IL-37-a putative therapeutic agent in cardiovascular diseases.

Although it is a member of the Interleukin (IL)-1 family, IL-37 is unique in that it has wide-ranging anti-inflammatory characteristics. It was originally thought to prevent IL-18-mediated inflammation by binding to the IL-18-binding protein. However, upon discovery that it binds to the orphan receptor, IL-1R8, further studies have revealed an expanded role of IL-37 to include several intracellular and extracellular pathways that affect various aspects of inflammation. Its potential role specifically in cardiovascular diseases (CVD) stemmed initially from the discovery of elevated plasma IL-37 levels in human patients with acute coronary syndrome and atrial fibrillation. Other studies using mouse models of ischemia/reperfusion injury, vascular calcification and myocardial infarction have revealed that IL-37 can have a beneficial role in these conditions. This review will explore recent research on the effects of IL-37 on the pathogenesis of CVD.

Risk factors for surgical site infection after groin hernia repair: does the mesh or technique matter?

INTRODUCTION: Surgical site infections (SSIs) following groin hernia repair (GHR) are getting rarer in high income countries despite a wider use of meshes. Among the risk factors for SSIs, those related to the mesh and the surgical technique have rarely been described. METHODS: A registry-based multicenter study using prospectively collected data, including SSIs and their potential risk factors, was conducted in the French Hernia-Club. RESULTS: Between 2012 and 2019, 21,976 consecutive unselected adult patients aged 64.8 ± 15.4 years old (88.9% male) underwent GHR (83.5% unilateral). Fifty four percent were laparoscopic; 97.6% used mesh. The overall incidence of SSI was 0.26%. The incidence of SSI was respectively, 0.24% and 0.19% (p = 0.420) in open vs laparoscopic repairs; 0.19% and 0.25% (p = 0.638) for polyester vs polypropylene mesh; In adjusted multivariate analysis focusing on macroporous meshes (which were the most implanted meshes: 23,148 out of 24,099), there were no differences in terms of SSIs' rates regarding the technique: open versus laparoscopy (p = 0.762) nor the type of mesh used: polypropylene versus polyester (p = 0.557). CONCLUSION: The rate of SSI following GHR was low in this large registry study. Mesh type and surgical technique did not affect SSIs rates. Caution is advised when interpreting these data due to this very low rate of SSI and the potential for a type II error.

Levator ani and puborectalis muscle rupture: diagnosis and repair for perineal instability.

BACKGROUND: Puborectalis muscle rupture usually arises from peri-partum perineal trauma and may result in anterior, middle compartment prolapses, posterior compartment prolapse which includes rectocele and rectal prolapse, with or without associated anal sphincter damage. Patients with puborectalis muscle and levator ani rupture may present some form of incontinence or evacuation disorder, sexual dysfunction or pelvic organ descent. However, the literature on this subject is scarce. The aim of our study was to evaluate management and treatment of functional disorders associated with puborectalis and/or pubococcygei rupture at the level of the insertion in the pubis in a cohort of patients referred to a tertiary care coloproctology center. METHODS: We conducted a prospective cohort study of patients with levator ani and puborectalis muscle avulsion in the Proctology and Pelvic Floor Unit, Division of Digestive Surgery of the University Hospitals of Geneva from January 2001 to November 2018. Clinical examination, anoscopy and ultrasound were performed on a routine basis. Rupture of the levator ani muscle was diagnosed by clinical examination and ultrasound. A Wexner incontinence score was completed before and 6 months after surgery. Levator ani muscle repair was performed using a transvaginal approach. RESULTS: Fifty-two female patients (median age 56 ± 11.69 SD years, range 38-86 years) were included in the study. Thirty-one patients (59.6%) had anal incontinence, 25 (48.1%) urinary incontinence, 28 (53.9%) dyschezia (obstructive defecation or excessive straining to defecate), 20 (38.5%) dyspareunia, 17 (32.7%) colpophony, and 13 (25.0%) impaired sensation during sexual intercourse. Deviation of the anus on the side opposite the lesion was observed in 50 patients (96.2%), confirmed with clinical examination and both endoanal and perineal ultrasound. Out of these 52 patients, levator ani rupture (including puborectalis rupture) were categorized into right sided, 43 (82.69%), left sided, 7 (13.46%) and bilateral, 2 (3.85%). Levator ani muscle repair was performed in all patients, associated with posterior repair and levatorplasty in 26 patients (50%) and with sphincteroplasty in 34 patients (63.4%). Four patients (7.7%) experienced postoperative complications: significant postoperative pain (n = 3; 5.77%), urinary retention (n = 2; 3.85%), hematoma (n = 1; 1.92%), and perineal abscess (n = 1; 1.92%). Forty-one patients (78.8%) had full restoration of normal puborectalis muscle function (Wexner score: 0/20) after surgery, and overall, all patients had an improvement in the Wexner score and in sexual function. Dyschezia was reported by 28 patients (53.9%) preoperatively, resolved in 18 (64.3%) and improved by 50% or more in 10 (35.71%). CONCLUSIONS: Diagnosis of levator ani and puborectalis muscle rupture requires careful history taking, clinical examination, endoanal and perineal ultrasound. Surgical repair improved anal continence as well as sexual function in all patients. Transvaginal levator ani repair seems to be well tolerated with good short-term results.

Sinecatechins ointment as a potential novel treatment for usual type vulval intraepithelial neoplasia: a single-centre double-blind randomised control study.

OBJECTIVE: To compare the safety and efficacy of 10% sinecatechins (Veregen® ) ointment against placebo in the treatment of usual type vulvar intraepithelial neoplasia (uVIN). DESIGN: A Phase II double-blind randomised control trial. SETTING: A tertiary gynaecological oncology referral centre. POPULATION: All women diagnosed with primary and recurrent uVIN. METHODS: Eligible patients were randomised 1:1 to receive either sinecatechins or placebo ointment (applied three times daily for 16 weeks) and were followed up at 2, 4, 8, 16, 32 and 52 weeks. MAIN OUTCOME MEASURES: The primary outcome measure, recorded at 16 and 32 weeks, was histological response (HR). Secondary outcome measures included clinical (CR) response, toxicity, quality of life and pain scores. RESULTS: There was no observed difference in HR between the two arms. However, of the 26 patients who were randomised, all 13 patients who received sinecatechins showed either complete (n = 5) or partial (n = 8) CR, when best CR was evaluated. In placebo group, three patients had complete CR, two had partial CR, six had stable disease and two were lost to follow up. Patients in the sinecatechins group showed a statistically significant improvement in best observed CR as compared with the placebo group (P = 0.002). There was no difference in toxicity reported in either group. CONCLUSION: Although we did not observe a difference in HR between the two treatment arms, we found that 10% sinecatechins application is safe and shows promise in inducing clinical resolution of uVIN lesions and symptom improvement, thus warranting further investigation in a larger multicentre study. TWEETABLE ABSTRACT: A randomised control study indicating that sinecatechins ointment may be a novel treatment for uVIN.

Initial experience with the convergent procedure for longstanding persistent atrial fibrillation: A 5 year dataset.

In patients with longstanding persistent atrial fibrillation (AF), outcomes from catheter ablation remain suboptimal. The convergent procedure combines minimally invasive surgical ablation with subsequent catheter ablation, and may contribute towards maintenance of sinus rhythm in this patient group. We performed the convergent procedure on 43 patients with longstanding persistent AF from 2013-2018. Patients underwent clinical review at 3, 6, and 12 months and thereafter as necessitated by their symptoms. Our dataset describes patients' baseline characteristics and rhythm control protocols, as well as outcomes including arrhythmia recurrence, the need for antiarrhythmic drugs, requirement for repeat rhythm control procedures, and complications. These data provide a real world insight into the risks and benefits of the convergent procedure in patients with longstanding persistent AF.

The convergent procedure versus catheter ablation alone in longstanding persistent atrial fibrillation: A single centre, propensity-matched cohort study.

BACKGROUND: Maintenance of sinus rhythm is challenging in patients with longstanding persistent atrial fibrillation (PeAF). Minimally invasive surgical AF ablation may improve outcomes when combined with catheter ablation (the 'convergent' procedure). This study evaluates the safety and efficacy of the convergent procedure versus catheter ablation alone in longstanding PeAF. METHODS: 43 consecutive patients with longstanding PeAF underwent subxiphoid endoscopic ablation of the posterior left atrium followed by catheter ablation from 2013 to 2018. The primary outcome was AF-free survival at 12 months; secondary outcomes included change in EHRA class, echocardiographic data, procedural complications, freedom from anti-arrhythmic drugs (AADs), and long term arrhythmia-free survival. Outcomes were compared with a matched group of 43 patients who underwent catheter ablation alone. Both groups underwent multiple catheter ablations as required. Baseline characteristics were similar between groups. RESULTS: After 12 months, the convergent procedure was associated with increased AF-free survival on AADs (60.5% versus 25.6%, p = .002) and off AADs (37.2% versus 13.9%, p = .025), versus catheter ablation. Allowing for multiple procedures, after 30.5 ±â€¯13.3 months' follow-up the convergent procedure was associated with increased arrhythmia-free survival on AADs (58.1% versus 30.2%, p = .016) and off AADs (32.5% versus 11.6%, p = .036) versus catheter ablation. There were more complications in the convergent procedure group (11.6% versus 2.3%, p = .2). Multivariate analysis identified only the convergent procedure (OR 3.06 (1.23-7.6), p = .017) as predictive of arrhythmia-free survival long term. CONCLUSIONS: In longstanding PeAF, the convergent procedure is associated with improved arrhythmia-free survival versus catheter ablation alone. Complication rates are significant but have been shown to depreciate with experience.

Diagnostic accuracy of content-based dermatoscopic image retrieval with deep classification features.

BACKGROUND: Automated classification of medical images through neural networks can reach high accuracy rates but lacks interpretability. OBJECTIVES: To compare the diagnostic accuracy obtained by using content-based image retrieval (CBIR) to retrieve visually similar dermatoscopic images with corresponding disease labels against predictions made by a neural network. METHODS: A neural network was trained to predict disease classes on dermatoscopic images from three retrospectively collected image datasets containing 888, 2750 and 16 691 images, respectively. Diagnosis predictions were made based on the most commonly occurring diagnosis in visually similar images, or based on the top-1 class prediction of the softmax output from the network. Outcome measures were area under the receiver operating characteristic curve (AUC) for predicting a malignant lesion, multiclass-accuracy and mean average precision (mAP), measured on unseen test images of the corresponding dataset. RESULTS: In all three datasets the skin cancer predictions from CBIR (evaluating the 16 most similar images) showed AUC values similar to softmax predictions (0·842, 0·806 and 0·852 vs. 0·830, 0·810 and 0·847, respectively; P > 0·99 for all). Similarly, the multiclass-accuracy of CBIR was comparable with softmax predictions. Compared with softmax predictions, networks trained for detecting only three classes performed better on a dataset with eight classes when using CBIR (mAP 0·184 vs. 0·368 and 0·198 vs. 0·403, respectively). CONCLUSIONS: Presenting visually similar images based on features from a neural network shows comparable accuracy with the softmax probability-based diagnoses of convolutional neural networks. CBIR may be more helpful than a softmax classifier in improving diagnostic accuracy of clinicians in a routine clinical setting.

Effects of branched chain amino acid supplementation on patient care outcomes in adults and children with liver cirrhosis: A systematic review.

BACKGROUND & AIMS: Malnutrition is highly prevalent in chronic liver disease (CLD) due to alterations in nutrient utilization, malabsorption and poor intake. Low serum concentrations of branched chain amino acids (BCAA) in the presence of elevated aromatic acid concentrations is commonly observed in adult and children with liver cirrhosis and is associated with malnutrition and other adverse patient outcomes. The efficacy of BCAA supplementation has not been well established in adults and children with CLD. The purpose of this review was to critically evaluate the literature regarding the impact of BCAA supplementation related to changes in body composition, muscle strength, liver biomarkers, medical and hepatic complications (hepatic encephalopathy (HE), ascites, edema) and patient care outcomes (event free survival, health related quality of life, length of hospitalization). METHODS: A total of 40 articles retrieved from PubMed or Web of Science databases (1989-2017) were included. RESULTS: BCAA supplementation may be beneficial in improving muscle strength, ascites and edema with potential clinically significant improvements in HE in adult liver patients. In children, limited data have shown that BCAA supplementation may exert favourable effects on weight, fat mass, fat free mass and serum albumin level. CONCLUSIONS: Heterogeneity of study findings attributed to variability in BCAA dose (total, relative proportions), duration, disease severity and lack of uniformity in tools used for assessing patient outcomes limit overall conclusions. Longitudinal studies examining the efficacy of BCAA supplementation as a therapeutic treatment of malnutrition in chronic liver disease is warranted.

Successful treatment of chronic hepatitis C infection with crushed elbasvir/grazoprevir administered via a percutaneous endoscopic gastrostomy tube.

WHAT IS KNOWN AND OBJECTIVE: Elbasvir/grazoprevir is an all-oral regimen approved for patients with hepatitis C virus (HCV) genotypes 1 and 4, and in renal insufficiency. However, to date, no data exist on the efficacy of this regimen when it is crushed and administered through a percutaneous endoscopic gastrostomy (PEG) tube. Here, we illustrate the case of a 63-year-old man who is the only known patient with HCV infection in the English literature to have successfully achieved a sustained viral response (SVR) when elbasvir/grazoprevir oral combination was administered through a PEG tube. CASE SUMMARY: A 63-year-old man with worsening HCV-associated membranoproliferative glomerulonephritis was referred to the gastroenterology clinic for prompt HCV treatment. He had history of high-grade mucoepidermoid carcinoma of the parotid status post-resection and was expected to develop severe mucositis and dysphagia during radiation precluding typical oral therapy of his HCV. He received a PEG tube for nutrition and underwent a 16 week course of crushed Elbasvir/Grazoprevir for HCV treatment through the PEG. At the end of the therapy he achieved SVR and his kidney function also improved. WHAT IS NEW AND CONCLUSION: We present the first known clinical case of a non-cirrhotic patient with HCV genotype 1A with HCV-related MPGN treated successfully with crushed Elbasvir/Grazoprevir administered through a PEG tube. With the prevalence of PEG tube insertion and HCV on a rise, we expect these 2 population cohorts to intersect in the future. Our report may serve as a guidance in such clinical scenario.

Continuous infusion vs. intermittent bolus injection of furosemide in acute decompensated heart failure: systematic review and meta-analysis of randomised controlled trials.

Loop diuretics remain a fundamental pharmacological therapy to remove excess fluid and improve symptom control in acute decompensated heart failure. Several recent randomised controlled trials have examined the clinical benefit of continuous vs. bolus furosemide in acute decompensated heart failure, but have reported conflicting findings. The aim of this review was to compare the effects of continuous and bolus furosemide with regard to mortality, length of hospital stay and its efficacy profile in acute decompensated heart failure. All parallel-arm randomised controlled trials from MEDLINE, EMBASE, PubMed and the Cochrane Database of Systematic Reviews from inception until May 2017 were included. Cross-over randomised controlled trials, observational studies, case reports, case series and non-systematic reviews that involved children were excluded. Eight trials (n = 669) were eligible for inclusion. There was no difference between furosemide continuous infusion and bolus administration for all-cause mortality (four studies; n = 491; I2 = 0%; OR 1.65; 95%CI 0.93-2.91; p = 0.08) or duration of hospitalisation (six studies; n = 576; I2 = 71%; mean difference 0.27; 95%CI -1.35 to 1.89 days; p = 0.74). Continuous infusion of intravenous furosemide was associated with increased weight reduction (five studies; n = 516; I2 = 0%; mean difference 0.70; 95%CI 0.12-1.28 kg; p = 0.02); increased total urine output in 24 h (four studies; n = 390; I2 = 33%; mean difference 461.5; 95%CI 133.7-789.4 ml; p < 0.01); and reduced brain natriuretic peptide (two studies; n = 390; I2 = 0%; mean difference 399.5; 95%CI 152.7-646.3 ng.l-1 ; p < 0.01), compared with the bolus group. There was no difference in the incidence of raised creatinine and hypokalaemia between the two groups. In summary, there was no difference between continuous infusion and bolus of furosemide for all-cause mortality, length of hospital stay and electrolyte disturbance, but continuous infusion was superior to bolus administration with regard to diuretic effect and reduction in brain natriuretic peptide.

Repurposing Zidovudine in combination with Tigecycline for treating carbapenem-resistant Enterobacteriaceae infections.

The global emergence of carbapenem-resistant Enterobacteriaceae (CRE) presents a significant clinical concern, prompting the WHO to prioritize CRE as a top priority pathogen in their 2017 global antibiotic-resistant bacteria priority list. Due to the fast-depleting antibiotic arsenal, clinicians are now resorting to using once-abandoned, highly toxic antibiotics such as the polymyxins and aminoglycosides, creating an urgent need for new antibiotics. Drug repurposing, the application of an approved drug for a new therapeutic indication, is deemed a plausible solution to this problem. A total of 1,163 FDA-approved drugs were screened for activity against a clinical carbapenem- and multidrug-resistant E. coli isolate using a single-point 10 µM assay. Hit compounds were then assessed for their suitability for repurposing. The lead candidate was then tested against a panel of clinical CREs, a bactericidal/static determination assay, a time-kill assay and a checkerboard assay to evaluate its suitability for use in combination with Tigecycline against CRE infections. Three drugs were identified. The lead candidate was determined to be Zidovudine (azidothymidine/AZT), an oral anti-viral drug used for HIV treatment. Zidovudine was shown to be the most promising candidate for use in combination with Tigecycline to treat systemic CRE infections. Further experiments should involve the use of animal infection models.

Acute liver failure with amiodarone infusion: A case report and systematic review.

WHAT IS KNOWN AND OBJECTIVE: Amiodarone, a commonly used class III antiarrhythmic agent notable for a relatively long half-life of up to 6 months and its pronounced adverse effect profile, is used for both acute and chronic management of cardiac arrhythmias. Chronic use of amiodarone has been associated with asymptomatic hepatotoxicity; however, acute toxicity is thought to be uncommon. There are only six reported cases of acute liver failure (ALF) secondary to amiodarone. In all these cases the outcome of death during the same hospitalization resulted. We aimed to report the only case of acute liver failure secondary to amiodarone infusion in the existing literature where the patient survived. CASE SUMMARY: A 79-year-old woman admitted with atrial flutter was being treated with intravenous (IV) amiodarone when she abruptly developed coagulopathy, altered mental status and liver enzyme derangement. She was diagnosed with acute liver failure (ALF) secondary to an amiodarone adverse drug reaction, with a calculated score of seven on the Naranjo adverse drug reaction probability scale. Amiodarone was immediately withheld, and N-acetylcysteine (NAC) was initiated. Clinical improvement was seen within 48 hours of holding the drug and within 24 hours of initiating NAC. On post-hospital follow-up visit she was reported to have complete recovery. WHAT IS NEW AND CONCLUSION: This report emphasizes the importance of monitoring liver enzymes and mental status while a patient is being administered IV amiodarone. N-acetylcysteine administration may have possibly contributed to the early and successful recovery from ALF in our patient. To date, she is the only patient in the existing literature who has been reported to survive ALF secondary to amiodarone administration.

The role of antimicrobial sutures in preventing surgical site infection.

INTRODUCTION Healthcare associated infections (HCAIs) are falling following widespread and enforced introduction of guidelines, particularly those that have addressed antibiotic resistant pathogens such as methicillin resistant Staphylococcus aureus or emergent pathogens such as Clostridium difficile, but no such decline has been seen in the incidence of surgical site infection (SSI), either in the UK, the EU or the US. SSI is one of the HCAIs, which are all avoidable complications of a surgical patient's pathway through both nosocomial and community care. METHODS This report is based on a meeting held at The Royal College of Surgeons of England on 21 July 2016. Using PubMed, members of the panel reviewed the current use of antiseptics and antimicrobial sutures in their specialties to prevent SSI. FINDINGS The group agreed that wider use of antiseptics in surgical practice may help in reducing reliance on antibiotics in infection prevention and control, especially in the perioperative period of open elective colorectal, hepatobiliary and cardiac operative procedures. The wider use of antiseptics includes preoperative showering, promotion of hand hygiene, (including the appropriate use of surgical gloves), preoperative skin preparation (including management of hair removal), antimicrobial sutures and the management of dehisced surgical wounds after infection. The meeting placed emphasis on the level I evidence that supports the use of antimicrobial sutures, particularly in surgical procedures after which the SSI rate is high (colorectal and hepatobiliary surgery) or when a SSI can be life threatening even when the rate of SSI is low (cardiac surgery).

Interleukin-11 up-regulates endoplasmic reticulum stress induced target, PDIA4 in human first trimester placenta and in vivo in mice.

Interleukin (IL)11 is a crucial factor for human trophoblast function and placentation. Elevated levels are associated with pregnancy complications including preeclampsia, intrauterine growth restriction (IUGR) and preterm birth. However, the regulation of IL11 in the placenta has not been investigated. We examined the effect of pro-inflammatory cytokines IL1ß and TNFα, as well as low oxygen tension (2%) on IL11 levels in first trimester placental villous explants. IL1ß upregulated IL11 mRNA and protein, while TNFα and low oxygen had no effect. Using mass spectrometry, we identified protein disulfide isomerase 4 (PDIA4) in IL11-treated first trimester human placental explants (100 ng/ml, 24 h, n = 3), but not PBS control tissues. PDIA4 is a member of the PDI family, also known as endoplasmic reticulum (ER) stress protein (ERP)72. We previously identified GRP78 (a master regulator for ER stress) in human placenta for the first time and demonstrated that IL11 up-regulates GRP78 in the placenta. In this report, we demonstrated that IL11 upregulates PDIA4 protein in human placental villous tissue, HTR8-SVneo trophoblasts (cell line) and in vivo in IL11-treated mouse placenta. We aimed to determine whether IL11 upregulates other ER stress proteins in human first trimester placental villous. IL11 stimulated ERP44, but not GRP94, or PDI. Placental endoplasmic reticulum stress has been postulated in the pathophysiology of preeclampsia and IUGR, but its activation remains elusive. Together, these data suggest that IL11 could trigger an ER stress response in the placenta, which may contribute to obstetric complications such as preeclampsia.

Adjacent Lichen Sclerosis predicts local recurrence and second field tumour in women with vulvar squamous cell carcinoma.

OBJECTIVE: In this study, we investigated if the presence of histologically abnormal epithelium adjacent to the primary tumour influenced the frequency, timing, and topography of local vulvar recurrences (LVR) following treatment for squamous cell carcinoma of the vulva (VSCC). METHODS: The study population comprised a cohort of 201 consecutive cases with incident VSCC. LVR were categorised as local relapses (LR) if they occurred <2cm from the tumour margins, and as second field tumours (SFT) when ≥2cm from these margins. Univariable and multivariable competing risk modelling was performed to identify the prognostic factors associated with local disease recurrence. RESULTS: The characterization of the epithelium adjacent to the invasive component was possible for 199 (99.0%) patients. Of these, 171 (85.9%) were found to have intraepithelial abnormalities found adjacent to the surgical specimen. Multivariable analyses revealed that, following adjustment, Lichen Sclerosis (LS) was associated with an increase in the incidence of LVR, LR and SFT (SHRs: 3.4, 2.7 and 4.4, respectively). Although the incidence of LR and SFT in women with LS associated VSCC was similar, the peak incidence of SFT occurred more than two years before that of LR. CONCLUSIONS: Women with VSCC arising in a field of LS may continue to have an increased risk of developing LR and SFT for many years after resection of their primary tumour. Our study suggests that these women should be followed up more regularly so that LVR can be detected earlier; unless a more robust surveillance programme or chemopreventative treatments become available.

Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy.

BACKGROUND: This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST. PATIENTS AND METHODS: The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg once daily, days 1-21 of a 28-day cycle. Clinical benefit rate (CBR), defined as complete or partial response (PR), or stable disease lasting ≥16 weeks per RECIST 1.1, progression-free survival (PFS), overall survival (OS), long-term safety data, and metabolic response by functional imaging were assessed. RESULTS: Thirty-three patients received at least one dose of regorafenib. The median follow-up was 41 months. CBR was documented in 25 of 33 patients [76%; 95% confidence interval (CI) 58% to 89%], including six PRs. The median PFS was 13.2 months (95% CI 9.2-18.3 months) including four patients who remained progression-free at study closure, each achieving clinical benefit for more than 3 years (range 36.8-43.5 months). The median OS was 25 months (95% CI 13.2-39.1 months). Patients whose tumors harbored a KIT exon 11 mutation demonstrated the longest median PFS (13.4 months), whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumors experienced a median 1.6 months PFS (P < 0.0001). Long-term safety profile is consistent with previous reports; hand-foot skin reaction and hypertension were the most common reasons for dose reduction. Notably, regorafenib induced objective responses and durable benefit in SDH-deficient GIST. CONCLUSIONS: Long-term follow-up of patients with metastatic GIST treated with regorafenib suggests particular benefit among patients with primary KIT exon 11 mutations and those with SDH-deficient GIST. Dose modifications are frequently required to manage treatment-related toxicities. CLINICAL TRIAL NUMBER: NCT01068769.

Tailored therapy for different presentations of chronic pain after stapled hemorrhoidopexy.

BACKGROUND: As stapled hemorrhoidopexy (SH) becomes more widely used, we see more patients with chronic postoperative anal pain after this surgery. Its presentation is variable and difficult to treat. The aim of our study was to investigate the impact of chronic anal pain after SH and whether tailored therapy was likely to achieve a favorable outcome. METHODS: We retrospectively analyzed 31 consecutive patients with chronic anal pain who had undergone SH in other hospitals and were referred to our institutions. Depending on the type of pain, unrelated (at rest) or related to defecation, two groups of patients were identified. Moreover, the mean distance of the staple line from the anal verge was calculated in both groups. Treatments included: topical nifedipine, local anesthetic and steroid infiltration, removal of retained staples, anal dilation, and scar excision with mucosal suturing. A visual analog scale (VAS) was used to compare pain at baseline, postoperatively, and in the follow-up. This mean difference of the VAS score between stages was always used as the main outcome measure, depending on the type of presentation, type of pain, and type of treatment. Treatment response was defined as a 50 % decrease of VAS from baseline. RESULTS: There were 22 males and 9 females. The overall median age was 43 years (range 21-62 years). On digital examination and proctoscopy, 15 (48 %) patients had inflammatory changes, 19 (61 %) patients had staple retention, 8 (26 %) patients had anorectal stenosis, and 30 (97 %) patients had scar tissue. All patients had one or more of the following treatments listed from the least to most invasive: topical nifedipine in 12 (39 %) patients, anal dilation in 6 (19 %) patients, anesthetic and steroid infiltration in 18 (58 %) patients, removal of staples in 10 (32 %) patients, and scar excision in 18 (58 %) patients. The mean VAS score at baseline was 6.100, ± 1.953 SD, which dropped significantly after treatment to 1.733, ± 1.658 SD (p < 0.001) and remained low at follow-up (1.741 ± SD 1.251; p < 0.743). In patients with pain at rest (n = 20, 65 %), the symptoms improved in 19 (95 %) patients, while the VAS score decreased from 5.552 ± 2.115 SD to 1.457 ± 1.440 SD (95 % CI 3.217-4.964; p < 0.001). In patients with post-evacuation pain (n = 11, 35 %), the symptoms improved in 11 (100 %) patients, while the VAS score decreased from 6.429 ± 1.835 SD to 1.891 ± 1.792 SD (95 % CI 3.784-5.269; p < 0.001). Rating of response based on presentation was 90.0 % (0.9/10) after treatment of staple retention, which led to a significant decrease in the mean VAS score from 6.304 ± 1.845 SD to 1.782 ± 1.731 SD (95 % CI 3.859-5.185; p < 0.001). Anal stenosis was successfully treated in 100.0 % (n = 8/8) of cases with the mean VAS score dropping from 6.500 ± 1.309 SD to 2.125 ± 1.808 SD (95 % CI 2.831-5.919; p < 0.001). Anal inflammation improved in 60.0 % (n = 9/15) of patients and the mean VAS score dropped from 6.006 ± 2.138 SD to 1.542 ± 1.457 SD (95 % CI 3.217-4.964; p < 0.001). The response after scar tissue treatment was 94 % (n = 17/18) of patients with a mean VAS decreasing from 6.117 ± 2.006 SD to 1.712 ± 1.697 SD (95 % CI 3.812-4.974; p < 0.001). Success for topical nifedipine was between 13 and 25 % of patients depending on the clinical presentation. Anal dilation was successful in 75 % of patients, while Anesthetic and steroid infiltration in 23-54 % of patients depending on the clinical presentation. Staple removal was successful in 77 % of patients, and scar excision with mucosal suturing in 94 % of patients. CONCLUSIONS: Our retrospective study suggests that most patients with chronic anal pain after SH may be cured with treatment by applying a stepwise approach from the least to the most invasive treatment.