Boosting pro-vitamin A content and bioaccessibility in leaves by combining engineered biosynthesis and storage pathways with high-light treatments.

Biofortification of green leafy vegetables with pro-vitamin A carotenoids, such as ß-carotene, has remained challenging to date. Here, we combined two strategies to achieve this goal. One of them involves producing ß-carotene in the cytosol of leaf cells to avoid the negative impacts on photosynthesis derived from changing the balance of carotenoids and chlorophylls in chloroplasts. The second approach involves the conversion of chloroplasts into non-photosynthetic, carotenoid-overaccumulating chromoplasts in leaves agroinfiltrated or infected with constructs encoding the bacterial phytoene synthase crtB, leaving other non-engineered leaves of the plant to sustain normal growth. A combination of these two strategies, referred to as strategy C (for cytosolic production) and strategy P (for plastid conversion mediated by crtB), resulted in a 5-fold increase in the amount of ß-carotene in Nicotiana benthamiana leaves. Following several attempts to further improve ß-carotene leaf contents by metabolic engineering, hormone treatments and genetic screenings, it was found that promoting the proliferation of plastoglobules with increased light-intensity treatments not only improved ß-carotene accumulation but it also resulted in a much higher bioaccessibility. The combination of strategies C and P together with a more intense light treatment increased the levels of accessible ß-carotene 30-fold compared to controls. We further demonstrated that stimulating plastoglobule proliferation with strategy P, but also with a higher-light treatment alone, also improved ß-carotene contents and bioaccessibility in edible lettuce (Lactuca sativa) leaves.

Arabidopsis FIBRILLIN6 influences carotenoid biosynthesis by directly promoting phytoene synthase activity.

Carotenoids are health-promoting plastidial isoprenoids with essential functions in plants as photoprotectants and photosynthetic pigments in chloroplasts. They also accumulate in specialized plastids named chromoplasts, providing color to non-photosynthetic tissues such as flower petals and ripe fruit. Carotenoid accumulation in chromoplasts requires specialized structures and proteins such as fibrillins (FBNs). The FBN family includes structural components of carotenoid sequestering structures in chromoplasts and members with metabolic roles in chloroplasts and other plastid types. However, the association of FBNs with carotenoids in plastids other than chromoplasts has remained unexplored. Here, we show that Arabidopsis (Arabidopsis thaliana) FBN6 interacts with phytoene synthase (PSY), the first enzyme of the carotenoid pathway. FBN6, but not FBN4 (a FBN that does not interact with PSY), enhances the activity of plant PSY (but not of the bacterial PSY crtB) in Escherichia coli cells. Overexpression of FBN6 in Nicotiana benthamiana leaves results in a higher production of phytoene, the product of PSY activity, whereas loss of FBN6 activity in Arabidopsis mutants dramatically reduces the production of carotenoids during seedling de-etiolation and after exposure to high light. Our work hence demonstrates that FBNs promote not only the accumulation of carotenoids in chromoplasts but also their biosynthesis in chloroplasts.

Thinking small to win big? A critical review on the potential application of extracellular vesicles for biomarker discovery and new therapeutic approaches in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely deadly form of cancer, with limited progress in 5-year survival rates despite significant research efforts. The main challenges in treating PDAC include difficulties in early detection, and resistance to current therapeutic approaches due to aggressive molecular and microenvironment features. These challenges emphasize the importance of identifying clinically validated biomarkers for early detection and clinical management. Extracellular vesicles (EVs), particularly exosomes, have emerged as crucial mediators of intercellular communication by transporting molecular cargo. Recent research has unveiled their role in initiation, metastasis, and chemoresistance of PDAC. Consequently, utilizing EVs in liquid biopsies holds promise for the identification of biomarkers for early detection, prognosis, and monitoring of drug efficacy. However, numerous limitations, including challenges in isolation and characterization of homogeneous EVs populations, as well as the absence of standardized protocols, can affect the reliability of studies involving EVs as biomarkers, underscoring the necessity for a prudent approach. EVs have also garnered considerable attention as a promising drug delivery system and novel therapy for tumors. The loading of biomolecules or chemical drugs into exosomes and their subsequent delivery to target cells can effectively impede tumor progression. Nevertheless, there are obstacles that must be overcome to ensure the accuracy and efficacy of therapies relying on EVs for the treatment of tumors. In this review, we examine both recent advancements and remaining obstacles, exploring the potential of utilizing EVs in biomarker discovery as well as for the development of drug delivery vehicles.

Potential association between PSCA rs2976395 functional variant and pancreatic cancer risk.

Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single-nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV-SNPs and 133,615 CoRSIV-mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10-5). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan-meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association.

Photoprotective mechanisms in Elysia species hosting Acetabularia chloroplasts shed light on host-donor compatibility in photosynthetic sea slugs.

Sacoglossa sea slugs have garnered attention due to their ability to retain intracellular functional chloroplasts from algae, while degrading other algal cell components. While protective mechanisms that limit oxidative damage under excessive light are well documented in plants and algae, the photoprotective strategies employed by these photosynthetic sea slugs remain unresolved. Species within the genus Elysia are known to retain chloroplasts from various algal sources, but the extent to which the metabolic processes from the donor algae can be sustained by the sea slugs is unclear. By comparing responses to high-light conditions through kinetic analyses, molecular techniques, and biochemical assays, this study shows significant differences between two photosynthetic Elysia species with chloroplasts derived from the green alga Acetabularia acetabulum. Notably, Elysia timida displayed remarkable tolerance to high-light stress and sophisticated photoprotective mechanisms such as an active xanthophyll cycle, efficient D1 protein recycling, accumulation of heat-shock proteins and α-tocopherol. In contrast, Elysia crispata exhibited absence or limitations in these photoprotective strategies. Our findings emphasize the intricate relationship between the host animal and the stolen chloroplasts, highlighting different capacities to protect the photosynthetic organelle from oxidative damage.

Da Vinci single-port robotic system current application and future perspective in general surgery: A scoping review.

BACKGROUND: The da Vinci Single-Port Robot System (DVSP) allows three robotic instruments and an articulated scope to be inserted through a single small incision. It received FDA approval in 2014 and was first introduced in 2018. The aim of this new system was to overcome the limitations of single-incision laparoscopic and robotic surgery. Since then, it has been approved for use only for urologic and transoral surgeries in some countries. It has been used as part of experimental protocols in general surgery. OBJECTIVE: By obtaining the CE mark at the end of January 2024, DVSP will soon enter the European market. This review aims to comprehensively describe the applications of DVSP in general surgery. DESIGN: A search of PubMed, Embase, and Ebsco databases up to March 2024 was conducted, with registration in PROSPERO (CRD42024536430), following the preferred reporting items for Systematic reviews and Meta-analyses for scoping review (PRISMA-Scr) guidelines. All the studies about the use of DVSP in general surgery were included. RESULTS: Fifty-six studies were included. The following surgical areas of use were identified: transabdominal and transanal colorectal, cholecystectomy, abdominal wall repair, upper gastroesophageal tract, liver, pancreas, breast, and thyroid surgery. The reported surgical and short-term outcomes are promising; a wide range of procedures have been performed safely. Some groups have found advantages, such as faster discharge, shorter operative time, and less postoperative pain compared to multiport robotic surgery. CONCLUSION: Five years after its initial clinical applications, the use of the DVSP in general surgery procedures has demonstrated feasibility and safety. Hernia repair, cholecystectomy, and colorectal surgery emerge as the most frequently conducted interventions with this robotic system. Nevertheless, there is anticipation for further studies with larger sample sizes and extended follow-up periods to provide more comprehensive insights and data on the long-term outcomes, including the incidence of incisional hernia.

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma.

INTRODUCTION: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. MATERIALS AND METHODS: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. RESULTS: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10-8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1. CONCLUSION: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.

Fashioning esophagogastric anastomosis in robotic Ivor-Lewis esophagectomy: a multicenter experience.

BACKGROUND: The aim of the present study is to compare outcomes of the robotic hand-sewn, linear- and circular-stapled techniques performed to create an intrathoracic esophagogastric anastomosis in patients who underwent Ivor-Lewis esophagectomy. METHODS: Patients who underwent a planned Ivor-Lewis esophagectomy were retrospectively analysed from prospectively maintained databases. Only patients who underwent a robotic thoracic approach with the creation of an intrathoracic esophagogastric anastomosis were included in the study. Patients were divided into three groups: hand-sewn-, circular stapled-, and linear-stapled anastomosis group. Demographic information and surgery-related data were extracted. The primary outcome was the rate of anastomotic leakages (AL) in the three groups. Moreover, the rate of grade A, B and C anastomotic leakage were evaluated. In addition, patients of each group were divided in subgroups according to the characteristics of anastomotic fashioning technique. RESULTS: Two hundred and thirty patients were enrolled in the study. No significant differences were found between the three groups about AL rate (p = 0.137). Considering the management of the AL for each of the three groups, no significant differences were found. Evaluating the correlation between AL rate and the characteristics of anastomotic fashioning technique, no significant differences were found. CONCLUSIONS: No standardized anastomotic fashioning technique has yet been generally accepted. This study could be considered a call to perform ad hoc high-quality studies involving high-volume centers for upper gastrointestinal surgery to evaluate what is the most advantageous anastomotic technique.

Conversion to open surgery in obese patients undergoing minimally invasive distal pancreatectomy: results from a multicenter analysis.

BACKGROUND: Although minimally invasive distal pancreatectomy (MIDP) is considered a standard approach it still presents a non-negligible rate of conversion to open that is mainly related to some difficulty factors, as obesity. The aim of this study is to analyze the preoperative factors associated with conversion in obese patients with MIDP. METHODS: In this multicenter study, all obese patients who underwent MIDP at 18 international expert centers were included. The preoperative factors associated with conversion to open surgery were analyzed. RESULTS: Out of 436 patients, 91 (20.9%) underwent conversion to open, presenting higher blood loss, longer operative time and similar rate of major complications. Twenty (22%) patients received emergent conversion. At univariate analysis, the type of approach, radiological invasion of adjacent organs, preoperative enlarged lymphnodes and ASA ≥ III were significantly associated with conversion to open. At multivariate analysis, robotic approach showed a significantly lower conversion rate (14.6 % vs 27.3%, OR = 2.380, p = 0.001). ASA ≥ III (OR = 2.391, p = 0.002) and preoperative enlarged lymphnodes (OR = 3.836, p = 0.003) were also independently associated with conversion. CONCLUSION: Conversion rate is significantly lower in patients undergoing robotic approach. Radiological enlarged lymphnodes and ASA ≥ III are also associated with conversion to open. Conversion is associated with poorer perioperative outcomes, especially in case of intraoperative hemorrhage.

Lactate Dehydrogenase and its clinical significance in pancreatic and thoracic cancers.

The energy metabolism of tumor cells is considered one of the hallmarks of cancer because it is different from normal cells and mainly consists of aerobic glycolysis, fatty acid oxidation, and glutaminolysis. It is about one hundred years ago since Warburg observed that cancer cells prefer aerobic glycolysis even in normoxic conditions, favoring their high proliferation rate. A pivotal enzyme driving this phenomenon is lactate dehydrogenase (LDH), and this review describes prognostic and therapeutic opportunities associated with this enzyme, focussing on tumors with limited therapeutic strategies and life expectancy (i.e., pancreatic and thoracic cancers). Expression levels of LDH-A in pancreatic cancer tissues correlate with clinicopathological features: LDH-A is overexpressed during pancreatic carcinogenesis and showed significantly higher expression in more aggressive tumors. Similarly, LDH levels are a marker of negative prognosis in patients with both adenocarcinoma or squamous cell lung carcinoma, as well as in malignant pleural mesothelioma. Additionally, serum LDH levels may play a key role in the clinical management of these diseases because they are associated with tissue damage induced by tumor burden. Lastly, we discuss the promising results of strategies targeting LDH as a treatment strategy, reporting recent preclinical and translational studies supporting the use of LDH-inhibitors in combinations with current/novel chemotherapeutics that can synergistically target the oxygenated cells present in the tumor.

A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma.

Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.

Association between a polymorphic variant in the CDKN2B-AS1/ANRIL gene and pancreatic cancer risk.

Genes carrying high-penetrance germline mutations may also be associated with cancer susceptibility through common low-penetrance genetic variants. To increase the knowledge on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability of PDAC familial genes was analysed in our study. We conducted a multiphase study analysing 7745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour a high-penetrance PDAC-associated mutation in at least one published study. To assess the effect of the SNPs on PDAC risk, a total of 14 666 PDAC cases and 221 897 controls across five different studies were analysed. The T allele of the rs1412832 polymorphism, that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association with increased risk of developing PDAC (OR = 1.11, 95% CI = 1.07-1.15, P = 5.25 × 10-9 ). CDKN2B-AS1/ANRIL is a long noncoding RNA, situated in 9p21.3, and regulates many target genes, among which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations and deregulation in PDAC. Our results strongly support the role of the genetic variability of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary analysis as a tool for discovering new risk loci in complex human diseases.

Novel insights into the contribution of plastoglobules and reactive oxygen species to chromoplast differentiation.

Plant tissues can be enriched in phytonutrients not only by stimulating their biosynthesis but also by providing appropriate sink structures for their sequestering and storage. In the case of carotenoids, they accumulate at high levels in chromoplasts naturally found in flowers and fruit. Chromoplasts can also be artificially differentiated from leaf chloroplasts by boosting carotenoid production with the bacterial protein crtB. Here we used electron and confocal microscopy together with subplastidial fractionation and transcript, protein and metabolite analyses to analyze the structural and biochemical changes occurring in crtB-induced artificial chromoplasts and their impact on the accumulation of health-related isoprenoids. We show that leaf chromoplasts develop plastoglobules (PG) harboring high levels of carotenoids (mainly phytoene and pro-vitamin A ß-carotene) but also other nutritionally relevant isoprenoids, such as tocopherols (vitamin E) and phylloquinone (vitamin K1). Further promoting PG proliferation by exposure to intense (high) light resulted in a higher accumulation of these health-related metabolites but also an acceleration of the chloroplast-to-chromoplast conversion. We further show that the production of reactive oxygen species (ROS) stimulates chromoplastogenesis. Our data suggest that carotenoid accumulation and ROS production are not just consequences but promoters of the chromoplast differentiation process.

Initial 50 consecutive full-robotic pancreatoduodenectomies without conversion by a single surgeon: a learning curve analysis from a tertiary referral high-volume center.

BACKGROUND: Several studies report on a learning curve for robotic pancreatoduodenectomy (R-PD) ranging between 20 and 80 operations, with conversion rates varying between 1.1 and 35%. However, as these publications mostly refer to initial robotic experiences and do not take into account the previous surgical background in pancreatic surgery (PS) and in robotic-assisted surgery (RAS), the center's volume, as well as the platform used, we aimed to perform a surgical outcomes analysis with a particular view to these aspects. METHODS: Intraoperative and perioperative outcomes of the first 50 consecutive R-PD performed with the da Vinci Xi by the same surgeon, within a tertiary referral high-volume center, between January 2018 and March 2022, were analyzed. The surgeon was previously experienced in both PS and RAS. Shewhart control chart and cumulative sum (CUSUM) analysis were used to evaluate the learning curve of R-PD. RESULTS: All the operations were performed with a full-robotic technique, without any conversion to open surgery. Twenty of 50 patients (40%) had a BMI ≥ 25 kg/m2, while 24/50 (48%) had undergone previous abdominal surgery. Mean console time was 276.30 ± 31.16 min. The median post-operative length of hospital stay was 10 days, while 20/50 (40%) patients were discharged within post-operative day 8. Six patients (12%) had major complications (Clavien-Dindo grade 3 or above). There was no 30-day mortality. Shewhart control chart and CUSUM analysis did not show a significant learning curve during the study period. CONCLUSIONS: An extensive prior experience in both PS and RAS, within a tertiary referral high-volume center with availability of the da Vinci Xi platform, can significantly flatten the learning curve and, therefore, enable safe performance of challenging operations, i.e., pancreatoduodenectomies with a minimally invasive approach, with very low risk of conversion to open surgery, even in the first 50 operations.

Robotic versus laparoscopic distal pancreatectomy in obese patients.

BACKGROUND: Although robotic distal pancreatectomy (RDP) has a lower conversion rate to open surgery and causes less blood loss than laparoscopic distal pancreatectomy (LDP), clear evidence on the impact of the surgical approach on morbidity is lacking. Prior studies have shown a higher rate of complications among obese patients undergoing pancreatectomy. The primary aim of this study is to compare short-term outcomes of RDP vs. LDP in patients with a BMI ≥ 30. METHODS: In this multicenter study, all obese patients who underwent RDP or LDP for any indication between 2012 and 2022 at 18 international expert centers were included. The baseline characteristics underwent inverse probability treatment weighting to minimize allocation bias. RESULTS: Of 446 patients, 219 (50.2%) patients underwent RDP. The median age was 60 years, the median BMI was 33 (31-36), and the preoperative diagnosis was ductal adenocarcinoma in 21% of cases. The conversion rate was 19.9%, the overall complication rate was 57.8%, and the 90-day mortality rate was 0.7% (3 patients). RDP was associated with a lower complication rate (OR 0.68, 95% CI 0.52-0.89; p = 0.005), less blood loss (150 vs. 200 ml; p < 0.001), fewer blood transfusion requirements (OR 0.28, 95% CI 0.15-0.50; p < 0.001) and a lower Comprehensive Complications Index (8.7 vs. 8.9, p < 0.001) than LPD. RPD had a lower conversion rate (OR 0.27, 95% CI 0.19-0.39; p < 0.001) and achieved better spleen preservation rate (OR 1.96, 95% CI 1.13-3.39; p = 0.016) than LPD. CONCLUSIONS: In obese patients, RDP is associated with a lower conversion rate, fewer complications and better short-term outcomes than LPD.

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians.

BACKGROUND: The genomes of present-day non-Africans are composed of 1-3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50-60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations. RESULTS: The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19-1.54, P = 3.59 × 10-6), with a P-value close to a threshold that takes into account multiple testing. CONCLUSIONS: Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.

Synthetic conversion of leaf chloroplasts into carotenoid-rich plastids reveals mechanistic basis of natural chromoplast development.

Plastids, the defining organelles of plant cells, undergo physiological and morphological changes to fulfill distinct biological functions. In particular, the differentiation of chloroplasts into chromoplasts results in an enhanced storage capacity for carotenoids with industrial and nutritional value such as beta-carotene (provitamin A). Here, we show that synthetically inducing a burst in the production of phytoene, the first committed intermediate of the carotenoid pathway, elicits an artificial chloroplast-to-chromoplast differentiation in leaves. Phytoene overproduction initially interferes with photosynthesis, acting as a metabolic threshold switch mechanism that weakens chloroplast identity. In a second stage, phytoene conversion into downstream carotenoids is required for the differentiation of chromoplasts, a process that involves a concurrent reprogramming of nuclear gene expression and plastid morphology for improved carotenoid storage. We hence demonstrate that loss of photosynthetic competence and enhanced production of carotenoids are not just consequences but requirements for chloroplasts to differentiate into chromoplasts.

Late complications of cochlear implant: a case report of necrotizing meningoencephalitis similar to a CPA tumor.

OBJECTIVE: Report a case of localized necrotizing meningoencephalitis as the cause of functional hearing loss after cochlear implant (CI) surgery. CASE REPORT: A 12-year-old with bilateral CI presented to our quaternary center due to severe functional hearing loss after 11 years since left ear CI surgery. CT with contrast was conducted showing a CPA tumor-like mass. Pre-operative computed tomography (CT) scans and magnetic resonance imaging (MRI) performed at the age of 1 year showed no inner ear abnormalities and in particular no evidence of a tumor in the cerebellopontine angle (CPA). CONCLUSION: Following removal of the CI and the mass, histopathological, immunohistochemical and cultural examinations revealed a necrotizing meningoencephalitis, with the CI electrode as the focus.

Surgical treatment of recurrent retroperitoneal sarcoma in its different patterns: A 15-years' two-centers experience.

INTRODUCTION: There is limited data available regarding the role of surgery in the treatment of retroperitoneal sarcoma (RPS) recurrences. We herein report the short- and mid-term outcomes of patients who underwent surgical treatment of RPS recurrences at two Italian centers over a 15-years' experience. MATERIALS AND METHODS: From January 2005 to January 2020, 33 patients underwent surgical treatment of isolated locally recurrent RPS (LR group), locally recurrent RPS associated with the presence of distant recurrence (LR + DM group), and distant-only recurrent RPS (DM group). Only procedures performed to obtain a macroscopically radical treatment with curative intent were included. Data regarding pre-, intra-, post-operative course, and follow-up, collected in an Institutional database, were retrospectively analyzed, and compared. RESULTS: LR-group was composed of 15 patients, LR + DM group of 9 patients, and DM group of 9 patients. During the follow-up, 78.5% of the LR group, 77.8% of the DM group and 100% of the LR + DM group (p = 0.244) experienced a second recurrence. 7/11 (63.6%) patients in the LR group, 2/7 (28.5%) patients in the DM-group, and 0/9 (0.0%) patients in the LR + DM group underwent to almost one further local treatments of their recurrences (p = 0.010). No differences in the mean disease-free survival (p = 0.127), overall survival (OS) (p = 0.165) was reported among the three groups. Repeated surgery was an independent factor affecting survival in multivariate analysis (p = 0.01). CONCLUSIONS: A surgical treatment of RPS recurrences should always be taken into consideration, also in metastatic patients and/or in those who have already undergone surgery for previous RPS recurrence, because this approach may offer survival benefits.

A polymorphic variant in telomere maintenance is associated with worrisome features and high-risk stigmata development in IPMNs.

Intraductal papillary mucinous neoplasms (IPMNs) are nonobligatory precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The identification of molecular biomarkers able to predict the risk of progression of IPMNs toward malignancy is largely lacking and sorely needed. Telomere length (TL) is associated with the susceptibility of developing cancers, including PDAC. Moreover, several PDAC risk factors have been shown to be associated with IPMN transition to malignancy. TL is genetically determined, and the aim of this study was to use 11 SNPs, alone or combined in a score (teloscore), to estimate the causal relation between genetically determined TL and IPMNs progression. For this purpose, 173 IPMN patients under surveillance were investigated. The teloscore did not show any correlation, however, we observed an association between PXK-rs6772228-A and an increased risk of IPMN transition to malignancy (HR = 3.17; 95%CI 1.47-6.84; P = 3.24 × 10-3). This effect was also observed in a validation cohort of 142 IPMNs even though the association was not statistically significant. The combined analysis was consistent showing an association between PXK-rs6772228-A and increased risk of progression. The A allele of this SNP is strongly associated with shorter LTL that in turn have been reported to be associated with increased risk of developing PDAC. These results clearly highlight the importance of looking for genetic variants as potential biomarkers in this setting in order to further our understanding the etiopathogenesis of PDAC and suggest that genetically determined TL might be an additional marker of IPMN prognosis.