Claudio Luchini

Inflammation and frailty in the elderly: A systematic review and meta-analysis

The pathogenesis of frailty and the role of inflammation is poorly understood. We examined the evidence considering the relationship between inflammation and frailty through a systematic review and meta-analysis. A systematic literature search of papers providing data on inflammatory biomarkers and frailty was carried out in major electronic databases from inception until May 2016. From 1856 initial hits, 35 studies (32 cross-sectional studies n=3232 frail, n=11,483 pre-frail and n=8522 robust, and 563 pre-frail+robust; 3 longitudinal studies n=3402 participants without frailty at baseline) were meta-analyzed. Cross-sectional studies reported that compared to 6757 robust participants, both 1698 frail (SMD=1.00, 95%CI: 0.40-1.61) and 8568 pre-frail (SMD=0.33, 95%CI: 0.04-0.62) participants had significantly higher levels of C-reactive protein (CRP). Frailty (n=1057; SMD=1.12, 95%CI: 0.27-2.13) and pre-frailty (n=4467; SMD=0.56, 95%CI: 0.00-1.11) were associated with higher serum levels of interleukin-6 compared to people who were robust (n=2392). Frailty and pre-frailty were also significantly associated with elevated white blood cell and fibrinogen levels. In three longitudinal studies, higher serum CRP (OR=1.06, 95%CI: 0.78-1.44,) and IL-6 (OR=1.19, 95%CI: 0.87-1.62) were not associated with frailty. In conclusion, frailty and pre-frailty are associated with higher inflammatory parameters and in particular CRP and IL-6. Further longitudinal studies are needed.

ReviewInflammation and frailty in the elderly: A systematic review and meta-analysis

The pathogenesis of frailty and the role of inflammation is poorly understood. We examined the evidence considering the relationship between inflammation and frailty through a systematic review and meta-analysis. A systematic literature search of papers providing data on inflammatory biomarkers and frailty was carried out in major electronic databases from inception until May 2016. From 1856 initial hits, 35 studies (32 cross-sectional studies n=3232 frail, n=11,483 pre-frail and n=8522 robust, and 563 pre-frail+robust; 3 longitudinal studies n=3402 participants without frailty at baseline) were meta-analyzed. Cross-sectional studies reported that compared to 6757 robust participants, both 1698 frail (SMD=1.00, 95%CI: 0.40-1.61) and 8568 pre-frail (SMD=0.33, 95%CI: 0.04-0.62) participants had significantly higher levels of C-reactive protein (CRP). Frailty (n=1057; SMD=1.12, 95%CI: 0.27-2.13) and pre-frailty (n=4467; SMD=0.56, 95%CI: 0.00-1.11) were associated with higher serum levels of interleukin-6 compared to people who were robust (n=2392). Frailty and pre-frailty were also significantly associated with elevated white blood cell and fibrinogen levels. In three longitudinal studies, higher serum CRP (OR=1.06, 95%CI: 0.78-1.44,) and IL-6 (OR=1.19, 95%CI: 0.87-1.62) were not associated with frailty. In conclusion, frailty and pre-frailty are associated with higher inflammatory parameters and in particular CRP and IL-6. Further longitudinal studies are needed.

Inflammation and sarcopenia: A systematic review and meta-analysis

Inflammatory cytokines have been shown to prompt muscle wasting, ultimately stimulating protein catabolism and suppressing muscle synthesis. However, the possible association between inflammatory parameters and sarcopenia is poorly understood. We therefore aimed to summarize the current evidence about this topic with a meta-analysis of studies reporting serum inflammatory parameters in patients with sarcopenia vs. people without sarcopenia (controls). An electronic PubMed and Scopus search through to 09/01/2016 and meta-analysis of cross-sectional studies comparing serum levels of inflammatory cytokines between patients with sarcopenia and controls was made, calculating random-effects standardized mean differences (SMDs) ±95% confidence intervals (CIs) as the effect size. Out of 1370 initial hits, 17 studies with a total of 11249 participants (3072 with sarcopenia and 8177 without) were meta-analyzed. Sarcopenic participants had significantly higher levels of CRP (SMD=0.51; 95%CI 0.26, 0.77; p<0.0001; I2=96%) than controls. Conversely, serum IL6 levels were not significantly different (SMD=0.35; 95%CI: -0.19, 0.89; p=0.21; I2=97%) in people with sarcopenia versus controls. Sarcopenic people did not have higher levels of TNF-α than controls (SMD=0.28; 95%CI -0.26, 0.83; p=0.31; I2=97%). In conclusion, sarcopenia seems to be associated with elevated serum CRP levels; future longitudinal studies are needed to clarify this relationship.

Prognostic impact and implications of extracapsular lymph node involvement in colorectal cancer: a systematic review with meta-analysis

BACKGROUND The extranodal extension (ENE) of nodal metastasis (i.e. the extension of tumor cells through the nodal capsule into the perinodal adipose tissue) has recently emerged as an important prognostic factor in different types of malignancies. However, the tumor-node-metastasis (TNM) staging system for colorectal cancer does not consider it as a prognostic parameter. Therefore, we conducted a systematic review and meta-analysis to determine the prognostic role of ENE in patients with lymph node-positive colorectal cancer. MATERIALS AND METHODS Two independent authors searched PubMed and SCOPUS until 7 January 2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with colorectal cancer, comparing participants with the presence of ENE (ENE+) versus only intranodal extension (ENE-) were eligible. Data were summarized using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) together with 95% confidence intervals (CIs) for time-dependent risk related to ENE+, adjusted for potential confounders. RESULTS Thirteen studies including 1336 patients were identified with a median follow-up of 4.7 years. ENE was associated with a higher T stage and tumor grading. In addition, ENE was associated with a significantly increased risk of all-cause mortality (RR = 1.75; 95% CI 1.42-2.16, P < 0.0001, I(2) = 60%; HR = 1.69, 95% CI 1.32-2.17, P < 0.0001, I(2) = 46%) and of recurrence of disease (RR = 2.07, 95% CI 1.65-2.61, P < 0.0001, I(2) = 47%; HR = 2.31, 95% CI 1.54-3.44, P < 0.0001, I(2) = 48%). CONCLUSIONS Based of these results, in colorectal cancer, ENE should be considered from the gross sampling to the pathology report, as well as in future oncologic staging systems.

Bone mineral density, osteoporosis, and fractures among people with eating disorders: a systematic review and meta-analysis

To provide meta‐analytical evidence of bone mineral density (BMD), fractures, and osteoporosis rates in eating disorders (ED) vs. healthy controls (HCs).

Targeted DNA Sequencing Reveals Patterns of Local Progression in the Pancreatic Remnant Following Resection of Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas

Objective: The aim of this study was to characterize patterns of local progression following resection for pancreatic intraductal papillary mucinous neoplasms (IPMN) using targeted next-generation sequencing (NGS). Background: Progression of neoplastic disease in the remnant pancreas following resection of IPMN may include development of a new IPMN or ductal adenocarcinoma (PDAC). However, it is not clear whether this progression represents recurrence of the same neoplasm or an independent second neoplasm. Methods: Targeted-NGS on genes commonly mutated in IPMN and PDAC was performed on tumors from (1) 13 patients who developed disease progression in the remnant pancreas following resection of IPMN; and (2) 10 patients who underwent a resection for PDAC and had a concomitant IPMN. Mutations in the tumors were compared in order to determine the relationship between neoplasms. In parallel, clinical and pathological characteristics of 260 patients who underwent resection of noninvasive IPMN were reviewed to identify risk factors associated with local progression. Results: We identified 3 mechanisms underlying local progression in the remnant pancreas: (1) residual microscopic disease at the resection margin, (2) intraparenchymal spread of neoplastic cells, leading to an anatomically separate but genetically related recurrence, and (3) multifocal disease with genetically distinct lesions. Analysis of the 260 patients with noninvasive IPMNs showed that family history of pancreatic cancer (P = 0.027) and high-grade dysplasia (HGD) (P = 0.003) were independent risk factors for the development of an IPMN with HGD or an invasive carcinoma in the remnant pancreas. Conclusions: Using NGS, we identify distinct mechanisms for development of metachronous or synchronous neoplasms in patients with IPMN. Patients with a primary IPMN with HGD or with positive family history are at an increased risk to develop subsequent high-risk neoplasms in the remnant pancreas.

Prognostic role and implications of mutation status of tumor suppressor gene ARID1A in cancer: a systematic review and meta-analysis

Loss of the tumor suppressor gene AT-rich interactive domain-containing protein 1A (ARID1A) has been demonstrated in several cancers, but its prognostic role is unknown. We aimed to investigate the risk associated with loss of ARID1A (ARID1A−) for all-cause mortality, cancer-specific mortality and recurrence of disease in subjects with cancer. PubMed and SCOPUS search from database inception until 01/31/2015 without language restriction was conducted, contacting authors for unpublished data. Eligible were prospective studies reporting data on prognostic parameters in subjects with cancer, comparing participants with presence of ARID1A (ARID1A+) vs. ARID1A−, assessed either via immunohistochemistry (loss of expression) or with genetic testing (presence of mutation). Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) for time-dependent risk related to ARID1A− adjusted for potential confounders. Of 136 hits, 25 studies with 5,651 participants (28 cohorts; ARID1A−: n = 1,701; ARID1A+: n = 3,950), with a mean follow-up period of 4.7 ± 1.8 years, were meta-analyzed. Compared to ARID1A+, ARID1A− significantly increased cancer-specific mortality (studies = 3; RR = 1.55, 95% confidence interval (CI) = 1.19–2.00, I2 = 31%). Using HRs adjusted for potential confounders, ARID1A− was associated with a greater risk of cancer-specific mortality (studies = 2; HR = 2.55, 95%CI = 1.19–5.45, I2 = 19%) and cancer recurrence (studies = 10; HR = 1.93, 95%CI = 1.22–3.05, I2 = 76%). On the basis of these results, we have demonstrated that loss of ARID1A shortened time to cancer-specific mortality, and to recurrence of cancer when adjusting for potential confounders. For its role, this gene should be considered as an important potential target for personalized medicine in cancer treatment.

Prognostic implications of extranodal extension in node-positive squamous cell carcinoma of the vulva: A systematic review and meta-analysis

Squamous cell carcinoma (SCC) of the vulva is the fourth most common gynecological cancer, usually staged with the TNM or FIGO systems. Since 2009, FIGO staging has taken the extranodal extension (ENE) of lymph node metastases into account. ENE is defined as the spread of a lymph node metastasis into surrounding soft tissue. Although the TNM and FIGO systems acknowledge the importance of ENE in SCC, no comprehensive studies have analyzed the prognostic impact of this parameter. We therefore queried the PubMed and SCOPUS databases from their inception up until 04/01/2015, adopting no language restrictions: all prospective studies reporting on prognostic parameters in patients with vulvar SCC, and comparing participants with and without ENE were eligible for our analysis. Data were summarized using risk ratios (RR) for the number of deaths/recurrences and hazard ratios (HR) for the time-dependent risk related to ENE positivity, adjusting for potential confounders. Among 859 hits, 13 studies were found eligible and were included in our meta-analysis. Compared with ENE-negative (ENE-) cases, the ENE-positive (ENE+) patients had significantly higher rates of all-cause mortality (6 studies: RR = 3.18; 95%CI: 2.02-5.00, p < 0.0001, I(2) = 56%), cancer-specific mortality (3 studies: RR = 2.03; 95%CI: 1.12-3.69, p = 0.02, I(2) = 80%), and recurrence (4 studies: RR = 2.69, 95%CI: 1.61-3.76, p < 0.0001, I(2) = 57%). Using HRs after adjusting for potential confounders, ENE + carried a significantly higher risk of all-cause mortality (6 studies: HR = 3.08, 95%CI: 1.73-5.48, p < 0.0001, I(2) = 66%), and recurrence (5 studies: HR = 3.93, 95%CI: 2.33-6.62, p < 0.0001, I(2) = 28%). Our meta-analysis clarifies the prognostic significance of ENE in vulvar SCC, also pointing to its implications for gross sampling, histology and oncological staging.

Osteoarthritis and mortality: A prospective cohort study and systematic review with meta-analysis

OBJECTIVES Osteoarthritis (OA) is a leading cause of disability, but the relationship with premature mortality remains uncertain. We aimed to investigate the relationship between OA and mortality from any cause and from cardiovascular disease (CVD). METHODS Electronic literature databases searches were conducted to identify prospective studies comparing mortality in a sample of people with and without OA. Risk of all-cause and CVD mortality were summarized using adjusted hazard ratios (HRs) for joint specific (hand, hip, and knee) and joint non-specific OA. New data from the Progetto Veneto Anziani (PRO.V.A.) study were also included. RESULTS From the PRO.V.A. study (N = 2927), there was no significant increase in mortality risk for participants with any joint OA (N = 1858) compared to non-OA (all-cause, HR = 0.95, 95% CI: 0.77-1.15 and CVD, HR = 1.12, 95% CI: 0.82-1.54). On meta-analysis, seven studies (OA = 10,018/non-OA = 18,541), with a median 12-year follow-up, reported no increased risk of any-cause mortality in those with OA (HR = 1.10, 95% CI: 0.97-1.25). After removing data on hand OA, a significant association between OA and mortality was observed (HR = 1.18, 95% CI: 1.08-1.28). There was a significant higher risk of overall mortality for (1) studies conducted in Europe, (2) patients with multi-joint OA; and (3) a radiological diagnosis of OA. OA was associated with significantly higher CVD mortality (HR = 1.21, 95% CI: 1.10-1.34). CONCLUSIONS People with OA are at increased risk of death due to CVD. The relationship with overall mortality is less clear and may be moderated by the presence of hand OA.

Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma

Ampullary carcinomas are highly malignant neoplasms that can have either intestinal or pancreatobiliary differentiation. To characterize somatic alterations in ampullary carcinomas, we performed whole-exome sequencing and DNA copy-number analysis on 60 ampullary carcinomas resected from clinically well-characterized Japanese and American patients. We next selected 92 genes and performed targeted sequencing to validate significantly mutated genes in an additional 112 cancers. The prevalence of driver gene mutations in carcinomas with the intestinal phenotype is different from those with the pancreatobiliary phenotype. We identified a characteristic significantly mutated driver gene (ELF3) as well as previously known driver genes (TP53, KRAS, APC, and others). Functional studies demonstrated that ELF3 silencing in normal human epithelial cells enhances their motility and invasion.