Open vs. laparoscopic vs. robotic pouch excision: unveiling the best approach for optimal outcomes.

INTRODUCTION: Despite advantages for patients with ulcerative colitis, Crohn's disease, and familial adenomatous polyposis, restorative proctocolectomy with ileal pouch-anal anastomosis carries a risk of pouch failure, necessitating pouch excision. The traditional open approach is associated with potential complications. Robotic and laparoscopic techniques are emerging, but comparative outcome data are limited. METHODS: We conducted a retrospective study of consecutive adult patients undergoing robotic, laparoscopic, and open ileal pouch excision at Mayo Clinic, Rochester, MN, between January 2015 and December 2023. We analyzed data on patient characteristics, perioperative variables, and postoperative outcomes, focusing on short-term complications. Statistical analysis included appropriate tests. RESULTS: The study included 123 patients: 23 underwent robotic-assisted pouch excision, 12 laparoscopic, and 82 open. The robotic approach had the longest median operative time (334 ± 170 min, p = 0.03). However, it demonstrated significantly lower estimated blood loss than open (150 ± 200 ml vs. 350 ± 300 ml, p = 0.002) and laparoscopic surgery (250 ± 250 ml, p = 0.005). Robotic and laparoscopic groups required fewer preoperative ureteral stents than the open group (p = 0.001). Additionally, the robotic approach utilized fewer pelvic drainages (p < 0.0001) and had a lower rate of lysis of adhesions > 60 min compared to open surgery (p = 0.003). Robotic procedures had significantly lower 30-day postoperative complications than the open approach (30.4% vs. 65.9%, p = 0.002) while also demonstrating fewer 30-day reoperations than the laparoscopic group (p = 0.04). CONCLUSIONS: Robotic-assisted pouch excision offered significant benefits, including decreased EBL, reduced need for preoperative ureteral stents, and significantly fewer 30-day postoperative complications compared to open surgery.

Assessing robotic-assisted surgery versus open approach in penetrating Crohn's disease: advantages and outcomes in ileocolic resection.

INTRODUCTION: Penetrating Crohn's disease (CD) often necessitates surgical intervention, with the open approach traditionally favored. Robotic-assisted surgery offers potential benefits but remains understudied in this complex patient population. Additionally, the lack of standardized surgical complexity scoring in CD hinders research and comparisons. METHODS: We retrospectively analyzed adult patients with penetrating CD who underwent either robotic-assisted ileocolic resection (RICR) or open ileocolic resection (OICR) at our institution from January 2007 to December 2021. We assessed endpoints, including length of stay, complications, readmissions, reoperations, and other perioperative outcomes. RESULTS: RICR demonstrated safety outcomes comparable to OICR. Importantly, RICR patients experienced significantly reduced estimated blood loss (p < 0.0001), shorter hospital stays (median 4.5 days versus 6.9 days; p = 0.01), lower surgical site infection rates (0% versus 15.4%; p = 0.01), and decreased 30-day readmission rates (0% versus 15.4%; p = 0.01). Linear regression analysis revealed the need for additional strictureplasties (coefficient: 84.8; p = 0.008), colonic resections (coefficient: 41.7; p = 0.008), and estimated blood loss (coefficient: 0.07; p = 0.002) independently correlated with longer operative times). CONCLUSION: Robotic-assisted surgery appears to be a safe and potentially beneficial alternative for the surgical management of penetrating CD, offering advantages in perioperative outcomes reducing length of stay, blood loss, surgical site infection rates, and readmission rates. Further validation with larger cohorts is warranted.

Induced pluripotent stem cell production (CSSi019-A)(14432) from an asymptomatic subject carrying a expansion of C9orf72 gene.

One of the genetic mutations most associated with the onset of amyotrophic lateral sclerosis, both in sporadic and familial cases, is the expansion of the C9orf72 gene. The presence of more than 30 repeats (GGGGCC) correlates with uncertain ALS symptomatology. Here we collected a dermal biopsy from a subject carrying 36 hexanucleotide repeats and reprogrammed it into an induced pluripotent stem cell line. Despite the number of repeat elements, the subject had no symptoms at the age of the biopsy (76 years), thus resulting in a healthy carrier of the mutation.

Effects of Fitlight training on cognitive-motor performance in élite judo athletes.

Aims: The aims of this study were to verify if a 5-week cognitive-motor training (CMT) using FitlightsTM induced changes in young adult judo athletes compared to a non-intervention group. Specifically, it was verified if CMT influenced executive functions (EFs), physical fitness and brain-derived neurotrophic factor (BDNF) levels. Additionally, athletes' competitive results were compared between groups. Method: Twenty-seven athletes (14 males and 13 females; age = 19.5 ± 2.0 years) were assigned to the Fitlight (FG) and control (CG) groups which performed 5 weeks of CMT, respectively, including 25 min per day of Fitlight training or traditional judo practice. All participants performed cognitive (flanker task and forward/backward digit span) and fitness tests (counter movement jump, handgrip test, dynamic and isometric chin up). In addition, BDNF was collected by saliva sampling and competitive results after the intervention period were considered. Results: RM-ANOVA showed significant differences in FG for the accuracy of flanker (p = 0.028) and backward digit span (p < 0.001). Moreover, significant differences in FG were found for relative dynamic chin up (p = 0.027) and counter movement jump (p = 0.05). In addition, a significant difference in FG was found for competitive results after the intervention period (p < 0.01).No significant differences were found for BDNF and other cognitive and fitness measures (p > 0.05). Conclusion: A 5-week judo-specific CMT improved EFs and motor performance in élite judo athletes. It seems that CMT with Fitlight™ could be considered an additional support to coaches during the training period.

Generation of induced pluripotent stem cells (CSSi017-A)(12862) from an ALS patient carrying a repeat expansion in the C9orf72 gene.

Genetic expansions of the hexanucleotide repeats (GGGGCC) in the C9orf72 gene appear in approximately 40% of patients with familial ALS and 7% of patients with sporadic ALS in the European population, making this mutation one of the most prevalent genetic mutations in ALS. Here, we generated a human induced pluripotent stem cell (hiPSC) line from the dermal fibroblasts of a patient carrying a 56-repeat expansion in an ALS disease-causing allele of C9orf72. These iPSCs showed stable amplification in vitro with normal karyotype and high expression of pluripotent markers and differentiated spontaneously in vivo into three germ layers.

Robotic resection of presacral tumors.

BACKGROUND: Presacral tumors are a rare entity typically treated with an open surgical approach. A limited number of minimally invasive resections have been described. The aim of the study is to evaluate the safety and efficacy of roboticresection of presacral tumors. METHODS: This is a retrospective single system analysis, conducted at a quaternary referral academic healthcare system, and included all patients who underwent a robotic excision of a presacral tumor between 2015 and 2023. Outcomes of interest were operative time, estimated blood loss, complications, length of stay, margin status, and recurrence rates. RESULTS: Sixteen patients (11 females and 5 males) were included. The median age of the cohort was 51 years (range 25-69 years). The median operative time was 197 min (range 98-802 min). The median estimated blood loss was 40 ml, ranging from 0 to 1800 ml, with one patient experiencing conversion to open surgery after uncontrolled hemorrhage. Urinary retention was the only postoperative complication that occurred in three patients (19%) and was solved within 30 days in all cases. The median length of stay was one day (range 1-6 days). The median follow-up was 6.7 months (range 1-110 months). All tumors were excised with appropriate margins, but one benign and one malignant tumor recurred (12.5%). Ten tumors were classified as congenital (one was malignant), two were mesenchymal (both malignant), and five were miscellaneous (one malignant). CONCLUSIONS: Robotic resection of select presacral pathology is feasible and safe. Further studies must be conducted to determine complication rates, outcomes, and long-term safety profiles.

Predicting postoperative hypocortisolism in patients with non-aldosterone-producing adrenocortical adenoma: a retrospective single-centre study.

BACKGROUND: Limited information exists on postoperative hypocortisolism and hypothalamus-pituitary-adrenal axis recovery in patients with adrenal incidentaloma following unilateral adrenalectomy. We evaluated frequency of postoperative hypocortisolism and predictors for recovery in non-aldosterone-producing adrenocortical adenoma patients after unilateral adrenalectomy. METHODS: A retrospective analysis of 32 adrenal incidentaloma patients originally included in the ITACA trial (NCT04127552) with confirmed non-aldosterone-producing adrenocortical adenoma undergoing unilateral adrenalectomy from September 2019 to April 2023 was conducted. Preoperative assessments included adrenal MRI, anthropometrics, evaluation of comorbidities, adrenal function assessed via ACTH, urinary free cortisol, and 1 mg dexamethasone suppression test. ACTH and serum cortisol or Short Synacthen test were performed within 6 days, 6 weeks, 6 months, and a year after surgery. RESULTS: Six days postoperative, 18.8% of patients had normal adrenal function. Among those with postoperative hypocortisolism, 53.8% recovered by 6 weeks. Patients with earlier adrenal recovery (6 weeks) had lower preoperative 1 mg dexamethasone suppression test (median 1 mg dexamethasone suppression test 76.2 [61.8-111.0] nmol/L vs 260.0 [113.0-288.5] nmol/L, p < 0.001). Univariate analysis showed preoperative 1 mg dexamethasone suppression test negatively related with baseline ACTH levels (r = - 0.376; p = 0.041) and negatively associated with the 6-week baseline (r = - 0.395, p = 0.034) and 30-min cortisol levels during Short Synacthen test (r = - 0.534, p = 0.023). Logistic regression analysis demonstrated preoperative 1 mg dexamethasone suppression test as the only biochemical predictor for 6-week adrenal recovery: ROC curve identified a 1 mg dexamethasone suppression test threshold of 131 nmol/L predicting 6-week recovery with 89.5% sensitivity and 72.7% specificity (AUC 0.87; 95% CI 66.9-98.7, p < 0.001). Other preoperative assessments (tumor size, ACTH levels and anthropometrics) were not associated with postoperative hypothalamus-pituitary-adrenal axis function, but the presence of diabetes was associated with a lower probability of recovery (OR = 24.55, p = 0.036). ACTH levels increased postoperatively in all patients but did not predict hypothalamus-pituitary-adrenal axis recovery. CONCLUSIONS: The preoperative 1 mg dexamethasone suppression test cortisol value and presence of diabetes are the only relevant predictor of hypothalamus-pituitary-adrenal axis recovery in patients with non-aldosterone- producing adrenocortical adenoma undergoing surgery, regardless other clinical and biochemical variables. Notably, pre- and postoperative ACTH levels did not predict hypothalamus-pituitary-adrenal axis recovery. These findings point towards the potential for saving resources by optimizing their allocation during follow-up assessments for patients with non-aldosterone-producing adrenocortical adenoma undergoing unilateral adrenalectomy.

A comparison of surgical techniques for perineal wound closure following perineal excision: a systematic review and network meta-analysis.

BACKGROUND: To mitigate pelvic wound issues following perineal excision of rectal or anal cancer, a number of techniques have been suggested as an alternative to primary closure. These methods include the use of a biological/dual mesh, omentoplasty, muscle flap, and/or pelvic peritoneum closure. The aim of this network analysis was to compare all the available surgical techniques used in the attempt to mitigate issues associated with an empty pelvis. METHODS: An electronic systematic search using MEDLINE databases (PubMed), EMBASE, and Web of Science was performed (Last date of research was March 15th, 2023). Studies comparing at least two of the aforementioned surgical techniques for perineal wound reconstruction during abdominoperineal resection, pelvic exenteration, or extra levator abdominoperineal excision were included. The incidence of primary healing, complication, and/or reintervention for perineal wound were evaluated. In addition, the overall incidence of perineal hernia was assessed. RESULTS: Forty-five observational studies and five randomized controlled trials were eligible for inclusion reporting on 146,398 patients. All the surgical techniques had a comparable risk ratio (RR) in terms of primary outcomes. The pooled network analysis showed a lower RR for perineal wound infection when comparing primary closure (RR 0.53; Crl 0.33, 0.89) to muscle flap. The perineal wound dehiscence RR was lower when comparing both omentoplasty (RR 0.59; Crl 0.38, 0.95) and primary closure (RR 0.58; Crl 0.46, 0.77) to muscle flap. CONCLUSIONS: Surgical options for perineal wound closure have evolved significantly over the last few decades. There remains no clear consensus on the "best" option, and tailoring to the individual remains a critical factor.

Glucocorticoids and cognitive function: a walkthrough in endogenous and exogenous alterations.

PURPOSE: The hypothalamic-pituitary-adrenal (HPA) axis exerts many actions on the central nervous system (CNS) aside from stress regulation. Glucocorticoids (GCs) play an important role in affecting several cognitive functions through the effects on both glucocorticoid (GR) and mineralocorticoid receptors (MR). In this review, we aim to unravel the spectrum of cognitive dysfunction secondary to derangement of circulating levels of endogenous and exogenous glucocorticoids. METHODS: All relevant human prospective and retrospective studies published up to 2022 in PubMed reporting information on HPA disorders, GCs, and cognition were included. RESULTS: Cognitive impairment is commonly found in GC-related disorders. The main brain areas affected are the hippocampus and pre-frontal cortex, with memory being the most affected domain. Disease duration, circadian rhythm disruption, circulating GCs levels, and unbalanced MR/GR activation are all risk factors for cognitive decline in these patients, albeit with conflicting data among different conditions. Lack of normalization of cognitive dysfunction after treatment is potentially attributable to GC-dependent structural brain alterations, which can persist even after long-term remission. CONCLUSION: The recognition of cognitive deficits in patients with GC-related disorders is challenging, often delayed, or mistaken. Prompt recognition and treatment of underlying disease may be important to avoid a long-lasting impact on GC-sensitive areas of the brain. However, the resolution of hormonal imbalance is not always followed by complete recovery, suggesting irreversible adverse effects on the CNS, for which there are no specific treatments. Further studies are needed to find the mechanisms involved, which may eventually be targeted for treatment strategies.

Efficacy of laparoscopic Toupet fundoplication compared to endoscopic and surgical procedures for GERD treatment: a randomized trials network meta-analysis.

PURPOSE: We aim to review and quantitatively compare laparoscopic Toupet fundoplication (LTF), Nissen fundoplication (LNF), anterior partial fundoplication (APF), magnetic augmentation sphincter (MSA), radiofrequency ablation (RFA), transoral incisionless fundoplication (TIF), proton pump inhibitor (PPI), and placebo for the treatment of GERD. A number of meta-analyses compared the efficacy of surgical and endoscopic procedures for recalcitrant GERD, but considerable debate on the effectiveness of operative strategies remains. METHODS: A systematic review of MEDLINE databases, EMBASE, and Web of Science for randomized controlled trials (RCTs) comparing the aforementioned surgical and endoscopic GERD treatments was performed. Risk ratio and weighted mean difference were used as pooled effect size measures, whereas 95% credible intervals (CrI) were used to assess relative inference. RESULTS: Thirty-three RCTs were included. Surgical and endoscopic treatments have similar RR for heartburn, regurgitation, bloating. LTF has a lower RR of post-operative dysphagia when compared to APF (RR 3.3; Crl 1.4-7.1) and LNF (RR 2.5; Crl 1.3-4.4). The pooled network meta-analysis did not observe any significant improvement regarding LES pressure and pH < from baseline. LTF, APF, LNF, MSA, RFA, and TIF had have a similar post-operative PPI discontinuation rate. CONCLUSION: LTF has a lower rate of post-operative dysphagia when compared to APF and LNF. The pre-post effects, such as GERD-HQRL, LES pressure, and pH <4, should be avoided in meta-analyses because results may be biased. Last, a consensus about the evaluation of GERD treatments' efficacy and their outcomes is needed.

A quantitative cholinergic and catecholaminergic 3D Atlas of the developing mouse brain.

The complex organization of brain regions during development requires a three-dimensional approach to facilitate the visualization and quantification of dynamic changes taking place throughout this important period. Using the tissue clearing method combined with immunohistochemistry, three-dimensional (3D) lightsheet microscopy and a multiresolution registration technique, we provide the first 3D atlases of the main cholinergic (CH) and catecholaminergic (CA) systems in the mouse brain from embryonic day 12 (E12) to post-natal day 8 (P8). We report that in several brain structures, there is a logarithmic scale increase of choline acetyltransferase and tyrosine hydroxylase positive neurons from E18 to P8. In addition, a detailed voxel-wise analysis revealed abrupt modifications in the developmental trajectory of many brain structures during the transition from E18 to P0. Our atlases will not only facilitate developmental studies aimed at quantitatively determining the fate of CH or CA neurons in utero but also be used as an anatomical reference to quantify other neuronal populations present in the annotated regions. In the future, these maps will be a reliable tool to study developmental malformations associated with neurological and psychiatric disorders.

Laparoscopic transperitoneal hernia repair (TAPP) in emergency: long-term follow-up in a high volume centre.

PURPOSE: Aim of this study was to analyse feasibility, safety and effectiveness of laparoscopic transperitoneal hernia repair (TAPP) approach to inguinal hernias in the emergency setting, with a longer follow-up than the studies present in literature. METHODS: We retrospectively analysed all patients who underwent emergency TAPP hernia repair in San Marco Hospital (Zingonia, Italy), from September 2010 to June 2020. A prospectively collected database of 685 consecutive TAPP hernia repair was reviewed. Feasibility and safety were evaluated through operative time, conversion rate, perioperative mortality, morbidity and prosthesis infection rate. Effectiveness was assessed by recurrence and complication rate, acute (during admission) and chronic (during follow-up) pain by Visual Analogic Scale (VAS), and recovery to normal activity in a long-term follow-up (mean period 1718 days). RESULTS: The final study group included 47 patients. The mean age was 59.6 years (range 22-89), 29 patients were male and 18 were female. The mean operation time was 64 min. Two cases were converted to open approach (4%). In four cases bowel resection became necessary (8.5%). Appendicectomy and omentectomy occurred once and twice, respectively (2% and 4%), and orchiectomy was required in two patients (4%). Seroma was the only postoperative complication that we registered in four patients. During a mean follow-up period of 1718 days, there was no recurrence of the hernia or other complications. Five patients referred mild occasional groin pain (VAS < 3), with quick relief without taking any pain killers. CONCLUSION: TAPP approach is a safe, feasible and effective therapeutic option for groin hernias in emergency setting. No recurrence or severe complications were reported in over 4 years of follow-up.

Interferon-γ Involvement in the Neuroinflammation Associated with Parkinson's Disease and L-DOPA-Induced Dyskinesia.

Interferon-γ (IFN-γ) is a proinflammatory cytokine that activates glial cells. IFN-γ is increased in the plasma and brain of Parkinson's disease patients, suggesting its potential role in the disease. We investigated whether the IFN-γ deficiency could interfere with nigrostriatal degeneration induced by the neurotoxin 6-hydroxydopamine, L-DOPA-induced dyskinesia, and the neuroinflammatory features as astrogliosis, microgliosis, and induced nitric oxide synthase (iNOS) immunoreactivity induced by L-DOPA treatment. Wild type (WT) and IFN-γ knockout (IFN-γ/KO) mice received unilateral striatal microinjections of 6-hydroxydopamine. Animals were sacrificed 1, 3, 7, and 21 days after lesions. Additional group of WT and IFN-γ/KO parkinsonian mice, after 3 weeks of neurotoxin injection, received L-DOPA (intraperitoneally, for 21 days) resulting in dyskinetic-like behavior. Tyrosine hydroxylase immunostaining indicated the starting of dopaminergic lesion since the first day past toxin administration, progressively increased until the third day when it stabilized. There was no difference in the lesion and L-DOPA-induced dyskinesia intensity between WT and IFN-γ/KO mice. Remarkably, IFN-γ/KO mice treated with L-DOPA presented in the lesioned striatum an increase of iNOS and glial fibrilary acid protein (GFAP) density, compared with the WT group. Morphological analysis revealed the rise of astrocytes and microglia reactivity in IFN-γ/KO mice exibiting dyskinesia. In conclusion, IFN-γ/KO mice presented an intensification of the inflammatory reaction accompanying L-DOPA treatment and suggest that iNOS and GFAP increase, and the activation of astrocytes and microglia induced afterward L-DOPA treatment was IFN-γ independent events. Intriguingly, IFN-γ absence did not affect the degeneration of dopaminergic neurons or LID development.

Metastasis-directed stereotactic body radiation therapy in the management of oligometastatic head and neck cancer.

INTRODUCTION: Recently major efforts have been made to define the oligometastatic setting, but for head and neck cancer (HNC) limited data are available. We aimed to evaluate outcome of oligometastatic HNC treated with Stereotactic body radiotherapy (SBRT) as metastasis-directed therapy. MATERIALS AND METHODS: We analyzed patients treated with SBRT on a maximum of five oligometastases from HNC, in up to two organs. Concomitant treatment was allowed. End points were toxicity, local control of treated metastases (LC), progression-free survival (PFS) and overall survival (OS). RESULTS: 48 consecutive patients and 71 lesions were treated. With a follow-up of 20.2 months, most common primary tumors were larynx (29.2%) and salivary glands (29.2%), while common site of metastases was lung (59.1%). Median dose was 48 Gy (21-75) in 3-8 fractions. Treatment was well tolerated, with two patients reporting mild pain and nausea. LC rates at 1 and 2 years were 83.1% and 70.2%. Previous local therapy (HR 4.97; p = 0.002), oligoprogression (HR 4.07; p = 0.031) and untreated metastases (HR 4.19; p = 0.027) were associated with worse LC. PFS at 1 and 2 years were 42.2% and 20.0%. Increasing age (HR 1.03; p = 0.010), non-adenoid cystic carcinoma (HR 2.57; p = 0.034) and non-lung metastases (HR 2.20; p = 0.025) were associated with worse PFS. One- and 2-years OS were 81.0% and 67.1%. Worse performance status (HR 2.91; p = 0.049), non-salivary primary (HR 19.9; p = 0.005), non-lung metastases (HR 2.96; p = 0.040) were correlated with inferior OS. CONCLUSIONS: SBRT can be considered a safe metastasis-directed therapy in oligometastatic HNC. Efficacy of the treatment seems to be higher when administered upfront in the management of metastatic disease; however, selection of patients need to be improved due to the relevant risk of appearance of new metastatic site after SBRT.

Clinical and functional outcomes of the remplissage technique to repair anterior shoulder dislocation: average 7 years of follow-up.

PURPOSE: The purpose of this work is to report mid- to long-term clinical results, recurrence rates and instability following surgery to repair anterior dislocation of the shoulder by the remplissage technique. METHODS: This was a retrospective case series at a single center with patients with anterior shoulder instability that received surgery using the remplissage technique. Rowe questionnaire, instability complaints, recurrence episodes and return to sport were analyzed. RESULTS: Of all patients screened, 21 (92.3%) were enrolled and only 2 patients were lost to follow-up. The mean age of the patients at the time of surgery was 27.8y.o., and the mean number of dislocations before surgery was 3.2 episodes. The follow-up average was 83.8 months (range 28-126). No case of postoperative infection was observed. Two patients (9.5%) had recurrent shoulder instability and required reintervention after 18 and 48 months. The average final Rowe score was 92.9 (range 75-100). All patients that played sports before surgery returned to the sport, and 73.7% of them returned to the same activity level. CONCLUSION: The remplissage technique applied to repair anterior shoulder dislocation with humeral bone loss presents good results regarding clinical scores, shoulder stability and acceptable rates of return to sports, even in a mid- to long-term follow-up. LEVEL OF EVIDENCE: IV.

Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial.

BACKGROUND: Oxaliplatin-based adjuvant chemotherapy is the standard treatment of high-risk colon cancer (CC). A shorter duration (3 months) can achieve a similar outcome [in terms of relapse-free survival (RFS)] to a longer duration. This study reports the overall survival (OS) analysis of the three or six colon adjuvant (TOSCA) phase III study. It assessed different adjuvant chemotherapy durations in patients with resected high-risk stage II and stage III CC. MATERIAL AND METHODS: TOSCA was an open-label, phase III, multicentre, non-inferiority trial conducted in 130 Italian centres. Patients were randomly assigned, in a 1 : 1 ratio, to receive 3 months of standard doses of FOLFOX/CAPOX, or 6 months of FOLFOX/CAPOX. Patients with histologically confirmed high-risk stage II and III CC were included, with RFS being the primary end point. OS was a secondary end point. RESULTS: From June 2007 to March 2013, 3759 patients were accrued. At a median follow-up of 7 years, the hazard ratio (HR) for RFS of the 3-month versus 6-month arms was 1.13; 95% confidence interval (CI) 0.99-1.29, P for non-inferiority = 0.380, P for superiority = 0.068, crossing the non-inferiority limit of 1.20. This result did not allow us to reject the null hypothesis of the inferiority of the 3-month arm. The HR for OS of the 3-month versus 6-month arms was 1.09 (95% CI 0.93-1.26, P for superiority = 0.288). At the last follow-up analysis, the absolute OS difference between arms was <1%. CONCLUSIONS: The present analysis of the TOSCA trial does not indicate any significant difference in OS between the treatment groups. The extra benefit provided by the longer treatment should be balanced against the extra toxicity of more prolonged therapy. The trial is registered with ClinicalTrials.gov, registration number: NCT0064660.

Onset of granulomatosis with polyangiitis obscured by heart disease in an elderly man.

We describe a case of 85-year-old man who presented to the Emergency Department with sudden dyspnea. He had a past medical history of cardiomyopathy and radiography and nonenhanced computed tomography (CT) of the chest showed pulmonary edema. Despite intravenous diuretic therapy, there was no clinical improvement. Cardiac CT was then performed showing a solid pulmonary nodular lesion with intralesional cavitations, ground-glass opacities, and peripheral vascularization. CT-guided needle lung biopsy yielded a diagnosis of granulomatosis with polyangiitis (Wegener granulomatosis). Medical treatment with cyclophosphamide and prednisone produced rapid symptomatic improvement and complete resolution of the radiological findings. This case demonstrates the challenges in making this diagnosis in an elderly patient with heart disease. We found very few documented cases where there was onset of granulomatosis with polyangiitis at this age.

Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth.

Genetic mutations of the Methyl-CpG-binding protein-2 (MECP2) gene underlie Rett syndrome (RTT). Developmental processes are often considered to be irrelevant in RTT pathogenesis but neuronal activity at birth has not been recorded. We report that the GABA developmental shift at birth is abolished in CA3 pyramidal neurons of Mecp2-/y mice and the glutamatergic/GABAergic postsynaptic currents (PSCs) ratio is increased. Two weeks later, GABA exerts strong excitatory actions, the glutamatergic/GABAergic PSCs ratio is enhanced, hyper-synchronized activity is present and metabotropic long-term depression (LTD) is impacted. One day before delivery, maternal administration of the NKCC1 chloride importer antagonist bumetanide restored these parameters but not respiratory or weight deficits, nor the onset of mortality. Results suggest that birth is a critical period in RTT with important alterations that can be attenuated by bumetanide raising the possibility of early treatment of the disorder.

Pyramidal neuron growth and increased hippocampal volume during labor and birth in autism.

We report that the apical dendrites of CA3 hippocampal pyramidal neurons are increased during labor and birth in the valproate model of autism but not in control animals. Using the iDISCO clearing method, we show that hippocampal, especially CA3 region, and neocortical volumes are increased and that the cerebral volume distribution shifts from normal to lognormal in valproate-treated animals. Maternal administration during labor and birth of the NKCC1 chloride transporter antagonist bumetanide, which reduces [Cl-]i levels and attenuates the severity of autism, abolished the neocortical and hippocampal volume changes and reduced the whole-brain volume in valproate-treated animals. These results suggest that the abolition of the oxytocin-mediated excitatory-to-inhibitory shift of GABA actions during labor and birth contributes to the pathogenesis of autism spectrum disorders by stimulating growth during a vulnerable period.