20-Year trends of hospitalisation among people with dementia: a region-wide retrospective cohort study from Lombardy, Italy.

OBJECTIVES: The aim of this study was to investigate the trends of hospitalisations among people with dementia, linking region-wide hospital and demographic health records. STUDY DESIGN: A retrospective cohort study was conducted using hospitalisation health records from the Lombardy region in Italy. METHODS: The study included people aged ≥65 years with a diagnosis of dementia who were hospitalised between 2002 and 2020 in Lombardy, which is the most populated region in Italy with 10 million inhabitants. Using data on resident population, this study computed rates of hospitalisation by calendar year, age, sex and cause of hospitalisation. RESULTS: In total, 340,144 hospitalised patients with dementia were included in the study. The rate of hospitalisation was 100.6 per 10,000 in 2002 and progressively decreased to 65.1 per 10,000 in 2020. The average age at hospitalisation in 2002 was 78.9 years for men and 81.8 years for women, which increased to 82.0 years and 84.2 years, respectively, in 2020. Respiratory diseases caused 10.4% of all hospitalisations in 2002 and grew steadily to 26.8% in 2020, becoming the leading cause of hospital admissions since 2017. CONCLUSIONS: Hospitalisation patterns for people with dementia have changed over the last 20 years, reflecting evolving epidemiological trends and the impact of healthcare policies. Region-wide administrative health record data analysis should be further utilised to explore the health needs of people with dementia and inform the planning, implementation and monitoring of effective prevention strategies in this population group.

Source and symptoms of COVID-19 among hospital workers in Milan.

BACKGROUND: Healthcare workers (HCWs) are commonly infected by SARS-CoV-2 and represent one of the most vulnerable groups. Adequate prevention strategies are necessary to guarantee HCWs' safety, as well as to prevent dissemination of the infection among patients. AIMS: To describe a case series of SARS-CoV-2-positive HCWs in a large public healthcare organization in Milan (Italy) during the most devastating weeks of the epidemic and analyse the sources, symptoms and duration of SARS-CoV-2 infection. METHODS: This study included 172 SARS-CoV-2-positive HCWs who were infected between the 25th of February and the 7th of April 2020. A nasopharyngeal swab (NPS) and RT-PCR were used to indicate. RESULTS: Initially, the most common sources of infection were other positive HCWs (49%). Medical doctors and nursing assistants were most frequently infected, with infection rates of 53/1000 and 50/1000, respectively. COVID-19 departments were less affected than internal medicine, surgery, intensive care, or emergency room. The most commonly reported symptom was mild cough, while loss of smell (anosmia) and loss of taste (ageusia) were reported as moderate and severe by 30-40% of HCWs. The time necessary for 50% of workers to recover from the infection was 23 days, while it took 41 days for 95% of HCWs to become virus-free. CONCLUSIONS: HCWs are commonly infected due to close contacts with other positive HCWs, and non-COVID departments were most affected. Most HCWs were asymptomatic or subclinical but contact tracing and testing of asymptomatic HCWs help identify and isolate infected workers.

Ink spot lentigo: singular clinical features in a case series of patients.

Ink spot lentigo, also known as reticulated black solar lentigo, is a melanotic macula commonly described in fair-skinned individuals on sun-exposed areas of the body. Clinically it is a darkly pigmented type of solar lentigo; herein the term ink spot lentigo. In contrast to common solar lentigines, ink spot lentigo is reported as a unique lesion. However usually ink spot lentigo appears among several common solar lentigines. We report a series of 5 patients who presented ink spot lentigo with typical dermoscopic pattern but singular clinical features.

Jaw osteonecrosis in patients treated with bisphosphonates: an ultrastructural study.

Osteonecrosis of the jaw is a severe bone disorder traditionally associated with periodontal disease, local malignancy, chemotherapy, glucocorticoid therapy, or trauma. Recently a growing number of publications reported the occurrence of osteonecrosis of the jaw in patients undergoing treatment with bisphosphonates. The mechanism by which bisphosphonates might contribute to the development of osteonecrosis of the jaw is far from being fully elucidated. Suppression of bone turnover, infection, tissue hypoxia and cellular toxicity were proposed as possible mechanisms by which bisphosphonates may exert adverse effects on bone metabolism. Here, we studied 25 consecutive patients treated with bisphosphonates for osteoporosis or tumoral pathologies. We provide good evidence of hyperactive osteoclastic bone resorption and suggest a direct cytotoxic effect of bisphosphonates on bone tissue through induction of osteocyte cell death. We also demonstrate that bisphosphonates only have limited adverse effects on bone vascular network.

Pathological findings in subsynovial connective tissue in idiopathic carpal tunnel syndrome.

Recent studies suggest that in patients with carpal tunnel syndrome, pathological changes occur in the subsynovial connective tissue. Such changes are non-inflammatory synovial fibrosis and vascular proliferation. Thickening of the tendon sheet may cause an increase of canal pressure and damages to the median nerve in the wrist; however, the causes of such events still remain to be clarified. We examined synovial specimens from 26 patients operated on for idiopathic carpal tunnel syndrome. Analysis included histological, ultrastructural and immunohistochemical examination in order to establish a pathological underlying pattern. An explanation for the pathogenesis of the found changes suggested. Our data confirm the presence of a non-inflammatory fibrosis with irregular bundles of collagen. De novo blood vessel formation was also noted. Interestingly the neo-angiogenesis consists of anomalous vessels and may be triggered from various cell types secreting vascular endothelial growth factor (VEGF), including macrophage-like elements similar to endothelial progenitor cells. Therefore, we believe that in the future a non-surgical management of carpal tunnel syndrome might be conjecturable via anti-VEGF drugs.

Analysis of UbcH10 expression represents a useful tool for the diagnosis and therapy of astrocytic tumors.

Previous studies suggest the expression of UbcH10 gene, that codes for a protein belonging to the ubiquitin-conjugating enzyme family, as a valid indicator of the proliferative and aggressive status of tumors of different origin. Therefore, to look for possible tools to be used as diagnostic markers in astrocytic neoplasias, we investigated UbcH10 expression in normal brain, gliosis and low-grade and high-grade astrocytic tumors by immunohistochemistry. UbcH10 expression was observed in low-grade astrocytoma and in glioblastoma. Our data indicate a clear correlation between UbcH10 expression and the histological grade of the astrocytic tumors. Moreover, the analysis of UbcH10 expression allows the differentiation between gliotic and malignant tissues. Finally, since proteasome inhibitors have recently been considered as possible drugs in the chemotherapy of various tumors, our results would suggest new perspectives for the treatment of brain malignancies based on the suppression of the UbcH10 function.

Eccrine porocarcinoma of the face involving eyelids: a rare case report.

Eccrine porocarcinomas (EP) are skin appendage tumors originating from the acrosyringium. Pagetoid form is rare and exceptionally it can involve eyelid. We report a 70-year-old patient presenting a lesion sited on the left cheek region involving the internal canthus, the dorsum of nose and the half inferior eyelid in full thickness. A wide surgical excision was performed and after 2 years of follow up no recurrences have been seen.

Mutations of the K-ras and p53 genes in gastric adenocarcinomas from a high-incidence region around Florence, Italy.

K-ras and p53 gene mutations in intestinal-type gastric carcinomas from a high-incidence area around Florence, Italy, were studied by single strand conformation polymorphism and DNA sequencing analysis. Single-strand conformation polymorphism analysis of K-ras indicated aberrant bands in 13 of 34 cases. Sequencing revealed point mutations in 7 (including two at a previously unreported site in codon 11), a significantly higher frequency than reported in countries other than Japan. No K-ras mutations were identified in stage III tumors. Single-strand conformation polymorphisms in p53 exons 5-8 occurred in 30 of 34 cases, with mutations identifiable by direct sequencing in 65% of the cases. Of these, 91% were base substitutions, a value similar to that usually reported, but the percentage of G:C to A:T transitions (90% in this study, 89% in all published European cases combined) differed significantly from that in Oriental cases (48%). The percentage of A:T to G:C transitions was greater in Oriental (22%) than European cases (2%), as was also true for transversions (30% in Oriental tumors, 9% in European tumors). The frequency of mutations at CpG sites (14%) varied significantly from the 67% in cases from a neighboring region in Italy. Helicobacter pylori infection was established in 19 cases and was somewhat more common in cases lacking a p53 mutation.

Microsatellite instability in gastric cancer is associated with tumor location and family history in a high-risk population from Tuscany.

We studied the presence of microsatellite instability (MSI) in a series of 108 gastric cancers (GCs) previously identified in an epidemiological study carried out in a high-risk area around Florence. To investigate associations between MSI and GC family history, 34 cases (31.5%) who had a GC-affected first-degree relative were included in the series. A family history positive for colorectal cancer was reported quite rarely (5.6%). The analysis of 6 microsatellite loci in DNA from paired normal tissue and tumor samples microdissected from paraffin-embedded specimens revealed varying degrees of instability: 56 cases (51.8%) did not show instability at any of the 6 loci; 19 (17.6%) showed instability at 1 locus; 16 (14.8%) showed instability at 2 loci; 11 (10.2%) showed instability at 3 loci; 4 (3.7%) showed instability at 4 loci; and 2 (1.9%) showed instability at 5 loci. The replication error-positive (RER+) phenotype, defined as the presence of MSI at 2 or more loci, had a frequency of 30.6% (33 of 108) and tended to be positively associated with female sex, intestinal histological type, advanced tumor stage, vascular invasion, positive GC family history, and blood group of A type. No correlation emerged between age at diagnosis and RER+ phenotype, whereas a significant association with the RER+ phenotype was shown by the antral location. A multivariate analysis adjusting for a selected group of potential confounding factors confirmed the strong association of the RER+ phenotype with the antral location (P = 0.001) and with a positive GC family history (P < 0.05). Survival analyses at 5 and 8 years showed no difference between RER+ and RER- patients, even when corrected for stage distribution. By the microdissection technique, we also used microsatellite allele patterns to investigate intratumoral heterogeneity and genetic relationships between tumors and adjacent dysplasia and/or intestinal metaplasia. Areas of metaplasia and dysplasia demonstrated MSI only in cases with MSI-positive tumors. In MSI-positive tumors, there was consistent evidence of intratumoral microsatellite allele heterogeneity, indicating the presence of genetically divergent tumor cell clones within the same neoplasm.

Red meat, family history, and increased risk of gastric cancer with microsatellite instability.

Microsatellite instability (MSI) occurs frequently in sporadic gastric cancer (GC) and may define a distinctive molecular pathway of carcinogenesis. We evaluated the role of dietary risk factors in GC according to MSI status. A large series of 382 GC cases and 561 controls were originally identified in a population-based case-control study carried out in the high-risk area around Florence, Italy; 126 GC patients were typed for MSI status. A MSI+ phenotype was detected in 43 of 126 cases (34.1%), whereas 83 cases were classified as MSI-. A multinomial logistic regression model was used to compare the two subgroups of GC classified according to MSI status in the same analysis, with all of the available population controls. A case-case approach was also used. The risk of MSI+ tumors was positively associated with high consumption of red meat and meat sauce and negatively associated with consumption of white meat. A positive association was also seen with total protein and nitrite intake, whereas no relation was found with micronutrient intake. Risk was especially high among subjects reporting both a positive GC family history and a high consumption of red meat (odds ratio, 25.7; 95% confidence interval, 6.4-102.8). For MSI- tumors, a significant protective effect was associated with frequent consumption of citrus and other fresh fruit, garlic, legumes, vegetables, and olive oil and with high intake of beta-carotene and other antioxidants and sugar, whereas positive associations were seen with protein and sodium intake. In summary, a specific dietary pattern emerged for MSI+ gastric tumors, suggesting that factors related to red meat consumption are involved in this pathway, particularly among individuals with a positive family history. In contrast, the risk of MSI- tumors was strongly reduced by the frequent consumption of fresh fruit and vegetables.

Mutations at coding mononucleotide repeats in gastric cancer with the microsatellite mutator phenotype.

We analysed 50 gastric carcinomas (GCs) to verify whether mutations at coding repeats were associated with microsatellite instability (MSI). The tumors included: ten cases with no MSI, 14 cases with MSI = 1 locus, 13 cases with MSI = two loci and 13 cases with MSI > or = 3 loci. We investigated coding repeats within the TGF-beta RII, IGFIIR, BAX, hMSH6, hMSH3 and BRCA2 genes. The TGF-beta RII, IGFIIR, BAX, hMSH6 and hMSH3 repeats were altered in 11 (22%), five (10%), four (8%), 16 (32%) and five (10%) cases respectively. Mutations occurred only in MSI-positive (MSI+) tumors and correlated with increasing MSI levels. No alterations of the BRCA2 repeat were found. Mutations in genes other than hMSH6 were strongly associated to hMSH6 mutations, suggesting a key role of this gene. The non-coding BAT-26 and E-Cadherin 3' UTR poly(A)8/(T)15 repeats were analysed in 44 of the 50 cases. Novel tumor-associated alleles were observed only in MSI-positive GCs and were in most cases associated with mutations at coding repeats. Further investigations with BAT-40 confirmed that four cases manifested mononucleotide repeat alterations restricted to hMSH6 and one case to TGF-beta RII. A subset of tumors with MSI at two or more dinucleotide loci resulted negative for mutations at coding and non-coding mononucleotide repeats.

Progression of uremic hyperparathyroidism involves allelic loss on chromosome 11.

In occasional cases of secondary hyperparathyroidism, long term stimulation of the parathyroid glands leads from compensatory to autonomous hyperfunction, and thus, hypercalcemia develops. This clinical entity, named tertiary hyperparathyroidism, is possibly due to the formation of an adenoma in one of the hyperplastic glands. Previous studies have shown that parathyroid adenomas may arise with allelic loss on chromosome 11. We tested for allelic loss at several loci on chromosome 11 in 12 enlarged parathyroid glands from 6 uremic patients and found loss of heterozygosity in 2 of the glands from 2 different patients with higher serum calcium levels (11.3 +/- 0.29 vs. 9.8 +/- 0.28 mg/dL; P < 0.004) and, therefore, ascribable to the so-called tertiary hyperparathyroidism. The 2 glands with allelic loss were significantly greater in mass than those without loss (3.42 +/- 0.37 vs. 1.60 +/- 0.54 g; P < 0.001). These data offer new evidence that autonomous parathyroid proliferation in uremic patients can develop through overgrowth by a monoclonal tumor, presumably with inactivation of a tumor suppressor gene(s) on chromosome 11.

Allelic loss in parathyroid tumors from individuals homozygous for multiple endocrine neoplasia type 1.

Homozygosity for the multiple endocrine neoplasia type 1 (MEN1) gene mutation was described in two of three affected siblings of a kindred in which both parents and the third daughter were heterozygotes. Surprisingly, in the two homozygotes, the disease history did not differ from the one of the heterozygotes. In the attempt to unravel genetic differences in parathyroid tumorigenesis between homozygotes and heterozygotes, restriction fragment length polymorphism analysis and microsatellite PCR analysis for loss of heterozygosity (LOH) at the MEN1 gene region on chromosome 11q13 was performed in parathyroid tissues removed at surgery from the mother, her heterozygous sister, and the three siblings. Allelic losses were evidenced in the larger glands of each patient, with a similar pattern of chromosome 11q12-13 losses. The somatic mutation consisted of a large lose of genetic material from chromosome 11. No gross differences exist in the 11q12-13 LOH observed between homozygous and heterozygous carriers. Interestingly, one of the parathyroid tumors from one heterozygote exhibited region of skipped LOH at the 11q12-13 region. The region in the depth of the critical interval retained heterozygosity, whereas those flanking it shared LOH. These findings indicate that inactivation of both copies of the MEN1 gene are not sufficient for parathyroid tumor development in MEN 1 patients and that tumor suppressor genes, other than the MEN1 gene on chromosome 11 or on other chromosomes, can be involved in the pathogenesis of parathyroid tumorigenesis in MEN 1 syndrome.

Genetic and immunohistochemical analyses of p53 independently predict regional metastasis of gastric cancers.

Either p53 gene mutation or immunohistochemical detection of p53 protein has not been consistently shown to have prognostic significance in human cancers, including gastric carcinomas. One hypothesis to explain this inconsistency is that some p53 mutations and p53 protein accumulation are not indicative of tumor progression. To test this hypothesis, we categorized p53 status in 105 gastric carcinomas according to types of mutations, numerical scores of immunohistochemical staining (IHC), or combinations thereof. The p53 status was then correlated with metastasis to liver or peritoneum. Gastric cancers with no p53 mutations were significantly less likely to metastasize than tumors with mutations. Intermediate IHC scores were inversely associated with metastasis. A substantial number of gastric cancers (31 of 105) showed positive p53 immunostaining without detectable mutations (p53-/IHC+), which suggested an accumulation of wild-type p53 protein, and also a significantly lower risk for metastasis. After adjusting for depth of invasion and lymph node involvement, the p53-/IHC+ combination predicted low metastatic risk better than either p53- or IHC+ with intermediate scores. These findings suggest that an accumulation of wild-type p53 protein occurs in gastric cancer cells and represents a stress-response mechanism that lowers metastatic potential.

Diet, Helicobacter pylori, and p53 mutations in gastric cancer: a molecular epidemiology study in Italy.

A series of 105 gastric cancer (GC) cases with paraffin-embedded specimens interviewed in a previous population-based case-control study conducted in a high-risk area around Florence, Italy, was examined for the presence of p53 mutations. Overall, 33 of 105 cases had a mutation (p53+) identified by single-strand conformational polymorphism and confirmed by sequencing (Y-H. Shiao et al., submitted for publication). p53+ cases had a more traditional dietary pattern (i.e., corn meal mush, meat soup, and other homemade dishes) and reported less frequent consumption of raw vegetables (particularly lettuce and raw carrots). A positive association with a high nitrite intake and a negative association with raw vegetables and diffuse type histology persisted in a multivariate analysis. In addition, p53+ cases tended to be located in the upper portion of the stomach and to be associated with advanced age and blood group A. No relation was found between the presence of p53 mutations and histologically defined Helicobacter pylori infection, smoking history, family history of gastric cancer, education, and social class. Of the 33 p53+ cases, 19 had G:C-->A:T transitions at CpG sites. These tumors tended to occur in females and in association with H. pylori infection but not other risk factors. The remaining 14 cases with a p53 mutation had mainly transversions but also two deletions and two transitions at non-CpG sites. These tumors showed a strong positive association with a traditional dietary pattern and with the estimated intake of selected nutrients (nitrite, protein, and fat, particularly from animal sources). The findings of this case-case analysis suggest that p53 mutations at non-CpG sites are related to exposure to alkylating compounds from diet, whereas p53 mutations at CpG sites might be related to H. pylori infection.

Long-term prognosis of gastric cancer in a European country: a population-based study in Florence (Italy). 10-year survival of cases diagnosed in 1985-1987.

This paper analysed, in a population-based series of 1976 gastric cancers diagnosed in Florence (Italy), from 1985 to 1987, the relationship between prognostic variables (demographic, clinical and pathological) and 10-year survival rates. Gastric cancer was mostly detected in elderly patients (mean age: 70.5 years) and at advanced stages (i.e. approximately 50% of the patients could not undergo radical surgery). Ten-year observed survival was 12.1% (95% confidence interval (CI): 10.6-13.6%) for the whole series and 20.8% (95% CI: 18.3-23.3%) for resected cases; relative survival was, respectively, 20.9% (95% CI: 18.4-23.4%) and 32.0% (95% CI: 28.1-35.9%). Ten-year relative survival was 86% for stage IA (95% CI: 73-99%) and 67% for stage IB (95% CI: 52-82%). Multivariate analysis showed a significantly better prognosis in females and a significantly worse prognosis in patients aged 65 years or more (reference: < or = 59 years). In addition, an independent prognostic effect was observed for pT in the resected cases (reference: pT3; pT1: RR = 0.47, 95% CI: 0.34-0.64; pT2 = 0.71, 95% CI: 0.58-0.87; pT4: RR = 2.02, 95% CI: 1.49-2.75), pN (reference: pN0; pN1: RR = 2.13, 95% CI: 1.70-2.68; pN2-3: RR = 3.14, 95% CI: 2.42-4.07; pN+ no. nodes involved unspecified: RR = 4.26, 95% CI: 3.11-5.83) and surgical margin involvement (reference: not involved; involved: RR = 1.36, 95% CI: 1.08-1.72). In addition, the stage, after adjustment for age, gender and surgical margin involvement, showed a strong independent prognostic value (reference: stage II; IA: RR=0.37, 95% CI: 0.25-0.57; IB: RR=0.70, 95% CI: 0.50-0.98; IIIA: RR = 1.80, 95% CI: 1.40-2.33; IIIB: RR = 2.82, 95% CI: 2.14-3.72; IV: RR = 3.29, 95% CI: 2.36-4.59). In conclusion, on the basis of a large population-based series, our results confirm the prognostic effect on long-term gastric cancer survival of pathological and demographic variables. In addition, the study shows that Italy had a relatively good, long-term survival when diagnosis was performed at early stages. However, only a few cases were diagnosed at stages when cure by radical surgery is more likely (i.e. stage I accounted for approximately 20% of the resected cases and less than 10% of all incident cases).

HPE cells: a clonal endothelial cell line established from human parathyroid tissue (human parathyroid cell line).

We report the culture and cloning of human endothelial cells derived from parathyroid tissue surgically removed from a patient affected by Multiple Endocrine Neoplasia Type 1 syndrome. These cells, known as HPE, have been isolated and maintained in culture by serial passages for more than 15 months. The clonal cell line grows in a medium containing serum substitutes which favour endothelial cell growth. HPE cells replicate with a mean doubling time of 120 h, showing typical functional and morphological features of endothelial cells, such as uptake of acetylated low density lipoprotein and positive reaction for Factor VIII-Related Antigen. Basic fibroblast growth factor, vascular endothelial growth factor, insulin-like growth factor type I and ascorbic acid stimulate cell proliferation, whereas transforming growth factor beta and heparin act as inhibitory factors. Prostaglandin E2, secretin and epinephrine increased cAMP production, while human parathyroid hormone, histamine and glucagon were inert. Cells were found to express pro-collagen alpha 1 (type I) mRNA. In HPE cells Restriction Fragments Length Polymorphism and PCR analysis did not show allelic loss at chromosome 11q12-13, known to be a typical feature of MEN 1 parathyroid tumors. These cells are the first example of an established normal human clonal cell line with an endothelial phenotype.

Periurethral neurofibroma.

A periurethral neurofibroma presenting as a midline perineal mass was removed in a three-year-old boy. An immunohistochemical study of S-100 protein distribution within the tumor tissue was performed.

Asynchronous bilateral non-Hodgkin's lymphoma of the testis: report of three cases.

Asynchronous involvement of both testes by non-Hodgkin's lymphoma was observed in 3 patients ranging in age from 38 to 82 years. According to the Working Formulation, all cases were classified as large cell immunoblastic lymphomas, and immunohistochemical studies demonstrated a T-cell phenotype in 1 patient and a B-cell phenotype in 2 patients. Relapse to the contralateral testis occurred after a mean interval of 6 months. The negative prognostic impact of these neoplasms is confirmed in the present series, since 2 patients died of disease 7 and 9 months after diagnosis and 1 patient had a laterocervical and Waldeyer's ring recurrence after 1 year.

Villous and serrated adenomatous growth bordering carcinomas in inflammatory bowel disease.

The histologic phenotype of the dysplastic lesion juxtaposing colorectal carcinomas was assessed in 100 consecutive colectomy specimens: in 50 patients with inflammatory bowel disease (IBD) and in 50 controls (non-IBD patients). Adenomatous growths (AG) were regarded both Dysplasia Associated Lesion or Mass (DALM) and sporadic adenomas. AGs juxtaposing carcinomas were found in 76% (n = 38) of the IBD cases: 52.3% (20 out of 38) were villous, 28.9% (11 out of 38) serrated, 5.3% (2 out of 38) tubular and the remaining 13.2% (5 out of 38) were mixed AGs. Juxtaposing AGs (sporadic adenomas) were also found in 58% (n = 29) of the control cases: 51.7% (15 out of 29) were villous, 6.9% (2 out of 29) tubular, 3.4% (1 out of 9) serrated and the remaining 37.9% (11 out of 29) were mixed. The majority or 81.2% (31 out of 38) of the dysplastic lesions juxtaposing IBD carcinomas were villous or serrated AGs, but only 55.1% (16 out of 29) in control cases. Serrated AGs in particular accounted for nearly 29% of the non-invasive dysplastic lesions abutting IBD carcinomas but only for 3% in control specimens. It would appear that villous and serrated AGs are the most common non-invasive neoplastic lesions from which IBD carcinomas originate.