A pleiotropy scan to discover new susceptibility loci for pancreatic ductal adenocarcinoma.

Pleiotropic variants (i.e., genetic polymorphisms influencing more than one phenotype) are often associated with cancer risk. A scan of pleiotropic variants was successfully conducted ten years ago in relation to pancreatic ductal adenocarcinoma susceptibility. However, in the last decade, genetic association studies performed on several human traits have greatly increased the number of known pleiotropic variants. Based on the hypothesis that variants already associated with a least one trait have a higher probability of association with other traits, 61,052 variants reported to be associated by at least one genome wide association study (GWAS) with at least one human trait were tested in the present study consisting of two phases (discovery and validation), comprising a total of 16,055 pancreatic ductal adenocarcinoma (PDAC) cases and 212,149 controls. The meta-analysis of the two phases showed two loci (10q21.1-rs4948550 (P=6.52×10-5) and 7q36.3-rs288762 (P=3.03×10-5) potentially associated with PDAC risk. 10q21.1-rs4948550 shows a high degree of pleiotropy and it is also associated with colorectal cancer risk while 7q36.3-rs288762 is situated 28,558 base pairs upstream of the Sonic Hedgehog (SHH) gene, which is involved in the cell differentiation process and PDAC etiopathogenesis. In conclusion, none of the single nucleotide polymorphisms (SNPs) showed a formally statistically significant association after correction for multiple testing. However, given their pleiotropic nature and association with various human traits including colorectal cancer, the two SNPs showing the best associations with PDAC risk merit further investigation through fine mapping and ad hoc functional studies.

Minimal supergravity scalar neutrino dark matter and inverse seesaw neutrino masses.

We show that within the inverse seesaw mechanism for generating neutrino masses, minimal supergravity naturally provides the scalar neutrino as the lightest superparticle. We also demonstrate that such schemes naturally reconcile the small neutrino masses with the correct relic scalar neutrino dark matter abundance and accessible direct detection rates in nuclear recoil experiments. This way, inverse seesaw minimal supergravity offers a common solution to the generation of the neutrino mass and to the origin of dark matter.

[Influence of histologic type on prognosis of patients undergoing curative intervention for gastric adenocarcinoma. Italian multicenter study]. / Influenza del tipo istologico sulla prognosi dei pazienti sottoposti ad intervento curativo per adenocarcinoma gastrico. Studio multicentrico italiano.

BACKGROUND: The prognostic significance of the histological type in gastric cancer is still debated. The correlation between intestinal-diffuse type and tumor recurrence was investigated in a prospective multicentric study which collects the cases from three surgical Departments of Italy. PATIENTS AND METHODS: Four-hundred and twelve patients who underwent a potentially curative resection between 1988 and 1995 were considered; 273 cases were classified as intestinal type (group A), and 139 cases as diffuse type (group B). Mixed cases were excluded from the study. All patients were included in a complete follow-up program for the early diagnosis of recurrence. Clinical, histopathological and surgical factors were examined for their influence on tumor recurrence by univariate and multivariate analysis. RESULTS: Recurrence rate was 41.4% in intestinal type, and 65.5% in diffuse type cases (p < 0.0001). In group A, multivariate analysis identified nodal status (p < 0.0001), depth of invasion (p < 0.005), lymph node dissection (D1 vs. D2-D4, p < 0.01), advanced age (p < 0.01) and male sex (p < 0.05) as significant prognostic factors. In group B, depth of invasion (p < 0.0005), lymph node dissection (p < 0.005), tumor size (p < 0.01) and nodal status (p < 0.05) resulted as significant variables; no preventive effect on tumor recurrence was found for D2 vs. D1 lymphadenectomy. Multivariate analysis performed on the totality of the cases demonstrated diffuse type as an independent predictor of poor prognosis (relative risk: 1.67, p < 0.001). CONCLUSIONS: Diffuse type of gastric cancer is an independent risk factor for tumor recurrence as compared with intestinal type; clinical and pathological variables play a different role as prognostic factors in the two histotypes.

Lymph node micrometastases in patients with early gastric cancer: experience with 139 patients.

BACKGROUND: Although lymph node metastases in patients with early gastric cancer (EGC) is an important prognostic factor, the prognostic relevance of lymph node micrometastases is still uncertain. METHODS: The authors studied 1488 lymph nodes, which were histologically confirmed as pN0, dissected from 139 patients who were treated for EGC between 1976-1994. Micrometastases were defined as a single or small cluster of neoplastic cells identifiable only by immunohistochemical methods. RESULTS: Lymph node micrometastases was observed in 24 of the 139 patients (17%). No significant correlation was observed between micrometastases and other clinicopathological characteristics. Analysis of overall survival showed no significant difference between the micrometastases positive and negative groups. CONCLUSION: The results of our study show that the presence of lymph node micrometastases in EGC does not have an influence on patient prognosis.

Identification of occult micrometastases in patients with early gastric cancer using anti-cytokeratin monoclonal antibodies.

The presence of occult micrometastases was evaluated in 1488 lymph nodes removed from 139 patients with node-negative early gastric cancer (EGC). Additional multiple levels of the lymph nodes were examined with haematoxylin-eosin staining and keratin immunostaining. Occult nodal micrometastases were detected in 24 patients (17%) in one or more lymph nodes dissected after a gastrectomy. The cases investigated were a small group from a total of 412 EGC patients who underwent surgical treatment in our hospital between 1976 and 1997; the mean follow-up period was 9 years (range 1-22). We found no significant differences between cytokeratin-negative and positive patients regarding the following clinicopathological parameters: age, gender, tumour size and site, macroscopic and microscopic type, depth of invasion and type of infiltration, according to Kodama's classification. The survival rate at 5 years was 88% and 87% for cytokeratin-negative and positive patients, respectively (log-rank = 0.6; ns). Our data suggest that occult micrometastases do not add useful information and immunohistochemical studies to detect them are probably unnecessary.

[Surgical treatment of rectal cancer: comparison of anterior resection and abdominoperineal excision]. / Trattamento chirurgico del cancro del retto: resezione anteriore e amputazione addomino-perineale a confronto.

From 1987 to 1992, 91 rectal neoplasms were operated in the Istituto di Patologia Speciale Chirurgica of the University of Bologna: 50 anterior resections and 41 abdomino-perineal amputations. The local recurrence rate shows no significant difference between the two groups. The mortality rate is 7.6% in anterior resections and 14.2% in abdomino-perineal amputations. Our results and literature review show that local recurrence and mortality rates depend more from the tumor stage than from the surgical procedure.

Mucinous cystic tumour of the pancreas. A histological and histochemical study.

A histological and histochemical analysis of two new cases of mucinous cystic tumors of the pancreas is reported. Histochemical study revealed a predominantly sulphated acidic mucin secretion with some neutral mucins. Argyrophilic elements were also observed. The authors propose an origin from intestinal type epithelium through a metaplastic process.

[Exogenous lipid pneumonia. Clinico-radiologic characteristics]. / Polmoniti lipidiche esogene. Caratteristiche clinico-radiologiche.

Exogenous lipid pneumonia (ELP) is caused by the aspiration of animal, vegetal or, more often, mineral oils. Even though it may also be acute, ELP is most frequently a chronic disease, affecting people with predisposing factors, such as neuromuscular disorders, structural abnormalities and so on; very often exogenous lipid pneumonia is found in tracheotomized patients. The pathology of lipid pneumonia is a chronic inflammatory process evolving in foreign-body-like reaction, and eventually in "end-stage lung" condition. Clinically, most patients are asymptomatic; few cases only present with cough, dyspnea and chest pain. Eight cases of ELP, studied over the past 3 years, are described in this paper. All the patients were examined by chest radiographs and standard tomograms; 3 patients underwent CT. X-ray features were mono/bilateral consolidation of the lower zones, with air bronchogram and variable reduction in volume. CT density was not specific for fat tissue. In all cases the diagnosis was confirmed at biopsy. In 5 patients, followed for at least one year, clinical-radiological features showed no change. Thus, complications of ELP (especially malignant evolution) could be excluded. The authors conclude that lipid pneumonia must be considered in differential diagnosis of patients with history of usage of oils and compatible X-ray findings. The usefulness of an accurate follow-up is stressed.

Signet-ring cells in advanced gastric cancer. A clinical, pathological and histochemical study.

A pathological and histochemical study on the presence of signet-ring cells (SRC) in 108 advanced gastric cancer (AGC) has been evaluated. According to Laurén's classification, 59 were of intestinal (I) and 49 of diffuse (D) type. The amount of SRC seems to be a prognostic parameter in D-carcinoma: the 5-year survival rate was 49% and 22% in cases with 1-24% and 75-100% SRC, respectively. Histochemically, in our series of SRC D-carcinoma the quality of mucin secretion of SRC closely resembled the goblet cells of intestinal metaplasia. The histogenetic origin of D-gastric carcinoma was discussed.

Intermediate-sized filament proteins (keratin, vimentin, desmin) in metaplastic carcinomas, carcinosarcomas and stromal sarcomas of the breast.

The distribution of intermediate-filament (IF) proteins of the keratin, vimentin and desmin type in breast stromal sarcomas, carcinosarcomas, metaplastic carcinomas and phyllodes tumors has been compared using the avidin-biotin complex immunoperoxidase technique. Keratin reactivity was found in carcinomatous and pseudosarcomatous areas of all metaplastic carcinomas, in the cuboidal epithelial cells of carcinosarcomas and in the epithelial component of phyllodes tumors. Vimentin and desmin were detected in the sarcomatous portion of carcinosarcoma, focally in the stromal component of phyllodes tumors and not always in the stromal sarcomas. These data confirm that combined analysis of IF expression is a reliable and convincing way to differentiate stromal sarcomas, metaplastic carcinomas and carcinosarcomas in breast pathology.

Juvenile papillomatosis (epitheliosis) of the breast. A clinical and pathologic study of 13 cases.

The clinical and pathologic findings of 13 patients with juvenile papillomatosis (JP) (epitheliosis) of the breast are analyzed. The average age was 25 years, with a range from 15 to 42. Family history of breast carcinoma was observed in 33%. Carcinoma did not develop in any patient after the diagnosis of JP. A co-existing carcinoma was present in 15% of the patients. This study confirms that JP may be related to family history of breast carcinoma and that the patients themselves may be at increased risk for the development of cancer. A long-term follow-up for these patients and relatives is needed so that additional information and better knowledge of this entity can be obtained.

Tissue antigen distribution in hepatocellular carcinoma.

An immunohistochemical study on 63 hepatocellular carcinomas (HCC) was performed for the demonstration of alpha 1-antitrypsin (AAT), alpha-fetoprotein (AFP) and hepatitis B virus (HBV) antigens. AAT and AFP were also investigated in 54 cases of cirrhosis not associated with HCC. AAT was frequently expressed both in HCC (82.5%) and in cirrhosis (53.7%), whereas AFP was present in 41.2% of HCC and never detected in cirrhosis used as controls. These findings suggest that AFP is the more specific antigen for use as a marker of malignant cellular transformation. The HBsAg-positivity in 31.7% of HCC supports the hypothesis of a close link between virus B infection and the tumor.

Mammary carcinoma with argyrophilic cells: an immunohistochemical and ultrastructural study.

The immunohistochemical and ultrastructural findings of 7 primary argyrophilic tumors of the breast are described. Five cases were selected because of a growth pattern reminiscent of a "carcinoid" tumor and 2 were obtained from 70 consecutive common carcinomas. All patients were females (mean age 68.8) and none had clinical evidence of hormonal secretion. On ultrastructural examination dense-core granules were seen in addition to findings more suggestive of a common carcinoma. Immunoperoxidase stainings for ACTH, calcitonin etc. were negative in all tumors. The authors believe that organoid growth pattern, argyrophilia and dense-core neurosecretory-like granules are not sufficient elements to demonstrate the endocrine nature of a breast neoplasm.

Clinical and pathologic prognostic features of leiomyosarcoma of the uterus.

A clinico-pathologic study of 20 consecutive patients with leiomyosarcoma of the uterus seen over a 12-year period has been evaluated. Tumor extent at the time of diagnosis seems to be the main prognostic factor: 62.5% of the patients in stage I are alive and well from 1 to 7 years after the diagnosis as compared to 0% of the patients in all the other stages. The age of the patients and the number of mitotic figures also appear to have some prognostic value.

Myeloid metaplasia of the breast. A lesion which clinically mimics carcinoma.

The authors report a case of myeloid metaplasia of the breast presenting as a tumor mass with homolateral axillary lymphadenopathy. The lesion was clinically misinterpreted as a breast cancer and developed in an elderly woman 8 years after the diagnosis of primary myelofibrosis was made. Immunohistochemical and ultrastructural studies confirmed the haematopoietic nature of the proliferating cells. The differential diagnosis from other breast lesions is discussed.