Behavioral, neural and ultrastructural alterations in a graded-dose 6-OHDA mouse model of early-stage Parkinson's disease.

Studying animal models furthers our understanding of Parkinson's disease (PD) pathophysiology by providing tools to investigate detailed molecular, cellular and circuit functions. Different versions of the neurotoxin-based 6-hydroxydopamine (6-OHDA) model of PD have been widely used in rats. However, these models typically assess the result of extensive and definitive dopaminergic lesions that reflect a late stage of PD, leading to a paucity of studies and a consequential gap of knowledge regarding initial stages, in which early interventions would be possible. Additionally, the better availability of genetic tools increasingly shifts the focus of research from rats to mice, but few mouse PD models are available yet. To address these, we characterize here the behavioral, neuronal and ultrastructural features of a graded-dose unilateral, single-injection, striatal 6-OHDA model in mice, focusing on early-stage changes within the first two weeks of lesion induction. We observed early onset, dose-dependent impairments of overall locomotion without substantial deterioration of motor coordination. In accordance, histological evaluation demonstrated a partial, dose-dependent loss of dopaminergic neurons of substantia nigra pars compacta (SNc). Furthermore, electron microscopic analysis revealed degenerative ultrastructural changes in SNc dopaminergic neurons. Our results show that mild ultrastructural and cellular degradation of dopaminergic neurons of the SNc can lead to certain motor deficits shortly after unilateral striatal lesions, suggesting that a unilateral dose-dependent intrastriatal 6-OHDA lesion protocol can serve as a successful model of the early stages of Parkinson's disease in mice.

Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting.

Although several studies have explored the molecular landscape of metastatic melanoma, the genetic determinants of therapy resistance are still largely unknown. Here, we aimed to determine the contribution of whole-exome sequencing and circulating free DNA (cfDNA) analysis in predicting response to therapy in a consecutive real-world cohort of 36 patients, undergoing fresh tissue biopsy and followed during treatment. Although the underpowered sample size limited statistical analysis, samples from non-responders had higher copy number variations and mutations in melanoma driver genes compared to responders in the BRAF V600+ subset. In the BRAF V600- subset, Tumor Mutational Burden (TMB) was twice that in responders vs. non-responders. Genomic layout revealed commonly known and novel potential intrinsic/acquired resistance driver gene variants. Among these, RAC1, FBXW7, GNAQ mutations, and BRAF/PTEN amplification/deletion were present in 42% and 67% of patients, respectively. Both Loss of Heterozygosity (LOH) load and tumor ploidy were inversely associated with TMB. In immunotherapy-treated patients, samples from responders showed higher TMB and lower LOH and were more frequently diploid compared to non-responders. Secondary germline testing and cfDNA analysis proved their efficacy in finding germline predisposing variants carriers (8.3%) and following dynamic changes during treatment as a surrogate of tissue biopsy, respectively.

The role of sentinel node tumor burden in modeling the prognosis of melanoma patients with positive sentinel node biopsy: an Italian melanoma intergroup study (N = 2,086).

BACKGROUND: The management of melanoma patients with metastatic melanoma in the sentinel nodes (SN) is evolving based on the results of trials questioning the impact of completion lymph node dissection (CLND) and demonstrating the efficacy of new adjuvant treatments. In this landscape, new prognostic tools for fine risk stratification are eagerly sought to optimize the therapeutic path of these patients. METHODS: A retrospective cohort of 2,086 patients treated with CLND after a positive SN biopsy in thirteen Italian Melanoma Centers was reviewed. Overall survival (OS) was the outcome of interest; included independent variables were the following: age, gender, primary melanoma site, Breslow thickness, ulceration, sentinel node tumor burden (SNTB), number of positive SN, non-sentinel lymph nodes (NSN) status. Univariate and multivariate survival analyses were performed using the Cox proportional hazard regression model. RESULTS: The 3-year, 5-year and 10-year OS rates were 79%, 70% and 54%, respectively. At univariate analysis, all variables, except for primary melanoma body site, were found to be statistically significant prognostic factors. Multivariate Cox regression analysis indicated that older age (P < 0.0001), male gender (P = 0.04), increasing Breslow thickness (P < 0.0001), presence of ulceration (P = 0.004), SNTB size (P < 0.0001) and metastatic NSN (P < 0.0001) were independent negative predictors of OS. CONCLUSION: The above results were utilized to build a nomogram in order to ease the practical implementation of our prognostic model, which might improve treatment personalization.

Combined robotic inguinal and iliac-obturator lymphadenectomy for stage III skin cancers: Surgical technique and preliminary results.

BACKGROUND: Ilio-inguinal lymphadenectomy for stage III melanoma and skin cancers still represents the best therapeutic option for a subset of patients, although the incidence of post-operative complications is dramatically high. Only a paucity of papers on robotic approach have been published, reporting experiences on isolated pelvic or inguinal lymphadenectomy, and no series on combined dissections have been described yet. We present the preliminary results achieved with combined robotic approach, with special emphasis on lymph nodal mapping, dissection technique and postoperative complications linked with the lymphatic system. METHODS: Between September 2019 and September 2021, 10 patients were submitted to robotic inguinal and iliac-obturator lymphadenectomy. RESULTS: Post-operative course was characterised by early mobilisation and minimal post-operative pain. Only one lymphoedema occurred and lymph nodal harvesting was more than satisfactory. CONCLUSIONS: Robotic surgery provides meticulous lymph nodal dissections, with promising functional and oncologic outcomes. Further series are advocated to confirm these preliminary results.

Magnetic Resonance Imaging or Ultrasound in Localized Intermediate- or High-Risk Soft Tissue Tumors of the Extremities (MUSTT): Final Results of a Prospective Comparative Trial.

OBJECTIVES: To report final results of the MUSTT trial, which has been designed to independently compare magnetic resonance imaging (MRI) and ultrasound (US) for local recurrences of non-metastatic patients operated for malignant soft tissue tumors (STT). METHODS: Magnetic resonance imaging or ultrasound in soft tissue tumors (MUSTT) is a prospective monocentric study recruiting asymptomatic, non-metastatic patients operated on for localized soft tissue sarcomas between 2015 and April. Eligible patients had MRI and physician-performed ultrasound (US) with an independent interpretation of imaging. Outcome measures were compared using ROC analysis and the X2 test. An analysis of all patients was performed on a per-follow-up event basis. RESULTS: A total of n = 51 patients who met the inclusion criteria agreed to participate. Among them, n = 8 were lost to follow-up, n = 6 had US and MRI acquired after a time frame > 7 days and were therefore excluded. Complete data available for 37 patients with 232 MRI and 232 US scan were finally considered (men/women: 18/20; age range, 18-84 years). Recurrences within 5 years occurred in 10/37 patients (27%). ROC analysis comparing US and MRI showed an AUC with 95% confidence intervals of 0.909 (0.832 to 0.981) for US and 0.966 (0.939 to 0.989) for MRI with Prob > X2 = 0. CONCLUSIONS: Each of these tests detected local recurrences with suitable accuracy. MRI did not result clearly superior to US in terms of diagnostic accuracy, but US showed some false positive or negative results.

A multicenter retrospective study on 4480 implanted PICC-ports: A GAVeCeLT project.

BACKGROUND: PICC-ports may be defined as totally implantable central venous devices inserted in the upper limb using the current state-of-the-art techniques of PICC insertion (ultrasound-guided venipuncture of deep veins of the arm, micro-puncture kits, proper location of the tip preferably by intracavitary ECG), with placement of the reservoir at the middle third of the arm. A previous report on breast cancer patients demonstrated the safety and efficacy of these devices, with a very low failure rate. METHODS: This retrospective multicenter cohort study-developed by GAVeCeLT (the Italian Group of Long-Term Venous Access Devices)-investigated the outcomes of PICC-ports in a large cohort of unselected patients. The study included 4480 adult patients who underwent PICC-port insertion in five Italian centers, during a period of 60 months. The primary outcome was device failure, defined as any serious adverse event (SAE) requiring removal. The secondary outcome was the incidence of temporary adverse events (TAE) not requiring removal. RESULTS: The median follow-up was 15.5 months. Device failure occurred in 52 cases (1.2%), the main causes being local infection (n = 7; 0.16%) and CRBSI (n = 19; 0.42%). Symptomatic catheter-related thrombosis occurred in 93 cases (2.1%), but removal was required only in one case (0.02%). Early/immediate and late TAE occurred in 904 cases (20.2%) and in 176 cases (3.9%), respectively. CONCLUSIONS: PICC-ports are safe venous access devices that should be considered as an alternative option to traditional arm-ports and chest-ports when planning chemotherapy or other long-term intermittent intravenous treatments.

Effects of magnesium supplementation on post-thyroidectomy hypocalcemia: a prospective single-center study.

BACKGROUND: Severe and/or symptomatic hypocalcemia due to hypoparathyroidism is the main contraindication for discharge in patients who have undergone thyroid surgery. Hypomagnesemia may contribute to the onset of hypoparathyroidism and is frequently observed after thyroid surgery in hypocalcemic patients. The impact of prophylactic and postoperative Magnesium supplementation on postoperative hypocalcemia and hypomagnesemia was prospectively evaluated by comparing patients undergoing prophylactic supplementation to a control group of patients who had only received Magnesium after evidence of postoperative hypoMg. METHODS: One hundred and twenty patients who underwent a total thyroidectomy participated in the study. Seventy-three patients were included in the study group, 47 in the control group. Prior to surgery, patients in the study group were given Magnesium orally for 5 days; postoperatively, Calcium and Magnesium was administered to all patients who displayed hypocalcemia and hypomagnesemia. RESULTS: Postoperative biochemical hypocalcemia (serum Calcium<8.5 mg/dL, regardless of its clinical severity) was found in 60 patients (50%) on D1 and in 58 patients (48.4%) on D2. Among hypocalcemic patients, hypomagnesemia was recorded in 29 at D1 (48%), and in 46 at D2 (79%). A significant positive correlation was found between Magnesium, Calcium, and parathyroid hormone in the first two postoperative days, while a significant inverse correlation occurred for these same parameters and length of hospital stay (p<0.001). One hundred and five patients (87.5%) were discharged as expected on the second postoperative day (Study group = 65, Control group = 40, p = 0.724), whereas 15 patients (12.5%) required prolonged hospitalization (Study group = 8, Control group = 7, p = 0.721). The Study group only showed significantly higher Magnesium levels on the first postoperative day (p=0.03). CONCLUSIONS: Although Magnesium and Calcium levels showed the same trend after thyroidectomy, neither Magnesium prophylaxis nor Magnesium treatment influenced the clinical course of postoperative hypocalcemia.

How to Make Immunotherapy an Effective Therapeutic Choice for Uveal Melanoma.

Uveal melanoma (UM), though a rare form of melanoma, is the most common intraocular tumor in adults. Conventional therapies of primary tumors lead to an excellent local control, but 50% of patients develop metastases, in most cases with lethal outcome. Somatic driver mutations that act on the MAP-kinase pathway have been identified, yet targeted therapies show little efficacy in the clinics. No drugs are currently available for the G protein alpha subunitsGNAQ and GNA11, which are the most frequent driver mutations in UM. Drugs targeting the YAP-TAZ pathway that is also activated in UM, the tumor-suppressor gene BRCA1 Associated Protein 1 (BAP1) and the Splicing Factor 3b Subunit 1 gene (SF3B1) whose mutations are associated with metastatic risk, have not been developed yet. Immunotherapy is highly effective in cutaneous melanoma but yields only poor results in the treatment of UM: anti-PD-1 and anti-CTLA-4 blocking antibodies did not meet the expectations except for isolated cases. Here, we discuss how the improved knowledge of the tumor microenvironment and of the cross-talk between tumor and immune cells could help to reshape anti-tumor immune responses to overcome the intrinsic resistance to immune checkpoint blockers of UM. We critically review the dogma of low mutational load, the induction of immune-suppressive cells, and the expression of alternative immune checkpoint molecules. We argue that immunotherapy might still be an option for the treatment of UM.

The critical view of safety during laparoscopic cholecystectomy: Strasberg Yes or No? An Italian Multicentre study.

BACKGROUND: Laparoscopic cholecystectomy is considered the gold standard for the treatment of gallbladder lithiasis; nevertheless, the incidence of bile duct injuries (BDI) is still high (0.3-0.8%) compared to open cholecystectomy (0.2%). In 1995, Strasberg introduced the "Critical View of Safety" (CVS) to reduce the risk of BDI. Despite its widespread use, the scientific evidence supporting this technique to prevent BDI is controversial. METHODS: Between March 2017 and March 2019, the data of patients submitted to laparoscopic cholecystectomy in 30 Italian surgical departments were collected on a national database. A survey was submitted to all members of Italian Digestive Pathology Society to obtain data on the preoperative workup, the surgical and postoperative management of patients and to judge, at the end of the procedure, if the isolation of the elements was performed according to the CVS. In the case of a declared critical view, iconographic documentation was obtained, finally reviewed by an external auditor. RESULTS: Data from 604 patients were analysed. The study population was divided into two groups according to the evidence (Group A; n = 11) or absence (Group B; N = 593) of BDI and perioperative bleeding. The non-use of CVS was found in 54.6% of procedures in the Group A, and 25.8% in the Group B, and evaluating the operator-related variables the execution of CVS was associated with a significantly lower incidence of BDI and intraoperative bleeding. CONCLUSIONS: The CVS confirmed to be the safest technique to recognize the elements of the Calot triangle and, if correctly performed, it significantly impacted on preventing intraoperative complications. Additional educational programs on the correct application of CVS in clinical practice would be desirable to avoid extreme conditions that may require additional procedures.

Left lower limb fasciitis due to sigmoid colonic perforated diverticulitis: a rare case of colocutaneous fistula.

Up to 25% of patients with acute diverticulitis develop complicated disease. Colocutaneous fistula with lower limb fasciitis secondary to complicated diverticulitis is a rare event. A 71-year-old woman with Class 3 obesity and Type 2 diabetes was admitted to the hospital because of left lower limb fasciitis associated with acute sigmoid diverticulitis complicated by covered perforation. The fasciitis was treated with multiple fasciotomies, antibiotics and hyperbaric oxygen therapy. The patient was readmitted 25 days after discharge because of the formation of a left leg colocutaneous fistula associated with an enterocolic fistula. Patient underwent sigmoid resection with primary anastomosis and ileal loop repair. Three-month follow-up showed fistula healing and absence of symptoms. Fasciitis secondary to acute diverticulitis is a rare clinical scenario. Although our therapeutic strategy was successful, the optimal treatment timing and surgical technique for fasciotomy and colon resection remain to be assessed.

In vivo localization of chronically implanted electrodes and optic fibers in mice.

Electrophysiology provides a direct readout of neuronal activity at a temporal precision only limited by the sampling rate. However, interrogating deep brain structures, implanting multiple targets or aiming at unusual angles still poses significant challenges for operators, and errors are only discovered by post-hoc histological reconstruction. Here, we propose a method combining the high-resolution information about bone landmarks provided by micro-CT scanning with the soft tissue contrast of the MRI, which allowed us to precisely localize electrodes and optic fibers in mice in vivo. This enables arbitrating the success of implantation directly after surgery with a precision comparable to gold standard histology. Adjustment of the recording depth with micro-drives or early termination of unsuccessful experiments saves many working hours, and fast 3-dimensional feedback helps surgeons avoid systematic errors. Increased aiming precision enables more precise targeting of small or deep brain nuclei and multiple targeting of specific cortical or hippocampal layers.

Neoadjuvant treatments in patients with high-risk resectable stage III/IV melanoma.

Introduction: In recent years, the introduction of targeted therapy and immunotherapy into clinical practice has radically changed the management of advanced melanoma. More recently, these treatments also became the standard of care in the adjuvant setting. However, high-risk resectable stage III melanoma (i.e. with clinically detected regional lymph node involvement and/or satellites/in transit metastases) still has a high risk of relapse, even after adjuvant treatment, suggesting that the activity of immunotherapy and targeted therapy may play a relevant role in a neoadjuvant setting.Area covered: In this review, we discuss the results of the main clinical trials conducted in the neoadjuvant setting for patients with resectable stage III and stage IV melanoma, with a focus on the hot topics and a look at the future perspectives of the field.Expert opinion: The long-term effects of immunotherapy and the high response rate of targeted therapy provided the strong rationale to start neoadjuvant clinical trials for patients with resectable stage III and oligometastatic stage IV melanoma. Neoadjuvant therapy may play an important role not only for its possible impact on overall survival, but also as a predictive biological marker to allow for a more accurate personalization of adjuvant treatments.

Sentinel lymph node biopsy in patients with malignant melanoma: analysis of post-operative complications.

BACKGROUND: This study investigates the incidence of post-operative complications and risk factors of sentinel lymph node biopsy (SLNB) in melanoma patients. METHODS: A retrospective cohort study was conducted at a single cancer institution on 408 consecutive SLNBs. RESULTS: Fifty-five post-operative complications occurred in 39 (9.5%) patients and included: wound infection in 24 (5.9%), seroma and lymphorrhea in 15 (3.7%), wound dehiscence in seven (1.7%), lymphocele in six (1.5%) and others in three (0.7%). Univariate analysis failed to identify possible risk factors (i.e. gender, age, lymph node region, number of excised lymph nodes, Breslow index, pT levels, comorbidities, length of surgery and hospital stay). Metastatic sentinel nodes occurred in four of 135 (3%) patients with thin melanoma (Breslow <1 mm) and in 68 of 262 (25.9%) patients with Breslow >1 mm. CONCLUSION: For patients with thin melanoma in whom the incidence of lymph node metastasis is low, the reported post-operative morbidity of almost 10% of SLNB highlights the need for careful patient selection.

Sentinel lymph node biopsy in porocarcinoma: A case reports.

INTRODUCTION: Eccrine porocarcinoma (EPC) is a slow-growing carcinoma arising from the eccrine sweat glands. Based on its clinical presentation it can be confused with malignant and benign skin lesions, both. Histological examination is essential to formulate a correct diagnosis. Surgical excision with clear margins is the standard therapeutic approach while the role of sentinel lymph node biopsy (SNLB) remains controversial. CASE PRESENTATION: The Authors report two cases of EPC of the lower limbs occurred in two women. Patients were treated by wide surgical excision of the lesion and SNLB. 6 months follow-up was disease free for both patients. CONCLUSION: Although a rare cutaneous tumor, EPC has to be taken into account in the differential diagnosis of malignant skin lesions because of its possible loco-regional aggressiveness and related morbidity. Among the available treatment options, surgical excision is considered the standard approach whereas the role of SNLB is controversial although the Authors discuss a possible usefulness for staging and diagnosis.

Cholinergic modulation of spatial learning, memory and navigation.

Spatial learning, including encoding and retrieval of spatial memories as well as holding spatial information in working memory generally serving navigation under a broad range of circumstances, relies on a network of structures. While central to this network are medial temporal lobe structures with a widely appreciated crucial function of the hippocampus, neocortical areas such as the posterior parietal cortex and the retrosplenial cortex also play essential roles. Since the hippocampus receives its main subcortical input from the medial septum of the basal forebrain (BF) cholinergic system, it is not surprising that the potential role of the septo-hippocampal pathway in spatial navigation has been investigated in many studies. Much less is known of the involvement in spatial cognition of the parallel projection system linking the posterior BF with neocortical areas. Here we review the current state of the art of the division of labour within this complex 'navigation system', with special focus on how subcortical cholinergic inputs may regulate various aspects of spatial learning, memory and navigation.

Open Source Tools for Temporally Controlled Rodent Behavior Suitable for Electrophysiology and Optogenetic Manipulations.

Understanding how the brain controls behavior requires observing and manipulating neural activity in awake behaving animals. Neuronal firing is timed at millisecond precision. Therefore, to decipher temporal coding, it is necessary to monitor and control animal behavior at the same level of temporal accuracy. However, it is technically challenging to deliver sensory stimuli and reinforcers as well as to read the behavioral responses they elicit with millisecond precision. Presently available commercial systems often excel in specific aspects of behavior control, but they do not provide a customizable environment allowing flexible experimental design while maintaining high standards for temporal control necessary for interpreting neuronal activity. Moreover, delay measurements of stimulus and reinforcement delivery are largely unavailable. We combined microcontroller-based behavior control with a sound delivery system for playing complex acoustic stimuli, fast solenoid valves for precisely timed reinforcement delivery and a custom-built sound attenuated chamber using high-end industrial insulation materials. Together this setup provides a physical environment to train head-fixed animals, enables calibrated sound stimuli and precisely timed fluid and air puff presentation as reinforcers. We provide latency measurements for stimulus and reinforcement delivery and an algorithm to perform such measurements on other behavior control systems. Combined with electrophysiology and optogenetic manipulations, the millisecond timing accuracy will help interpret temporally precise neural signals and behavioral changes. Additionally, since software and hardware provided here can be readily customized to achieve a large variety of paradigms, these solutions enable an unusually flexible design of rodent behavioral experiments.

Prediction of Non-sentinel Node Status in Patients with Melanoma and Positive Sentinel Node Biopsy: An Italian Melanoma Intergroup (IMI) Study.

BACKGROUND AND PURPOSE: Approximately 20% of melanoma patients harbor metastases in non-sentinel nodes (NSNs) after a positive sentinel node biopsy (SNB), and recent evidence questions the therapeutic benefit of completion lymph node dissection (CLND). We built a nomogram for prediction of NSN status in melanoma patients with positive SNB. METHODS: Data on anthropometric and clinicopathological features of patients with cutaneous melanoma who underwent CLND after a positive SNB were collected from nine Italian centers. Multivariate logistic regression was utilized to identify predictors of NSN status in a training set, while model efficiency was validated in a validation set. RESULTS: Data were available for 1220 patients treated from 2000 through 2016. In the training set (n = 810), the risk of NSN involvement was higher when (1) the primary melanoma is thicker or (2) sited in the trunk/head and neck; (3) fewer nodes are excised and (4) more nodes are involved; and (5) the lymph node metastasis is larger or (6) is deeply located. The model showed high discrimination (area under the receiver operating characteristic curve 0.74, 95% confidence interval [CI] 0.70-0.79) and calibration (Brier score 0.16, 95% CI 0.15-0.17) performance in the validation set (n = 410). The nomogram including these six clinicopathological variables performed significantly better than five other previously published models in terms of both discrimination and calibration. CONCLUSIONS: Our nomogram could be useful for follow-up personalization in clinical practice, and for patient risk stratification while conducting clinical trials or analyzing their results.

Multiple Lymph Node Basin Drainage in Trunk Melanoma Is Not Associated with Survival of Sentinel Lymph Node-Positive Patients.

OBJECTIVES: This study was aimed at investigating the prognostic role of multiple lymph node basin drainage (MLBD) in patients with positive sentinel lymph node (SLN) biopsy. BACKGROUND: MLBD is frequently observed in patients with trunk melanoma undergoing SLN. The prognostic value of MLBD in SLN-positive patients is still debated. METHODS: Retrospective data from 312 trunk melanoma patients with positive SLN biopsy (1991-2012) at 6 Italian referral centres were gathered in a multicentre database. MLBD was defined at preoperative lymphoscintigraphy. Clinical and pathological data were analysed for their association with disease-free interval (DFI) and disease-specific (DSS) survival. RESULTS: MLBD was identified in 34.6% of patients (108/312) and was significantly associated with >1 positive SLN (37 vs. 15.2%; p < 0.001) and with >1 positive lymph node (LN) after complete lymph node dissection (CLND) (50.9 vs. 34.8%; p = 0.033). No differences were observed according to drainage pattern in patients who had negative and positive non-SLN at CLND. MLBD was not associated with either DFI or DSS. Multivariate analyses showed that tumour thickness, ulceration, and number of metastatic LNs were associated with worse DFI and DSS, while regression confirmed its protective role in survival. CONCLUSION: In positive SLN patients, MLBD has no association with survival, which is mainly related to American Joint Committee on Cancer (AJCC) prognostic factors. Since the overall number of positive LNs drives the prognosis, the importance of a CLND in all the positive basins is confirmed.

Severe Intellectual Disability and Enhanced Gamma-Aminobutyric Acidergic Synaptogenesis in a Novel Model of Rare RASopathies.

BACKGROUND: Dysregulation of Ras-extracellular signal-related kinase (ERK) signaling gives rise to RASopathies, a class of neurodevelopmental syndromes associated with intellectual disability. Recently, much attention has been directed at models bearing mild forms of RASopathies whose behavioral impairments can be attenuated by inhibiting the Ras-ERK cascade in the adult. Little is known about the brain mechanisms in severe forms of these disorders. METHODS: We performed an extensive characterization of a new brain-specific model of severe forms of RASopathies, the KRAS12V mutant mouse. RESULTS: The KRAS12V mutation results in a severe form of intellectual disability, which parallels mental deficits found in patients bearing mutations in this gene. KRAS12V mice show a severe impairment of both short- and long-term memory in a number of behavioral tasks. At the cellular level, an upregulation of ERK signaling during early phases of postnatal development, but not in the adult state, results in a selective enhancement of synaptogenesis in gamma-aminobutyric acidergic interneurons. The enhancement of ERK activity in interneurons at this critical postnatal time leads to a permanent increase in the inhibitory tone throughout the brain, manifesting in reduced synaptic transmission and long-term plasticity in the hippocampus. In the adult, the behavioral and electrophysiological phenotypes in KRAS12V mice can be temporarily reverted by inhibiting gamma-aminobutyric acid signaling but not by a Ras-ERK blockade. Importantly, the synaptogenesis phenotype can be rescued by a treatment at the developmental stage with Ras-ERK inhibitors. CONCLUSIONS: These data demonstrate a novel mechanism underlying inhibitory synaptogenesis and provide new insights in understanding mental dysfunctions associated to RASopathies.

Videoscopic Inguinal-iliac-obturator Lymph-node Dissection: New Videoscopic Technique for Regional Lymphadenectomy in Patients with Melanoma.

AIM: The feasibility of videoscopic inguinal-iliac-obturator lymphadenectomy (VIIOL) was assessed in 20 patients with melanoma and compared with a retrospective sample of 24 patients undergoing standard 'open' technique (IIOL). RESULTS: No postoperative death occurred; the mean operative time was lower in the IIOL series (190 min vs. 302 min) but the quality of life was greatly improved in the VIIOL group thanks to earlier bladder catheter removal, no nasogastric suction, less pain, earlier mobilization, lower in-hospital stay, and earlier resumption of daily activities (27.6 vs. 83.2 days, p<0.001). Six out of 20 patients in the IIOL series had wound complications (30%) as compared to one in the VIIOL series (4%) (p=0.035). CONCLUSION: Staging and therapeutic efficacy of VIIOL were similar to the standard technique; the longer operative time of VIIOL was greatly compensated by less pain, lower wound complication rate, and earlier discharge from hospital and recovery of daily activities.