Adolescent inguinal hernia repair: a review of the literature and recommendations for selective management.

BACKGROUND: The choice of how to repair inguinal hernias in adolescents has historically been a matter of experience and differed between pediatric surgeons who traditionally performed a high ligation of the sac and general surgeons who typically perform a repair using mesh. This up-to-date review thoroughly examines the subject and discusses the suitability of both types of repairs in this unique age group. METHODS: A 20-year Pub Med search was performed for the following terms: adolescent hernia repair including reports of mesh hernia repair in adolescents and postoperative complications including chronic inguinal pain and recurrences. RESULTS: The evidence in the literature suggests that while there appears to be no difference between the two types of repairs with regards to recurrence and complications, changes in the pelvic floor physiology in adolescents suggest that a selective, individualized approach can be recommended depending on the size and nature of the presenting pathology. CONCLUSIONS: A selective approach to the inguinal hernia in adolescent patients based on the size of the defect appears justified.

Preventing transmission among operating room staff during COVID-19 pandemic: the role of the Aerosol Box and other personal protective equipment.

The COVID-19 pandemic is highly challenging for the operating room staff and healthcare workers in emergency departments. SARS-CoV-2 is a positive-sense single-stranded RNA beta-coronavirus that primarily targets the human respiratory system, with fever, cough, myalgia, and pneumonia as the most common manifestations. However, since SARS-CoV-2 RNA was detected in stool specimens much more attention has been paid to gastrointestinal symptoms such as loss of appetite, nausea, and diarrhea. Furthermore, the expression of ACE-2 receptors in absorptive enterocytes from ileum and colon suggests that these organs should also be considered as a potential high risk for SARS-CoV-2 infection. During aerosol-generating medical procedures (AGMP; e.g. intubating and extubating patients or any surgical procedures), the production of both airborne particles and droplets may increase the risk of infection. In this situation, the surgical staff is strongly recommended to wear personal protective equipment (PPE). A transparent plastic cube, the so-called "Aerosol Box" (AB), has been recently designed to lend further protection against droplets and aerosol exposure during the AGMP.

Mid-transverse colon cancer and extended versus transverse colectomy: Results of the Italian society of surgical oncology colorectal cancer network (SICO CCN) multicenter collaborative study.

INTRODUCTION: Transverse colon cancer (TCC) is poorly studied, and TCC cases are often excluded from large prospective randomized trials because of their complexity and their potentially high complication rate. The best surgical approach for TCC has yet to be established. The aim of this large retrospective multicenter Italian series is to investigate the advantages and disadvantages of both hemicolectomy and transverse colectomy in order to identify the best surgical approach. MATERIALS AND METHODS: This was a retrospective cohort study of patients with mid-transverse colon cancer treated with a segmental colon resection or an extended hemicolectomy (right or left) between 2006 and 2016 in 28 high-volume (more than 70 procedures/year) Italian referral centers for colorectal surgery. RESULTS: The study included 1529 patients, 388 of whom underwent a segmental resection while 1141 underwent an extended resection. A higher number of complications has been reported in the segmental group than in the extended group (30.1% versus 23.6%; p 0.010). In 42 cases the main complication was the anastomotic leak (4.4% versus 2.2%; p 0.020). Recovery outcomes also showed statistical differences: time to first flatus (p 0.014), time to first mobilization (p 0.040), and overall hospital stay (p < 0.001) were significantly shorter in the extended group. Even if overall survival were similar between the groups (95.1% versus 97%; p 0.384), 3-year disease-free survival worsened after segmental resection (78.1% versus 86.2%; p 0.001). CONCLUSIONS: According to our results, an extended right colon resection for TCC seems to be surgically safer and more oncologically valid.

Removal of polycyclic aromatic hydrocarbons during anaerobic biostimulation of marine sediments.

This study proposes the supplementation of digestate, fresh organic fraction of municipal solid waste (OFMSW) and a nutrient solution during the anaerobic biostimulation of marine sediments contaminated by polycyclic aromatic hydrocarbons (PAHs). The experimental activity was conducted with four PAHs (i.e. phenanthrene, anthracene, fluoranthene and pyrene) under controlled mesophilic conditions (37 ± 1 °C) in 100 mL serum bottles maintained at 130 rpm. After 120 days of incubation, the highest total PAH degradation of 53 and 55% was observed in the experiments with digestate + nutrients and OFMSW + nutrients, respectively. Phenanthrene was the most degraded PAH and the highest removal of 69% was achieved with OFMSW + nutrients. The anaerobic PAH degradation proceeded through the accumulation of volatile fatty acids and the production of hydrogen and methane as biogas constituents. The highest cumulative biohydrogen production of 80 mL H2·g VS-1 was obtained when OFMSW was used as the sole amendment, whereas the highest biomethane yield of 140 mL CH4·g VS-1 was obtained with OFMSW + nutrients. The evolution of PAH removal during anaerobic digestion revealed a higher impact of the methanogenic phase rather than acidogenic phase on PAH degradation.

Surgical treatment of a colon neoplasm of the splenic flexure: a multicentric study of short-term outcomes.

AIM: The optimal surgical treatment of splenic flexure neoplasm is still not well defined. Extended right hemicolectomy (ERH) and left colic resection (LCR) have been proposed but conclusive evidence concerning postoperative morbidity and oncological results is lacking. The aim of this study was to analyse the short-term outcomes after surgery for splenic flexure cancer with regard to surgical procedure and surgeon's specialty. METHODS: This was a multicentre study on patients who underwent surgery for primary colon cancer of the splenic flexure. RESULTS: From 2004 to 2015, 324 patients fulfilled the criteria for inclusion into the study; 270 (83.4%) had elective surgery while 54 (16.6%) had emergency resection: 158 (48.8%) underwent ERH and 166 (51.2%) LCR; 176 (54.3%) procedures were performed by colorectal surgeons, 148 (46.7%) by general surgeons. In the ERH group a significantly higher rate of emergency operations was carried out (P = 0.005). After elective surgery, no significant differences between ERH and LCR concerning 30-day mortality (3.3% vs 2.0%) and the need for reoperation (10.6% vs 7.4%) were found. Nodal harvesting was significantly higher in the ERH and colorectal surgeon groups in any clinical scenario. At multivariate analysis, age and smoking habit were predictive of the need for reoperation and major morbidity while the general surgeon group showed a higher risk of anastomotic failure (OR = 1.92; P = 0.168). CONCLUSION: We analysed the largest series in literature of curative resections for splenic flexure tumours. The optimal procedure still remains debatable as ERH and LCR appear to achieve comparable short-term outcomes. Surgeon's specialty seems to positively affect patient's outcomes.

Multicentre randomized clinical trial of colonic J pouch or straight stapled colorectal reconstruction after low anterior resection for rectal cancer.

BACKGROUND: Colonic J pouch reconstruction has been found to be associated with a lower incidence of anastomotic leakage than straight anastomosis. However, studies on this topic are underpowered and retrospective. This randomized trial evaluated whether the incidence of anastomotic leakage was reduced after colonic J pouch reconstruction compared with straight colorectal anastomosis following anterior resection for rectal cancer. METHODS: This multicentre RCT included patients with rectal carcinoma who underwent low anterior resection followed by colorectal anastomosis. Patients were assigned randomly to receive a colonic J pouch or straight colorectal anastomosis. The main outcome measure was the occurrence of major anastomotic leakage. The incidence of global (major plus minor) anastomotic leakage and general complications were secondary outcomes. Risk factors for anastomotic leakage were identified by regression analysis. RESULTS: Of 457 patients enrolled, 379 were evaluable (colonic J pouch arm 190, straight colorectal arm 189). The incidence of major and global anastomotic leakage, and general complications was 14·2, 19·5 and 34·2 per cent respectively in the colonic J pouch group, and 12·2, 19·0 and 27·0 per cent in the straight colorectal anastomosis group. No statistically significant differences were observed between the two arms. In multivariable logistic regression analysis, male sex (odds ratio 1·79, 95 per cent c.i. 1·02 to 3·15; P = 0·042) and high ASA fitness grade (odds ratio 2·06, 1·15 to 3·71; P = 0·015) were independently associated with the occurrence of anastomotic leakage. CONCLUSION: Colonic J pouch reconstruction does not reduce the incidence of anastomotic leakage and postoperative complications compared with conventional straight colorectal anastomosis. Registration number NCT01110798 (http://www.clinicaltrials.gov).

Comparison of endoscopic vacuum therapy versus endoscopic stenting for esophageal leaks: systematic review and meta-analysis.

Esophageal leaks remain a life-threatening postoperative complication of esophagectomy. Currently, self-expanding metal stents (SEMS) represent the endoscopic mainstay of treatment. Recently, endoscopic vacuum therapy (EVT) has emerged and shown promising results in these patients. We conducted an electronic systematic search using MEDLINE databases (PubMed, EMBASE, and Web of Science) looking for studies comparing EVT and SEMS for the treatment of esophageal leak and/or perforation. Four studies including 163 patients matched the inclusion criteria. Esophageal leak closure rate is significantly higher with EVT than SEMS [pooled odds ratio 5.51 (95% CI 2.11-14.88; P < 0.001)]. Additionally, EVT has a shorter treatment duration [pooled mean difference -9.0 days (95% CI 16.6-1.4; P = 0.021)], lower major complication (P = 0.011), and in-hospital mortality (P = 0.002) rate compared to SEMS. EVT for esophageal leak is feasible and safe. It has the potential to become the new gold standard in the endoscopic treatment of esophageal leaks and perforations. However, further comparative studies with SEMS are needed to strengthen the current evidence.

INPP4B overexpression and c-KIT downregulation in human achalasia.

BACKGROUND: Achalasia is a rare motility disorder characterized by myenteric neuron and interstitial cells of Cajal (ICC) abnormalities leading to deranged/absent peristalsis and lack of relaxation of the lower esophageal sphincter. The mechanisms contributing to neuronal and ICC changes in achalasia are only partially understood. Our goal was to identify novel molecular features occurring in patients with primary achalasia. METHODS: Esophageal full-thickness biopsies from 42 (22 females; age range: 16-82 years) clinically, radiologically, and manometrically characterized patients with primary achalasia were examined and compared to those obtained from 10 subjects (controls) undergoing surgery for uncomplicated esophageal cancer (or upper stomach disorders). Tissue RNA extracted from biopsies of cases and controls was used for library preparation and sequencing. Data analysis was performed with the "edgeR" option of R-Bioconductor. Data were validated by real-time RT-PCR, western blotting and immunohistochemistry. KEY RESULTS: Quantitative transcriptome evaluation and cluster analysis revealed 111 differentially expressed genes, with a P ≤ 10-3 . Nine genes with a P ≤ 10-4 were further validated. CYR61, CTGF, c-KIT, DUSP5, EGR1 were downregulated, whereas AKAP6 and INPP4B were upregulated in patients vs controls. Compared to controls, immunohistochemical analysis revealed a clear increase in INPP4B, whereas c-KIT immunolabeling resulted downregulated. As INPP4B regulates Akt pathway, we used western blot to show that phospho-Akt was significantly reduced in achalasia patients vs controls. CONCLUSIONS & INFERENCES: The identification of altered gene expression, including INPP4B, a regulator of the Akt pathway, highlights novel signaling pathways involved in the neuronal and ICC changes underlying primary achalasia.

Mesenchymal stem cells from tumor microenvironment favour breast cancer stem cell proliferation, cancerogenic and metastatic potential, via ionotropic purinergic signalling.

Interaction between tumor cells and the microenvironment is key in initiation, progression, and invasiveness of cancer. In particular, mesenchymal stem cells (MSCs) are recruited to the sites of developing tumors, thus promoting metastasis formation. Although it is well known that MSCs migrate and integrate in the tumor microenvironment (TME), their fate and function inside the tumor is still not clear. In this study, we analyzed the role played by MSCs in breast cancer oncogenesis. Data indicate that interaction of breast cancer cells with MSCs results in an increased proliferation and metabolic activity of breast cancer cells, partially due to MSC-derived microvesicles that are shed in the TME. Moreover, we addressed the question of whether we could modulate such interaction by acting on P2X-mediated intercellular communication. By inhibiting P2X-mediated purinergic signaling, we succeeded in reducing both the cancerogenic as well as the metastatic potential of breast cancer cells co-cultured with MSCs, in 2D as well as in 3D in vitro models. Data obtained demonstrate for the first time that the trophic effect of MSCs on breast cancer cell growth is exerted via ionotropic purinergic signaling, thus suggesting the inhibition of the purinergic signaling system as a potential target for therapeutic intervention.

Rectal sparing approach after preoperative radio- and/or chemotherapy (RESARCH) in patients with rectal cancer: a multicentre observational study.

BACKGROUND: Rectum-sparing approaches appear to be appropriate in rectal cancer patients with a major (mCR) or complete clinical response (cCR) after neoadjuvant therapy. The aim of the present study is to evaluate the effectiveness of rectum-sparing approaches at 2 years after the completion of neoadjuvant treatment. STUDY DESIGN: Patients with rectal adenocarcinoma eligible to receive neoadjuvant therapy will be prospectively enrolled. Patients will be restaged 7-8 weeks after the completion of neoadjuvant therapy and those with mCR (defined as absence of mass, small mucosal irregularity no more than 2 cm in diameter at endoscopy and no metastatic nodes at MRI) or cCR will be enrolled in the trial. Patients with mCR will undergo local excision, while patients with cCR will either undergo local excision or watch and wait policy. The main end point of the study is to determine the percentage of rectum preservation at 2 years in the enrolled patients. CONCLUSION: This protocol is the first prospective trial that investigates the role of both local excision and watch and wait approaches in patients treated with neoadjuvant therapy for rectal cancer. The trial is registered at clinicaltrials.gov (NCT02710812).

T1 colon cancer in the era of screening: risk factors and treatment.

BACKGROUND: The aim of this study was to identify risk factors for lymph node positivity in T1 colon cancer and to carry out a surgical quality assurance audit. METHODS: The sample consisted of consecutive patients treated for early-stage colon lesions in 15 colorectal referral centres between 2011 and 2014. The study investigated 38 factors grouped into four categories: demographic information, preoperative data, indications for surgery and post-operative data. A univariate and multivariate logistic regression analysis was performed to analyze the significance of each factor both in terms of lymph node (LN) harvesting and LN metastases. RESULTS: Out of 507 patients enrolled, 394 patients were considered for analysis. Thirty-five (8.91%) patients had positive LN. Statistically significant differences related to total LN harvesting were found in relation to central vessel ligation and segmental resections. Cumulative distribution demonstrated that the rate of positive LN increased starting at 12 LN harvested and reached a plateau at 25 LN. CONCLUSIONS: Some factors associated with an increase in detection of positive LN were identified. However, further studies are needed to identify more sensitive markers and avoid surgical overtreatment. There is a need to raise the minimum LN count and to use the LN count as an indicator of surgical quality.

Could ICG-aided robotic cholecystectomy reduce the rate of open conversion reported with laparoscopic approach? A head to head comparison of the largest single institution studies.

Comparative studies between robotic and laparoscopic cholecystectomy (LC) focus heavily on economic considerations under the assumption of comparable clinical outcomes. Advancement of the robotic technique and the further widespread use of this approach suggest a need for newer comparison studies. 676 ICG-aided robotic cholecystectomies (ICG-aided RC) performed at the University of Illinois at Chicago (UIC) Division of General, Minimally Invasive and Robotic Surgery were compiled retrospectively. Additionally, 289 LC were similarly obtained. Data were compared to the largest single institution LC data sets from within the US and abroad. Statistically significant variations were found between UIC-RC and UIC-LC in minor biliary injuries (p = 0.049), overall open conversion (p ≤ 0.001), open conversion in the acute setting (p = 0.002), and mean blood loss (p < 0.001). UIC-RC open conversions were also significantly lower than Greenville Health System LC (p ≤ 0.001). Additionally, UIC ICG-RC resulted in the lowest percentages of major biliary injuries (0 %) and highest percentage of biliary anomalies identified (2.07 %). ICG-aided cholangiography and the technical advantages associated with the robotic platform may significantly decrease the rate of open conversion in both the acute and non-acute setting. The sample size discrepancy and the non-randomized nature of our study do not allow for drawing definitive conclusions.

Extralevator with vs nonextralevator abdominoperineal excision for rectal cancer: the RELAPe randomized controlled trial.

AIM: A randomized controlled trial was conducted to test the null hypothesis that there is no difference in circumferential resection margin (CRM) between extralevator abdominoperineal excision (ELAPE) and non-ELAPE for rectal cancer. METHOD: This was a multicentre, randomized controlled trial registered as NCT01702116. Patients with rectal cancer involving the external anal sphincter were randomized to ELAPE or non-ELAPE following neoadjuvant chemoradiation. Randomization was performed according to Consolidated Standards of Reporting Trials (CONSORT) guidelines. The primary end-point was CRM (in mm), defined as the shortest distance between the tumour and the cut edge of the specimen. Pathologists and centralized pathology were blinded to the patients' study arm. Interrater reliability (IRR) was assessed using Kendall's coefficient. Intra-operative perforation (IOP) was any rectal defect determined at pathology. Complications were classified using the Clavien-Dindo classification. Participating surgeons were retrained and credentialed. A sample size calculation showed that 34 subjects would provide sufficient power to reject the null hypothesis. RESULTS: Thirty-four patients underwent the allocated intervention. Seventeen patients treated with ELAPE were comparable with 17 patients treated with non-ELAPE regarding age, gender, body mass index (BMI), American Society of Anesthesiology (ASA) class and pre-existing comorbidities. CRM depth (7.14 ± 5.76 mm vs 2.98 ± 3.28 mm, P = 0.016) and involvement rates (5.8% vs 41.0%, P = 0.04) were significantly increased in patients treated with ELAPE. The IRR for CRM was 0.78. There were no significant differences in IOP (5.8% vs 11.7%, P = 0.77) and complication rates (29% vs 29%, P = 0.97). CONCLUSIONS: ELAPE was associated with statistically improved CRM with no difference in IOP and complication rates compared with non-ELAPE for rectal cancer involving the external anal sphincter.

Downregulation of neuronal vasoactive intestinal polypeptide in Parkinson's disease and chronic constipation.

BACKGROUND: Chronic constipation (CC) is a common and severe gastrointestinal complaint in Parkinson's disease (PD), but its pathogenesis remains poorly understood. This study evaluated functionally distinct submucosal neurons in relation to colonic motility and anorectal function in PD patients with constipation (PD/CC) vs both CC and controls. METHODS: Twenty-nine PD/CC and 10 Rome III-defined CC patients were enrolled. Twenty asymptomatic age-sex matched subjects served as controls. Colonic transit time measurement and conventional anorectal manometry were evaluated in PD/CC and CC patients. Colonoscopy was performed in all three groups. Colonic submucosal whole mounts from PD/CC, CC, and controls were processed for immunohistochemistry with antibodies for vasoactive intestinal polypeptide (VIP) and peripheral choline acetyltransferase, markers for functionally distinct submucosal neurons. The mRNA expression of VIP and its receptors were also assessed. KEY RESULTS: Four subgroups of PD/CC patients were identified: delayed colonic transit plus altered anorectal manometry (65%); delayed colonic transit (13%); altered manometric pattern (13%); and no transit and manometric impairment (9%). There were no differences in the number of neurons/ganglion between PD/CC vs CC or vs controls. A reduced number of submucosal neurons containing VIP immunoreactivity was found in PD/CC vs controls (P<.05). VIP, VIPR1, and VIPR2 mRNA expression was significantly reduced in PD/CC vs CC and controls (P<.05). CONCLUSIONS AND INFERENCES: Colonic motor and rectal sensory functions are impaired in most PD/CC patients. These abnormalities are associated with a decreased VIP expression in submucosal neurons. Both sensory-motor abnormalities and neurally mediated motor and secretory mechanisms are likely to contribute to PD/CC pathophysiology.

Focalyx Dx, Bx, Tx et Apps: A novel contemporary fusion paradigm for the management of prostate cancer.

FocalyxTM conceived as a response to emerging evidence data across numerous cancer lesions that questions current standard treatment approaches that too often lead to detrimental quality of life yet delivering limited survival benefit, especially in-lieu of advances in imaging technology applicable to cancer patients. The Focalyx paradigm aims to control cancer with improvement in quality of life. We initially devised 5 milestones: 1- Consistently optimize Prostate MRI imaging using the novel published protocols adopted as guidelines by societies such as the European Society of Urology and Radiology; 2- Evaluate fusion platform software solutions that existed; 3- Determine best fusión platform for Focalyx on practicality, precision, and workflow premises; 4- Evaluate commercially available FDA approved ablative technologies to implement our treatment vision; 5- Design a treatment option that can be performed in the office setting under local anesthesia, which would not impact negatively QOL outcomes of Prostate Cancer patients and seamless constant nonintrusive practical patient-physician interaction by the Focalyx app that facilitates follow up and provides early warning signals shall any change in the disease dynamics emerge. Prostate cancer was identified as the pilot disease for Focalyx to deliver a "GPS" like solution for the prostate gland that destroys identifiable disease without adverse effects such as: cancer anxiety, urinary incontinence, loss of erections and ejaculation. Since September of 2013, over 300 men have been accrued in NCT02381990- clintrials.gov evaluating the feasibility of our solutions for imaging (FocalyxDx), Biopsy (FocalyxBx) and Treatment (FocalyxTx). In this review we detail the tools available to achieve the Focalyx paradigm for men with Prostate Cancer.

Surgical management of papillary thyroid carcinoma in childhood and adolescence: an Italian multicenter study on 250 patients.

PURPOSE: The extent of surgery for pediatric papillary thyroid carcinoma is debatable. The aim of this study was to evaluate the feasibility of offering pediatric patients a tailored surgical approach based on certain clinical features. METHODS: A national multicenter retrospective review of 250 pediatric patients treated for papillary thyroid carcinoma in a 14-year period was performed. Outcomes of interest included tumor-related features, type of surgery, surgical morbidity, disease-free and overall survival rates. Recurrence was thoroughly analyzed with particular focus on how it correlated with certain patient- and tumor-related features. RESULTS: The majority of patients (58.8 %) had tumors >2 cm in size. Nodal involvement occurred in 115/250 (46 %) patients and distant metastasis in 4 % (10/250). Total thyroidectomy and lobectomy were performed in 90.4 % (226/250) and 9.6 % (24/250) of patients, respectively. The overall rate of surgical complications was 20.8 % (52/250). These included transient and permanent hypoparathyroidism (13.6 and 4.4 %, respectively), and vocal fold palsy (2.8 %). All surgical complications occurred exclusively in the total thyroidectomy group. The rate of recurrent disease was 12 % (30/250) with the vast majority of recurrences (96.6 %) occurring in the total thyroidectomy group. The risk of recurrence correlated significantly with certain tumor-related features (size > 2 cm, multifocality, extrathyroidal invasion, nodal positivity, and distant metastasis). However, it did not correlate with the patient's age or sex. Overall survival was 100 %. CONCLUSION: Pediatric patients are likely to benefit from a tailored surgical strategy. Uniformly offering patients total thyroidectomy seems to be an overly radical approach.

Practice parameters for early colon cancer management: Italian Society of Colorectal Surgery (Società Italiana di Chirurgia Colo-Rettale; SICCR) guidelines.

Early colon cancer (ECC) has been defined as a carcinoma with invasion limited to the submucosa regardless of lymph node status and according to the Royal College of Pathologists as TNM stage T1 NX M0. As the potential risk of lymph node metastasis ranges from 6 to 17% and the preoperative assessment of lymph node metastasis is not reliable, the management of ECC is still controversial, varying from endoscopic to radical resection. A meeting on recent advances on the management of colorectal polyps endorsed by the Italian Society of Colorectal Surgery (SICCR) took place in April 2014, in Genoa (Italy). Based on this material the SICCR decided to issue guidelines updating the evidence and to write a position statement paper in order to define the diagnostic and therapeutic strategy for ECC treatment in context of the Italian healthcare system.

Practice parameters for early rectal cancer management: Italian Society of Colorectal Surgery (Società Italiana di Chirurgia Colo-Rettale; SICCR) guidelines.

The introduction of new technologies for diagnosis and screening programs led to an increasing rate of early detection of colorectal cancer. This, associated with the evolution of endoscopic techniques of local excision, led to the assessment of new strategies to reduce morbidity related to treatment, especially for early rectal cancer (ERC). Nevertheless, the definition of ERC and its staging and treatment algorithm are still under debate. The Italian Society of Colorectal Surgery developed practice guidelines to provide recommendations on the diagnosis, staging and treatment of ERC. A systematic review on the topic was performed by a multidisciplinary group of experts selected based on their clinical and scientific expertise in endoscopy, endoscopic ultrasound, magnetic resonance and surgery, with the aid of an external international audit.

Exploring the role of MKK7 in excitotoxicity and cerebral ischemia: a novel pharmacological strategy against brain injury.

Excitotoxicity following cerebral ischemia elicits a molecular cascade, which leads to neuronal death. c-Jun-N-terminal kinase (JNK) has a key role in excitotoxic cell death. We have previously shown that JNK inhibition by a specific cell-permeable peptide significantly reduces infarct size and neuronal death in an in vivo model of cerebral ischemia. However, systemic inhibition of JNK may have detrimental side effects, owing to blockade of its physiological function. Here we designed a new inhibitor peptide (growth arrest and DNA damage-inducible 45ß (GADD45ß-I)) targeting mitogen-activated protein kinase kinase 7 (MKK7), an upstream activator of JNK, which exclusively mediates JNK's pathological activation. GADD45ß-I was engineered by optimizing the domain of the GADD45ß, able to bind to MKK7, and by linking it to the TAT peptide sequence, to allow penetration of biological membranes. Our data clearly indicate that GADD45ß-I significantly reduces neuronal death in excitotoxicity induced by either N-methyl-D-aspartate exposure or by oxygen-glucose deprivation in vitro. Moreover, GADD45ß-I exerted neuroprotection in vivo in two models of ischemia, obtained by electrocoagulation and by thromboembolic occlusion of the middle cerebral artery (MCAo). Indeed, GADD45ß-I reduced the infarct size when injected 30 min before the lesion in both models. The peptide was also effective when administrated 6 h after lesion, as demonstrated in the electrocoagulation model. The neuroprotective effect of GADD45ß-I is long lasting; in fact, 1 week after MCAo the infarct volume was still reduced by 49%. Targeting MKK7 could represent a new therapeutic strategy for the treatment of ischemia and other pathologies involving MKK7/JNK activation. Moreover, this new inhibitor can be useful to further dissect the physiological and pathological role of the JNK pathway in the brain.