Stefano Rausei

The role of heat shock proteins in cancer

Heat shock proteins (HSPs) are an evolutionary family of proteins that act as molecular chaperones. According to their size they have been classified into the following families; HSP90, HSP70, HSP60, HSP40 and HSP27. They prevent the formation of nonspecific protein aggregates and they assist proteins in the acquisition of their normal architecture. Moreover, HSPs are likely to have anti-apoptotic properties and are actively involved in various processes as tumor cell proliferation, invasion, metastases and death. Notably, these proteins have been reported to be significantly elevated in a plethora of human cancers. Their over-expression has been robustly associated with therapeutic resistance and poor survival. In this way, HSPs may have important therapeutic implications and they can be targeted by specific drugs. In this review, we discuss the influence of HSP27, HSP40, HSP60, HSP70 and HSP90 on human cancers. In addition, we report the existing scientific data on this issue with an effort to highlight the possible future implication of HSPs as tumor biomarkers or drug targets for improving prognosis and treatment of cancer patients around the world.

Polymorphisms in metabolic genes, their combination and interaction with tobacco smoke and alcohol consumption and risk of gastric cancer: a case-control study in an Italian population

BackgroundThe distribution and the potential gene-gene and gene-environment interaction of selected metabolic genetic polymorphisms was investigated in relation to gastric cancer risk in an Italian population.MethodsOne hundred and seven cases and 254 hospital controls, matched by age and gender, were genotyped for CYP1A1, CYP2E1, mEH, GSTM1, GSTT1, NAT2 and SULT1A1 polymorphisms. Haplotype analysis was performed for EPHX1 exons 3 and 4, as well as CYP2E1 RsaI (*5 alleles) and CYP2E1 DraI (*5A or *6 alleles). The effect modification by alcohol and cigarette smoking was tested with the heterogeneity test, while the attributable proportion (AP) was used to measure the biological interaction from the gene-gene interaction analysis.ResultsGastric cancer risk was found to be associated with the inheritance of GSTT1 null genotype (OR = 2.10, 95%CI: 1.27–3.44) and the SULT1A1 His/His genotype (OR = 2.46, 95%CI: 1.03–5.90). No differences were observed for the haplotype distributions among cases and controls. For the first time an increased risk was detected among individuals carrying the *6 variant allele of CYP2E1 if ever-drinkers (OR = 3.70; 95%CI: 1.45–9.37) with respect to never-drinkers (OR = 0.18; 95% CI: 0.22–1.46) (p value of heterogeneity among the two estimates = 0.001). Similarly, the effect of SULT1A1 variant genotype resulted restricted to ever-smokers, with an OR of 2.58 (95%CI: 1.27–5.25) for the carriers of His allele among smokers, and an OR of 0.86 (95%CI: 0.45–1.64) among never-smokers (p value of heterogeneity among the two estimates = 0.03). The gene-gene interaction analyses demonstrated that individuals with combined GSTT1 null and NAT2 slow acetylators had an additional increased risk of gastric cancer, with an OR of 3.00 (95%CI: 1.52–5.93) and an AP of 52%.ConclusionGSTT1, SULT1A1 and NAT2 polymorphisms appear to modulate individuals susceptibility to gastric cancer in this Italian population, particularly when more than one unfavourable genotype is present, or when combined with cigarette smoke. The increased risk for the carriers of CYP2E1*5A or *6 alleles among drinkers need to be confirmed by larger prospective studies.

Complicated intra-abdominal infections in Europe: a comprehensive review of the CIAO study

The CIAO Study (“C omplicated Intra-A bdominal infection O bservational” Study) is a multicenter investigation performed in 68 medical institutions throughout Europe over the course of a 6-month observational period (January-June 2012).Patients with either community-acquired or healthcare-associated complicated intra-abdominal infections (IAIs) were included in the study.2,152 patients with a mean age of 53.8 years (range: 4–98 years) were enrolled in the study. 46.3% of the patients were women and 53.7% were men. Intraperitoneal specimens were collected from 62.2% of the enrolled patients, and from these samples, a variety of microorganisms were collectively identified.The overall mortality rate was 7.5% (163/2.152).According to multivariate analysis of the compiled data, several criteria were found to be independent variables predictive of patient mortality, including patient age, the presence of an intestinal non-appendicular source of infection (colonic non-diverticular perforation, complicated diverticulitis, small bowel perforation), a delayed initial intervention (a delay exceeding 24 hours), sepsis and septic shock in the immediate post-operative period, and ICU admission.Given the sweeping geographical distribution of the participating medical centers, the CIAO Study gives an accurate description of the epidemiological, clinical, microbiological, and treatment profiles of complicated intra-abdominal infections (IAIs) throughout Europe.

A case–control study on the effect of p53 and p73 gene polymorphisms on gastric cancer risk and progression

The p53 protein and its functional homologue p73 share several functions in modulating cell-cycle control and apoptosis. Based on the functional interaction between p53 and p73 in carcinogenesis, we investigated the combined effect of p73 G4C14-to-A4T14 and p53 gene polymorphisms and their interaction with selected environmental factors, on the risk for gastric cancer in a hospital-based case-control study conducted in Italy. The effect of these polymorphisms on cancer progression was also investigated. One hundred and fifteen gastric cancer cases and 295 hospital controls were genotyped for p73 G4C14-to-A4T14, and p53 exon 4 (Arg72Pro), intron 3 and intron 6 polymorphisms. An increased risk for gastric cancer was found to be associated with the inheritance of the p73 homozygous variant genotype among the gastric cancer intestinal histotype (odds ratio (OR)=6.75; 95% confidence interval (95% CI)=1.88-24.24). An effect modification of the p73 variant allele by gender was observed [(OR=2.82; 95%CI=1.24-6.40) among females, versus an OR of 0.70 (95%CI=0.32-1.54) among males; p-value for homogeneity among strata estimates =0.03]. Gene-gene interaction analyses demonstrated that individuals with combined p53 exon 4 and intron 6 variant alleles are borderline significantly protected from gastric cancer (OR=0.52; 95% CI=0.26-1.07; p-value for interaction =0.005), which was confirmed by the haplotype analysis. Finally, a poorer survival was observed among carriers of the variant allele of p53 intron 6 if compared with those carrying both wild-type alleles (p-value for log-rank test =0.02). This study shows that the p73 G4C14-to-A4T14 polymorphism may be a risk factor for gastric cancer, as reported from other studies in different tumour sites among Caucasians. Along with the protective effect of p53 exon 4-intron 6 allelic variants, already noted for breast and lung cancer, our results require confirmation from larger studies.

The safety of energy-based devices in open thyroidectomy: a prospective, randomised study comparing the LigaSure™ (LF1212) and the Harmonic® FOCUS.

PurposeThe options for haemostasis and dissection during modern thyroid surgery include the use of a bipolar vessel sealing system and ultrasonic technology. The aim of this study was to compare these energy-based devices (EBDs) with respect to their use in open thyroidectomy.MethodsThe FOCUS Shear (F) and LigaSure LF1212 (L) were evaluated. A total of 182 consecutive patients scheduled for open thyroidectomy were prospectively randomised into two similarly sized groups. The parameters of operative time, morbidity, incision length, postoperative pain and hospital stay were analysed.ResultsThe main clinically primary endpoints of the two devices were identical in the study as the rate of nerve lesions, bleeding, drainage, operative time and postoperative calcium concentration with no significant differences with respect to the instrument utilised. The mean length of the incision was greater in the F group (p < 0.05). Patients in the F group were more likely to complain of pain while swallowing (p < 0.001). Early postoperative measurements of intact parathyroid hormone plasma levels revealed that although the levels were within the reference range, they were significantly lower in the F group (p < 0.001). Oral calcium supplementation was significantly higher and more prolonged in the F group.ConclusionsThe present study demonstrated no significant difference in the rates of postoperative morbidity associated with these two different EBDs used. Differences in clinically less significant were founded and focused on.

Determinants of surgical morbidity in gastric cancer treatment

BACKGROUND The occurrence of early surgical complications after gastrectomy as a treatment for gastric cancer has been reported to have a negative impact on longterm survival. The aim of this study was to identify treatment-related factors that can predict morbidity and mortality in patients undergoing operations for gastric cancer. STUDY DESIGN The charts of 388 patients who underwent different operations for gastric cancer at A Gemelli General Hospital, Catholic University of Rome, Italy, between January 1992 and April 2007, were reviewed. Patients were grouped according to the type of surgical treatment performed. The study end points were postoperative morbidity, mortality, and the length of hospital stay after surgery. RESULTS Overall morbidity and mortality rates were 16.2% (63 patients) and 2.3% (9 patients), respectively. Overall morbidity rates were higher in patients more than 64 years of age, when a gastric tumor was resected along with the spleen, and when an extended lymphadenectomy was performed. Patients older than 64 years had longer postoperative hospital stays, and Roux-en-Y gastrojejunostomy was predictive of a shorter stay. Mortality was not influenced by any surgically related factors. CONCLUSIONS Age, splenectomy, and extended lymphadenectomy were independently associated with the development of complications after gastric cancer operations. After subtotal gastrectomy, Roux-en-Y gastrojejunostomy was associated with a shorter postoperative length of stay than conventional Billroth I and Billroth II reconstructions.

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and susceptibility to gastric adenocarcinoma in an Italian population

Abstract Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the metabolism of folate, which provides a methyl donor for DNA methylation and deoxynucleoside synthesis. We performed a case–control study to explore the relationship between two common MTHFR polymorphisms (C677T and A1298C), their combination and interaction with environmental exposures, on gastric adenocarcinoma susceptibility and progression in an Italian population. One hundred and two cases and 254 hospital controls, matched by age and gender, were enrolled. Individuals carrying the MTHFR 677T allele showed an increased risk of gastric cancer (odds ratio (OR) 1.62, 95% confidence interval (CI) 0.98–2.67), particularly among ever smokers (OR 2.10, 95% CI 1.07–5.33) and, among 677 TT individuals, those with a low intake of fruit and vegetables (OR 2.18, 95% CI 1.05–4.54). The strongest effect, however, was noted for the MTHFR 677 TT genotype among the diffuse gastric cancer histotype (OR 2.92, 95% CI 1.12–7.60). No association was detected for the effect of MTHFR A1298C polymorphism. Survival analysis did not show any association between each polymorphism on the overall survival, although when the analysis was restricted to the first year of follow-up after the surgical intervention an improved survival was noted among MTHFR 677 CC subjects compared with the T allele carriers (p value for log-rank test 0.02). In conclusion, MTHFR 677 (any T genotype) appears to modulate an individuals susceptibility to gastric cancer, particularly when combined with cigarette smoking and among those with a low intake of fruit and vegetables. Our results also suggest that an aberrant DNA methylation pattern, through impaired folate metabolism, might play a key role in gastric carcinogenesis. A possible survival effect of the MTHFR C677T genotype in gastric cancer patients deserves further investigations with larger sample sizes.

Visualization versus Neuromonitoring of Recurrent Laryngeal Nerves during Thyroidectomy: What About the Costs?

BackgroundThe objective of the present study was to evaluate costs for thyroidectomy performed with the aid of intraoperative neural monitoring (IONM), which has gained widespread acceptance during thyroid surgery as an adjunct to the gold standard of visual nerve identification.MethodsThrough a micro-costing approach, the thyroidectomy patient-care process (with and without IONM) was analyzed by considering direct costs (staff time, consumables, equipment, drugs, operating room, and general expenses). Unit costs were collected from hospital accounting and standard tariff lists. To assess the impact of the IONM technology on hospital management, three macro-scenarios were considered: (1) traditional thyroidectomy; (2) thyroidectomy with IONM in a high-volume setting (5 procedures per week); and (3) thyroidectomy with IONM in a low-volume setting (1 procedure per week). Energy-based devices (EBD) for hemostasis and dissection in thyroidectomy were also evaluated, as well as the reimbursement made by the Italian Healthcare System on the basis of diagnosis related groups (DRGs), about €2,600.ResultsComparison between costs and the DRG fee shows an underfunding of total hospitalization costs for all thyroidectomies, regardless of IONM use (scenario 1: €3,471). The main cost drivers are consumables and technologies (25%), operating room (16%), and staff (14%). Hospitalization costs for a thyroidectomy with IONM range from €3,713 to €3,770 (scenarios 2 and 3), 5–7% higher than those for traditional thyroidectomy. Major economic differences emerge when an EBD is used (€3,969).ConclusionsThe regional DRG tariff for thyroid surgery is barely sufficient to cover conventional surgery costs. Intraoperative neural monitoring accounts for 5–7% of the hospitalization costs for a thyroidectomy.

Multivisceral Resection for Locally Advanced Gastric Cancer: An Italian Multicenter Observational Study

IMPORTANCE The role of multivisceral resection, in the setting of locally advanced gastric cancer, is still debated. Previous studies have reported a higher risk for perioperative morbidity and mortality, with limited objective benefit in terms of survival. Conversely, recent studies have shown the feasibility of enlarged resections and the potential advantage of extended resection for clinical stage T4b gastric adenocarcinoma with good long-term results. OBJECTIVE To analyze the role of multivisceral resection for locally advanced gastric cancer with particular attention to the brief and long-term results and to the prognostic value of clinical and pathologic factors. DESIGN Prospective multicenter study using data from between January 1, 1995, and December 31, 2008. SETTINGS Seven Italian surgery centers. PATIENTS A total of 2208 patients underwent curative resections for gastric carcinoma at the centers. Among them, 206 patients presented with a clinical T4b carcinoma. One hundred twelve underwent a combined resection of the adjacent organs with a gastrectomy owing to suspicion or direct invasion of these organs by the gastric cancer. MAIN OUTCOMES AND MEASURES Clinical and pathologic variables were prospectively collected and the feasibility and efficacy of multivisceral resection for locally advanced clinical T4b gastric cancer were assessed. RESULTS Postoperative mortality and complication rates of patients who underwent a gastrectomy with a combined resection of the involved organs were 3.6% and 33.9%, respectively. Pathologic factors revealed that the nodal involvement was present in about 89.3% of patients and the mean (SD) number of pathologic lymph nodes was 14.8 (16.6). The overall 5-year survival rate was 27.2%. The completeness of resection and lymph node invasion represent independent prognostic parameters at multivariate analysis. CONCLUSIONS AND RELEVANCE Our study indicates that patients undergoing extended resections experience acceptable postoperative morbidity and mortality rates, and an en bloc multivisceral resection should be performed in patients when a complete resection can be realistically obtained and when lymph node metastasis is not evident.

Safety of neural monitoring in thyroid surgery

During thyroid surgery, the functional integrity of the recurrent laryngeal nerve (RLN) is not only threatened by direct nerve injury resulting from accidental transection, clipping or ligation. In fact, indirect trauma, e.g. traction and compression occurring repeatedly throughout gland dissection, contribute to long-term nerve impairment. In order to avoid RLN lesions and preserve nerve function the surgeon must adhere to and comply with a strict standardized intraoperative neuromonitoring (IONM) technique to preserve results, quality and safety. IONM should be a team work between the surgeon and the anesthesiologist.