Familial aggregation of malignant tumors in patients with pancreatic cancer: Findings from the Ragusa Cancer Registry (Sicily)

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A Decentralized Scheduler for On-line Self-test Routines in Multi-core Automotive System-on-Chips

Modern System-on-Chips (SoCs) deployed for safety-critical applications typically embed one or more processing cores along with a variable number of peripherals. The compliance of such designs with functional safety standards is achieved by a combination of different techniques based on hardware redundancy and in-field test mechanisms. Among these, Software Test Libraries (STLs) are rapidly becoming adopted for testing the CPU and peripherals modules. The STL is usually composed of two sets of self-test procedures: boot-time and run-time tests. The former set is typically executed during the boot or power-on phase of the SoC since it requires full access to the available hardware (e.g., these programs need to manipulate the Interrupt Vector Table and to access the system RAM). The latter set instead, is designed to coexist with the user application and can be executed without requiring special constraints. When the STL is intended for testing the different cores within a multi-core SoC, the concurrent execution of the boot-time self-tests becomes an issue since this could lead to a longer power-up phase and excessive utilization of system resources. The main intent of this work is to present the architecture of a decentralized software scheduler, conceived for the concurrent execution of the STL on the available cores. The proposed solution considers the typical constraints of an STL in a multi-core scenario when deployed in field, namely minimum system resources usage (i.e., code and data memory). The effectiveness of the proposed scheduler was experimentally evaluated on an industrial STL developed for a multi-core SoC manufactured by STMicroelectronics

Different expression of thymidylate synthase in primary tumour and metastatic nodes in breast cancer patients.

BACKGROUND: To date an accurate evaluation of predictive markers in breast cancer is mainly conducted at the primary site, although the main goal of the adjuvant therapy is the control of micrometastases. Adjuvant therapy drugs need a high proliferative cell rate to be effective. The proliferating activity can be evaluated by the Ki-67 marker and even by thymidylate synthase (TS), a cell cycle enzyme present in proliferating cells. In this study the TS levels in primary tumours were compared to those of their metastases. PATIENTS AND METHODS: The TS expression and Ki-67 were evaluated by means of immunohistochemistry in 80 primary breast tumours (PTs) and in their matched axillary metastatic lymph-nodes (ALNs). RESULTS: In 16% of patients, malignant cells of involved nodes showed a lower TS expression than the PTs. In the same group, we also found a lower number of Ki-67 immunoreactive cells in lymph node metastases when compared with primary tumours. CONCLUSION: The group of patients with lower TS and Ki-67 expression in lymph node metastatic cells may be less sensitive to 5-fluorouracil and high dose methotrexate requiring them to be treated with other drug combinations

Lymph node metastases displaying lower Ki-67 immunostaining activity than the primary breast cancer

The aim of the study was to verify by Ki-67 immunostaining if any difference exists in the cell proliferating fraction between primary breast tumors (PTs) and matching positive axillary lymph nodes (ALNs). PATIENTS AND METHODS: Immunohistochemistry with the monoclonal antibody against Ki-67 was performed in 160 node-positive breast carcinomas and in their respective lymph node metastases. RESULTS: An increase of Ki-67 immunoreactive cells in ALN compared with that of PTs was observed in 84% of cases (ALN: mean 17%, PTs: mean 8%; p < 0.001), whereas 16% of the cases showed Ki-67 value two to six times lower in the ALNs than in the corresponding PTs (ALN: mean 3.2%, PTs mean 12.5%; p < 0.005). The decrease of Ki-67 positive cells in the ALN was independent from the histotype and the histological grade of the tumor. CONCLUSION: A different cell proliferation fraction between PTs and matching positive ALNs was demonstrated and underlined that the existence of a group of patients with decreased number of Ki-67 immunoreactive cells in lymph node metastases compared with that of the primary tumors could be taken into account in the choice of therapeutic strategy

Thymidylate synthase gene promoter polymorphisms are associated with TSmRNA expressions but not with microsatellite instability in colorectal cancer

Abstract BACKGROUND: Microsatellite instability (MSI) is a biological characteristic of most tumours, being involved in 85% of hereditary non-polyposis colorectal cancer (HNPCC). It also occurs in 10-15% of sporadic colorectal cancers (CRC). HNPCC appears to be caused by germline mutations in mismatch repair (MMR) genes, which are responsible for repairing single base-pair mismatches. MSI is also associated with a better response of CRC to adjuvant chemotherapy with fluoropyrimidines. We investigated any relationship between the MSI status and the TSmRNA expression, the polymorphisms of 5-Fluorouracil (5-FU cellular target, the enzyme thymidylate synthase (TS) and TS expression evaluated by means of immunohistochemistry. MATERIALS AND METHODS: A series of 80 colorectal cancers was evaluated for MSI and polymorphisms in the 3'UTR and the 5'UTR of the TS gene by a PCR assay. TSmRNA was quantified by real-time PCR and the TS expression by immunohistochemical assay. RESULTS: There was no significant association between the polymorphisms in the TS gene and the MSI or between the TSmRNA expression and the MSI status. CRC with a 3R/3R or 2R/3R genotype showed a significantly higher TSmRNA expression than those with the 2R/2R genotype (p = 0.001 and p = 0.028, respectively). Another significant association was found between the TSmRNA expression and the TS immunohistochemical determination (p = < 0.05). No association was found between the polymorphism of the 3'UTR and the TSmRNA expression. CONCLUSION: Our data show that there is no association between MSI status and the polymorphisms in the 3' and 5' UTRs and the TS expression. Tumour samples displaying the 3R/3R or 2R/3R genotype of TS have higher TSmRNA levels than the 2R/2R genotype. Polymorphic variant of the 3'UTR does not influence the TSmRNA level. We found a relationship between the TSmRNA expression, evaluated by real-time PCR, and with the TS level determined by immunohistochemical assay. Thus, genotyping of the 5'UTR and quantification of the TSmRNA expression in human CRC could be considered as predictors for response to SFU-based chemotherapy. The evaluation of the TS expression by means of immunohistochemistry assay remains a safe and reliable assay in CRC

Deterministic Cache-based Execution of On-line Self-Test Routines in Multi-core Automotive System-on-Chips

Traditionally, the usage of caches and deterministic execution of on-line self-test procedures have been considered two mutually exclusive concepts. At the same time, software executed in a multi-core context suffers of a limited timing predictability due to the higher system bus contention. When dealing with selftest procedures, this higher contention might lead to a fluctuating fault coverage or even the failure of some test programs. This paper presents a cache-based strategy for achieving both deterministic behaviour and stable fault coverage from the execution of self-test procedures in multi-core systems. The proposed strategy is applied to two representative modules negatively affected by a multi-core execution: synchronous imprecise interrupts logic and pipeline hazard detection unit. The experiments illustrate that it is possible to achieve a stable execution while also improving the state-of-the-art approaches for the on-line testing of embedded microprocessors. The effectiveness of the methodology was assessed on all the three cores of a multi-core industrial System- on-Chip intended for automotive ASIL D applications

SELF-EXPANDABLE METAL STENT PLACEMENT FOR CLOSURE OF A LEAK AFTER TOTAL GASTRECTOMY FOR GASTRIC CANCER: REPORT ON THREE CASES AND REVIEW OF THE LITERATURE

consequently the management of this problem has become more critically focused than was previously possible. We report here three cases of placement of a partially silicone-coated SEMS (Evolution Controlled Release Esophageal Stent System, CookMedical, Winston-Salem, NC, USA) in patients who underwent total gastrectomy with Roux-en-Y end-to-side esophagojejunostomy for a gastric adenocarcinoma. The promising results of our report, despite the small number of patients, suggest that early stenting (through a partially silicone-coated SEMS) is a feasible alternative to surgical treatment in this subset of patients. In fact, in the treatment of leakage after total gastrectomy, plastic stents and totally covered metallic stents may not adhere sufficiently to the esophagojejunal walls and, as a result, migrate beyond the anastomosis. However, prospective studies with a larger number of patients might assess the real effectiveness and safety of this procedure

ITALIAN CANCER FIGURES - REPORT 2015: The burden of rare cancers in Italy = I TUMORI IN ITALIA - RAPPORTO 2015: I tumori rari in Italia

OBJECTIVES: This collaborative study, based on data collected by the network of Italian Cancer Registries (AIRTUM), describes the burden of rare cancers in Italy. Estimated number of new rare cancer cases yearly diagnosed (incidence), proportion of patients alive after diagnosis (survival), and estimated number of people still alive after a new cancer diagnosis (prevalence) are provided for about 200 different cancer entities. MATERIALS AND METHODS: Data herein presented were provided by AIRTUM population- based cancer registries (CRs), covering nowadays 52% of the Italian population. This monograph uses the AIRTUM database (January 2015), which includes all malignant cancer cases diagnosed between 1976 and 2010. All cases are coded according to the International Classification of Diseases for Oncology (ICD-O-3). Data underwent standard quality checks (described in the AIRTUM data management protocol) and were checked against rare-cancer specific quality indicators proposed and published by RARECARE and HAEMACARE (www.rarecarenet.eu; www.haemacare.eu). The definition and list of rare cancers proposed by the RARECAREnet "Information Network on Rare Cancers" project were adopted: rare cancers are entities (defined as a combination of topographical and morphological codes of the ICD-O-3) having an incidence rate of less than 6 per 100,000 per year in the European population. This monograph presents 198 rare cancers grouped in 14 major groups. Crude incidence rates were estimated as the number of all new cancers occurring in 2000-2010 divided by the overall population at risk, for males and females (also for gender-specific tumours).The proportion of rare cancers out of the total cancers (rare and common) by site was also calculated. Incidence rates by sex and age are reported. The expected number of new cases in 2015 in Italy was estimated assuming the incidence in Italy to be the same as in the AIRTUM area. One- and 5-year relative survival estimates of cases aged 0-99 years diagnosed between 2000 and 2008 in the AIRTUM database, and followed up to 31 December 2009, were calculated using complete cohort survival analysis. To estimate the observed prevalence in Italy, incidence and follow-up data from 11 CRs for the period 1992-2006 were used, with a prevalence index date of 1 January 2007. Observed prevalence in the general population was disentangled by time prior to the reference date (≤2 years, 2-5 years, ≤15 years). To calculate the complete prevalence proportion at 1 January 2007 in Italy, the 15-year observed prevalence was corrected by the completeness index, in order to account for those cancer survivors diagnosed before the cancer registry activity started. The completeness index by cancer and age was obtained by means of statistical regression models, using incidence and survival data available in the European RARECAREnet data. RESULTS: In total, 339,403 tumours were included in the incidence analysis. The annual incidence rate (IR) of all 198 rare cancers in the period 2000-2010 was 147 per 100,000 per year, corresponding to about 89,000 new diagnoses in Italy each year, accounting for 25% of all cancer. Five cancers, rare at European level, were not rare in Italy because their IR was higher than 6 per 100,000; these tumours were: diffuse large B-cell lymphoma and squamous cell carcinoma of larynx (whose IRs in Italy were 7 per 100,000), multiple myeloma (IR: 8 per 100,000), hepatocellular carcinoma (IR: 9 per 100,000) and carcinoma of thyroid gland (IR: 14 per 100,000). Among the remaining 193 rare cancers, more than two thirds (No. 139) had an annual IR &lt;0.5 per 100,000, accounting for about 7,100 new cancers cases; for 25 cancer types, the IR ranged between 0.5 and 1 per 100,000, accounting for about 10,000 new diagnoses; while for 29 cancer types the IR was between 1 and 6 per 100,000, accounting for about 41,000 new cancer cases. Among all rare cancers diagnosed in Italy, 7% were rare haematological diseases (IR: 41 per 100,000), 18% were solid rare cancers. Among the latter, the rare epithelial tumours of the digestive system were the most common (23%, IR: 26 per 100,000), followed by epithelial tumours of head and neck (17%, IR: 19) and rare cancers of the female genital system (17%, IR: 17), endocrine tumours (13% including thyroid carcinomas and less than 1% with an IR of 0.4 excluding thyroid carcinomas), sarcomas (8%, IR: 9 per 100,000), central nervous system tumours and rare epithelial tumours of the thoracic cavity (5%with an IR equal to 6 and 5 per 100,000, respectively). The remaining (rare male genital tumours, IR: 4 per 100,000; tumours of eye, IR: 0.7 per 100,000; neuroendocrine tumours, IR: 4 per 100,000; embryonal tumours, IR: 0.4 per 100,000; rare skin tumours and malignant melanoma of mucosae, IR: 0.8 per 100,000) each constituted &lt;4% of all solid rare cancers. Patients with rare cancers were on average younger than those with common cancers. Essentially, all childhood cancers were rare, while after age 40 years, the common cancers (breast, prostate, colon, rectum, and lung) became increasingly more frequent. For 254,821 rare cancers diagnosed in 2000-2008, 5-year RS was on average 55%, lower than the corresponding figures for patients with common cancers (68%). RS was lower for rare cancers than for common cancers at 1 year and continued to diverge up to 3 years, while the gap remained constant from 3 to 5 years after diagnosis. For rare and common cancers, survival decreased with increasing age. Five-year RS was similar and high for both rare and common cancers up to 54 years; it decreased with age, especially after 54 years, with the elderly (75+ years) having a 37% and 20% lower survival than those aged 55-64 years for rare and common cancers, respectively. We estimated that about 900,000 people were alive in Italy with a previous diagnosis of a rare cancer in 2010 (prevalence). The highest prevalence was observed for rare haematological diseases (278 per 100,000) and rare tumours of the female genital system (265 per 100,000). Very low prevalence (&lt;10 prt 100,000) was observed for rare epithelial skin cancers, for rare epithelial tumours of the digestive system and rare epithelial tumours of the thoracic cavity. COMMENTS: One in four cancers cases diagnosed in Italy is a rare cancer, in agreement with estimates of 24% calculated in Europe overall. In Italy, the group of all rare cancers combined, include 5 cancer types with an IR&gt;6 per 100,000 in Italy, in particular thyroid cancer (IR: 14 per 100,000).The exclusion of thyroid carcinoma from rare cancers reduces the proportion of them in Italy in 2010 to 22%. Differences in incidence across population can be due to the different distribution of risk factors (whether environmental, lifestyle, occupational, or genetic), heterogeneous diagnostic intensity activity, as well as different diagnostic capacity; moreover heterogeneity in accuracy of registration may determine some minor differences in the account of rare cancers. Rare cancers had worse prognosis than common cancers at 1, 3, and 5 years from diagnosis. Differences between rare and common cancers were small 1 year after diagnosis, but survival for rare cancers declined more markedly thereafter, consistent with the idea that treatments for rare cancers are less effective than those for common cancers. However, differences in stage at diagnosis could not be excluded, as 1- and 3-year RS for rare cancers was lower than the corresponding figures for common cancers. Moreover, rare cancers include many cancer entities with a bad prognosis (5-year RS &lt;50%): cancer of head and neck, oesophagus, small intestine, ovary, brain, biliary tract, liver, pleura, multiple myeloma, acute myeloid and lymphatic leukaemia; in contrast, most common cancer cases are breast, prostate, and colorectal cancers, which have a good prognosis. The high prevalence observed for rare haematological diseases and rare tumours of the female genital system is due to their high incidence (the majority of haematological diseases are rare and gynaecological cancers added up to fairly high incidence rates) and relatively good prognosis. The low prevalence of rare epithelial tumours of the digestive system was due to the low survival rates of the majority of tumours included in this group (oesophagus, stomach, small intestine, pancreas, and liver), regardless of the high incidence rate of rare epithelial cancers of these sites. This AIRTUM study confirms that rare cancers are a major public health problem in Italy and provides quantitative estimations, for the first time in Italy, to a problem long known to exist. This monograph provides detailed epidemiologic indicators for almost 200 rare cancers, the majority of which (72%) are very rare (IR&lt;0.5 per 100,000). These data are of major interest for different stakeholders. Health care planners can find useful information herein to properly plan and think of how to reorganise health care services. Researchers now have numbers to design clinical trials considering alternative study designs and statistical approaches. Population-based cancer registries with good quality data are the best source of information to describe the rare cancer burden in a population

Expression of a specific Thymidylate synthase polimorfic allele in metastatic colorectal patients is regulated by Myeloid Zinc Finger 1.

Thymidylate Synthase (TS) is the target enzyme for fluoropyrimidine anticancer drugs. Its expression is regulated by the number of functional upstream stimulatory factor (USF) E box consensus elements present on its 5’ untranslated region. To date are known different polymorphisms, the first one consisting of 2 or 3 repeat of a 28 bp sequence, a further single nucleotide polymorphism (SNP) consisting in a G>C substitution within the second repeat of 3R (3RG>3RC) and recently it has been identified an additional SNP a G>C substitution at the 12th nucleotide in the first repeat of the 2R allele (2RG>2RC). These polymorphisms can influence TS expression, in particular 3R/3R genotype and the presence of 3RG alleles are associated to an increased transcriptional activity and to higher TS levels. The sequence of promoter region of colorectal cancer (CRC) samples was subjected to an in silico analysis (http://www.cbrc.jp/research/db/TFSEARCH.html) to search for all potential transcription factors binding this region. We found that Myeloid zinc finger 1(MZF-1) binds the analyzed consensus. By the literature it is known that this factor induces invasion and in vivo metastasis in CRC, so we investigated a possible correlation between TS and MZF-1 expression in the same pathological samples. Materials and Methods: we analyzed the distribution of these polimorphisms in a group of 68 healthy Caucasian subjects, in the normal tissue, in primary tumour and in liver metastasis of 13 CRC patients. Tandem repeat length and the presence of SNP was determined by direct sequencing of genomic DNA. TS and MZF 1 expression were analyzed by immunohistochemistry. Results: In healthy population the allele frequency was respectively 2RG(35%) 3RG (44%) 3RC (21%), in colorectal patients while both primary that normal and metastatic samples showed the same genotype: 2RG/3RG. TS and MZF-1 expression were related and gradually increased from normal tissue (negative) to the primary tumour (focally positive) in the metastases (overexpressing). Conclusions: These unexpected results lead to the hypothesis of a genetic selection towards a more aggressive disease and enough suggest that regardless of genotype other factors are involved in regulation of TS expression as MZF 1, therefore the only genetic marker is not a valid predictor of eventual fluoropyrimidine response