Behçet's syndrome as a tool to dissect the mechanisms of thrombo-inflammation: clinical and pathogenetic aspects.

Behçet's syndrome (BS) is a complex disease with different organ involvement. The vascular one is the most intriguing, considering the existence of a specific group of patients suffering from recurrent vascular events involving the venous and, more rarely, the arterial vessels. Several clinical clues suggest the inflammatory nature of thrombosis in BS, especially of the venous involvement, thus BS is considered a model of inflammation-induced thrombosis. Unique among other inflammatory conditions, venous involvement (together with the arterial one) is currently treated with immunosuppressants, rather than with anti-coagulants. Although many in-vitro studies have suggested the different roles of the multiple players involved in clot formation, in-vivo models are crucial to study this process in a physiological context. At present, no clear mechanisms describing the pathophysiology of thrombo-inflammation in BS exist. Recently, we focused our attention on BS patients as a human in-vivo model of inflammation-induced thrombosis to investigate a new mechanism of clot formation. Indeed, fibrinogen displays a critical role not only in inflammatory processes, but also in clot formation, both in the fibrin network and in platelet aggregation. Reactive oxygen species (ROS)-derived modifications represent the main post-translational fibrinogen alterations responsible for structural and functional changes. Recent data have revealed that neutrophils (pivotal in the pathogenetic mechanisms leading to BS damage) promote fibrinogen oxidation and thrombus formation in BS. Altogether, these new findings may help understand the pathogenetic bases of inflammation-induced thrombosis and, more importantly, may suggest potential targets for innovative therapeutic approaches.

Expanding the histopathological spectrum of CFL2-related myopathies.

Congenital myopathies (CMs) caused by mutation in cofilin-2 gene (CFL2) show phenotypic heterogeneity ranging from early-onset and rapid progressive forms to milder myopathy. Muscle histology is also heterogeneous showing rods and/or myofibrillar changes. Here, we report on three new cases, from two unrelated families, of severe CM related to novel homozygous or compound heterozygous loss-of-function mutations in CFL2. Peculiar histopathological changes showed nemaline bodies and thin filaments accumulations together to myofibrillar changes, which were evocative of the muscle findings observed in Cfl2-/- knockout mouse model.

WES in a family trio suggests involvement of TECPR2 in a complex form of progressive motor neuron disease.

We have performed whole-exome sequencing in a family trio with a 16-year-old girl suffering of progressive motor neuron disease. There was no family history of the disease and no parental consanguinity. Our exome analysis indicated the proband as a compound heterozygote for two missense variants in the TECPR2 gene according to a recessive mode of inheritance. The TECPR2 gene has been reported as a positive regulator of autophagy which is an essential mechanism for maintaining neuron homeostasis and survival and plays a key role in major adult and pediatric neurodegenerative diseases. Variants in this gene have been found responsible for a recently described form of hereditary spastic paraplegia called SPG49 in two previous reports. We propose that both variants causing amino acid substitution, p.Leu684Val and p.Thr903Met, inherited in trans-phase compound heterozygote form, can be responsible for the phenotype observed in our patient. We also consider the possible contribution of a heterozygous variant in the SPG7 gene. Sanger sequencing confirmed the segregation of variants within the family tree including the patient's unaffected brother.

Rapid communication: a vegetable oil extract restores redox status in fibroblasts from psoriatic patients.

Psoriasis is an inflammatory skin disease that affects 2-5% of the worldwide population. It is a chronic immune-mediated hyperproliferative inflammatory skin disease of unknown etiology, characterized by the appearance of sore patches of thick, red skin with silvery scales.

Allelic and phenotypic heterogeneity in 49 Italian patients with the muscle form of CPT-II deficiency.

As genotype-phenotype correlations require the study of large patient populations, we investigated 49 Italian patients (33 unreported) with the muscle form of carnitine-palmitoyl-transferase-II (CPT-II) deficiency and CPT2 gene mutations. CPT enzyme activity below 25% of controls would lead to the development of muscle symptoms, and CPT activity below 15% would cause a relatively severe phenotype of the muscle form. Of the 15 different mutations found, 6 are novel (40%). A functional significance of mutations could be derived only for the two homozygous missense mutations found: both the p.S113L and the p.R631C (recurring in four unrelated patients from a genetic isolate) alleles caused a severe CPT enzyme defect (15% and 7%, respectively) and a relatively severe clinical phenotype of the muscle form. We identified three genotypes (homozygous p.R631C, homozygous p.S113L, and heterozygous null mutations) usually associated with a relatively severe and often life-threatening condition, which should be considered both in the clinical management of newly diagnosed patients (to prevent symptoms) and in their possible inclusion in therapeutic trials. We confirmed the existence of symptomatic heterozygous patient(s), through a family study, providing an important issue when offering genetic counseling and suggesting the crucial role of polymorphisms or environmental factors in determining the phenotype.

Management of Small Bowel Obstruction (SBO) in older adults (>80 years): a propensity score-matched analysis on predictive factors for a (un)successful non-operative management (NOM).

OBJECTIVE: Small Bowel Obstruction (SBO) is a common emergency in older patients. The most appropriate treatment strategy is still matter of debate. The aim of this study was to compare a non-operative management (NOM) vs. a surgical procedure for patients ≥ 80 years with SBO. PATIENTS AND METHODS: All patients ≥ 80 years admitted to our Emergency Department (ED) for SBO between January 1st, 2015, and December 31st, 2020 were included in this study. In order to correct for baseline covariates and factors associated to clinical management, we used a 1:1 propensity score matching (PSM) analysis. The primary outcome was to compare the overall in-hospital mortality. Secondary outcomes included occurrence of major complications and in-hospital length of stay (LOS). RESULTS: A total of 561 patients were enrolled. After propensity score matching (PSM) analysis, 302 patients (151 each group) were included in the analysis. Mortality did not differ between the two groups. After PSM mechanical ventilation, sepsis, cumulative major complications, and LOS were significantly higher in the operative treatment group [15.9% vs. 1.5%, 9.4% vs. 4.1%, 27.6% vs. 19.2%, and 9.4 (6.4-14.3) days vs. 8.1 (4.5-13.3) days, respectively; p<0.001, p=0.013, p=0.025, and p=0.003, respectively]. CONCLUSIONS: In patients ≥ 80 years with SBO, a NOM could yield similar results, in terms of overall mortality, compared to a surgical management. Thus, particularly in patients with multiple comorbidities or functional impairments, a conservative approach should always be considered.

Sinus venous stenosis-associated IIHWOP is a powerful risk factor for progression and refractoriness of pain in primary headache patients: a review of supporting evidences.

Reported prevalence of idiopathic intracranial hypertension without papilledema (IIHWOP) in series of patients with chronic or transformed migraine is significantly higher than expected; yet, IIHWOP is not included among the risk factors for migraine progression. However, several studies provided evidences suggesting that IIHWOP could represent a possible, largely underestimated, risk factor for progression of pain in migraine and, possibly, in other primary headaches. Data from two recent studies, albeit aimed to different end-points, strongly support this hypothesis. In the first study, conducted on a large series of neurological patients without any sign or symptom of raised intracranial pressure (ICP), including chronic headache, the prevalence of bilateral central venous stenosis at magnetic resonance venography (MRV) was 23% and an IIHWOP at opening pressure was found in 48% of this subgroup (11% of the whole sample) while it was not detected in any of the subjects with normal MRV. This indicates that IIHWOP may be much more prevalent than believed in general population and that it can run without any symptom or sign of raised ICP in most of affected subjects. In the second paper, sinus venous stenosis-associated IIHWOP has been found in about one half of a large chronic primary headache patients series with poor response to treatments and in none of those with normal MRV. Moreover, after the diagnostic lumbar puncture, a transient improvement of headache frequency has been observed in the majority of intracranial hypertensive chronic headache subjects. Taken together, the data of these two recent papers rise the following hypothesis: (1) asymptomatic IIHWOP is much more prevalent than expected in general population; (2) IIHWOP is a powerful and largely unrecognized risk factor for progression of pain in primary headache patients; (3) sinus venous stenosis at MRV is a reliable predictor of raised intracranial hypertension also in asymptomatic patients; (4) sinus venous stenosis has a causative role in IIH pathophysiology. These assumptions share a potential high clinical impact and need to be urgently tested in adequately designed controlled studies.

Nanocomposite hyaluronic acid-based hydrogel for the treatment of esophageal fistulas.

Fistulas are abnormal connections between two body parts that can impair the quality of life. The use of biological glues represents the least invasive procedure to fill the fistula; however, it is limited by the need of multiple injections, the persistence of infection and the failure in the treatment of high-output fistulas. We describe herein the use of an injectable nanocomposite hydrogel that is able to form in situ a tissue-mimicking matrix as an innovative material for the treatment of esophageal fistulas. Injectable hydrogels that have the dual advantage of being implantable with a minimally invasive approach and of adapting their shape to the target cavity, while the introduction of mesoporous silica nanoparticles opens the possibility of drug/biomolecules delivery. The hydrogel is based on hyaluronic acid (HA), the crosslinking process occurs at physiological conditions leading to a hydrogel made of >96% by water and with a large-pore micro-architecture. The kinetic profile of the hydrogel formation is studied as a function of HA molecular weight and concentration with the aim of designing a material that is easily injectable with an endoscopic needle, is formed in a time compatible with the surgical procedure and has final mechanical properties suitable for cell proliferation. The in vivo experiments (porcine model) on esophageal-cutaneous fistulas, showed improved healing in the animals treated with the hydrogel compared with the control group.

The impact of the multidisciplinary tumor board (MDTB) on the management of pancreatic diseases in a tertiary referral center.

BACKGROUND: The implementation of multidisciplinary tumor board (MDTB) meetings significantly ameliorated the management of oncological diseases. However, few evidences are currently present on their impact on pancreatic cancer (PC) management. The aim of this study was to evaluate the impact of the MDTB on PC diagnosis, resectability and tumor response to oncological treatment compared with indications before discussion. PATIENTS AND METHODS: All patients with a suspected or proven diagnosis of PC presented at the MDTB from 2017 to 2019 were included in the study. Changes of diagnosis, resectability and tumor response to oncological/radiation treatment between pre- and post-MDTB discussion were analyzed. RESULTS: A total of 438 cases were included in the study: 249 (56.8%) were presented as new diagnoses, 148 (33.8%) for resectability assessment and 41 (9.4%) for tumor response evaluation to oncological treatment. MDTB discussion led to a change in diagnosis in 54/249 cases (21.7%), with a consequent treatment strategy variation in 36 cases (14.5%). Change in resectability was documented in 44/148 cases (29.7%), with the highest discrepancy for borderline lesions. The treatment strategy was thus modified in 27 patients (18.2%). The MDTB brought a modification in the tumor response assessment in 6/41 cases (14.6%), with a consequent protocol modification in four (9.8%) cases. CONCLUSIONS: MDTB discussion significantly impacts on PC management, especially in high-volume centers, with consistent variations in terms of diagnosis, resectability and tumor response assessment compared with indications before discussion.

Surgical emergencies during SARS-CoV-2 pandemic lockdown: what happened?

OBJECTIVE: The pandemic from SARS-CoV-2 is having a profound impact on daily life of a large part of world population. Italy was the first Western country to impose a general lockdown to its citizens. Implications of these measures on several aspects of public health remain unknown. The aim of this study was to investigate the effects of the lockdown on surgical emergencies volumes and care in a large, tertiary referral center. MATERIALS AND METHODS: Electronic medical records of all patients visited in our Emergency Department (ED) and admitted in a surgical ward from February 21st 2020 to May 3rd 2020 were collected, analyzed and compared with the same periods of 2019 and 2018 and a cross-sectional study was performed. RESULTS: Number of surgical admissions dropped significantly in 2020 with respect to the same periods of 2019 and 2018, by almost 50%. The percentage distribution of admissions in different surgical wards did not change over the three years. Time from triage to operating room significantly reduced in 2020 respect to 2019 and 2018 (p<0.001). CONCLUSIONS: The lockdown in Italy due to SARS-CoV-2 pandemic arguably represents the largest social experiment in modern times. Data provided by our study provide useful information to health authorities and policymakers about the effects of activity restriction on surgical accesses and changing epidemiology due to an exceptional external event.

Atypical presentation of acute pancreatitis: a single center case-match analysis of clinical outcomes.

OBJECTIVE: Acute pancreatitis (AP) may present an aspecific clinical picture without abdominal symptoms (atypical AP). We compared clinical outcomes between typical and atypical AP. PATIENTS AND METHODS: Thirty out of 1163 patients (2.6%) presented an atypical AP. Demographic, clinical data, laboratory and radiological findings, management type, length of hospital stay (LOS) and mortality rate were retrospectively reviewed. A case match analysis 2:1 was performed. The final groups comprised 50 typical APs (TAP group) and 25 atypical APs (AAP group). RESULTS: The AAP patients presented fever (36%), syncope (32%) and dyspnea (16%) as the most frequent symptoms. Laboratory values showed similarity between the two groups. We noted a comparable edematous AP rate in both groups (p=0.36). Ten (20%) TAP and 3 (12%) AAP patients needed ERCP, respectively (p=0.38). Cholecystectomy was similarly performed in both cohorts (p=0.81). One TAP patient underwent a percutaneous drainage and subsequent surgical necrosectomy compared to none in the AAP cohort (p=0.47). LOS and mortality rate were comparable (p=0.76 and 0.3, respectively). CONCLUSIONS: Similar outcomes have been reached in the two groups. Routine evaluation of the serum amylase values fundamentally contributed to early diagnosis and appropriate treatment.

The impact of preoperative ASA-physical status on postoperative complications and long-term survival outcomes in gastric cancer patients.

OBJECTIVE: The aim of this study was to investigate the impact of the preoperative American Society of Anesthesiologists-Physical status (ASA-PS) on both the short-term and long-term outcomes in patients with Gastric Cancer (GC). PATIENTS AND METHODS: In a retrospective observational study, a total of 473 GC patients were divided into the following 3 groups: ASA 1, ASA 2, and ASA 3-4. RESULTS: The ASA 3-4 group included significantly older patients compared to the other groups (p<0.0001). In ASA 1 patients, there was a higher number of lymph nodes dissected (p=0.006), and more patients received adjuvant treatment (p<0.001). In the three groups, no difference regarding the postoperative surgical and medical complications (p=0.29 and p=0.1, respectively) nor in terms of mortality rate (p=0.17) were demonstrated. The multivariate analysis showed that age, tumor stage, number of lymph nodes dissected, positive lymph nodes, adjuvant treatments, and postoperative surgical complications were significant predictive factors for mortality. Five-year overall and disease-free survival for ASA 1, ASA 2, and ASA 3-4 groups was 56%, 57.6%, and 44%, respectively; and 37%, 44.3%, and 39.2%, respectively. CONCLUSIONS: Preoperative ASA-PS alone cannot serve as a direct operative risk indicator for GC patients.

Colonoscopy quality assessment and accuracy: analysis of the influencing factors and surgical sequelae on 216 colonoscopies.

OBJECTIVE: Colonoscopy is recognized as the primary screening test for colorectal cancer. However, its inaccuracy in identifying the exact tumor localization is still high. As a consequence, repeated colonoscopies and changes in the surgical management have been reported. This study aims to evaluate the quality of 216 colonoscopies, to define colonoscopy accuracy and to investigate the surgical sequelae of an incorrect localization. PATIENTS AND METHODS: A retrospective analysis of 216 colonoscopies has been conducted. Colonoscopy quality was assessed on: quality of bowel preparation, completeness of the examination, video and/or photographic documentation, and reported the distance of the lesion from the anal verge. Colonoscopy accuracy was evaluated in terms of correspondence between the endoscopic and intra-operative tumor localization. RESULTS: Bowel preparation adequateness was reported in 121 out of 216 (56%) colonoscopies, with an adequate grade in 68.6% of cases. A complete colonoscopy was accomplished in 86.9% of cases with photo documentation in only 59 colonoscopies (27.3%). The lesion distance from the anal verge was documented only in 93 out of 216 colonoscopies. Of the 157 lesions described at the colonoscopy, 117 matched with the intra-operative localization (accuracy 74.5%). Fifteen of the 40 incorrectly localized lesions (37.5%) required changes in the surgical management. At multivariate analysis, the colonoscopy completeness was the only influencing factor on the concordance between endoscopic and intra-operative localization. CONCLUSIONS: Colonoscopy demonstrated adequate accuracy in localizing lesions. However, the incorrect tumor localization leads to a high rate of changes in surgical management. Increase in.

Amphetamine selectively blocks inhibitory glutamate transmission in dopamine neurons.

Amphetamine is a highly addictive psychostimulant that promotes the release of the catecholamines dopamine and norepinephrine. Amphetamine-induced release of dopamine in the midbrain inhibits the activity of dopamine neurons through activation of D2 dopamine autoreceptors. Here we show that amphetamine may also excite dopamine neurons through modulation of glutamate neurotransmission. Amphetamine potently inhibits metabotropic glutamate receptor (mGluR)-mediated IPSPs in dopamine neurons, but has no effect on ionotropic glutamate receptor-mediated EPSCs. Amphetamine desensitizes the mGluR-mediated hyperpolarization through release of dopamine, activation of postsynaptic alpha1 adrenergic receptors, and suppression of InsP3-induced calcium release from internal stores. By selectively suppressing the inhibitory component of glutamate-mediated transmission, amphetamine may promote burst firing of dopamine neurons. Through this mechanism, amphetamine may enhance phasic release of dopamine, which is important in the neural processing of reward.

The hyperthermic intraoperative intraperitoneal chemotherapy in the treatment of advanced abdominopelvic cancer. Personal experience on 103 procedures during a seventeen year period in a single Italian center.

OBJECTIVE: Integration of different therapeutic strategies in cancer surgery in the last years has led from treating primary lesions to the surgical treatment of metastases. The purpose of this paper is to report a single Italian center experience of treatment of peritoneal carcinosis of the abdominopelvic malignancies. PATIENTS AND METHODS: 103 HIPEC procedures were performed in 17 years on 94 selected patients affected by abdominopelvic cancer. The PCI score was calculated at laparotomy. The CC score was calculated before doing HIPEC. HIPEC was carried out according to the Coliseum technique. RESULTS: The surgical cytoreduction allowed 89 patients to be subjected to HIPEC treatment with a CC score 0; 9 patients with a CC 1; 3 patients with a CC 2 and 2 patients with a CC 3. In 22 patients postoperative complications were recorded. No operative mortality occurred. The median follow-up of 53 months shows a rate of survival equivalent to 49 %, with a relapse in 46 patients, 29 of them reached exitus. CONCLUSIONS: The surgical resection alone for patients affected by advanced cancer with peritoneal carcinomatosis cannot be considered a sufficient treatment any longer and HIPEC would help to prolong survival in these patients.

Treatment of giant paraesophageal hernia: pro laparoscopic approach.

PURPOSE: Giant paraesophageal hernias (GPEH) are relatively uncommon and account for less than 5% of all primary hiatal hernias. Giant Secondary GPEH can be observed after surgery involving hiatal orifice opening, such as esophagectomy, antireflux surgery, and hiatal hernia repair. Surgical treatment is challenging, and there are still residual controversies regarding the laparoscopic approach, even though a reduced morbidity and mortality, as well as a shorter hospital stay have been demonstrated. METHODS: A Pubmed electronic search of the literature including articles published between 1992 and 2016 was conducted using the following key words: hiatal hernia, paraesophageal hernias, mesh, laparoscopy, intrathoracic stomach, gastric volvulus, diaphragmatic hernia. RESULTS: Given the risks of non-operative management, GPEH surgical repair is indicated in symptomatic patients. Technical steps for primary hernia repair include hernia reduction and sac excision, correct repositioning of the gastroesophageal junction, crural repair, and fundoplication. For secondary hernias, the surgical technique varies according to hernia type and components and according to the approach used during the first surgery. There is an ongoing debate regarding the best and safest method to close the hiatal orifice. The laparoscopic approach has demonstrated a lower postoperative morbidity and mortality, and a shorter hospital stay as compared to the open approach. A high recurrence rate has been reported for primary GPEH repair. However, recent studies suggest that recurrence does not reduce symptomatic outcomes. CONCLUSIONS: The laparoscopic treatment of primary and secondary GPEH is safe and feasible in elective and emergency settings, especially in high-volume centers. The procedure is still challenging. The main steps are well defined. However, there is still room for improvement to lower the recurrence rate.