Luciana Rigoli

Prognostic value of intratumoral neutrophils in advanced gastric carcinoma in a high-risk area in northern Italy

Several lines of evidence indicate that neutrophils act nonspecifically against tumor cells. The correlation between tumor-infiltrating neutrophils (TINs) and clinicopathological features remains unclear and deserves to be investigated. To analyze the prognostic influence of TINs in gastric carcinoma, the authors selected 273 patients with advanced gastric carcinoma who underwent gastrectomy at Cremona Hospital (Lombardia, Italy) between 1990 and 1995 and followed them for a period of 5 years. The number of TINs was assessed in a semiquantitative manner using the mean value of 20 nonoverlapping high-power fields (magnification, 400×; 0.08 mm2). The patients were divided into two groups: patients with a moderate or extensive amount of TINs (n = 76; >10 TINs per 20 high-power fields) and patients with a minor amount of TINs (n = 197; ≤10 TINs per 20 high-power fields). The Kaplan-Meier method and Greenwood formula were used to estimate the crude survival rates in the two groups. Multivariate analyses based on the Cox proportional hazard regression model were performed to assess the effect of the prognostic factors on survival. Among the potential prognostic factors analyzed by univariate analysis, sex, age, location of neoplasia, pTNM stage, TINs, and surgical curability were significantly associated with higher survival rate. The study of the possible interaction effects of the clinical-pathological factors with TINs reveals that female patients with a moderate or extensive amount of TINs have about a 39% reduction in their risk of mortality, whereas male patients do not seem to be affected by the level of TINs. These results suggest that women appear to have a better prognosis than men in advanced gastric carcinoma. Gender differences in some host defense mechanisms and particularly in neutrophil function may be responsible for this event. Confirmation of these findings would give valuable insights about host reaction to gastric cancer growth and, ultimately, possibly would have implications regarding the identification of low-risk patients who could be spared adjuvant therapy.

Wolfram syndrome and WFS1 gene

Rigoli L, Lombardo F, Di Bella C. Wolfram syndrome and WFS1 gene.

MKS3/TMEM67 Mutations Are a Major Cause of COACH Syndrome, a Joubert Syndrome Related Disorder with Liver Involvement

The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the “molar tooth sign”, a midbrain‐hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel‐like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene‐phenotype correlates in JSRDs.

Angiotensin-Converting Enzyme and Angiotensin Type 2 Receptor Gene Genotype Distributions in Italian Children with Congenital Uropathies

Angiotensin I–converting enzyme (ACE) and angiotensin type 2 receptor (AT2R) gene polymorphisms have been associated with an increased incidence of congenital anomalies of the kidney and urinary tract (CAKUT). We investigated the genotype distribution of these polymorphisms in Italian children with CAKUT. We also evaluated the association between the ACE insertion/deletion and the AT2R gene polymorphisms with the progression of renal damage in subgroups of CAKUT patients. We recruited 102 Italian children with CAKUT; 27 with vesicoureteral reflux; 12 with hypoplastic kidneys; 20 with multicystic dysplastic kidneys; 13 with ureteropelvic junctions stenosis/atresia; 18 with nonobstructed, nonrefluxing primary megaureters; and 12 with posterior urethral valves and compared them with 92 healthy control subjects. ACE and AT2R gene polymorphisms were analyzed by PCR. The identification of AT2R gene polymorphisms in intron 1 and in exon 3 was revealed by enzymatic digestion. ACE genotype distribution in children with CAKUT was no different from that of the control subjects, but the subgroup of patients with radiographic renal parenchymal abnormalities showed an increased occurrence of the D/D genotype. The frequency of the G allele of AT2R gene in children with CAKUT was increased in respect to that of the control subjects. By contrast, no significant difference in the frequency of the C and A alleles of the AT2R gene was found. Our findings indicate that the ACE gene can be a risk factor in the progression of renal parenchymal damage in CAKUT patients. Moreover, a major role of the AT2R gene in the development of CAKUT has been found, at least in Italian children.

Gene-environment interaction in childhood asthma.

The importance of early life environmental influences on the etiology of asthma is implied by the observed geographic and temporal variation in the prevalence of the disease among children. There is evidence pointing to the role of exposure to allergen, various aspects of diet and hygiene-related factors in the etiology of asthma. There is also evidence that heritable factors influence the impact of hygiene-related exposures on the risk of having asthma. A number of important gene-environment interactions have been identified. These interactions point to the biology of environmental exposures as the involved genetic variation is suggestive of certain underlying mechanisms. Polymorphisms within genes coding for the toll-like receptor-lipopolysaccharide (TLR-LPS) signaling pathway may underlie variations in effects of hygiene-related exposures, including specifically endotoxin, on the risk of developing allergic sensitization and allergic disease. This review presents recent findings illustrating the role of gene-environment interactions in childhood asthma susceptibility.

Deferiprone versus deferoxamine in thalassemia intermedia: Results from a 5-year long-term Italian multicenter randomized clinical trial

In patients with thalassemia intermedia (TI), such as beta‐TI, alpha‐thalassemia (mainly HbH disease and mild/moderate forms of HbE/beta‐thalassemia), iron overload is an important challenge in terms of diagnosis, monitoring, and treatment. Moreover, to date, the only possible chelators available are deferoxamine, deferasirox, and deferiprone. Here, we report the first 5‐year long‐term randomized clinical trial comparing the effectiveness of deferiprone versus deferoxamine in patients with TI. Body iron burden, which was determined by measuring serum ferritin levels in the same patient over 5 years and analyzed according to the generalized linear mixed model (GLMM), showed a linear decrease over time in the mean serum ferritin levels in both treatment groups (P‐value = 0.035). The overall period of observation was 235.2 person‐years for the deferiprone patients compared with 214.3 person‐years for the deferoxamine patients. The results of the log‐rank test suggested that the deferiprone treatment did not affect survival compared with the deferoxamine treatment (P‐value = 0.360). The major adverse events observed included gastrointestinal symptoms and joint pain or arthralgia. Neutropenia and agranulocytosis were also detected, suggesting needing of strict hematological control. In conclusion, long‐term iron chelation therapy with deferiprone is associated with an efficacy and safety similar to that of deferoxamine, suggesting that this drug is an alternative option in cases in which deferoxamine and deferasirox are contraindicated. Am. J. Hematol. 90:634–638, 2015.

Serum IL-23 strongly and inversely correlates with FEV1 in asthmatic children.

Background: Recently, Th17 cells have been found to participate in the pathogenesis of allergic asthma. IL-23 is a cytokine that may be implicated in modulating Th17 response. This study aimed at evaluating IL-23 and relating it to lung function in asthmatic children. Methods: Seventy-eight asthmatic children and 40 healthy children were evaluated. Spirometry and serum IL-23 measurement (ELISA kit) were performed in all asthmatic children. Results: IL-23 levels were higher in asthmatic than in healthy children (p < 0.001). There was a strong inverse relationship between FEV1 and IL-23 (r = –0.787). Conclusions: This preliminary study suggests that serum IL-23 could be a suitable marker of bronchial function impairment in allergic asthmatic children.

A mitochondrial DNA mutation (A3243G mtDNA) in a family with cyclic vomiting

We report the incidence of mitochondrial DNA (mtDNA) mutations and/or deletions in a family from Southern Italy in which four members were affected by a cyclic vomiting syndrome (CVS). The A3243G mtDNA mutation was detected in a boy, his mother, maternal grandmother, and aunt but not in other relatives of the family. Patients with a CVS experience a minimum of three distinct episodes of vomiting and nausea, usually involving more than four emeses in one hour at the peak. They feel quite well between episodes. There is no apparent underlying cause for the vomiting [4]. In the differential diagnosis of CVS, mtDNA mutations should be considered when there is a maternal history of CVS and migraine, clinical findings of seizures, neuromuscular and gastrointestinal symptoms and laboratory evidence of lactate increase [5]. A family was recruited with four members suffering from CVS: a 5-year-old boy, his mother, the maternal grandmother and aunt. The three adults were affected by CVS during childhood, whilst they suffered from migraine at an adult age (Fig. 1). Metabolic investigations revealed permanent hyperlactataemia (5–8 mM) with elevated lactate/pyruvate ratios (L/P) (25–30) in the boy’s mother. In the maternal grandmother and aunt, lactate levels (2.6 and 3.0 mM respectively) were slightly elevated and L/P molar ratios remained in the normal range. The young patient suffered from vomiting fits which lasted for many hours until spontaneous resolution and recurrence with the same characteristics after an interval of 15–20 days. Metabolic acidosis (pH 7.3, bicarbonate 16 mM) with hyperlactataemia (2.5–5.35 mM) and elevated L/P (19–32; normal <16) and ketone body molar ratios were found (2–4.6, normal <2). Hyperalaninaemia, lactic aciduria, and an abnormal excretion of suberic, adipic, and 3-hydroxybutyric acids was observed. Laboratory, clinical and instrumental findings of all four patients excluded organic diseases. To check for point mutations and for a previously described 8.1 kb deletion [3], the region between nucleotides 6687 and 15123 was amplified by the polymerase chain reaction (PCR) in ten overlapping segments and completely sequenced. Screening for the 3243 np mutation in mtDNA was carried out by PCR-RFLP. The relevant region of mtDNA was amplified using the following primers according to the Cambridge sequence [1]: 5’CCCACAGGTCCTAAACTACC-3’ (np 2770–2789) and 5’AGCGAAGGGTTGTAGTAGCC-3’ (np 3456– 3437). The PCR products (10 ll) were then purified and digested with 15 U of the restriction endonuclease ApaI for 1 h at 32 C. The A-to-G mutation at 3243 np created an ApaI restriction site (GAGCCC to GGGCCC) and was easily detected by ethidium bromide staining in a 2.5% agarose gel. In order to detect small amounts of mutated mtDNA in the presence of an excess of wildFig. 1 Pedigree of the family with CVS; the arrow indicates the index case. The percentage of mutated mtDNA in blood and muscle of the patients is I:2=25% and 30%; II:2=35% and 38%; II:3=30% and 32%; III:1=70% and 75% respectively. Affected individuals are indicated by solid symbols Eur J Pediatr (2003) 162: 727–728 DOI 10.1007/s00431-003-1280-1

Endocrinopathies, metabolic disorders, and iron overload in major and intermedia thalassemia: serum ferritin as diagnostic and predictive marker associated with liver and cardiac T2* MRI assessment.

Endocrinopathies and metabolic disorders‐characterized β thalassemic (βT) patients and the prevention and treatment of these comorbidities are important targets to be achieved. The aim of the study was to analyze the diagnostic and prognostic role of ferritin for endocrinopathies and metabolic disorders in βT patients. The ability of iron chelators to treat iron overload and to prevent or reverse metabolic disorders and endocrinopathies was also evaluated.

Inflammatory bowel disease in pediatric and adolescent patients: A biomolecular and histopathological review

Crohns disease (CD) and ulcerative colitis (UC) are the two main forms of inflammatory bowel disease (IBD) with both overlapping and distinct clinical, pathological and biomolecular features. It has been suggested that pediatric IBD is a distinct disease entity, with probably different disease subtypes.The aim of this study is to review and summarize the evolution of the current concept of pediatric IBD. The results of this review reinforce the idea that pediatric CD and UC may be further classified in various clinicopathologic entities. For clinicians and pathologists convenience, practical algorithms for the distinction of the various subphenotypes of pediatric IBD are also provided.