Surgical outcomes for colon and rectal cancer over a decade: results from a consecutive monocentric experience in 902 unselected patients

Background

This study evaluates the surgical morbidity and long-term outcome of colorectal cancer surgery in an unselected group of patients treated over the period 1994–2003.

Methods

A consecutive series of 902 primary colorectal cancer patients (489 M, 413 F; mean age: 63 years ± 11 years, range: 24–88 years) was evaluated and prospectively followed in a university hospital (mean follow-up 36 ± 24 months; range: 3–108 months). Perioperative mortality, morbidity, overall survival, curative resection rates, recurrence rates were analysed.

Results

Of the total, 476 colorectal cancers were localized to the colon (CC, 53%), 406 to the rectum (RC, 45%), 12 (1%) were multicentric, and 8 were identified as part of HNPCC (1%). Combining all tumours, there were 186 cancers (20.6%) defined as UICC stage I, 235 (26.1%) stage II, 270 (29.9%) stage III and 187 (20.6%) stage IV cases. Twenty-four (2.7%) cases were of undetermined stage. Postoperative complications occurred in 38% of the total group (37.8% of CC cases, 37.2% of the RC group, 66.7% of the synchronous cancer patients and 50% of those with HNPCC, p = 0.19) Mortality rate was 0.8%, (1.3% for colon cancer, 0% for rectal cancer; p = 0.023). Multivisceral resection was performed in 14.3% of cases. Disease-free survival in cases resected for cure was 73% at 5-years and 72% at 8 years. The 5- and 8-year overall survival rates were 71% and 61% respectively (total cases). At 5-year analysis, overall survival rates are 97% for stage I disease, 87% for stage II, 73% for stage III and 22% for stage IV respectively (p < 0.0001). The 5-year overall survival rates showed a marked difference in R0, R1+R2 and non resected patients (82%, 35% and 0% respectively, p < 0.0001). On multivariate analysis, resection for cure and stage at presentation but not tumour site (colon vs. rectum) were independent variables for overall survival (p < 0.0001).

Conclusion

A prospective, uniform follow-up policy used in a single institution over the last decade provides evidence of quality assurance in colorectal cancer surgery with high rates of resection for cure where only stage at presentation functions as an independent variable for cancer-related outcome.     

A plastic SQSTM1/p62-dependent autophagic reserve maintains proteostasis and determines proteasome inhibitor susceptibility in multiple myeloma cells

Multiple myeloma (MM) is the paradigmatic proteasome inhibitor (PI) responsive cancer, but many patients fail to respond. An attractive target to enhance sensitivity is (macro)autophagy, recently found essential to bone marrow plasma cells, the normal counterpart of MM. Here, integrating proteomics with hypothesis-driven strategies, we identified the autophagic cargo receptor and adapter protein, SQSTM1/p62 as an essential component of an autophagic reserve that not only synergizes with the proteasome to maintain proteostasis, but also mediates a plastic adaptive response to PIs, and faithfully reports on inherent PI sensitivity. Lentiviral engineering revealed that SQSTM1 is essential for MM cell survival and affords specific PI protection. Under basal conditions, SQSTM1-dependent autophagy alleviates the degradative burden on the proteasome by constitutively disposing of substantial amounts of ubiquitinated proteins. Indeed, its inhibition or stimulation greatly sensitized to, or protected from, PI-induced protein aggregation and cell death. Moreover, under proteasome stress, myeloma cells selectively enhanced SQSTM1 de novo expression and reset its vast endogenous interactome, diverting SQSTM1 from signaling partners to maximize its association with ubiquitinated proteins. Saturation of such autophagic reserve, as indicated by intracellular accumulation of undigested SQSTM1-positive aggregates, specifically discriminated patient-derived myelomas inherently susceptible to PIs from primarily resistant ones. These aggregates correlated with accumulation of the endoplasmic reticulum, which comparative proteomics identified as the main cell compartment targeted by autophagy in MM. Altogether, the data integrate autophagy into our previously established proteasome load-versus-capacity model, and reveal SQSTM1 aggregation as a faithful marker of defective proteostasis, defining a novel prognostic and therapeutic framework for MM.     

Relationship between human oral lichen planus and oral squamous cell carcinoma at a genomic level: a datamining study

The leader gene approach is a data mining method based on the systematic search for genes involved in a specific process and their ranking according to the number of interconnections with the other genes identified. The genes with the strongest interconnections are termed leader genes, since they may be supposed to play an important role in the process. The potential of malignant progression of OLP to oral squamous cell carcinoma (OSCC) is still not completely clear. In this study, the leader gene approach is applied to investigate the association between OLP and OSCC at a molecular level. Results were integrated with those obtained in an experimental analysis (see paper 1 of this series). Genes involved in OLP and OSCC were identified by systematic queries to dedicated databases. Interconnections among identified genes were calculated and given a confidence value using STRING database. Leader genes were identified by clustering genes according to their interconnections. This theoretical analysis shows that OLP and OSCC share two leader genes: TP53 and CDKN1A, involved in the PI3K signalling events mediated by AKT pathway. This finding and those obtained in the experimental analysis suggest the possible involvement of some key genes/proteins LCK, PIK3CA, BIRC5, TP53 and CDKN1A in the malignant progression from OLP to OSCC. Moreover, these findings support the role of some molecular pathways, namely IL2 signalling events mediated by PI3K, PI3K signalling events mediated by AKT, and, possibly, Aurora A signalling in the association between OLP and OSCC.     

Growth, lipid accumulation, and fatty acid composition in obligate psychrophilic, facultative psychrophilic, and mesophilic yeasts

Obligate psychrophilic, facultative psychrophilic, and mesophilic yeasts were cultured in a carbon-rich medium at different temperatures to investigate whether growth parameters, lipid accumulation, and fatty acid (FA) composition were adaptive and/or acclimatory responses. Acclimation of facultative psychrophiles and mesophiles to a lower temperature decreased their specific growth rate, but did not affect their biomass yield (Y_X/S). Obligate and facultative psychrophiles exhibited the highest Y_X/S. Acclimation to lower temperature decreased the lipid yield (Y_L/X) in mesophilic yeasts, but did not affect Y_L/X in facultative psychrophilic ones. Similar Y_L/X were found in both groups of psychrophiles, suggesting that lipid accumulation is not a distinctive characteristic of adaptation to permanently cold environments. The unsaturation of FAs was one major adaptive feature of the yeasts colonizing permanently cold ecosystems. Remarkable amounts of α-linolenic acid were found in obligate psychrophiles at the expense of linoleic acid, whereas it was scarce or absent in all the other strains. Increased unsaturation of FAs was also a general acclimatory response of facultative psychrophiles to a lower temperature. These results improve the knowledge of the responses enabling psychrophilic yeasts to cope with the cold and may be of support for potential biotechnological exploitation of these strains.     

Mitochondrial Haplogroup U5b3: A Distant Echo of the Epipaleolithic in Italy and the Legacy of the Early Sardinians

There are extensive data indicating that some glacial refuge zones of southern Europe (Franco-Cantabria, Balkans, and Ukraine) were major genetic sources for the human recolonization of the continent at the beginning of the Holocene. Intriguingly, there is no genetic evidence that the refuge area located in the Italian Peninsula contributed to this process. Here we show, through phylogeographic analyses of mitochondrial DNA (mtDNA) variation performed at the highest level of molecular resolution (52 entire mitochondrial genomes), that the most likely homeland for U5b3—a haplogroup present at a very low frequency across Europe—was the Italian Peninsula. In contrast to mtDNA haplogroups that expanded from other refugia, the Holocene expansion of haplogroup U5b3 toward the North was restricted by the Alps and occurred only along the Mediterranean coasts, mainly toward nearby Provence (southern France). From there, ∼7,000–9,000 years ago, a subclade of this haplogroup moved to Sardinia, possibly as a result of the obsidian trade that linked the two regions, leaving a distinctive signature in the modern people of the island. This scenario strikingly matches the age, distribution, and postulated geographic source of a Sardinian Y chromosome haplogroup (I2a2-M26), a paradigmatic case in the European context of a founder event marking both female and male lineages.     

Hematology and serum chemistry parameters in juvenile cynomolgus monkeys (Macaca fascicularis) of Mauritius origin: comparison between purpose-bred and captured animals

Background  The vast majority of non-human primates used for experimental activities are purpose-bred. However, in case of particular procedures or specific projects, it may still be necessary to use animals captured in the wild.
Methods  Sixty cynomolgus monkeys were randomly selected on the basis of breeding origin, and assigned to two groups, each of fifteen males and fifteen females. Analyses included the most frequently investigated parameters for hematology, coagulation, and biochemistry.
Results  Differences were observed in some parameters, particularly in eosinophils, basophils and monocytes, and in fibrinogen, total protein, globulins, alanine amino-transferase, creatinine, aspartate amino-transferase, alkaline phosphatase, γ-glutamyl transferase, lactate dehydrogenase, α-hydroxybutyrate dehydrogenase, iron, potassium, and phosphorus.
Conclusions  Some values in the cynomolgus monkey may show significant differences according to the breeding background of the animals. Only data obtained from animals of similar origin have to be compared, to avoid misinterpretation during the evaluation of the experimental results.     

The incidence of hip, forearm, humeral, ankle, and vertebral fragility fractures in Italy: results from a 3-year multicenter study

Introduction

We aimed to assess the incidence and hospitalization rate of hip and "minor" fragility fractures in the Italian population.

Methods

We carried out a 3-year survey at 10 major Italian emergency departments to evaluate the hospitalization rate of hip, forearm, humeral, ankle, and vertebral fragility fractures in people 45 years or older between 2004 and 2006, both men and women. These data were compared with those recorded in the national hospitalizations database (SDO) to assess the overall incidence of fragility fractures occurring at hip and other sites, including also those events not resulting in hospital admissions.

Results

We observed 29,017 fractures across 3 years, with hospitalization rates of 93.0% for hip fractures, 36.3% for humeral fractures, 31.3% for ankle fractures, 22.6% for forearm/wrist fractures, and 27.6% for clinical vertebral fractures. According to the analyses performed with the Italian hospitalization database in year 2006, we estimated an annual incidence of 87,000 hip, 48,000 humeral, 36,000 ankle, 85,000 wrist, and 155,000 vertebral fragility fractures in people aged 45 years or older (thus resulting in almost 410,000 new fractures per year). Clinical vertebral fractures were recorded in 47,000 events per year.

Conclusions

The burden of fragility fractures in the Italian population is very high and calls for effective preventive strategies.