Detection of somatic and germline pathogenic variants in adult cohort of drug-resistant focal epilepsies.

OBJECTIVE: This study investigates the prevalence of pathogenic variants in the mechanistic target of rapamycin (mTOR) pathway in surgical specimens of malformations of cortical development (MCDs) and cases with negative histology. The study also aims to evaluate the predictive value of genotype-histotype findings on the surgical outcome. METHODS: The study included patients with drug-resistant focal epilepsy who underwent epilepsy surgery. Cases were selected based on histopathological diagnosis, focusing on MCDs and negative findings. We included brain tissues both as formalin-fixed, paraffin-embedded (FFPE) or fresh frozen (FF) samples. Single-molecule molecular inversion probes (smMIPs) analysis was conducted, targeting the MTOR gene in FFPE samples and 10 genes within the mTOR pathway in FF samples. Correlations between genotype-histotype and surgical outcome were examined. RESULTS: We included 78 patients for whom we obtained 28 FFPE samples and 50 FF tissues. Seventeen pathogenic variants (22 %) were identified and validated, with 13 being somatic within the MTOR gene and 4 germlines (2 DEPDC5, 1 TSC1, 1 TSC2). Pathogenic variants in mTOR pathway genes were exclusively found in FCDII and TSC cases, with a significant association between FCD type IIb and MTOR genotype (P = 0.003). Patients carrying mutations had a slightly better surgical outcome than the overall cohort, however it results not significant. The FCDII diagnosed cases more frequently had normal neuropsychological test, a higher incidence of auras, fewer multiple seizure types, lower occurrence of seizures with awareness impairment, less ictal automatisms, fewer Stereo-EEG investigations, and a longer period long-life of seizure freedom before surgery. SIGNIFICANCE: This study confirms that somatic MTOR variants represent the primary genetic alteration detected in brain specimens from FCDII/TSC cases, while germline DEPDC5, TSC1/TSC2 variants are relatively rare. Systematic screening for these mutations in surgically treated patients' brain specimens can aid histopathological diagnoses and serve as a biomarker for positive surgical outcomes. Certain clinical features associated with pathogenic variants in mTOR pathway genes may suggest a genetic etiology in FCDII patients.

Resistance to osimertinib in advanced EGFR-mutated NSCLC: a prospective study of molecular genotyping on tissue and liquid biopsies.

BACKGROUND: Resistance to osimertinib in advanced EGFR-mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent therapeutic implications. METHODS: This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR-mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed. RESULTS: Sixty-five advanced EGFR-mutated NSCLC patients treated with osimertinib in first- (n = 56) or in second-line (n = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification (n = 8), EGFR C797S (n = 3), and SCLC transformation (n = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively. CONCLUSIONS: Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.

Open left thoracoabdominal esophagectomy a viable option in the era of minimally invasive esophagectomy.

Minimally invasive surgical technique has become standard at many institutions in esophageal cancer surgery. In some situations, however other surgical approaches are required. Left thoracoabdominal esophagectomy (LTE) facilitates complete resection of esophageal cancer particularly for bulky distal esophageal tumors, but there are concerns that this approach is associated with significant morbidity. Prospectively entered esophagectomy databases from three high-volume centers were reviewed for patients undergoing LTE or MIE 2009-2019. Patient demographics, tumor characteristics, operative outcomes, postoperative outcomes, and pathologic surrogates of oncologic efficacy (R0 resection rate, and number of resected lymph nodes) were compared. In total 915 patients were included in the study, LTE was applied in 684 (74.8%) patients, and MIE in 231 (25.2%) patients. LTE patients had more locally advanced tumor stage and received more neoadjuvant treatment. Patients treated with MIE had more comorbidities. The results showed no difference in overall postoperative complications (LTE = 61.7%, MIE = 65.7%, P = 0.289), severe complications (Clavien-Dindo ≥IIIa (LTE = 25.9%, MIE 26.8%, P = 0.806)), pneumonia (LTE = 29.0%, MIE = 24.7%, P = 0.211), anastomotic leak (LTE = 7.8%, MIE = 11.3%, P = 0.101), or in-hospital mortality (LTE = 2.6%, MIE = 3.5%, P = 0.511). Median number of resected lymph nodes was 24 for LTE and 25 for MIE (P = 0.491). LTE was used for more advanced tumors in patients that were more likely to have received neoadjuvant treatment compared with MIE, however postoperative morbidity, mortality, and oncologic outcomes were equivalent to that of MIE in this cohort. In conclusion open resection with left thoracoabdominal approach is a valid option in selected patients when performed at high-volume esophagectomy centers.

Age, Blasts, Performance Status and Lenalidomide Therapy Influence the Outcome of Myelodysplastic Syndrome With Isolated Del(5q): A Study of 58 South American Patients.

BACKGROUND: Myelodysplastic Syndrome (MDS) with isolated deletion 5q is associated with a low risk to leukemic evolution and long overall survival (OS); it comprises 3%-4.5% of MDS cases in Latin America classified according to the World Health Organization 2008. This study aims to describe clinical, laboratory and the outcome of patients according to the newest World Health Organization 2016 proposal. METHODS: We retrospectively reviewed patients from four Brazilian (BR) and four Argentinean (AR) centers diagnosed between 1999 and 2019. RESULTS: The 58 patients (16-AR and 42-BR) presented a median age of 67 (IQR 61-75) years old, women predominance (70.7%) and transfusion dependency (62.5%) at diagnosis. Median hemoglobin level was 8.1g/dL, 27.5% and 44.4% presented thrombocytosis and neutropenia, respectively. Bone marrow (BM) was predominantly hypercellular (43.1%) with 66% showing dysplasia >1 lineage and 37.9% with >2% of blasts. Deletion 5q was mostly isolated (79.3%) and a variety of abnormalities were observed in remaining cases. Most patients were treated with erythropoietin-stimulating agents (ESA), 18 with lenalidomide and 15 with thalidomide. Median follow-up was 7.6 years, with a median OS of 3.5 years and an 8-years leukemic evolution rate of 18.4%. Multivariate analysis showed that age >75 years (HR 2.19), ECOG ≥2 (HR 5.76), BM blasts >2% (HR 2.92) and lenalidomide treatment (HR 0.25) independently influenced the OS. CONCLUSION: Older age, worse performance status and higher percentage of blasts, that can be easily assessed, were associated to a worse prognosis. Also, our results corroborate the protective influence of lenalidomide in terms of OS in this South American series.

Neoadjuvant chemoradiotherapy or chemotherapy alone for oesophageal cancer: population-based cohort study.

BACKGROUND: Although both neoadjuvant chemoradiotherapy (nCRT) and chemotherapy (nCT) are used as neoadjuvant treatment for oesophageal cancer, it is unknown whether one provides a survival advantage over the other, particularly with respect to histological subtype. This study aimed to compare prognosis after nCRT and nCT in patients undergoing oesophagectomy for oesophageal adenocarcinoma (OAC) or squamous cell carcinoma (OSCC). METHODS: Data from the National Cancer Database (2006-2015) were used to identify patients with OAC and OSCC. Propensity score matching and Cox multivariable analyses were used to account for treatment selection biases. RESULTS: The study included 11 167 patients with OAC (nCRT 9972, 89.3 per cent; nCT 1195, 10.7 per cent) and 2367 with OSCC (nCRT 2155, 91.0 per cent; nCT 212, 9.0 per cent). In the matched OAC cohort, nCRT provided higher rates of complete pathological response (35.1 versus 21.0 per cent; P < 0.001) and margin-negative resections (90.1 versus 85.9 per cent; P < 0.001). However, patients who had nCRT had similar survival to those who received nCT (hazard ratio (HR) 1.04, 95 per cent c.i. 0.95 to 1.14). Five-year survival rates for patients who had nCRT and nCT were 36 and 37 per cent respectively (P = 0.123). For OSCC, nCRT had higher rates of complete pathological response (50.9 versus 30.4 per cent; P < 0.001) and margin-negative resections (92.8 versus 82.4 per cent; P < 0.001). A statistically significant overall survival benefit was evident for nCRT (HR 0.78, 0.62 to 0.97). Five-year survival rates for patients who had nCRT and nCT were 45.0 and 38.0 per cent respectively (P = 0.026). CONCLUSION: Despite pathological benefits, including primary tumour response to nCRT, there was no prognostic benefit of nCRT compared with nCT for OAC suggesting that these two modalities are equally acceptable. However, for OSCC, nCRT followed by surgery appears to remain the optimal treatment approach.

Simple fistula-in-ano: is it all simple? A systematic review.

BACKGROUND: Simple anal fistula is one of the most common causes of proctological surgery and fistulotomy is considered the gold standard. This procedure, however, may cause complications. The aim of this systematic review was to assess the surgical treatment of simple anal fistula with traditional and sphincter-sparing techniques. METHODS: A literature research was performed using PubMed, Cochrane, and Google Scholar to identify studies on the surgical treatment of simple anal fistulas. Observational studies and randomized clinical trials were included. We assessed the risk of bias of included studies using the Jadad scale for randomized controlled trials, and the MINORS Scale for the remaining studies. RESULTS: The search returned 456 records, and 66 studies were found to be eligible. The quality of the studies was generally low. A total of 4883 patients with a simple anal fistula underwent a sphincter-cutting procedure, mainly fistulotomy, with a weighted average healing rate of 93.7%, while any postoperative continence impairment was reported in 12.7% of patients. Sphincter-sparing techniques were adopted to treat 602 patients affected by simple anal fistula, reaching a weighted average success rate of 77.7%, with no study reporting a significant postoperative incontinence rate. The postoperative onset of fecal incontinence and the recurrence of the disease reduced patients' quality of life and satisfaction. CONCLUSIONS: Surgical treatment of simple anal fistulas with sphincter-cutting procedures provides excellent cure rates, even if postoperative fecal incontinence is not a negligible risk. A sphincter-sparing procedure could be useful in selected patients.

Fit-for-Discharge Criteria after Esophagectomy: An International Expert Delphi Consensus.

There are no internationally recognized criteria available to determine preparedness for hospital discharge after esophagectomy. This study aims to achieve international consensus using Delphi methodology. The expert panel consisted of 40 esophageal surgeons spanning 16 countries and 4 continents. During a 3-round, web-based Delphi process, experts voted for discharge criteria using 5-point Likert scales. Data were analyzed using descriptive statistics. Consensus was reached if agreement was ≥75% in round 3. Consensus was achieved for the following basic criteria: nutritional requirements are met by oral intake of at least liquids with optional supplementary nutrition via jejunal feeding tube. The patient should have passed flatus and does not require oxygen during mobilization or at rest. Central venous catheters should be removed. Adequate analgesia at rest and during mobilization is achieved using both oral opioid and non-opioid analgesics. All vital signs should be normal unless abnormal preoperatively. Inflammatory parameters should be trending down and close to normal (leucocyte count ≤12G/l and C-reactive protein ≤80 mg/dl). This multinational Delphi survey represents the first expert-led process for consensus criteria to determine 'fit-for-discharge' status after esophagectomy. Results of this Delphi survey may be applied to clinical outcomes research as an objective measure of short-term recovery. Furthermore, standardized endpoints identified through this process may be used in clinical practice to guide decisions regarding patient discharge and may help to reduce the risk of premature discharge or prolonged admission.

Laparoscopic versus open subtotal gastrectomy for gastric adenocarcinoma: cost-effectiveness analysis.

BACKGROUND: Laparoscopic subtotal gastrectomy (LSG) for cancer is associated with good perioperative outcomes and superior quality of life compared with the open approach, albeit at higher cost. An economic evaluation was conducted to compare the two approaches. METHODS: A cost-effectiveness analysis between LSG and open subtotal gastrectomy (OSG) for gastric cancer was performed using a decision-tree cohort model with a healthcare system perspective and a 12-month time horizon. Model inputs were informed by a meta-analysis of relevant literature, with costs represented in 2016 Canadian dollars (CAD) and outcomes measured in quality-adjusted life-years (QALYs). A secondary analysis was conducted using inputs extracted solely from European and North American studies. Deterministic (DSA) and probabilistic (PSA) sensitivity analyses were performed. RESULTS: In the base-case model, costs of LSG were $935 (€565) greater than those of OSG, with an incremental gain of 0·050 QALYs, resulting in an incremental cost-effectiveness ratio of $18 846 (€11 398) per additional QALY gained from LSG. In the DSA, results were most sensitive to changes in postoperative utility, operating theatre and equipment costs, as well as duration of surgery and hospital stay. PSA showed that the likelihood of LSG being cost-effective at willingness-to-pay thresholds of $50 000 (€30 240) per QALY and $100 000 (€60 480) per QALY was 64 and 68 per cent respectively. Secondary analysis using European and North American clinical inputs resulted in LSG being dominant (cheaper and more effective) over OSG, largely due to reduced length of stay after LSG. CONCLUSION: In this decision analysis model, LSG was cost-effective compared with OSG for gastric cancer.

ANTECEDENTES: Pese a su mayor coste, la gastrectomía subtotal laparoscópica se asocia con buenos resultados perioperatorios y una mejor calidad de vida en comparación con la cirugía abierta en el tratamiento del cáncer. Se realizó una evaluación económica comparando los dos abordajes. MÉTODOS: Se efectuó un análisis de coste-efectividad de la gastrectomía subtotal laparoscópica (laparoscopic subtotal gastrectomy, LSG) o de la gastrectomía subtotal abierta (open subtotal gastrectomy, OSG) en el cáncer gástrico utilizando un modelo de cohortes con árbol de decisión desde la perspectiva del sistema de salud y con un horizonte temporal de 12 meses. Los gastos del modelo fueron evaluados tras un metaanálisis de literatura relevante y expresados en dólares canadienses (Canadian dollars, CAD) del 2016. Los resultados se midieron en años de vida ajustados por su calidad (quality-adjusted life years, QALYs). Se realizó un análisis secundario utilizando los datos extraídos únicamente de estudios europeos y norteamericanos. Además, se realizaron análisis de sensibilidad determinístico y probabilístico (deterministic and probabilistic sensitivity analyses, DSA y PSA). RESULTADOS: En el modelo del caso base, los costes de la LSG fueron de 934,78$ (565€) más que en la OSG, con una ganancia incremental de 0,050 QALYs, que supuso una relación coste-efectividad incremental (incremental cost-effectiveness ratio, ICER) de 18.846,12$ (11.398€) por QALY adicional en la LSG. En el DSA, los resultados fueron más sensibles a cambios en el postoperatorio, quirófano y coste de los equipos, así como en la duración de la intervención y la hospitalización. El PSA demostró que la probabilidad de que la LSG fuera rentable en términos de disposición de pago (willingness-to-pay, WTP) para dos umbrales, de 50.000$ (30.240€) y 100.000$ (60.480€) por QALY fue del 64% y del 68%, respectivamente. En el análisis secundario utilizando los datos europeos y norteamericanos se demostró que la LSG era claramente dominante (más barata y más efectiva) que la OSG, en gran parte debido a la reducción de la estancia hospitalaria de la LSG. CONCLUSIÓN: En este modelo de análisis de decisión, la LSG fue coste-efectiva en comparación con la OSG para el cáncer gástrico.

Soluble PD-L1 and Circulating CD8+PD-1+ and NK Cells Enclose a Prognostic and Predictive Immune Effector Score in Immunotherapy Treated NSCLC patients.

INTRODUCTION: Upfront criteria to foresee immune checkpoint inhibitors (ICIs) efficacy are far from being identified. Thus, we integrated blood descriptors of pro-inflammatory/immunosuppressive or effective anti-tumor response to non-invasively define predictive immune profiles in ICI-treated advanced non-small cell lung cancer (NSCLC). METHODS: Peripheral blood (PB) was prospectively collected at baseline from 109 consecutive NSCLC patients undergoing ICIs as first or more line treatment. Soluble PD-L1 (sPD-L1) (immunoassay), CD8+PD-1+ and NK (FACS) cells were assessed and interlaced to generate an Immune effector Score (IeffS). Lung Immune Prognostic Index (LIPI) was computed by LDH levels and derived Neutrophil-to-Lymphocyte Ratio (dNLR). All these parameters were correlated with survival outcome and treatment response. RESULTS: High sPD-L1 and low CD8+PD-1+ and NK number had negative impact on PFS (P < 0.001), OS (P < 0.01) and ICI-response (P < 0.05). Thus, sPD-L1high, CD8+PD-1+low and NKlow were considered as risk factors encompassing IeffS, whose prognostic power outperformed that of individual features and slightly exceeded that of LIPI. Accordingly, the absence of these risk factors portrayed a favorable IeffS characterizing patients with significantly (P < 0.001) prolonged PFS (median NR vs 2.3 months) and OS (median NR vs 4.1) and greater benefit from ICIs (P < 0.01). We then combined each risk parameter composing IeffS and LIPI (LDHhigh, dNLRhigh), thus defining three distinct prognostic classes. A remarkable impact of IeffS-LIPI integration was documented on survival outcome (PFS, HR = 4.61; 95%CI = 2.32-9.18; P < 0.001; OS, HR=4.03; 95%CI=1.91-8.67; P < 0.001) and ICI-response (AUC=0.90, 95%CI=0.81-0.97, P < 0.001). CONCLUSION: Composite risk models based on blood parameters featuring the tumor-host interaction might provide accurate prognostic scores able to predict ICI benefit in NSCLC patients.

Dynamic Alteration of Neutrophil-to-Lymphocyte Ratio over Treatment Trajectory is Associated with Survival in Esophageal Adenocarcinoma.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been identified as a biomarker for multiple malignancies. There is emerging evidence that implicates neutrophils in cancer progression. Alterations of neutrophil counts and NLR during treatment may reflect a change in oncologic outcome that is more important than baseline values. The aim of this study is to investigate the prognostic role of NLR changes during the treatment trajectory of patients with esophageal adenocarcinoma. PATIENTS AND METHODS: NLR values of patients with esophageal adenocarcinoma who underwent surgery between 2005 and 2016 were measured at baseline and in the late postoperative period. Primary outcomes were overall survival (OS) and disease-free survival (DFS). The secondary outcome was pathological response to neoadjuvant chemotherapy. RESULTS: 330 patients were included; mean age was 65.6 years, and 82% were male. Most patients had cT3 (74.8%), cN-positive (59.7%) disease. Two-thirds (65.2%) received neoadjuvant chemotherapy. The independent predictors of OS were pathological N-stage, size of primary tumor, and delta NLR (late - baseline NLR). Patients with persistently elevated NLR did worse than those with decreasing NLR trends between baseline and postoperative time points (3-year OS 43.4% versus 71.3%, p < 0.0001, 3-year DFS 29.7% versus 61.9%, p < 0.0001). High baseline and postoperative NLR were associated with significantly worse OS and DFS. Patients with complete pathological response had lower mean baseline NLR. CONCLUSION: Dynamic changes in NLR during treatment are associated with survival and may be more informative than static baseline values.

Toll-like receptors: exploring their potential connection with post-operative infectious complications and cancer recurrence.

Cancer is the leading cause of death in North America. Despite modern advances in cancer therapy, many patients will ultimately develop cancer metastasis resulting in mortality. Surgery to resect early stage solid malignancies remains the cornerstone of cancer treatment. However, surgery places patients at risk of developing post-operative infectious complications that are linked to earlier cancer metastatic recurrence and cancer mortality. Toll-like receptors (TLRs) are evolutionarily-conserved sentinel receptors of the innate immune system that are activated by microbial products present during infection, leading to activation of innate immunity. Numerous types of solid cancer cells also express TLRs, with their activation augmenting their ability to metastasize. Similarly, healthy host-tissue TLRs activated during infection induce a prometastatic environment in the host. Cancer cells additionally secrete TLR activating ligands that activate both cancer TLRs and host TLRs to promote metastasis. Consequently, TLRs are an attractive therapeutic candidate to target infection-induced cancer metastasis and progression.

The Jacopo Tintoretto "Wedding Feast at Cana": A non-invasive and multi-technique analytical approach for studying painting materials.

This paper presents the results of a fully non-invasive photographic and spectroscopic study on a masterpiece by the famous Venetian painter Jacopo Tintoretto (1518-1594): "The Wedding feast at Cana" (1561), located inside the sacristy of the Santa Maria della Salute Basilica in Venice. A restoration campaign was carried out on the painting between 2016 and 2017. Various techniques were chosen to characterize in detail the materials used by the painter, especially pigments: Near Infrared Reflectography (NIR) to identify preparatory sketch and also allowing formulating hypothesis on some pigments; Raman and Fiber Optics Reflectance Spectroscopy (FORS) applied directly to the surface of the object, avoiding sample collection, to identify the pigments palette applied by Tintoretto. Information about binders was also obtained in a totally non-invasive way by using NIR spectroscopy. All analysis points were precisely (±2 mm) registered on a painting virtual map in order to recover them in a future possible conservation project.

Diagnostic criteria and symptom grading for delayed gastric conduit emptying after esophagectomy for cancer: international expert consensus based on a modified Delphi process.

Delayed gastric conduit emptying (DGCE) after esophagectomy for cancer is associated with adverse outcomes and troubling symptoms. Widely accepted diagnostic criteria and a symptom grading tool for DGCE are missing. This hampers the interpretation and comparison of studies. A modified Delphi process, using repeated web-based questionnaires, combined with live interim group discussions was conducted by 33 experts within the field, from Europe, North America, and Asia. DGCE was divided into early DGCE if present within 14 days of surgery and late if present later than 14 days after surgery. The final criteria for early DGCE, accepted by 25 of 27 (93%) experts, were as follows: >500 mL diurnal nasogastric tube output measured on the morning of postoperative day 5 or later or >100% increased gastric tube width on frontal chest x-ray projection together with the presence of an air-fluid level. The final criteria for late DGCE accepted by 89% of the experts were as follows: the patient should have 'quite a bit' or 'very much' of at least two of the following symptoms; early satiety/fullness, vomiting, nausea, regurgitation or inability to meet caloric need by oral intake and delayed contrast passage on upper gastrointestinal water-soluble contrast radiogram or on timed barium swallow. A symptom grading tool for late DGCE was constructed grading each symptom as: 'not at all', 'a little', 'quite a bit', or 'very much', generating 0, 1, 2, or 3 points, respectively. For the five symptoms retained in the diagnostic criteria for late DGCE, the minimum score would be 0, and the maximum score would be 15. The final symptom grading tool for late DGCE was accepted by 27 of 31 (87%) experts. For the first time, diagnostic criteria for early and late DGCE and a symptom grading tool for late DGCE are available, based on an international expert consensus process.

In vitro fertilization and autoimmunity: Evidence from an observational study.

INTRODUCTION: The aim of this study was to evaluate the prevalence of antiphospholipid antibodies (aPLs) in infertile women undergoing in vitro fertilization (IVF). METHOD OF STUDY: From January 2012 to December 2017, 520 consecutive clinical records of infertile women undergoing IVF were evaluated. Among them, 100 consecutive clinical records of patients with positive autoantibodies were selected. RESULTS: In 100/520 (19.23%) women, positive auto-antibodies were detected: 35/520 (6.73%) fulfilled classification criteria for a systemic disease. Positive aPLs were observed in 43 women (8.27%): 17/520 (3.27%) fulfilled diagnostic criteria for PAPS/APS, whereas patients with positive aPLs, who fulfilled diagnostic criteria for a systemic autoimmune disease other than APS were 18/520 (3.46%). LA and aCL were the main aPLs detected 53.49% and 44.19% respectively, whereas aB2GPI were found in 25.58%. CONCLUSIONS: we suggest that women with infertility may represent a subpopulation of patients with underhanded systemic autoimmune syndromes in which the main symptoms represented are obstetrical complications. We, therefore, recommend evaluating aPLs in all patients undergoing IVF with the aim of recognizing women at a higher risk of miscarriage or pregnancy morbidity.

Multivisceral Resection for Locally Advanced Gastric and Gastroesophageal Junction Cancers-11-Year Experience at a High-Volume North American Center.

INTRODUCTION: The oncologic benefit of multivisceral en bloc resections for T4 gastroesophageal tumors has been questioned, given the increased morbidity associated. We thus sought to investigate the surgical and oncologic outcomes of curative-intent en bloc multivisceral resections for T4 gastroesophageal carcinomas. METHODS: Between 2005 and 2016, 35 of the 525 patients who had gastric or EGJ carcinomas underwent curative-intent multivisceral resections for direct invasion or adhesion to adjacent organs. RESULTS: Postoperative complications occurred in 16(46%), 10 of which were Clavien-Dindo ≥ 3 (29%). Ninety-day mortality was 3%. The R0 resection rate was 94% (33). Direct organ invasion (pT4b) was confirmed on pathological analysis in 14 (40%) and did not affect survival. The majority (28, 80%) had lymph node involvement with a high nodal disease burden and was associated with decreased survival. Overall 5-year survival rate was 34%, and the vast majority of recurrences were distant/peritoneal (81%). On multivariate analysis, positive lymph nodes (H.R. 21.2; 95%CI 2.34-192) and R1 resection (H.R. 5.6; 95%CI 1.02-30.9) were predictors of survival. CONCLUSION: Multivisceral resections for T4 gastric and GEJ adenocarcinomas, in combination with effective systemic therapy, result in prolonged long-term survival with acceptable morbidity. Complete resection to negative margins should remain a mainstay of curative-intent treatment in carefully selected patients.

Psoriasis and the risk of acute coronary syndrome in the elderly.

BACKGROUND: Psoriasis has been associated with a higher prevalence of cardiovascular disease risk factors. However, there is inadequate quantification on the association between psoriasis and acute coronary syndrome (ACS), particularly in the elderly. Therefore, the aim of the present study was to assess the risk of ACS according to history of psoriasis in subjects aged 75 years and older. METHODS: We carried out a case control study based on 1455 cases and 1108 controls. Cases were all the patients admitted in the randomized Elderly ACS 2 trial. Controls were selected from subjects aged ≥75 years included in the Prevalence of Actinic Keratoses in the Italian Population Study (PraKtis), based on a representative sample of the general Italian population. Odds ratios (OR) of ACS according to history of psoriasis were obtained using a multiple logistic regression model including terms for age, sex and smoking. RESULTS: The prevalence of psoriasis was lower among cases (12/1455, 0.8%) than among controls (18/1108, 1.6%). The multivariate OR of ACS according to history of psoriasis was 0.51 (95% confidence interval: 0.23-1.09). CONCLUSIONS: Our data does not support an association between psoriasis and risk of ACS in the elderly.

Non-invasive study of natural dyes on historical textiles from the collection of Michelangelo Guggenheim.

A selection of historical textile fragments from the Venetian art dealer Moisè Michelangelo Guggenheim collection, ranging from XV to XVIII century, has been investigated by means of non-invasive techniques in order to reveal the coloring materials. Imaging was preliminarily used to visually investigate the selected artwork fragments in order to investigate their structure and conservation conditions; Fiber Optics Reflectance Spectroscopy (FORS) allowed recognizing the main natural dyestuffs, such as indigotin and anthraquinones-based compounds, except the yellow ones, difficultly identifiable when using this non-invasive technique. Collected spectroscopic data have been also elaborated by using a clustering algorithm that permitted to group collected spectra on the basis of similar properties and evidencing their inflection point wavelength as the most influencing feature.

Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Only a few studies have considered the role of comorbidities in the prognosis of amyotrophic lateral sclerosis (ALS) and have provided conflicting results. METHODS: Our multicentre, retrospective study included patients diagnosed from 1 January 2009 to 31 December 2013 in 13 referral centres for ALS located in 10 Italian regions. Neurologists at these centres collected a detailed phenotypic profile and follow-up data until death in an electronic database. Comorbidities at diagnosis were recorded by main categories and single medical diagnosis, with the aim of investigating their role in ALS prognosis. RESULTS: A total of 2354 incident cases were collected, with a median survival time from onset to death/tracheostomy of 43 months. According to univariate analysis, together with well-known clinical prognostic factors (age at onset, diagnostic delay, site of onset, phenotype, Revised El Escorial Criteria and body mass index at diagnosis), the presence of dementia, hypertension, heart disease, chronic obstructive pulmonary disease, haematological and psychiatric diseases was associated with worse survival. In multivariate analysis, age at onset, diagnostic delay, phenotypes, body mass index at diagnosis, Revised El Escorial Criteria, dementia, hypertension, heart diseases (atrial fibrillation and heart failure) and haematological diseases (disorders of thrombosis and haemostasis) were independent prognostic factors of survival in ALS. CONCLUSIONS: Our large, multicentre study demonstrated that, together with the known clinical factors that are known to be prognostic for ALS survival, hypertension and heart diseases (i.e. atrial fibrillation and heart failure) as well as haematological diseases are independently associated with a shorter survival. Our findings suggest some mechanisms that are possibly involved in disease progression, giving new interesting clues that may be of value for clinical practice and ALS comorbidity management.

When silence is noise: infantile-onset Barth syndrome caused by a synonymous substitution affecting TAZ gene transcription.

Barth syndrome (BTHS) is an X-linked inborn error of metabolism which affects males. The main manifestations are cardiomyopathy, myopathy, hypotonia, growth delay, intermittent neutropenia and 3-methylglutaconic aciduria. Diagnosis is confirmed by mutational analysis of the TAZ gene and biochemical dosage of the monolysocardiolipin/tetralinoleoyl cardiolipin (MLCL:L4-CL) ratio. We report a 6-year-old boy who presented with severe hypoglycemia, lactic acidosis and severe dilated cardiomyopathy soon after birth. The MLCL:L4-CL ratio confirmed BTHS (3.90 on patient's fibroblast, normal: 0-0.3). Subsequent sequencing of the TAZ gene revealed only the new synonymous variant NM_000116.3 (TAZ):c.348C>T p.(Gly116Gly), which did not appear to affect the protein sequence. In silico prediction analysis suggested the new c.348C>T nucleotide change could alter the TAZ mRNA splicing processing. We analyzed TAZ mRNAs in the patient's fibroblasts and found an abnormal skipping of 24 bases (NM_000116.3:c.346_371), with the consequent ablation of 8 amino acid residues in the tafazzin protein (NP_000107.1:p.Lys117_Gly124del). Molecular analysis of at risk female family members identified the patient's sister and mother as heterozygous carriers. Apparently harmless synonymous variants in the TAZ gene can damage gene expression. Such findings widen our knowledge of molecular heterogeneity in BTHS.