDT revealed that the -112A allele was not preferentially transmitted from the parents to asthmatic offspring (chi-square = 3.08; p = NS). Neither the presence of at least one A allele in an individual's genotype (sum of the G/A and A/A genotype) nor the -112A allele was more prevalent among the asthma subjects than among the control subjects. Our results suggest that the -112G/A polymorphism does not play a significant role in the genetic predisposition of the UGRP1 gene in atopic asthma in the Sicilian population.