Cancer Prevention for Survivors: Incidence of Second Primary Cancers and Sex Differences-A Population-Based Study from an Italian Cancer Registry.

BACKGROUND: The number of cancer survivors continues to increase, thanks to advances in cancer diagnosis and treatment. Unfortunately, the incidence of a second primary cancer (SPC) is also increasing, but limited studies reporting incidence data are available regarding multiple cancers. This study presents our observations on multiple primary malignant cancers, the associations between sites, and the inherent sex differences. PATIENTS AND METHODS: We report the data, disaggregated by sex, concerning the SPCs that were recorded in the "Registro Tumori Integrato" (RTI) a population-based cancer registry in Sicily, Italy, as observed in the period from 2003 to 2017, in a total population of approximately 2,300,000. SPCs were divided into synchronous and metachronous cancers. The International Classification of Diseases for Oncology, third edition (ICD-O-3), was used for topographical and morphological classifications. Multiple primary cancers with multi-organ primitiveness were selected from the database of the RTI by extracting patients with more than one diagnosis. SPCs had different histology or morphology from the particular cancer that was considered to be the index cancer case. Multicenter or multifocal cancers, or metastases, were excluded. The percentages of cancer by sex and topography, the average age of incidence, and a breakdown by age were computed. RESULTS: Differences were observed between sexes in terms of incidence and site for SPCs. The most frequent SPC was skin cancer (20% of the SPCs observed). The associations among sites of multiple cancers are reported. CONCLUSION: There are many gaps in our knowledge of sex differences in cancer. The study of multiple primary cancers could bring more likely opportunities for evaluation of the cancer burden and trends that can be used to identify new research areas by population health programs, as well as for clinical researchers.

Epidemiology of Primary Brain Tumors in the Province of Catania during the 2003-2016 Period.

INTRODUCTION: Primary brain tumors (PBTs) account for approximately 2% of all cancers and are associated with significant morbidity and mortality. However, only few epidemiological studies focus on PBTs in Italy. The aim of this study was to evaluate incidence, temporal trend, and survival rate of all PBTs in the province of Catania during the study period. METHODS: All patients diagnosed with PBTs in the province of Catania during the 2003-2016 were identified through the local cancer registry. All cases were classified by histology according to 2007 WHO classification of central nervous system tumors, using the International Classification of Diseases for Oncology, 3rd edition codes. The incidence rate (IR) was calculated for all PBTs and by gender, histology, age-groups, and behavior. Trend analysis was performed using a piecewise log-linear model. RESULTS: A total of 3,819 cases were identified with a female/male ratio of 1.45. The IR for all PBTs was 25.3/100,000 person-years (95% confidence interval 24.5-26.1). Most PBTs were nonmalignant (59.5%, IR = 15.0) with a female predominance. Conversely, malignant tumors (32.4%, IR = 8.2) were more common among men, with a female/male ratio of 0.9. The most frequently reported histology was meningioma (39.0%, IR = 9.8), followed by glioblastoma (11.6%, IR = 2.9). A peak of incidence was found in the 75-84 years age-group, with an IR of 77.6/100,000 person-years. Overall, no increase in incidence was observed along the study period. CONCLUSIONS: The IR of PBTs in the province of Catania is close to incidence reported worldwide. Further studies on risk factors are necessary.

Incidence, survival and geoepidemiological analysis of meningiomas and glioblastomas in the province of Catania during the 2003-2016 period.

BACKGROUND: Meningiomas are the most common primary brain tumors, followed by glioblastomas. Nevertheless, no previous studies have been conducted to evaluate the epidemiology of meningiomas and glioblastomas in the southern region of Italy. Thus, the aim of our study was to evaluate incidence, temporal trend and survival rate of meningiomas and glioblastomas in the province of Catania during the study period. Moreover, a geoepidemiological analysis was performed in order to identify possible geographical and temporal clusters. METHODS: All subjects with meningiomas and glioblastomas diagnosed from 2003 to 2016 in the province of Catania were collected, using the local cancer registry. Incidence rate (IR) was calculated by gender, age-groups and tumor behavior. Temporal changes in incidence trend were assessed using a Joinpoint regression analysis while survival analysis was performed using Kaplan-Meier method. Cluster analysis was performed using Kulldorff's spatial scan statistic. RESULTS: In the province of Catania, a total of 1488 cases of meningiomas and 443 cases of glioblastomas were identified from 2003 to 2016, with an IR of 9.8/100,000 person-years (95%CI 9.3-10.3) and 2.9/100,000 person-years (95%CI 2.7-3.2), respectively. Meningiomas were more common among women (p-value<0.0001), while glioblastomas among men (p-value<0.0001). IR progressively increased over the ages, reaching a peak in the 75-84 and 65-74 years-old group in, respectively, meningiomas and glioblastomas. Mean survival was higher in subjects diagnosed with meningiomas as compared to those with glioblastomas (10.7 years and 15.8 months, respectively), with age as the strongest risk factor for death. Spatial and space-time cluster of high incidence of meningiomas was detected in a small community on the eastern flank of the Mt. Etna volcano. CONCLUSIONS: Epidemiology of meningioma and glioblastoma in the province of Catania is close to that reported worldwide. Spatial and space-time cluster of meningiomas were found in Pedara. Further studies on risks factor are necessary.

Prognosis and cure of long-term cancer survivors: A population-based estimation.

BACKGROUND: Increasing evidence of cure for some neoplasms has emerged in recent years. The study aimed to estimate population-based indicators of cancer cure. METHODS: Information on more than half a million cancer patients aged 15-74 years collected by population-based Italian cancer registries and mixture cure models were used to estimate the life expectancy of fatal tumors (LEFT), proportions of patients with similar death rates of the general population (cure fraction), and time to reach 5-year conditional relative survival (CRS) >90% or 95% (time to cure). RESULTS: Between 1990 and 2000, the median LEFT increased >1 year for breast (from 8.1 to 9.4 years) and prostate cancers (from 5.2 to 7.4 years). Median LEFT in 1990 was >5 years for testicular cancers (5.8) and Hodgkin lymphoma (6.3) below 45 years of age. In both sexes, it was ≤0.5 years for pancreatic cancers and NHL in 1990 and in 2000. The cure fraction showed a 10% increase between 1990 and 2000. It was 95% for thyroid cancer in women, 94% for testis, 75% for prostate, 67% for breast cancers, and <20% for liver, lung, and pancreatic cancers. Time to 5-year CRS >95% was <10 years for testis, thyroid, colon cancers, and melanoma. For breast and prostate cancers, the 5-year CRS >90% was reached in <10 years but a small excess remained for >15 years. CONCLUSIONS: The study findings confirmed that several cancer types are curable. Became aware of the possibility of cancer cure has relevant clinical and social impacts.

The impact of overdiagnosis on thyroid cancer epidemic in Italy,1998-2012.

AIMS: In Italy, incidence rates of thyroid cancer (TC) are among the highest worldwide with substantial intracountry heterogeneity. The aim of the study was to examine time trends of TC incidence in Italy and to estimate the proportion of TC cases potentially attributable to overdiagnosis. METHODS: Data on TC cases reported to Italian cancer registries during 1998-2012 aged <85 years were included. Age-standardised incidence rates (ASR) were computed by sex, period, and histology. TC overdiagnosis was estimated by sex, period, age, and Italian region. RESULTS: In Italy between 1998-2002 and 2008-2012, TC ASR increased of 74% in women (from 16.2 to 28.2/100,000) and of 90% in men (from 5.3 to 10.1/100,000). ASR increases were nearly exclusively due to papillary TC (+91% in women, +120% in men). In both sexes, more than three-fold differences emerged between regions with highest and lowest ASR. Among TC cases diagnosed in 1998-2012 in Italy, we estimated that overdiagnosis accounted for 75% of cases in women and 63% in men and increased over the study period leading to overdiagnosis of 79% in women and 67% in men in 2008-2012. Notably, overdiagnosis was over 80% among women aged <55 years, and substantial variations were documented across Italian regions, in both genders. CONCLUSION(S): Incidence rates of TC are steadily increasing in Italy and largely due to overdiagnosis. These findings call for an update of thyroid gland examination practices in the asymptomatic general population, at national and regional levels.

Immunohistochemical expression of Wilms' tumor protein (WT1) in developing human epithelial and mesenchymal tissues.

The Wilms' tumor (WT1) gene and its protein product are known to exhibit a dynamic expression profile during development and in the adult organism. Apart from a nuclear expression observed in the urogenital system, its precise localization in other developing human tissues is still largely unknown. Accordingly, the aim of this study was to investigate immunohistochemically the temporal and spatial distribution of WT1 in epithelial and mesenchymal developing human tissues from gestational weeks 7-24. For this purpose we used antibodies against the N-terminal of WT1. As might be expected, WT1 nuclear expression was observed in mesonephric/metanephric glomeruli, metanephric blastema, celom-derived membranes (pleura, peritoneum, serosal surfaces) and sex cords. With regard to mesenchymal tissues, a similar nuclear staining was also obtained in the mesenchyme surrounding Müllerian and Wolffian ducts, as well as in the submesothelial mesenchymal cells of all celomatic-derived membranes. The most striking finding was the detection of strong WT1 cytoplasmic immunostaining in developing skeletal and cardiac muscle cells and endothelial cells. The tissue-specific expression of WT1, together with its different nuclear/cytoplasmic localization, both suggest that WT1 protein may have shuttling properties, acting as a protein with complex regulator activity in transcriptional/translation processes during human ontogenesis. The reported cytoplasmic expression of WT1 in human rhabdomyosarcomas and in many vascular tumors strongly suggests an oncofetal expression of this protein. Although not specific, WT1 cytoplasmic expression can be used as a marker of skeletal muscle and endothelial differentiation in an appropriate morphological context.

Aberrant expression of TfR1/CD71 in thyroid carcinomas identifies a novel potential diagnostic marker and therapeutic target.

BACKGROUND: Type I receptor for transferrin (TfR1/CD71) is overexpressed in several malignant tumors, but no studies are available on thyroid carcinomas. Our previous comparative analyses of the relative distribution of transferrin in benign versus papillary thyroid carcinoma (PTC) tissues highlighted a marked malignancy-associated abundance of the molecule. The aim of the present study was to evaluate whether TfR1/CD71 is also differentially expressed in benign versus malignant thyroid tissues. METHODS: Tissue samples, including benign lesions and follicular-derived carcinomas, from 241 patients and a total of 35 benign and malignant fresh specimens were assayed for TfR1/CD71 expression by reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry. RESULTS: We found that transcription of TfR1/CD71 gene is constitutive in thyroid epithelia, but the mRNA is differently translated in benign and malignant tissues. Western blot revealed higher levels of TfR1/CD71 protein in malignant versus benign tissues. Immunohistochemically, most carcinomas exhibited overexpression of the receptor, predominantly in the cytoplasm of neoplastic cells. The highest expression level was detected in primary and metastatic papillary carcinomas and anaplastic carcinomas, with positive results ranging from 86% to 100% of the cases. In contrast, most benign tissues were negative, with only a minority of cases showing focal and weak immunoreactivity. CONCLUSIONS: Our findings suggest that altered expression of TfR1/CD71 may be used as a marker helpful in distinguishing PTC from papillary hyperplasia and follicular variant PTC from benign follicular-patterned lesions. Additionally, the present observations support the rationale for the use of radiolabeled transferrin/transferrin analogs and/or anti-TfR1/CD71 antibodies for diagnostic and/or radiotherapeutic purposes in TfR1/CD71-expressing thyroid tumors.

High levels of connexin 43 mRNA in high grade astrocytomas. Study of 32 cases with in situ hybridization.

Gap junctions are composed of a family of evolutionarily conserved integral plasma membrane proteins termed connexins. The aims of the research reported here were (1) to evaluate the Cx43 protein and mRNA of both low histological grade and high histological grade astrocyte tumors; (2) to evaluate if the immunohistochemistry of the Cx43 protein in astrocytomas could be correlated to histological grade, to proliferative activity (Ki67/Mib1-index) and to immunolabelling of the epidermal growth factor receptor (EGFR); (3) to evaluate if the reduction in levels of the Cx43 protein correlates with reduction in levels of the Cx43 mRNA. This study showed that the immunohistochemical labelling of Cx43 is reduced in grade III and grade IV. Decreased gap junction-mediated intercellular communication corresponds to decreased Cx43 and increased cellular proliferation rates, as measured by immunolabelling of the Ki67 nuclear antigen. This study demonstrated also the persistence in high grade astrocytomas of elevated levels of Cx43 mRNA. The reduced levels of Cx43 protein should not to be ascribed to a reduced genetic transcription, but to an alteration of the post-transcriptional mechanisms such as the regulation of its synthesis and/or the intracellular transport to membrane sites.

A natural antisense transcript against Rad18, specifically expressed in neurons and upregulated during beta-amyloid-induced apoptosis.

Apoptosis, the main form of programmed cell death, is associated to a complex and dynamic transcriptional and post-transcriptional programme. By microarray analysis, we have previously implicated 241 genes differentially expressed in rat cortical neurons exposed to beta-amyloid (Abeta) protein, the major constituent of amyloid plaques in Alzheimer's disease. A large number of identified genes have no name or known function. In the present study, we have investigated one of these genes that encodes for a natural antisense transcript against Rad18 (NAT-Rad18). Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) confirmed differential expression of this transcript in cortical neurons exposed to Abeta. In situ hybridization, qRT-PCR and immunohistochemistry were used to assess the regional and cellular distribution of NAT-Rad18 in adult rat brain. These experiments showed a widespread distribution of NAT-Rad18, with the highest levels in the cerebellum, brainstem and cortex, where it was specifically expressed by neurons. NAT-Rad18 was also strongly expressed in epithelial cells of choroid plexus and cerebral vessels. At the cellular level, expression of Rad18 was counterbalanced by that of its natural antisense transcript, as shown by both in situ hybridization and immunohistochemistry. These experiments suggest the existence of a NAT that exerts a post-transcriptional control over Rad18.

Pathways and genes differentially expressed in the motor cortex of patients with sporadic amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal disorder caused by the progressive degeneration of motoneurons in brain and spinal cord. Despite identification of disease-linked mutations, the diversity of processes involved and the ambiguity of their relative importance in ALS pathogenesis still represent a major impediment to disease models as a basis for effective therapies. Moreover, the human motor cortex, although critical to ALS pathology and physiologically altered in most forms of the disease, has not been screened systematically for therapeutic targets. RESULTS: By whole-genome expression profiling and stringent significance tests we identify genes and gene groups de-regulated in the motor cortex of patients with sporadic ALS, and interpret the role of individual candidate genes in a framework of differentially expressed pathways. Our findings emphasize the importance of defense responses and cytoskeletal, mitochondrial and proteasomal dysfunction, reflect reduced neuronal maintenance and vesicle trafficking, and implicate impaired ion homeostasis and glycolysis in ALS pathogenesis. Additionally, we compared our dataset with publicly available data for the SALS spinal cord, and show a high correlation of changes linked to the diseased state in the SALS motor cortex. In an analogous comparison with data for the Alzheimer's disease hippocampus we demonstrate a low correlation of global changes and a moderate correlation for changes specifically linked to the SALS diseased state. CONCLUSION: Gene and sample numbers investigated allow pathway- and gene-based analyses by established error-correction methods, drawing a molecular portrait of the ALS motor cortex that faithfully represents many known disease features and uncovers several novel aspects of ALS pathology. Contrary to expectations for a tissue under oxidative stress, nuclear-encoded mitochondrial genes are uniformly down-regulated. Moreover, the down-regulation of mitochondrial and glycolytic genes implies a combined reduction of mitochondrial and cytoplasmic energy supply, with a possible role in the death of ALS motoneurons. Identifying candidate genes exclusively expressed in non-neuronal cells, we also highlight the importance of these cells in disease development in the motor cortex. Notably, some pathways and candidate genes identified by this study are direct or indirect targets of medication already applied to unrelated illnesses and point the way towards the rapid development of effective symptomatic ALS therapies.

Genomic profiling of cortical neurons following exposure to beta-amyloid.

In vitro and in vivo studies have shown that beta-amyloid peptide induces neuronal cell death. To explore the molecular basis underlying beta-amyloid-induced toxicity, we analyzed gene expression profiles of cultured rat cortical neurons treated for 24 and 48 h with synthetic beta-amyloid peptide. From the 8740 genes interrogated by oligonucleotide microarray analysis, 241 genes were found to be differentially expressed and segregated into distinct clusters. Functional clustering based on gene ontologies showed coordinated expression of genes with common biological functions and metabolic pathways. The comparison with genes differentially expressed in cerebellar granule neurons following serum and potassium deprivation indicates the existence of common regulatory mechanisms underlying neuronal cell death. Our results offer a genomic view of the changes that accompany beta-amyloid-induced neurodegeneration.

An unusual case of three synchronous tumors in a young woman.

The occurrence in the same young patient of three synchronous tumors deriving from different embryogenic tissues and without a clear correlation with a common etiopathogenic factor is very unusual. We report a case of a Caucasian woman submitted to wide resection of a large retroperitoneal liposarcoma and right radical nephrectomy for suspected tumor infiltration. Histological examination of the right ureter and renal pelvis showed the presence of a multifocal urothelial carcinoma that was clinically asymptomatic. Two months later, during follow-up, chest X-ray and computed tomography documented a coin lesion of the upper left lung, confirmed by positron emission tomography. This nodule was surgically removed and examined histologically, resulting in a diagnosis of sclerosing hemangioma. The patient is alive without evidence of recurrent disease.

Gastric cancer: prognostic significance of the Goseki histological classification.

The aim of this study was to evaluate the prognostic significance of the Goseki factor in patients undergoing potentially curative resection for gastric cancer. From 1989 to 1999 202 patients with gastric cancer came in for observation to the Ist Surgical Clinic of Catania University. For the purposes of this study we examined 86 patients with a 5-year follow-up, from whom it was possible to obtain samples which were mounted in paraffin blocks and stained (haematoxylin-eosin and PAS-Alcian blue). The 5-year survival rates of patients with Goseki I and II tumours with good tubular differentiation were 90% and 30% as compared with 42% and 32% in patients with tumours that showed poor tubular differentiation (Goseki III and IV). In contrast, the 5-year survival rates in patients with mucin-poor tumours (Goseki I and III) were 90% and 42%, as against 30% and 32% in patients with mucin-rich tumours (P < 0.05). Our conclusion is that of the two components of the Goseki system, i.e. tubular differentiation and intracellular mucus, mucus production was found to be the more important determinant of clinical outcome. Mucus production has a greater impact on survival than the degree of tubular differentiation and is independent of it.

Oxytocin is a growth factor for Kaposi's sarcoma cells: evidence of endocrine-immunological cross-talk.

Oxytocin receptors (OTRs) are expressed in numerous tissues, including human normal endothelium. Here we investigated the expression and biological significance of OTRs in Kaposi's sarcoma (KS), an intensely angioproliferative disease of possible vascular origin with a prominent inflammatory component. Immunohistochemistry and in situ hybridization studies showed OTR expression in tumor cells of cutaneous classic and AIDS-related KS lesions. OTR mRNA and protein were also detected on cultured KS-IMM spindle cells by reverse transcription-PCR and immunofluorescence procedures. In these cells, OTR expression was up-regulated by the supernatants of resting CD4+ and CD8+ lymphocytes through a still unidentified factor. Functionality of OTRs was demonstrated because OT treatment of KS-IMM cells led to a significant increase in cell proliferation, coupled to the increase of intracellular calcium, but did not effect cell migration in vitro or angiogenesis in vivo. In addition, we demonstrated that CD4+ and CD8+ cells produce OT themselves, thus constituting an intralesional source of peptide. These results indicate that: (a) functioning OTRs are expressed in KS cells and modulated by the inflammatory counterpart of KS lesions; (b) via OTRs, OT stimulates KS-IMM cell proliferation and could, therefore, be considered a new possible relevant growth factor involved in KS progression; and finally (c) the evidence of OT synthesis by CD4+ and CD8+ lymphocytes strongly suggests the existence of local endocrine-immunological cross-talk in Kaposi's sarcoma.

Intrarenal solitary fibrous tumor of the kidney report of a case with emphasis on the differential diagnosis in the wide spectrum of monomorphous spindle cell tumors of the kidney.

Solitary fibrous tumor (SFT) is a neoplasm that can occur in the urogenital tract, and is also reported occurring in the spermatic cord, seminal vesicles, urinary bladder, prostate, and kidney. Furthermore, it is most important to consider its existence in the kidney, because it is usually diagnosed as renal cell carcinoma pre-operatively. To our knowledge, only 10 cases of SFT have been reported in the kidney to date. We report the clinico-pathological features of an intrarenal SFT occurring in a 31-year-old woman. The tumor, measuring 8.6 cm in its greatest diameter, completely replaced the cortex and the medulla of the middle region of the right kidney, compressing the pelvis. Radiological imaging was consistent with a renal cell carcinoma. Histologically, the tumor was composed of a proliferation of bland-looking vimentin+, CD34+, bcl2+ and CD99+ spindle cells exhibiting a haphazard to storiform growth pattern, pushing borders, and a low mitotic rate (2 mitoses x 10 HPF). We placed emphasis on the differential diagnostic problems, i.e., its differentiation from other primary monomorphous benign and malignant spindle cell tumors of the kidney, such as fibroma, benign fibrous histiocytoma, hemangiopericytoma, inflammatory myofibroblastic (pseudo-)tumor, leiomyoma, angiomyolipoma with predominant spindle cell smooth muscle component, benign peripheral nerve sheath tumors, renal mixed epithelial/stromal tumors, adult type mesoblastic nephroma, fibrous type monophasic synovial sarcoma, malignant peripheral nerve sheath tumors, fibrosarcoma, and low-grade fibromyxoid sarcoma.