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Purpose: To assess the long-term oncological outcomes in patients with locally advanced rectal cancer who underwent neoadjuvant therapy followed by local or total mesorectal excision. Methods: Patients with locally advanced rectal adenocarcinoma who received neoadjuvant therapy from 2005 to 2017 were evaluated. Those with major or complete clinical response underwent a full-thickness local excision. Kaplan-Meier estimates were used to evaluate overall, disease-free, and local recurrence-free survival of patients who underwent local excision (LE group) and were compared with a matched cohort of patients who underwent total mesorectal excision (TME group). Results: Among 252 patients who received neoadjuvant therapy for rectal cancer, 51 (20.2%) underwent a local excision. At a median follow-up of 61 months, patients who underwent local excision were stoma-free in 88.2% of cases and with rectum preserved in 78.5% of cases, respectively. The estimated 5-year local, disease-free, and overall survival was 91.8% vs 97.6% (95% CI: 79.5–96.8 vs 84.6–99.6), 86.7% vs 86.4% (95% CI: 72.5–93.9 vs 70.1–94.1), and 85% vs 90% (95% CI: 69.0–93.0% vs 75.3–96.2), in the study and matched control group, respectively. None of the differences was statistically significant. Conclusions: One-fifth of patients with locally advanced rectal cancer are manageable with a rectum-sparing approach after neoadjuvant therapy. With this strategy, about 80% patients will have their rectum preserved and 90% will be without stoma at long term. [ABSTRACT FROM AUTHOR]

Abstract Batten diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration. We discovered increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and used fluorescent‐conjugated bacterial toxins to label Gb3 to develop a cell‐based high content imaging (HCI) screening assay for the repurposing of FDA‐approved compounds able to reduce this accumulation within BD cells. We found that tamoxifen reduced the lysosomal accumulation of Gb3 in CLN3 and CLN7 cell models, including neuronal progenitor cells (NPCs) from CLN7 patient‐derived induced pluripotent stem cells (iPSC). Here, tamoxifen exerts its action through a mechanism that involves activation of the transcription factor EB (TFEB), a master gene of lysosomal function and autophagy. In vivo administration of tamoxifen to the CLN7Δex2 mouse model reduced the accumulation of Gb3 and SCMAS, decreased neuroinflammation, and improved motor coordination. These data strongly suggest that tamoxifen may be a suitable drug to treat some types of Batten disease.

Background: The aim of this study was to evaluate the impact of Surgical Unit volume on the 30-day reoperation rate in patients with CRC. Methods: Data were extracted from the regional Hospital Discharge Dataset and included patients who underwent elective resection for primary CRC in the Veneto Region (2005-2013). The primary outcome measure was any unplanned reoperation performed within 30 days from the index surgery. Independent variables were: age, gender, comorbidity, previous abdominal surgery, site and year of the resection, open/laparoscopic approach and yearly Surgical Unit volume for colorectal resections as a whole, and in detail for colonic, rectal and laparoscopic resections. Multilevel multivariate regression analysis was used to evaluate the impact of variables on the outcome measure. Results: During the study period, 21,797 elective primary colorectal resections were performed. The 30-day reoperation rate was 5.5 % and was not associated with Surgical Unit volume. In multivariate multilevel analysis, a statistically significant association was found between 30-day reoperation rate and rectal resection volume (intermediate-volume group OR 0.75; 95 % CI 0.56-0.99) and laparoscopic approach (high-volume group OR 0.69; 95 % CI 0.51-0.96). Conclusions: While Surgical Unit volume is not a predictor of 30-day reoperation after CRC resection, it is associated with an early return to the operating room for patients operated on for rectal cancer or with a laparoscopic approach. These findings suggest that quality improvement programmes or centralization of surgery may only be required for subgroups of CRC patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: While the total number of persons affected by hip fractures may be increasing over time in the next decades, due to the progressive aging of the population, incidence rates appear to be declining in most countries. The objective of this study is to describe annual hip fracture incidence rate trends in the Veneto Region, Italy, over a decade (2001–2010). Methods: All incident hip fractures in men and women above or aged 65years old using ICD-9 diagnosis codes 820–820.9 in the Hospital Discharge Database were identified. Crude, sex- and age-specific and standardized annual incidence rates were calculated. Results: The median age of patients has increased from 82 to 84years in the last decade. The absolute number of hip fractures increased by 21%. The age-standardized hip fracture incidence rate for men increased from 304 per 100,000person-years in 2001 to 319 in 2010. For women, incidence declined from 787 in 2001 to 751 in 2010. Hip fracture rates decreased through the study period in the 65–74 age group, especially among females. In the age group 75–84, there was a clear increase up to 2004, then a progressive decline in both genders. Among subjects aged 85years or older, incidence rates were stable in women and showed a non-statistically significant increase in men. Conclusion: The aging of the population, with a rapid increase concentrated particularly in the oldest old segment, implies that the overall number of hip fracture will continue to represent a major public health challenge to health and social systems. [Copyright &y& Elsevier]

Abstract Metabolite accumulation in lysosomal storage disorders (LSDs) results in impaired cell function and multi‐systemic disease. Although substrate reduction and lysosomal overload‐decreasing therapies can ameliorate disease progression, the significance of lysosomal overload‐independent mechanisms in the development of cellular dysfunction is unknown for most LSDs. Here, we identify a mechanism of impaired chaperone‐mediated autophagy (CMA) in cystinosis, a LSD caused by defects in the cystine transporter cystinosin (CTNS) and characterized by cystine lysosomal accumulation. We show that, different from other LSDs, autophagosome number is increased, but macroautophagic flux is not impaired in cystinosis while mTOR activity is not affected. Conversely, the expression and localization of the CMA receptor LAMP2A are abnormal in CTNS‐deficient cells and degradation of the CMA substrate GAPDH is defective in Ctns−/− mice. Importantly, cysteamine treatment, despite decreasing lysosomal overload, did not correct defective CMA in Ctns−/− mice or LAMP2A mislocalization in cystinotic cells, which was rescued by CTNS expression instead, suggesting that cystinosin is important for CMA activity. In conclusion, CMA impairment contributes to cell malfunction in cystinosis, highlighting the need for treatments complementary to current therapies that are based on decreasing lysosomal overload.