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Intragastric balloon therapy is an endoluminal treatment of obesity that is indicated for patients with moderate obesity (body mass index, 30-35 kg/m2) who have failed to lose weight with lifestyle and medical management. Treatment duration ranges from 4 to 12 months, and percent total body weight loss ranges from 6% to 15% at the time of balloon removal. Adverse events, such as bowel obstruction or gastric perforation, are rare, and early balloon removal because of intolerance is the most common complication. Long-term data are lacking, although weight regain after balloon removal seems to be common.

Objective For patients with multilevel degenerative cervical myelopathy, laminectomy and fusion are widely accepted techniques for ameliorating the disorder. However, the idea of whether one should bridge the cervicothoracic junction to prevent instrument failure or adjacent segment disease has been a subject of controversial discussion. In the present study, we compared the incidence of these complications and the revision rates in multilevel fusions extending to C7 or T1–T3. Methods In the present single-center, retrospective cohort study, patients with multilevel degenerative cervical myelopathy treated with laminectomy and fusion to C7 or T1–T3 from 2004 to 2016 were included for evaluation. The primary outcome measure was radiologically proven complications at the most caudal level or the adjacent spinal fusion level. Results Laminectomy and multilevel fusion were performed in 84 patients. After applying the exclusion criteria, 20 patients with fusion to C7 (treated from 2004 to 2012; follow-up, 124.6 ± 10.6 months) and 38 patients with fusion to T1–T3 (treated from 2008 to 2016; follow-up, 58.2 ± 15.7 months) were evaluated. The incidence of complications at the most caudal or adjacent level of fusion was twice as high (P = 0.087; NS) in the C7 group (11 of 20; 55.0%) compared with the T1–T3 group (11 of 38; 28.9%). In the C7 group, 9 of the 20 patients (45.0%) had required revision surgery compared with 2 of 38 patients (5.3%) in the T1–T3 group (P = 0.001). Conclusions We found that fewer revisions were necessary if the fusion had extended to the thoracic spine. Thus, we recommend bridging the cervicothoracic junction when fusion starts at C0–C3.

Background and Study Objective One risk of established decompression techniques for lumbar spinal stenosis is the resection of facet joints, especially if they are steeply configured, promoting destabilization. Minimally invasive bilateral crossover decompression aims to preserve the facet joints and thus stability of the spine. The purpose of this study is to demonstrate the feasibility and early results of this technique. Methods This retrospective case series includes 10 consecutive patients with lumbar stenosis and steep-angle ( Results After a follow-up of 10.5 months, the Symptom Severity Scale and Physical Function Scale of the Swiss Spinal Stenosis Questionnaire improved by 0.9 (p Conclusion The results of this study indicate that minimally invasive bilateral crossover decompression is a promising technique for the treatment of spinal canal stenosis. With its design to spare facet joints, it can potentially reduce the risk of spinal instability, especially in patients with steep facet joints.

Background Endoscopic per-oral pyloromyotomy (POP) has emerged as a safe and effective first line option in medically refractory gastroparesis. Determining the appropriate extent of the pyloromyotomy continues to present a challenge as there are no standardized tools for measuring changes in pyloric distensibility during the procedure. The objective of this study was to evaluate the utility of using impedance planimetry with endoscopic functional luminal imaging probe (FLIP) to measure changes in pyloric distensibility after POP, and to compare these changes with improvement in symptoms and objective gastric emptying. Methods Patients with medically refractory gastroparesis underwent POP with FLIP measurements of the pylorus (EndoFLIP®, Medtronic, Fridley MN). FLIP measurements, as well as changes in symptoms measured by the validated gastroparesis cardinal symptom index (GCSI) and scintigraphic gastric emptying studies (GES), were evaluated before and after POP. Results A total of 14 patients underwent measurement with FLIP during POP, 12 of whom had pre- and post-POP measurements. Mean pyloric diameter increased by 1.4 mm, from 13.9 mm to 15.3 mm (p = 0.0012). Mean distensibility index increased from 6.2 mm2/mmHg to 9.1 mm2/mmHg (p = 0.0074). Successful division of the pylorus was achieved in 100% of patients with a mean operative time of 36 min and no perioperative complications. The mean length of stay was 0.7 days (0–3 days). Post-POP mean GCSI score improved from 2.97 to 2.28 at a mean follow-up time of 27 days (p Conclusions FLIP is a safe and feasible tool to provide objective measurements during POP. Larger cohorts with longer follow-up are required to determine if measured improvements in pyloric diameter and distensibility are predictive of sustained improvements in GCSI and GES.

OBJECTIVEClinical evidence on giant intracranial aneurysms (GIAs), intracranial aneurysms with a diameter of at least 25 mm, is limited. The authors aimed to investigate the natural history, case fatality, and treatment outcomes of ruptured and unruptured GIAs.METHODSIn this international observational registry study, patients with a ruptured or unruptured GIA received conservative management (CM), surgical management (SM), or endovascular management (EM). The authors investigated rupture rates and case fatality.RESULTSThe retrospective cohort comprised 219 patients with GIAs (21.9% ruptured GIAs and 78.1% unruptured GIAs) whose index hospitalization occurred between January 2006 and November 2016. The index hospitalization in the prospective cohort (362 patients with GIAs [17.1% ruptured and 82.9% unruptured]) occurred between December 2008 and February 2017. In the retrospective cohort, the risk ratio for death at a mean follow-up of 4.8 years (SD 2.2 years) after CM, compared with EM and SM, was 1.63 (95% CI 1.23–2.16) in ruptured GIAs and 3.96 (95% CI 2.57–6.11) in unruptured GIAs. In the prospective cohort, the 1-year case fatality in ruptured GIAs/unruptured GIAs was 100%/22.0% during CM, 36.0%/3.0% after SM, and 39.0%/12.0% after EM. Corresponding 1-year rupture rates in unruptured GIAs were 25.0% during CM, 1.2% after SM, and 2.5% after EM. In unruptured GIAs, the HR for death within the 1st year in patients with posterior circulation GIAs was 6.7 (95% CI 1.5–30.4, p < 0.01), with patients with a GIA at the supraclinoid internal carotid artery as reference. Different sizes of unruptured GIAs were not associated with 1-year case fatality.CONCLUSIONSRupture rates for unruptured GIAs were high, and the natural history and treatment outcomes for ruptured GIAs were poor. Patients undergoing SM or EM showed lower case fatality and rupture rates than those undergoing CM. This difference in outcome may in part be influenced by patients in the CM group having been found poor candidates for SM or EM.Clinical trial registration no.: NCT02066493 (clinicaltrials.gov)

Introduction CVT-301 (Inbrija®) is a levodopa inhalation powder for on-demand treatment of OFF episodes in Parkinson's disease patients treated with carbidopa/levodopa. Safety and efficacy results of a 12-month, dose-level blinded extension study of a phase 3 trial (SPAN℠-PD) of CVT-301 are presented. Methods Patients were receiving oral carbidopa/levodopa and adjunctive CVT-301 treatment, blinded to dose (60 mg or 84 mg, N = 325). Study visits occurred every 3 months. Pulmonary function was assessed by spirometry. Other safety assessments included dyskinesia and adverse events (AEs). Secondary objectives of the study included maintenance of improvement assessments for occurrence of an ON state during the 60-min post-dose period, change in total daily OFF time, and Patient Global Impression of Change (PGIC). Results Most frequent AEs (≥5%) were cough (15.4%), fall (13.1%), upper respiratory tract infection (7.1%), and dyskinesia (5.1%). Severe AEs (>1 event) were cough (1.9%) and dyskinesia (0.6%). Twelve-month mean changes from baseline for FEV1, FVC, and DLCO were −0.092 L, −0.097 L, and −0.922 mL/min/mmHg, respectively. At 12 months, 73.0% of patients on 84 mg achieved an ON state within 60 min. Total daily OFF time was reduced by 0.55 h (month 1) and 0.88 h (month 12) for the 84 mg dose. Percentage of patients self-reported as improved by PGIC was 65.5–91.9% over 12 months. Conclusion CVT-301 was generally well-tolerated. Twelve-month decline in pulmonary function was consistent with a prior PD control group. Exploratory efficacy results showed CVT-301 maintained improvement at achieving ON states in patients experiencing OFF episodes, decreasing daily OFF time, and maintaining improvement in PGIC.

Despite the widespread prescription of antibiotics for patients with chronic rhinosinusitis (CRS), the extent to which drug distribution to the sinonasal mucosa occurs remains largely undefined.Twenty subjects undergoing functional endoscopic sinus surgery (FESS) for CRS were randomized to one of two groups: 1) doxycycline (100 mg daily for seven days) 2) roxithromycin (300 mg daily for seven days). Drug levels were measured using liquid chromatography-tandem mass spectrometry in sinonasal mucus, sinonasal tissues and serum at steady state.Doxycycline concentrations measured in the mucus were significantly lower compared to that in the serum (mean mucus/serum ratio = 0.16, p p p = 0.002) and the tissue (mean mucus/tissue ratio = 0.60, p Although the efficacy of doxycycline and roxithromycin in sinonasal mucus in vivo cannot be predicted solely from reported minimum inhibitory concentrations, given the added complexity of bacterial biofilm antimicrobial tolerance, these results suggest that low mucosal penetration of antibiotics may be one of the factors contributing to the limited efficacy of these agents in the treatment of CRS. Despite the widespread prescription of antibiotics for patients with chronic rhinosinusitis (CRS), the extent to which drug distribution to the sinonasal mucosa occurs remains largely undefined. Twenty subjects undergoing functional endoscopic sinus surgery (FESS) for CRS were randomized to one of two groups: 1) doxycycline (100 mg daily for seven days) 2) roxithromycin (300 mg daily for seven days). Drug levels were measured using liquid chromatography-tandem mass spectrometry in sinonasal mucus, sinonasal tissues and serum at steady state. Doxycycline concentrations measured in the mucus were significantly lower compared to that in the serum (mean mucus/serum ratio = 0.16, p p p = 0.002) and the tissue (mean mucus/tissue ratio = 0.60, p Although the efficacy of doxycycline and roxithromycin in sinonasal mucus in vivo cannot be predicted solely from reported minimum inhibitory concentrations, given the added complexity of bacterial biofilm antimicrobial tolerance, these results suggest that low mucosal penetration of antibiotics may be one of the factors contributing to the limited efficacy of these agents in the treatment of CRS.

In peroral endoscopic myotomy for Zenker’s diverticulum (Z-POEM), the cricopharyngeus muscle is divided within a submucosal tunnel started in the hypopharynx. We aimed to evaluate the safety and preliminary outcomes in patients who underwent a modified version of the Z-POEM where the tunnel is made directly overlying the cricopharyngeus, the mucosal incision and muscular interruption (MIMI) approach, and to compare these with patients who underwent a non-tunneled flexible endoscopic approach. All patients with ZD who were treated by flexible endoscopy at our institution between January 2015 and February 2020 were identified by a retrospective chart review. Dysphagia symptoms were assessed using a validated scoring system. Nineteen patients with ZD underwent MIMI (mean age 76.1 years, 68.1% male) and seven patients underwent non-tunneled flexible endoscopic approach (mean age 64.4 years, 85.7% male) during the study period. Mean ZD size was 2.8 cm in the MIMI group and 1.9 cm in the non-tunneled group (p = 0.03). Clinical success was achieved in 17/19(89.5%) MIMI patients and 7/7(100%) of non-tunneled flexible endoscopic patients (p = 0.101). Dysphagia scores improved in both groups, although this difference was only significant in the MIMI group (p ≤ 0.001). Recurrence occurred in 2/17(11.7%) MIMI patients and 3/7(42.9%) non-tunneled flexible endoscopic patients (p = 0.096). There were 4 complications, including one pharyngeal perforation requiring open surgical repair in a patient with a small ZD with an associated cricopharyngeal bar in the MIMI group. Median length of follow-up was 290 [142; 465] days in the MIMI group and 1056 [258; 1206] days in the non-tunneled group (p = 0.094). MIMI is a technically feasible and effective treatment for ZD. Care should be taken in patients with a cricopharyngeal bar and small ZD, as this may increase the risk of perforation. Larger studies with long-term follow-up are needed to determine if MIMI reduces the risk of symptom recurrence when compared to non-tunneled flexible endoscopic approaches.

Ramadan is characterized by a month of fasting between dawn and sunset. Cleveland Clinic Abu Dhabi is located in the United Arab Emirates, where the majority of our patients observe Ramadan. In many practices, bariatric surgery has been delayed until after Ramadan in order to avoid postoperative complications. However, there are no studies that evaluate this theory. Our study aimed to evaluate perioperative outcomes between bariatric surgeries performed before/during Ramadan and at times distant to Ramadan. All patients who underwent primary bariatric surgery at Cleveland Clinic Abu Dhabi between September 2015 and July 2019 were retrospectively reviewed. The Pre-Ramadan (PR) cohort included patients that underwent surgery during the month of Ramadan and up to 3 months before Ramadan. The Non-Ramadan (NR) cohort included patients from the remainder 8 months. Our study included 542 patients: 185 patients in the PR cohort and 357 patients in the NR cohort. Baseline characteristics were similar. There were no statistically significant differences in perioperative outcomes, including emergency department (ED) visits (23.2% PR vs. 24.4% NR, p = .77), readmission rates (2.2% PR vs. 4.5% NR, p = .17), reoperation (1.1% PR vs. 3.6% NR, p = .09), and complications within 30 days (3.8% PR vs. 7.0% NR, p = .13). There is no difference among patients who undergo surgery before/during Ramadan and at times distant to Ramadan. Based on this data, there does not appear to be an increased risk of performing bariatric surgery prior to or during Ramadan in a comprehensive, multi-disciplinary program.

Background Technical advances in minimally invasive spine surgery have reduced blood loss, access trauma, and postoperative length of stay. However, operating on the susceptible group of octogenarians still poses a dilemma because of a plethora of age-related comorbidities. The aim of this study was to investigate the safety of minimally invasive surgery (MIS) transforaminal lumbar interbody fusion (TLIF) in octogenarians. Methods We conducted a retrospective single-center study of all patients over 80 years of age who, between March 2009 and February 2014, had undergone MIS TLIF. The primary outcome was recorded major and minor complications within 30 days of surgery. Results Twenty-one patients with an average age of 84.1 ± 2.7 years underwent MIS TLIF in 31 levels for degenerative lumbar disk disease with intolerable pain after failure of conservative treatment. Of the patients, 33.3% showed no perioperative complications. In the remaining 66.7%, 6 major complications and 24 minor complications occurred within 30 days of surgery. Two of these patients died within 30 days of surgery because of sepsis and pulmonary embolism (mortality rate 9.5%). Conclusions Our study spotlighted the susceptible group of octogenarians and evaluated the safety of MIS TLIF. The perioperative morbidity for octogenarians undergoing MIS TLIF is substantial and even higher than for patients over 65 years of age. Two thirds of patients in this subgroup suffer at least 1 complication. The 30-day mortality rate was 9.5%. Therefore, it is advisable for these patients to exploit all available conservative options prior to surgery.

Introduction Hemangioblastomas are rare, histologically benign, highly vascularized tumors of the brain, the spinal cord, and the retina, occurring sporadically or associated with the autosomal dominant inherited von Hippel-Lindau (VHL) disease. Children or adults with VHL disease have one of > 300 known germline mutations of the VHL gene located on chromosome 3. They are prone to develop hemangioblastomas, extremely rarely starting at age 6, rarely at age 12–18, and, typically and almost all, as adults. There is a plethora of VHL-associated tumors and cysts, mainly in the kidney, pancreas, adrenals, reproductive organs, and central nervous system. Due to a lack of causal treatment, alleviation of symptoms and prevention of permanent neurological deficits as well as malignant transformation are the main task. Paucity of data and the nonlinear course of tumor progression make management of pediatric VHL patients with hemangioblastomas challenging. Methods The Freiburg surveillance protocol was developed by combining data from the literature and our experience of examinations of > 300 VHL patients per year at our university VHL center. Results Key recommendations are to start screening of patients at risk by funduscopy with dilated pupils for retinal tumors with admission to school and with MRI of the brain and spinal cord at age 14, then continue biannually until age 18, with emergency MRI in case of neurological symptoms. Indication for surgery remains personalized and should be approved by an experienced VHL board, but we regard neurological symptoms, rapid tumor growth, or critically large tumor/cyst sizes as the key indications to remove hemangioblastomas. Since repeated surgery on hemangioblastomas in VHL patients is not rare, modern neurosurgical techniques should encompass microsurgery, neuronavigation, intraoperative neuromonitoring, fluorescein dye-based intraoperative angiography, intraoperative ultrasound, and minimally invasive approaches, preceded in selected cases by endovascular embolization. Highly specialized neurosurgeons are able to achieve a very low risk of permanent morbidity for the removal of hemangioblastomas from the cerebellum and spinal cord. Small retinal tumors of the peripheral retina can be treated by laser coagulation, larger tumors by cryocoagulation or brachytherapy. Conclusion We consider management at experienced VHL centers mandatory and careful surveillance and monitoring of asymptomatic lesions are required to prevent unnecessary operations and minimize morbidity.

Disease intervention specialists (DIS) prevent syphilis by ensuring treatment for patients' sex partners through partner notification (PN). Different interpretations of how to measure partners treated due to DIS efforts complicates PN evaluation. We measured PN impact by counting partners treated for syphilis after DIS interviewed the patient.We reviewed data from early syphilis cases reported during the 2015-2017 period in 7 jurisdictions. We compared infected partners brought to treatment using the following: (1) DIS-assigned disposition codes or (2) all infected partners treated 0 to 90 days after the patient's interview (adjusted treatment estimate). Stratified analyses assessed patient characteristics associated with the adjusted treatment estimate.Disease intervention specialists interviewed 23,613 patients who reported 20,890 partners with locating information. Many of the 3569 (17.1%) partners classified by DIS as brought to treatment were treated before the patient was interviewed. There were 2359 (11.3%) partners treated 0 to 90 days after the patient's interview. Treatment estimates were more consistent between programs when measured using our adjusted estimates (range, 6.1%-14.8% per patient interviewed) compared with DIS-assigned disposition (range, 6.1%-28.3%). Treatment for ≥1 partner occurred after 9.0% of interviews and was more likely if the patient was a woman (17.9%), younger than 25 years (12.6%), interviewed ≤7 days from diagnosis (13.9%), HIV negative (12.6%), or had no reported history of syphilis (9.8%).Counting infected partners treated 0 to 90 days after interview reduced variability in reporting and facilitates quality assurance. Identifying programs and DIS who are particularly good at finding and treating partners could improve program impact.

Serous endometrial cancer (SEC) and high grade serous ovarian cancer (HGSOC) are aggressive gynecological malignancies with high rates of metastasis and poor prognosis. Endometrial intraepithelial carcinoma (EIC), the precursor for SEC, and serous tubal intraepithelial carcinoma (STIC), believed to be the precursor lesion for HGSOC, can also be associated with intraabdominal spread. To provide insight into the etiology of these precancerous lesions and to explore the potential molecular mechanisms underlying their metastatic behavior, we performed a proteomic mass spectrometry analysis in a patient with synchronous EIC and STIC. Through histological and molecular identification of precancerous lesions followed by laser capture microdissection, we were able to identify over 450 proteins within the precancerous lesions and adjacent healthy tissue. The proteomic analysis of STIC and EIC showed remarkable overlap in the proteomic patterns, reflecting early neoplastic changes in proliferation, loss of polarity and attachment. Our proteomic analysis showed that both EIC and STIC, despite being regarded as premalignant lesions, have metastatic potential, which correlates with the common presentation of invasive serous gynecological malignancies at advanced stage. Refereed/Peer-reviewed

Tumorigenesis involves a complex interplay between genetically modified cancer cells and their adjacent normal tissue, the stroma. We used an established breast cancer mouse model to investigate this inter-relationship. Conditional activation of Rho-associated protein kinase (ROCK) in a model of mammary tumorigenesis enhances tumor growth and progression by educating the stroma and enhancing the production and remodeling of the extracellular matrix. We used peptide matrixassisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to quantify the proteomic changes occurring within tumors and their stroma in their regular spatial context. Peptides were ranked according to their ability to discriminate between the two groups, using a receiver operating characteristic tool. Peptides were identified by liquid chromatography tandem mass spectrometry, and protein expression was validated by quantitative immunofluorescence using an independent set of tumor samples. We have identified and validated four key proteins upregulated in ROCK-activated mammary tumors relative to those expressing kinase-dead ROCK, namely, collagen I, α-SMA, Rab14, and tubulin- β4. Rab14 and tubulin-β4 are expressed within tumor cells, whereas collagen I is localized within the stroma. α-SMA is predominantly localized within the stroma but is also expressed at higher levels in the epithelia of ROCK-activated tumors. High expression of COL1A, the gene encoding the pro-α 1 chain of collagen, correlates with cancer progression in two human breast cancer genomic data sets, and high expression of COL1A and ACTA2 (the gene encoding α-SMA) are associated with a low survival probability (COLIA, p = 0.00013; ACTA2, p = 0.0076) in estrogen receptor-negative breast cancer patients. To investigate whether ROCK-activated tumor cells cause stromal cancer-associated fibroblasts (CAFs) to upregulate expression of collagen I and α-SMA, we treated CAFs with medium conditioned by primary mammary tumor cells in which ROCK had been activated. This led to abundant production of both proteins in CAFs, clearly highlighting the inter-relationship between tumor cells and CAFs and identifying CAFs as the potential source of high levels of collagen 1 and α-SMA and associated enhancement of tissue stiffness. Our research emphasizes the capacity of MALDI-MSI to quantitatively assess tumor-stroma inter-relationships and to identify potential prognostic factors for cancer progression in human patients, using sophisticated mouse cancer models Refereed/Peer-reviewed

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation with accumulation of activated group 2 innate lymphoid cells (ILC2s) and elevation of thymic stromal lymphopoietin (TSLP). A member of the TNF superfamily (TNFSF), TNFSF15, is known to induce the production of type 2 cytokines in ILC2s. Although ILC2s have been implicated in CRSwNP, the presence and role of TNFSFs in ILC2-mediated type 2 inflammation in CRSwNP has not been elucidated. Here, we investigate the involvement of TNFSFs in ILC2-mediated type 2 inflammation in CRSwNP. We found that receptor activator of NF-κB (RANK) ligand (RANK-L (TNFSF11)) was significantly elevated in nasal polyps (NPs), and that the receptor of RANK-L, RANK, was expressed on ILC2s in human peripheral blood and NPs. An agonistic antibody against RANK induced production of type 2 cytokines in human ILC2s, and TSLP significantly enhanced this reaction. The membrane-bound RANK-L was detected mainly on CD45 + immune cells, including TH2 cells in NPs. The co-culture of NP-derived ILC2s and TH2 cells significantly enhanced production of type 2 cytokines, and anti-RANK-L monoclonal antibody suppressed this enhancement. In conclusion, RANK-L, together with TSLP, may play an inductive role in the ILC2-mediated type 2 inflammation in CRSwNP.

Introduction: To assess the current diagnostic, treatment, and documentation strategies for bladder cancer (BC) in German-speaking countries. Materials and Methods: A 14-item web-based survey was distributed among members of the German, Austrian, and Swiss Associations of Urology, addressing physicians who perform cystoscopies and transurethral resection of bladder tumors (TURB). Results: The survey was responded to by 308 of 5,564 urologists with a mean age of 49.5 years (response rate: 5.5%). The majority of participants (57.3%) practice in an outpatient setting. White light cystoscopy only is used by 60.2%, with additional photodynamic diagnosis and narrow band imaging by 36.8 and 12.5%, respectively. Endoscopic findings are documented in written form by 93.5%, followed by image capture (33.7%) and a central data archive (20.8%). Inpatient hospital urologists document cystoscopic findings by freehand drawing (21.4 vs. 11.4%, p = 0.017), and with a fixed bladder scheme (31.3 vs. 7.4%, p < 0.05). Conclusions: Significant differences exist in the approach to documenting and communicating cystoscopic BC findings. Accurate graphic documentation of lesions, visualization of the mucosa’s totality, and meticulous consultation of previous surgical reports require improvements to reduce recurrence and progression rates.

OBJECTIVEHemangioblastomas are benign, highly vascularized tumors that can occur sporadically or as part of von Hippel-Lindau (VHL) disease. Traditionally, spinal hemangioblastomas have been surgically treated via an open approach. In recent years, however, minimally invasive techniques using tubular retractors have been increasingly applied in spine surgery. Such procedures involve less tissue trauma but are also particularly demanding for the surgeon, especially in cases of highly vascular tumors such as hemangioblastomas. The object of this study was to evaluate the safety and efficacy of minimally invasive resection of selected spinal hemangioblastomas.METHODSThe authors conducted a retrospective single-center study of all patients who, between January 2010 and January 2018, had been operated on for spinal hemangioblastoma via a minimally invasive approach performed at the surgeon’s discretion. The surgical technique is described and the pre- and postoperative neurological and imaging results were analyzed descriptively. The primary outcome was the postoperative compared to preoperative neurological condition (McCormick grade). The secondary outcomes were the extent of tumor resection and postoperative complications.RESULTSEighteen patients, 12 female and 6 male, harboring a total of 19 spinal hemangioblastomas underwent surgery in the study period. Seventeen patients had stable neurological findings with stable or improved McCormick grades (94.5%) at a mean of 4.3 months after surgery. One (5.5%) of the 18 patients developed progressive neurological symptoms with a worsened McCormick grade that did not improve in the long-term follow-up. Sixteen of the 18 patients had VHL disease, whereas 2 patients had sporadic spinal hemangioblastomas. In all patients, postoperative MRI showed complete resection of the tumors. No other surgery-related perioperative or postoperative complications were recorded.CONCLUSIONSA minimally invasive approach for the resection of selected spinal hemangioblastomas is safe and allows complete tumor resection with good clinical results in experienced hands.

Fibrotic diseases are still a serious concern for public health, due to their high prevalence, complex etiology and lack of successful treatments. Fibrosis consists of excessive accumulation of extracellular matrix components. As a result, the structure and function of tissues are impaired, thus potentially leading to organ failure and death in several chronic diseases. Myofibroblasts represent the principal cellular mediators of fibrosis, due to their extracellular matrix producing activity, and originate from different types of precursor cells, such as mesenchymal cells, epithelial cells and fibroblasts. Profibrotic activation of myofibroblasts can be triggered by a variety of mechanisms, including the transforming growth factor-β signalling pathway, which is a major factor driving fibrosis. Interestingly, preclinical and clinical studies showed that fibrotic degeneration can stop and even reverse by using specific antifibrotic treatments. Increasing scientific evidence is being accumulated about the role of sirtuins in modulating the molecular pathways responsible for the onset and development of fibrotic diseases. Sirtuins are NAD+ -dependent protein deacetylases that play a crucial role in several molecular pathways within the cells, many of which at the crossroad between health and disease. In this context, we will report the current knowledge supporting the role of sirtuins in the balance between healthy and diseased myofibroblast activity. In particular, we will address the signalling pathways and the molecular targets that trigger the differentiation and profibrotic activation of myofibroblasts and can be modulated by sirtuins.

Simple Summary Classic histopathological examination of tissues remains the mainstay for cancer diagnosis and staging. However, in some cases histopathologic analysis yields ambiguous results, leading to inconclusive disease classification. We set out to explore the diagnostic potential of mass spectrometry-based imaging for tumour classification based on proteomic fingerprints. Combining mass spectrometry with supervised machine learning, we were able to distinguish colorectal tumor from normal tissue with an overall accuracy of 98%. In addition, this approach was able to predict the presence of lymph node metastasis in primary tumour of endometrial cancer with an overall accuracy of 80%. These results highlight the potential of this technology to determine the optimal treatment for cancer patients to reduce morbidity and improve patients’ outcomes. Abstract Matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) can determine the spatial distribution of analytes such as protein distributions in a tissue section according to their mass-to-charge ratio. Here, we explored the clinical potential of machine learning (ML) applied to MALDI MSI data for cancer diagnostic classification using tissue microarrays (TMAs) on 302 colorectal (CRC) and 257 endometrial cancer (EC)) patients. ML based on deep neural networks discriminated colorectal tumour from normal tissue with an overall accuracy of 98% in balanced cross-validation (98.2% sensitivity and 98.6% specificity). Moreover, our machine learning approach predicted the presence of lymph node metastasis (LNM) for primary tumours of EC with an accuracy of 80% (90% sensitivity and 69% specificity). Our results demonstrate the capability of MALDI MSI for complementing classic histopathological examination for cancer diagnostic applications.

The prediction of lymph node metastasis using clinic-pathological data and molecular information from endometrial cancers lacks accuracy and is therefore currently not routinely used in patient management. Consequently, although only a small percentage of patients with endometrial cancers suffer from metastasis, the majority undergo radical surgery including removal of pelvic lymph nodes. Upon analysis of publically available data and published research, we compiled a list of 60 proteins having the potential to display differential abundance between primary endometrial cancers with versus those without lymph node metastasis. Using data dependent acquisition LC-ESI-MS/MS we were able to detect 23 of these proteins in endometrial cancers, and using data independent LC-ESI-MS/MS the differential abundance of five of those proteins was observed. The localization of the differentially expressed proteins, was visualized using peptide MALDI MSI in whole tissue sections as well as tissue microarrays of 43 patients. The proteins identified were further validated by immunohistochemistry. Our data indicate that annexin A2 protein level is upregulated, whereas annexin A1 and α actinin 4 expression are downregulated in tumours with lymph node metastasis compared to those without lymphatic spread. Moreover, our analysis confirmed the potential of these markers, to be included in a statistical model for prediction of lymph node metastasis. The predictive model using highly ranked . m/z values identified by MALDI MSI showed significantly higher predictive accuracy than the model using immunohistochemistry data. In summary, using publicly available data and complementary proteomics approaches, we were able to improve the prediction model for lymph node metastasis in EC. Refereed/Peer-reviewed

Ovarian cancer is the most lethal gynecologic malignancy. Early detection would improve survival, but an effective diagnostic test does not exist. Novel biomarkers for early ovarian cancer diagnosis are therefore warranted. We performed intraoperative blood sampling from ovarian veins of stage I epithelial ovarian carcinomas and analyzed the serum proteome. Junction plakoglobin (JUP) was found to be elevated in venous blood from ovaries with malignancies when compared to those with benign disease. Peripheral plasma JUP levels were validated by ELISA in a multicenter international patient cohort. JUP was significantly increased in FIGO serous stage IA+B (1.97-fold increase; p < 0.001; n = 20), serous stage I (2.09-fold increase; p < 0.0001; n = 40), serous stage II (1.81-fold increase, p < 0.001, n = 23) and serous stage III ovarian carcinomas (1.98-fold increase; p < 0.0001; n = 34) vs. normal controls (n = 109). JUP plasma levels were not increased in early stage breast cancer (p = 0.122; n = 12). In serous ovarian cancer patients, JUP had a sensitivity of 85% in stage IA+B and 60% in stage IA-C, with specificities of 76 and 94%, respectively. A logistic regression model of JUP and Cancer Antigen 125 (CA125) revealed a sensitivity of 70% for stage IA+B and 75% for stage IA-C serous carcinomas at 100% specificity. Our novel ovarian blood sampling - proteomics approach identified JUP as a promising new biomarker for epithelial ovarian cancer, which in combination with CA125 might fulfill the test criteria for ovarian cancer screening. ispartof: FRONTIERS IN ONCOLOGY vol:10 ispartof: location:Switzerland status: published

It is well established that cell surface glycans play a vital role in biological processes and their altered form can lead to carcinogenesis. Mass spectrometry-based techniques have become prominent for analysing N-linked glycans, for example using matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS). Additionally, MALDI MS can be used to spatially map N-linked glycans directly from cancer tissue using a technique termed MALDI MS imaging (MALDI MSI). This powerful technique combines mass spectrometry and histology to visualise the spatial distribution of N-linked glycans on a single tissue section. Here, we performed N-glycan MALDI MSI on six endometrial cancer (EC) formalin-fixed paraffin-embedded (FFPE) tissue sections and tissue microarrays (TMA) consisting of eight EC patients with lymph node metastasis (LNM) and twenty without LNM. By doing so, several putative N-linked glycan compositions were detected that could significantly distinguish normal from cancerous endometrium. Furthermore, a complex core-fucosylated N-linked glycan was detected that could discriminate a primary tumour with and without LNM. Structural identification of these putative N-linked glycans was performed using porous graphitized carbon liquid chromatography tandem mass spectrometry (PGC-LC-MS/MS). Overall, we observed higher abundance of oligomannose glycans in tumour compared to normal regions with AUC ranging from 0.85-0.99, and lower abundance of complex N-linked glycans with AUC ranges from 0.03-0.28. A comparison of N-linked glycans between primary tumours with and without LNM indicated a reduced abundance of a complex core-fucosylated N-glycan (Hex)2(HexNAc)2(Deoxyhexose)1+(Man)3(GlcNAc)2, in primary tumour with associated lymph node metastasis. In summary, N-linked glycan MALDI MSI can be used to differentiate cancerous endometrium from normal, and endometrial cancer with LNM from endometrial cancer without. Refereed/Peer-reviewed

BACKGROUND/AIMS Retinal haemangioblastomas (RH) remain a major cause of visual impairment in patients with von Hippel-Lindau (VHL) disease. Identification of genotype-phenotype correlation is an important prerequisite for better management, treatment and prognosis. METHODS Retrospective, single-centre cohort study of 200 VHL patients. Genetic data and date of onset of RH, central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renal cell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected. The number and locations of RH were recorded. RESULTS The first clinical finding occurred at an age of 26 ± 14 years (y) [mean ± SD]. In 91 ± 3% (95% CI 88-94) of the patients, at least one RH occur until the age of 60y. A total of 42 different rare VHL gene variants in 166 patients were detected. A higher age-related incidence of RH, CNSH, ccRCC and PNEN was detected in patients with a truncating variant (TV) compared to patients with a single amino-acid substitution/deletion (AASD) (all p

Summary Objectives Staphylococcus aureus is the most common cause of pyogenic vertebral osteomyelitis (VO). Studies indicate that S. aureus VO results in poor outcome. We aimed to investigate risk factors for treatment failure in patients with Staphylococcus aureus bloodstream infection (SAB) and VO. Methods We conducted a post hoc-analysis of data from a German bi-center prospective SAB cohort (2006–2014). Patients were followed-up for one year. Primary outcome was treatment failure defined as relapse and/or death within one year. Results A total of 1069 patients with SAB were analyzed, with 92 VO patients. In addition to antibiotic treatment, surgery was performed in 60/92 patients. Treatment failed in 44/92 patients (death, n = 42; relapse, n = 2). Multivariable analysis revealed higher age (HR 1.04 [per year], 95%CI 1.01–1.07), Charlson comorbidity index (HR 1.20, 95%CI 1.06–1.36), presence of neurologic deficits (HR 2.53, 95%CI 1.15–5.53) and local abscess formation (HR 3.35, 95%CI 1.39–8.04) as independent risk factors for treatment failure. In contrast, surgery seemed to be associated with a favourable outcome (HR 0.45 (95%CI 0.20–0.997)). Conclusion SAB patients with VO exhibit a high treatment failure rate. Red flags are older age, comorbidities, neurologic deficits and local abscess formation. Whether these patients benefit from intensified treatment (e.g. radical surgery, prolongation of antibiotics) should be investigated further.

Per-oral pyloromyotomy (POP or G-POEM) provides significant short-term improvements in symptoms and objective emptying for patients with medically refractory gastroparesis, but it is unclear if patients with gastroparesis and co-existing dysmotility (small bowel or colonic delay) also benefit. In this study, we used wireless motility capsule (WMC) data to measure outcomes in patients with isolated gastroparesis (GP) and gastroparesis with co-existing dysmotility (GP + Dys) who underwent POP. We retrospectively analyzed patients who had POP and completed WMC data during their evaluation of intestinal dysmotility. WMC data were reviewed to identify patients who demonstrated isolated GP or GP + Dys. Each patient's pre-op and post-op Gastroparesis Cardinal Symptom Index (GCSI) and 4-h solid-phase scintigraphy gastric emptying studies (GES) scores were compared to evaluate improvement. Of the entire cohort (n = 73), 89% were female with a mean age of 47.0 ± 15.0 years old. Gastroparesis etiologies were divided among idiopathic (54.8%), diabetic (26%), postsurgical (8.2%), autoimmune (5.5%), and multifactorial (5.5%). Forty-one patients (56%) had GP and 32 patients (44%) had GP + Dys. GCSI improved after POP whether the patient had isolated GP (− 12.31, p

Background Little is known about decline in lung function in Parkinson's disease (PD). To assess these changes, we assessed the changes in lung function that occurred over 12 months in patients on standard PD therapy as part of the observational cohort of an open-label study of inhaled levodopa (CVT-301) in PD. Methods PD patients on stable oral PD therapy and no chronic respiratory disease had spirometry and diffusing capacity of the lungs for carbon monoxide (DLCO) measured at 3, 6, 9, and 12 months. Results 106 patients (81.5%) in the observational cohort on no investigational therapy completed the study. Mean FEV1 declined at 12 months from 2.88L at baseline with a mean change of −0.11L, greater than the −0.030–0.045L/year observed in healthy, non-smokers aged 60–70 years. FVC declined from 3.77L (mean change −0.19L); FEV1/FVC ratio remained relatively constant. DLCO mean change was −0.48 mL/min/mmHg from a baseline of 24.24 mL/min/mmHg. This change in DLCO, while not significant, was similar to that seen in non-smokers aged 60–70 years (DLCO -0.42–0.63 mL/min/mmHg/year). Decreases in alveolar volume (VA) and inspiratory vital capacity (IVC) rather than the transfer coefficient (DLCO/VA) were observed. Conclusions PD patients had greater declines in FEV1, and FVC, but not in DLCO, compared to healthy non-smokers of similar age. Declines in FEV1 and FVC with little change in FEV1/FVC, and decline in VA and IVC with little change in DLCO/VA, suggest these changes were due to decreases in lung volume and are compatible with progressive PD-associated respiratory muscle weakness. Trial registration ClinicalTrials.gov (NCT02352363 Registered January 26, 2015 [ https://clinicaltrials.gov/ct2/show/NCT02352363 ]) and EudraCT (2014-003799-22).

Background Laminectomy and multilevel fusion in patients with degenerative cervical myelopathy lead to severe restriction in cervical spine mobility. Since fusions from C2 to the thoracic spine result in a permanently stiff subaxial cervical spine, it seems obvious to restore physiological cervical lordosis, especially with regard to sagittal balance. However, there are reports that a fusion in a more lordotic position leads to a reduction of rotational cervical range of motion in the still mobile segments C0-C2. This study investigates the relationship between postoperative cervical lordosis and the objective rotational range of motion and subjective restriction. Methods In this single-center, retrospective cohort study, patients with degenerative cervical myelopathy operated via laminectomy and fusion from C2 to the thoracic spine were included. X-ray imaging was evaluated for common lordosis parameters. The patient-reported rotational restriction of cervical spine mobility was acquired by a five-step score. Objective rotational range of motion was measured. The radiological parameters for cervical lordosis (C2-C7 lordotic angle, C2-C7 Cobb angle) were correlated with the measurements and the patient-reported subjective scores. Findings We found a significant, medium negative correlation between the measurements for rotation and the C2-C7 lordotic angle and a significant, large negative correlation to the C2-C7 Cobb angle. For subjective restriction, no or only small correlation was observed. Interpretation We found significant negative correlations between radiological cervical lordosis and objective measurements for rotation. These results indicate that for this particular patient population, a stronger postoperative cervical lordosis does not seem favorable under the aspect of rotational range of motion.

Purpose Chronic Obstructive Pulmonary Disease (COPD) includes chronic bronchitis, small airways disease, and emphysema. Diagnosis of COPD requires spirometric evidence and may be normal even when small airways disease or emphysema is present. Emphysema increases the risk of exacerbations, and is associated with all-cause mortality and increased risk of lung cancer. We evaluated the prevalence of emphysema in participants with and without a prior history of COPD. Methods We reviewed a prospective cohort of 52,726 subjects who underwent baseline low dose CT screening for lung cancer from 2003 to 2016 in the International Early Lung Cancer Action Program. Results Of 52,726 participants, 23.8%(12,542) had CT evidence of emphysema. Of these 12,542 participants with emphysema, 76.5%(9595/12,542) had no prior COPD diagnosis even though 23.6% (2258/9595) had moderate or severe emphysema. Among 12,542 participants, significant predictors of no prior COPD diagnosis were: male (OR = 1.47, p Conclusion Emphysema was identified in 23.8% participants undergoing LDCT and was unsuspected in 76.5%. LDCT provides an opportunity to identify emphysema, and recommend smoking cessation.

For patients with multilevel degenerative cervical myelopathy (DCM), laminectomy and fusion is an established technique. A concomitant effect of multilevel fusion is a restriction of cervical spine mobility. This retrospective study on DCM-patients with at least 4 laminectomy and fusion levels, compares data between objective and subjective restriction of the postoperative cervical spine mobility. The patient-reported restriction of cervical spine mobility was acquired by a five-step score. Measurements of cervical range of motion were performed using the CROM device and were correlated with the subjective scores. Fusion was performed over 6 levels in most of the 36 patients. For the subjective cervical spine mobility, 52.8% reported none to medium, 38.9% severe and 8.3% complete restriction. Mean objective cervical range of motion was 45.0° for flexion-extension, 26.3° for total lateral flexion and 51.4° for total rotation and therefore evidently reduced compared to non-operated patient cohorts in literature. There was a significant medium, negative correlation between the objective measurements and the patient-reported general restriction of cervical spine mobility, and with the physical component summary of SF-8. The significant objective reduction of cervical range of motion after laminectomy and multilevel fusion correlates with the patient-reported assessment for general restriction.

Objective Patients affected with von Hippel-Lindau disease often develop multiple hemangioblastomas in the cerebellum and spinal cord. Timing of surgical intervention is difficult and depends largely on the anticipated surgical morbidity. However, data regarding surgical outcome after multiple cerebellar and medullary surgeries are scarce. Our objective was to evaluate cumulative surgical morbidity in patients operated on multiple cerebellar and medullary hemangioblastomas and to deduce recommendations for treatment. Methods We performed a retrospective analysis for a consecutive cohort of von Hippel-Lindau patients with surgical treatment of at least two cerebellar and/or medullary hemangioblastomas. Pre- and postoperative functional grades were reviewed in patients' files and compared by Modified Ranking Scale (cerebellar surgeries) or by Modified McCormick Score (medullary surgeries). Results Thirty-six patients were surgically treated for at least two cerebellar hemangioblastomas (12 patients), at least two medullary hemangioblastomas (19 patients) or at least two hemangioblastomas in both locations (5 patients). Fourthy-eight cerebellar and 80 medullary procedures were performed in total. On average, multiple cerebellar surgeries caused no clinical deterioration, whereas multiple medullary surgeries led to a slight cumulative deterioration of postoperative functional grades. The severity of this deterioration did not correlate to the number of performed medullary surgeries. Conclusion Resection of multiple cerebellar hemangioblastomas is not associated with cumulative morbidity. Although there is a certain cumulative surgical morbidity caused by medullary surgeries, its extent does not increase with the number of performed surgeries. Microsurgical removal of asymptomatic tumors with radiographic progression can also be considered for patients with multiple tumors and previous surgeries.

Objectives The negative effects of obesity on the health and quality of life of those afflicted has become an important public concern. Previous studies have shown an association between obesity and higher rates of complications and unfavorable outcomes following spine surgery. This study is to identify peri- and postoperative complication rates as well as short-term and long-term outcomes in morbidly obese patients who underwent minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) in comparison to age-matched normal-weight patients. Patients and methods We retrospectively reviewed medical records for all adult patients with a body mass index (BMI) ≥40 kg/m2 who underwent 1- to 2-level MIS TLIF for degenerative disease between February 2009 and February 2014 at a single institution and compared them to age-matched normal-weight patients (BMI 20–25 kg/m2). Duration of operation, length of hospital stay, use of analgesics, minor and major complications (infections and re-operations) as well as postoperative pain reduction within 30 days of surgery were recorded. Furthermore, we collected long-term follow-up data (>1 year) regarding complications and pain reduction. Results We identified 14 patients with a BMI ≥ 40 kg/m2 (mean, 43.2 kg/m2) who underwent MIS TLIF. Both groups showed comparable complication rates and clinical results in the short term ( Conclusion MIS TLIF is technically feasible in morbidly obese patients with no evidence of higher complication rates among this demographic compared to normal-weight individuals when followed-up in the short-term (

Objective Laminectomy and fusion is a standard technique in patients with multilevel degenerative cervical myelopathy (DCM). However, this procedure is associated with a reduction of cervical range of motion. This study examines how patients are subjectively restricted in cervical spine mobility, how they are impaired in activities of daily living (ADLs) and how this affects their quality of life. Methods In this single-center, retrospective cohort study patients with DCM operated via laminectomy and fusion over at least four segments were included. Clinical outcome was assessed via pain scores, NDI, patient satisfaction index, mJOA and SF-8. The patient-reported restriction of cervical spine mobility and the resulting impairment for various ADLs were acquired by a newly developed five-step score. Results 53 patients could be evaluated. 75.5 % were satisfied with the treatment. 41.5 % reported a moderate restriction of mobility, followed by severe restriction in 34.0 % and mild restriction in 15.1 %. Of the various directions of movement, flexion was indicated as the least restricted. Overhead work was the most impaired activity (26.4 % severe restriction, 37.7 % complete restriction). 60.4 % experienced none to moderate impairment when driving a car. The mean values for the SF-8 were 37.5 for the physical and 47.8 for the mental component summary. Conclusion Despite multilevel fusion and the reduced physical component summary of the SF-8, more than half of the patients reported only mild to moderate restriction. The concern about a complete impairment in various ADLs is unfounded for the majority of patients.

Eosinophilic esophagitis (EoE) is a chronic, food antigen–driven, inflammatory disease of the esophagus and is associated with impaired barrier function. Evidence is emerging that loss of esophageal expression of the serine peptidase inhibitor, kazal type 7 (SPINK7), is an upstream event in EoE pathogenesis. Here, we provide evidence that loss of SPINK7 mediates its pro-EoE effects via kallikrein 5 (KLK5) and its substrate, protease-activated receptor 2 (PAR2). Overexpression of KLK5 in differentiated esophageal epithelial cells recapitulated the effect of SPINK7 gene silencing, including barrier impairment and loss of desmoglein-1 expression. Conversely, KLK5 deficiency attenuated allergen-induced esophageal protease activity, modified commensal microbiome composition, and attenuated eosinophilia in a murine model of EoE. Inhibition of PAR2 blunted the cytokine production associated with loss of SPINK7 in epithelial cells and attenuated the allergen-induced esophageal eosinophilia in vivo. Clinical samples substantiated dysregulated PAR2 expression in the esophagus of patients with EoE, and delivery of the clinically approved drug α1 antitrypsin (A1AT, a protease inhibitor) inhibited experimental EoE. These findings demonstrate a role for the balance between KLK5 and protease inhibitors in the esophagus and highlight EoE as a protease-mediated disease. We suggest that antagonizing KLK5 and/or PAR2 has potential to be therapeutic for EoE.

Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell-autonomous gradual buildup of DNA double-strand break (DSB) misrepair. Here we report that single-dose radiotherapy (SDRT), a disruptive technique that ablates more than 90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase-mediated (ASMase-mediated) microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcirculatory vasoconstriction after SDRT conferred an ischemic stress response within parenchymal tumor cells, with ROS triggering the evolutionarily conserved SUMO stress response, specifically depleting chromatin-associated free SUMO3. Whereas SUMO3, but not SUMO2, was indispensable for homology-directed repair (HDR) of DSBs, HDR loss of function after SDRT yielded DSB unrepair, chromosomal aberrations, and tumor clonogen demise. Vasoconstriction blockade with the endothelin-1 inhibitor BQ-123, or ROS scavenging after SDRT using peroxiredoxin-6 overexpression or the SOD mimetic tempol, prevented chromatin SUMO3 depletion, HDR loss of function, and SDRT tumor ablation. We also provide evidence of mouse-to-human translation of this biology in a randomized clinical trial, showing that 24 Gy SDRT, but not 3×9 Gy fractionation, coupled early tumor ischemia/reperfusion to human cancer ablation. The SDRT biology provides opportunities for mechanism-based selective tumor radiosensitization via accessing of SDRT/ASMase signaling, as current studies indicate that this pathway is tractable to pharmacologic intervention.

Purpose Partial nephrectomy (PN) is standard for small renal masses, improving renal function by preserving renal parenchyma compared with radical nephrectomy. Recent work demonstrated that postoperative surgeon assessment of volume preservation (SAVP) and 3D imaging measurements agree and correlate with postoperative function. We hypothesize preoperative assessment of volume preservation (PAVP) with PN based on preoperative imaging will reliably indicate postoperative renal function. Materials and Methods Data were collected from 336 patients undergoing PN for suspected renal cancer by 40 surgeons at 12 centers in Europe and the United States within the Surface-Intermediate-Base International Consortium. Surgeons recorded PAVP and SAVP for individual patients; pre- and postoperative glomerular filtration rate (GFR) was estimated by Chronic Kidney Disease Epidemiology Collaboration equations. Correlations between PAVP, SAVP, and postoperative GFR were assessed with linear regression models. Bland–Altman analysis was used to assess agreement between PAVP and SAVP with a significant cutoff of 5%. Results Median PAVP was 90% (interquartile range [IQR] 85%–100%) and SAVP was 90% (IQR: 80%–94%). PAVP and SAVP were moderately correlated (R2 = 0.67, P Conclusion Renal function is closely linked to the amount of parenchymal volume preservation, whether estimated prior to surgery (PAVP) or afterward (SAVP). PAVP provides reasonably accurate information for decision-making in patients considering PN.

Background Chronic rhinosinusitis (CRS) without nasal polyps (CRSsNP) is a common disease that is characterized by multiple inflammatory endotypes. However, the molecular mechanisms in CRSsNP are poorly understood compared with those of polypoid CRS. Objective Our aim was to identify mechanisms and biomarkers associated with inflammatory endotypes underpinning CRSsNP. Methods Ethmoid tissues and nasal lavage fluids (NLFs) were obtained from control patients and patients with CRS. The gene expression profiles were determined by microarray analysis and quantitative RT-PCR, and expression of proteins was measured by ELISA and Luminex analysis. Results Microarray found that compared with their levels of expression in control tissue, the levels of expression of 126, 241, and 545 genes were more than 3-fold and significantly elevated in CRSsNP with type 1 (T1) endotype, type 2 (T2) endotype, and type 3 (T3) endotype, respectively. Selected identified genes were confirmed by RT-PCR. Gene set enrichment analysis suggested that T1 CRSsNP was associated with IFN-γ signaling and antiviral immunity controlled by T cells (TH1 and CD8+), natural killer cells, and antigen-presenting cells; T2 CRSsNP was associated with STAT6 signaling and IgE-mediated activation controlled by eosinophils, mast cells, TH2 cells, group 2 innate lymphoid cells, and antigen-presenting cells; and T3 CRSsNP was associated with IL-17 signaling, acute inflammatory response, complement-mediated inflammation, and infection controlled by neutrophils, TH17 cells, B cells, and antigen-presenting cells. The results suggest that T1 (CXCL9 and CXCL10), T2 (eosinophilic proteins and CCL26), and T3 (CSF3) endotypic biomarkers in NLF may be able to distinguish tissue endotypes in CRSsNP. Conclusions Inflammatory endotypes in CRSsNP were controlled by different molecular mechanisms. NLF biomarker assays may allow for more precise and personalized medical treatments in CRS.

KEY POINTS: During myotonia congenita, reduced chloride (Cl(−)) conductance results in impaired muscle relaxation and increased muscle stiffness after forceful voluntary contraction. Repetitive contraction of myotonic muscle decreases or even abolishes myotonic muscle stiffness, a phenomenon called ‘warm up’. Pharmacological inhibition of low Cl(−) channels by anthracene‐9‐carboxylic acid in muscle from mice and ADR (‘arrested development of righting response’) muscle from mice showed a relaxation deficit under physiological conditions compared to wild‐type muscle. At increased osmolarity up to 400 mosmol L(–1), the relaxation deficit of myotonic muscle almost reached that of control muscle. These effects were mediated by the cation and anion cotransporter, NKCC1, and anti‐myotonic effects of hypertonicity were at least partly antagonized by the application of bumetanide. ABSTRACT: Low chloride‐conductance myotonia is caused by mutations in the skeletal muscle chloride (Cl(−)) channel gene type 1 (CLCN1). Reduced Cl(−) conductance of the mutated channels results in impaired muscle relaxation and increased muscle stiffness after forceful voluntary contraction. Exercise decreases muscle stiffness, a phenomena called ‘warm up’. To gain further insight into the patho‐mechanism of impaired muscle stiffness and the warm‐up phenomenon, we characterized the effects of increased osmolarity on myotonic function. Functional force and membrane potential measurements were performed on muscle specimens of ADR (‘arrested development of righting response’) mice (an animal model for low gCl(–) conductance myotonia) and pharmacologically‐induced myotonia. Specimens were exposed to solutions of increasing osmolarity at the same time as force and membrane potentials were monitored. In the second set of experiments, ADR muscle and pharmacologically‐induced myotonic muscle were exposed to an antagonist of NKCC1. Upon osmotic stress, ADR muscle was depolarized to a lesser extent than control wild‐type muscle. High osmolarity diminished myotonia and facilitated the warm‐up phenomenon as depicted by a faster muscle relaxation time (T (90/10)). Osmotic stress primarily resulted in the activation of the NKCC1. The inhibition of NKCC1 with bumetanide prevented the depolarization and reversed the anti‐myotonic effect of high osmolarity. Increased osmolarity decreased signs of myotonia and facilitated the warm‐up phenomenon in different in vitro models of myotonia. Activation of NKCC1 activity promotes warm‐up and reduces the number of contractions required to achieve normal relaxation kinetics.

Objective We report on our experiences of navigated posterior C1–C2 spondylodesis in the elderly (≥ 70 years of age). Patients This retrospective cohort study evaluated all patients ≥ 70 years of age treated with navigated posterior spondylodesis C1-C2 (at the most to C3) from 2008 to 2015 with a minimum follow-up of 1 year. Minor and major complications within 30 days after surgery, patient outcome, and the rate of solid fusion in computed tomography were recorded. The follow-up over 1 year was conducted by outpatient examinations and via telephone interviews. Results Twenty-two patients with a mean age of 79.9 years (range: 71–91 years) were treated. Minor complications were mild pneumonia (18.2%), postoperative confusion (9.1%), and urinary tract infection (4.5%). Major complications were severe pneumonia (4.5%) and clinically asymptomatic vertebral artery injury (4.5%). The mortality rate was 13.6% (n = 3) within the first 30 days after surgery and 22.7% (n = 5) within 1 year. All deceased patients were > 85 years of age. Conclusion In our patient population, posterior spondylodesis was shown to be beneficial for patients > 70 years up to age ∼ 85 years. The mortality rate increased sharply in patients > 85 years. In these patients the indication for surgery should be critically evaluated.

The high diagnostic potential of 64Cu-PSMA PET–CT imaging was clinically investigated in prostate cancer patients with recurrent disease and in the primary staging of selected patients with advanced local disease. The aim of our study is to assess the uptake behavior in the clinical setting of 64Copper Prostate-Specific Membrane Antigen (64Cu PSMA) Positron Emission Tomography/Computed Tomography (PET/CT) in prostate cancer. A retrospective study was performed in 23 patients with intermediate, high risk and progressive disease at primary staging of prostate cancer. All patients underwent 64Cu-PSMA PET. Overall, 250 MBq (4 MBq per kg bodyweight, range 230–290 MBq) of 64Cu-NODAGA PSMA was intravenously applied. PET images were performed 30 min (pelvis and abdomen) and 1–2 h post-injection (skull base to mid-thigh). Maximum standardized uptake values (SUVmax) were measured in the organs with high physiological uptake such as liver and kidney, and, additionally, background activity was measured in the gluteal area and in suspected tumor lesions using a HERMES workstation. PSMA uptake was detected in prostate bed in nine patients, in six patients in distant metastases (bone, lung and liver) and in nine patients in lymph nodes. Of 23 patients, 5 (20.8%) did not show any focal pathological uptake in the whole body. The number of sites (prostate bed, lymph nodes, distant metastases) with positive PSMA uptake was significantly associated with PSA values before imaging (P = 0.0032). The 64Cu PSMA uptake increased significantly from 30 min to 1–3 h post-injection (Wilcoxon signed rank test, P = 0.002). 64Cu NODAGA-PSMA PET is a promising imaging tool in the detection of residual disease in patients with recurrent or primary progressive prostate cancer. Furthermore, the increased tracer uptake over time indicates in vivo stability of the diagnostic radiopharmaceutical.

Background Information about the histopathology in 3 Tesla MRI negative extratemporal epilepsies is relatively limited. Most common histopathological findings in earlier (mixed 1.5 or 3 Tesla) MRI-negative series are focal cortical dysplasia (FCD), gliosis or normal findings. These series mostly use the older Palmini criteria for classification and grading. We focus on histopathology of only 3 Tesla MRI-negative extratemporal epilepsies according to the current ILAE criteria and investigate potential correlation to seizure outcome 1 year postoperatively. Materials and methods Sixteen substrates of 3 Tesla MRI-negative extratemporal epilepsies were examined in two steps. Standard stains and immunohistochemical reactions and Palmini criteria were used prospectively during the initial examination. Retrospectively, all specimens were re-examined and re-evaluated. Phospho-6 and calretinin stains and ILAE criteria were used during the review examination. Results Initial examination revealed 5 FCDs Palmini 1b, two 1a, five 2a and 4 cases of gliosis. The review examination according to ILAE criteria revealed 6 FCDs type IIa, 2 FCDs Ib and 7 mild malformations of cortical development (mMCD) type II. None of our cases was labelled as isolated gliosis after the review examination. The incidence of FCD, after the review examination per ILAE criteria, was reduced to 56%; versus 75% per Palmini. Conclusions In “true” 3 Tesla MRI-negative extratemporal epilepsies, incidence of FCD may be lower than in earlier MRI-negative series that included weaker MRI-field. Furthermore, consistent review examination may confirm the diagnosis of mMCD type II as substrate in cases diagnosed as “gliosis” or “normal” in the past.

Metastasis is a crucial step of malignant progression and is the primary cause of death from endometrial cancer. However, clinicians presently face the challenge that conventional surgical-pathological variables, such as tumour size, depth of myometrial invasion, histological grade, lymphovascular space invasion or radiological imaging are unable to predict with accuracy if the primary tumour has metastasized. In the current retrospective study, we have used primary tumour samples of endometrial cancer patients diagnosed with (n = 16) and without (n = 27) lymph nodemetastasis to identify potential discriminators. Using peptide matrix assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI), we have identified m/z values which can classify 88% of all tumours correctly. The top discriminative m/z values were identified using a combination of in situ sequencing and LC-MS/MS from digested tumour samples. Two of the proteins identified, plectin and alpha-Actin-2, were used for validation studies using LC-MS/MS data independent analysis (DIA) and immunohistochemistry. In summary, MALDI-MSI has the potential to identify discriminators of metastasis using primary tumour samples. Refereed/Peer-reviewed

Protein glycosylation, particularly N‐linked glycosylation, is a complex post‐translational modification (PTM), which plays an important role in protein folding and conformation, regulating protein stability and activity, cell‐cell interaction, and cell signalling pathways. This review focuses on analytical techniques, primarily mass spectrometry‐based techniques, to qualitatively and quantitatively assess N‐glycosylation while successfully characterising compositional, structural and linkage features with high specificity and sensitivity. The analytical techniques explored in this review include liquid chromatography electrospray ionisation tandem mass spectrometry (LC‐ESI‐MS/MS) and matrix‐assisted laser desorption/ionisation time‐of‐flight mass spectrometry (MALDI‐TOF‐MS), which have been used to analyse clinical samples, such as serum, plasma, ascites and tissue. Targeting the aberrant N‐glycosylation patterns observed in MALDI mass spectrometry imaging (MSI) offers a platform to visualise N‐glycans in tissue‐specific regions. Our studies on the intra‐patient (i.e. a comparison of tissue‐specific regions from the same patient) and inter‐patient (i.e. a comparison of tissue‐specific regions between different patients) variation of early‐ and late‐stage ovarian cancer (OC) patients identified specific N‐glycan differences that improve our understanding of the tumour microenvironment and potentially improve therapeutic strategies for the clinic. Refereed/Peer-reviewed

BACKGROUND: Lacking information on men who have sex with men (MSM) for most reported cases, sexually transmitted disease (STD) programs in the United States have used crude measures such as male-to-female case ratios (MFCR) as a rule of thumb to gauge MSM involvement at the local level, primarily with respect to syphilis cases in the past. Suitability of this measure for gonorrhea incidence has not previously been investigated. METHODS: A random sample of gonorrhea cases reported from January 2010 through June 2013 were interviewed in selected counties participating in the STD Surveillance Network to obtain gender of sex partners and history of transactional sex. Weighted estimates of proportion of cases among MSM and proportion reporting transactional sex were developed; correlation between MFCR and proportion MSM was assessed. RESULTS: Male-to-female case ratio ranged from 0.66 to 8.7, and the proportion of cases occurring among MSM varied from 2.5% to 62.3%. The MFCR was strongly correlated with proportion of cases among MSM after controlling for transactional sex (Pearson partial r = 0.754, P < 0.0001). CONCLUSIONS: Male-to-female case ratio for gonorrhea at the county level is a reliable proxy measure indicating MSM involvement in gonorrhea case incidence and should be used by STD programs to tailor their programmatic mix to include MSM-specific interventions.

Introduction Histopathology of MRI-negative temporal lobe epilepsies (TLE) shows heterogeneous findings. The use of either 1.5 or 3 Tesla MRI for the selection of MRI-negative cases and use of older classification systems instead of the current ILAE classification system may account for this heterogeneity. We focus on histopathology of 3 Tesla MRI-negative TLE according to ILAE criteria and investigate potential correlation to seizure outcome 1 year postoperatively. Materials and methods Twenty specimens (9 neocortical, 11 hippocampal) from eleven 3 Tesla MRI-negative patients with TLE were examined in two steps. Standard stains and immunohistochemical reactions as well as Palmini and Wyler criteria were used prospectively during the initial examination. Retrospectively, all specimens were re-examined and re-evaluated. Phospho-6 and calretinin stains and the ILAE criteria were used during the review examination. Results Initial examination revealed 7 focal cortical dysplasias (FCDs) Palmini type 1, two cases of cortical gliosis, 4 cases of hippocampal sclerosis (HS) Wyler grade 1 and seven cases of hippocampal gliosis. The review examination according to ILAE criteria revealed 4 FCDs type I and 5 mild malformations of cortical development. All hippocampal specimens showed “no HS/gliosis only” after the review examination. Histopathology showed no correlation to seizure outcome. Discussion This is the first histopathological study to include only 3 Tesla MRI-negative cases. The use of ILAE criteria lead to the diagnosis of “no HS/gliosis only” of all hippocampal specimens, a finding not in line with previously reported series. The spectrum of diagnoses within neocortical specimens showed accordingly more mild findings.

Malignant hyperthermia (MH) is a fatal hypermetabolic state that may occur during general anesthesia in susceptible individuals. It is often caused by mutations in the ryanodine receptor RyR1 that favor drug-induced release of Ca2+ from the sarcoplasmic reticulum. Here, knowing that membrane depolarization triggers Ca2+ release in normal muscle function, we study the cross-influence of membrane potential and anesthetic drugs on Ca2+ release. We used short single muscle fibers of knock-in mice heterozygous for the RyR1 mutation Y524S combined with microfluorimetry to measure intracellular Ca2+ signals. Halothane, a volatile anesthetic used in contracture testing for MH susceptibility, was equilibrated with the solution superfusing the cells by means of a vaporizer system. In the range 0.2 to 3%, the drug causes significantly larger elevations of free myoplasmic [Ca2+] in mutant (YS) compared with wild-type (WT) fibers. Action potential–induced Ca2+ signals exhibit a slowing of their time course of relaxation that can be attributed to a component of delayed Ca2+ release turnoff. In further experiments, we applied halothane to single fibers that were voltage-clamped using two intracellular microelectrodes and studied the effect of small (10-mV) deviations from the holding potential (−80 mV). Untreated WT fibers show essentially no changes in [Ca2+], whereas the Ca2+ level of YS fibers increases and decreases on depolarization and hyperpolarization, respectively. The drug causes a significant enhancement of this response. Depolarizing pulses reveal a substantial negative shift in the voltage dependence of activation of Ca2+ release. This behavior likely results from the allosteric coupling between RyR1 and its transverse tubular voltage sensor. We conclude that the binding of halothane to RyR1 alters the voltage dependence of Ca2+ release in MH-susceptible muscle fibers such that the resting membrane potential becomes a decisive factor for the efficiency of the drug to trigger Ca2+ release.

Objective To investigate presurgical diagnostic modalities, clinical and seizure outcome as well as predictive factors after resective epilepsy surgery in 3 Tesla MRI-negative focal epilepsies. Patients and methods This retrospective study comprises 26 patients (11 males/15 females, mean age 34 ± 12 years, range 13–50 years) with 3 Tesla MRI-negative focal epilepsies who underwent resective epilepsy surgery. Non-invasive and invasive presurgical diagnostic modalities, type and localization of resection, clinical and epileptological outcome with a minimum follow-up of 1 year (range 1–11 years, mean 2.5 ± 2.3 years) after surgery as well as outcome predictors were evaluated. Results All patients underwent invasive video-EEG monitoring after implantation of intracerebral depth and/or subdural electrodes. Ten patients received temporal and 16 extratemporal or multilobar (n = 4) resections. There was no perioperative death or permanent morbidity. Overall, 12 of 26 patients (46%) were completely seizure-free (Engel IA) and 65% had a favorable outcome (Engel I–II). In particular, seizure-free ratio was 40% in the temporal and 50% in the extratemporal group. In the temporal group, long duration of epilepsy correlated with poor seizure outcome, whereas congruent unilateral FDG-PET hypometabolism correlated with a favorable outcome. Conclusions In almost two thirds of temporal and extratemporal epilepsies defined as “non-lesional” by 3 Tesla MRI criteria, a favorable postoperative seizure outcome (Engel I–II) can be achieved with accurate multimodal presurgical evaluation including intracranial EEG recordings. In the temporal group, most favorable results were obtained when FDG-PET displayed congruent unilateral hypometabolism.