Doppler-Derived Renal Functional Reserve in the Prediction of Postoperative Acute Kidney Injury in Patients Undergoing Robotic Surgery.

BACKGROUND: Postoperative acute kidney injury (PO-AKI) is a frequent complication after surgery. Various tools have been proposed to identify patients at high risk for AKI, including preoperative serum creatinine or estimated glomerular filtration rate (eGFR), urinary cell cycle arrest, and tubular damage biomarkers; however, none of these can appropriately assess AKI risk before surgery. Renal functional reserve (RFR) screened by the Doppler-derived intraparenchymal renal resistive index variation (IRRIV) test has been proposed to identify patients at risk for AKI before a kidney insult. IRRIV test has been developed in healthy individuals and previously investigated in cardiac surgery patients. This study aims to evaluate the value of the IRRIV test in identifying PO-AKI among patients undergoing robotic abdominal surgery in the Trendelenburg position for pelvic oncological disease. METHODS: We performed a prospective, double-blinded, observational study. Preoperative baseline renal function and RFR were assessed in 53 patients with baseline eGFR >60 mL/min/1.73 m2, undergoing robotic surgery in the Trendelenburg position for pelvic oncological disease. The capability of Doppler-derived RFR in predicting PO-AKI was investigated with the area under the receiver operating characteristic curve (ROC-AUC). RESULTS: Approximately 15.1% of patients developed AKI within the first 3 postoperative days. Thirty-one (58.5%) patients had a physiologic delta-RRI (ie, ≥0.05), while 22 (41.5%) patients did not. The ROC-AUC for PO-AKI was 0.85 (95% confidence interval [CI], 0.74-0.97; P = .007) for serum creatinine, 0.84 (95% CI, 0.71-0.96; P = .006) for eGFR, and 0.84 (95% CI, 0.78-0.91; P = .017) for delta-RRI. When combined with eGFR, the ROC-AUC for delta-RRI was 0.95 (95% CI, 0.9-1). CONCLUSIONS: Our findings show that the preoperative assessment of Doppler-derived RFR combined with baseline renal function improves the capability of identifying patients at high risk for PO-AKI with eGFR >60 mL/min/1.73 m2 after robotic abdominal surgery in Trendelenburg position for pelvic oncological disease.

B3 Breast Lesions: Positive Predictive Value and Follow-Up on a Large Single-Institution Series.

INTRODUCTION: Lesions of uncertain malignant potential (B3) represent 10% of core needle biopsies (CNBs) or vacuum-assisted breast biopsies (VABBs). Traditionally, B3 lesions are operated on. This study investigated the association between B3 subtypes and malignancy to determine the best management. METHODS: Pre- and postoperative histological reports from 226 patients, who had undergone excisional surgery for B3 lesions, following CNB or VABB, were retrospectively analyzed. The correlation between the CNB/VABB diagnosis and the final pathology was investigated, along with the correlation between malignancy upgrade and the type of mammographic lesion. The positive predictive value (PPV) of malignancy of B3 lesions was calculated by simple logistic regression. Patients without cancer diagnosis underwent a 7-y follow-up. RESULTS: Pathology showed 171 (75.6%) benign and 55 (24.3%) malignant lesions. The PPV was 24.3% (P = 0.043), including 31 (13.7%) ductal carcinomas in situ and 24 (10.6%) invasive carcinomas. The most frequently upgraded lesions were atypical ductal hyperplasia, 34.2% (P = 0.004), followed by lobular intraepithelial neoplasia, 27.5% (P = 0.025). The median diameter of mammographic lesions was 1.5 [0.9-2.5] cm, while for surgical specimens, it was 5 [4-7] cm (P < 0.0001). Mammographic findings and histology showed a significant correlation (P = 0.038). After a 7-y follow-up, 15 (8.9%) patients developed carcinoma, and 7 patients (4%) developed a new B3 lesion. CONCLUSIONS: We can conclude that atypical ductal hyperplasia and lobular intraepithelial neoplasia still require surgery for a significant PPV. Other types that lacked significance or confidence intervals were too wide to draw any conclusion.

Novel Biomarkers for Early Detection of Acute Kidney Injury and Prediction of Long-Term Kidney Function Decline after Partial Nephrectomy.

BACKGROUND: Identifying acute kidney injury (AKI) within few hours of onset is certainly helpful. However, early prediction of a long-term eGFR decline may be an even more important goal. Our aim was to identify and compare serum [creatinine, kineticGFR, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL)] and urinary (NephroCheck, NGAL, proteinuria, albuminuria, acantocytes at urinary sediment) predictors of AKI that might efficiently predict long-term GFR decline after robotic Nephron-Spearing Surgery (rNSS). METHODS: Monocentric prospective observational study. Patients scheduled for rNSS for suspected localized Renal Cell Carcinoma from May 2017 to October 2017 were enrolled. Samples were collected preoperatively and postoperatively (timepoints: 4 h, 10 h, 24 h, 48 h), while kidney function was re-assessed up to 24 months. RESULTS: 38 patients were included; 16 (42%) developed clinical AKI. The eGFR decline at 24 months was more pronounced after postoperative AKI (-20.75 vs. -7.20, p < 0.0001). KineticGFR at 4 h (p = 0.008) and NephroCheck at 10 h (p = 0.001) were, at multivariable linear regression analysis, efficient predictors of post-operative AKI and long-term eGFR decline if compared to creatinine (R2 0.33 vs. 0.04). CONCLUSIONS: NephroCheck and kineticGFR have emerged as promising noninvasive, accurate, and early biomarkers of postoperative AKI and long-term GFR decline after rNSS. Combining NephroCheck and kineticGFR in clinical practice would allow to identify high risk of postoperative AKI and long-term GFR decline as early as 10 h after surgery.

A Real-Life Study on the Use of Tildrakizumab in Psoriatic Patients.

Tildrakizumab is a humanized IgG1κ monoclonal antibody that selectively targets the p19 subunit of interleukin IL-23, thereby inhibiting the IL-23/IL-17 axis, which is primarily implicated in the immunopathogenesis of psoriasis. Tildrakizumab is approved for the treatment of moderate-to-severe plaque-type psoriasis in adults based on the evidence of two randomized and controlled phase-III clinical trials (reSURFACE 1 and reSURFACE 2). Here, we report our real-life experience treating 53 psoriatic patients (19 female and 34 male) who were administered tildrakizumab every 12 weeks and received follow-ups over 52 weeks. Descriptive and inferential statistical analyses were performed, in particular the Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI) and, if applicable, the Nail Psoriasis Severity Index (NAPSI) and Palmoplantar Psoriasis Physician Global Assessment (PPPGA). These were assessed at baseline and after different timepoints (weeks) during the follow-up period. We described and evaluated demographical and epidemiological characteristics in our cohort group, focusing on comorbidities. In this group, 35.9% of patients were female and 64.1% were male, with 47.1% being smokers and with a mean age of 51.2 years. A total of 37.7% of these patients was affected by scalp psoriasis; regarding comorbidities, hypertension was the most frequent (32.5%), followed by psoriatic arthritis (PsA) (18.60%) and diabetes (13.9%). At week 52, 93%, 90.2% and 77% of patients achieved a PASI reduction ≥75% (PASI 75), PASI 90 and PASI 100, respectively. In addition, NAPSI, PPPGA and DLQI scores were significantly reduced by week 52. In our cohort of complex psoriasis patients, disease remission began at the end of the fourth week of treatment and remained constant from week 16 to week 52.

Relationship between intensive care surge capacity and hospital factors: an extensive experience.

As a prolonged surge scenario, the COVID-19 pandemic has offered an unparalleled opportunity to improve hospital surge capacity (SC) understanding and the ability to manage it. In this study, the authors report the experience of a large hospital network and evaluate potential relationships between Intensive Care Units SC (ICU-SC) and some hospital-related variables: bed occupancy, emergency department admissions, ward admission from ED, and elective surgery procedures. Pearson's partial correlation coefficient (r) has been used to define the relationship between SC and the daily values of the above variables, collected through a dedicated digital platform that also ensured a regular quality check of the data. The observation has concerned several levels of analysis, namely two different types of SC calculation (SC base-SCb and SC actual-SCa), hospital category level and multi-hospital level, and two consecutive pandemic waves. Among the 16 hospitals observed, the correlation was shown to be moderate-positive with non-ICU bed occupancy (r/ = 0.62, r/ = 0.54), strong/moderate with ICU bed occupancy (r/ = 0.72, r/ = 0.54), and moderate with ward admissions from ED (r/ = 0.50, r/ = 0.51) On the contrary, the correlation proved to be moderate-negative with ED admissions (r/ = - 0.69, r/ = - 0.62) and low with the number of elective surgery procedures (r/ = - 0.10, r/ = - 0.16). This study identified a positive correlation between SC and three variables monitored: ICU bed occupancy, non-ICU bed occupancy, and ward admissions from ED. On the contrary, the correlation was negative for ED admission and the number of elective surgery procedures. The results have been confirmed across all levels of analysis adopted.

Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is characterized by resistance to chemotherapy and a poor prognosis. Therefore, treatments that can effectively suppress tumor growth are urgently needed. Aberrant activation of hedgehog (HH) signaling has been implicated in several cancers, including those of the hepatobiliary tract. However, the role of HH signaling in intrahepatic CCA (iCCA) has not been completely elucidated. In this study, we addressed the function of the main transducer Smoothened (SMO) and the transcription factors (TFs) GLI1 and GLI2 in iCCA. In addition, we evaluated the potential benefits of the combined inhibition of SMO and the DNA damage kinase WEE1. Transcriptomic analysis of 152 human iCCA samples showed increased expression of GLI1, GLI2, and Patched 1 (PTCH1) in tumor tissues compared with nontumor tissues. Genetic silencing of SMO, GLI1, and GLI2 inhibited the growth, survival, invasiveness, and self-renewal of iCCA cells. Pharmacologic inhibition of SMO reduced iCCA growth and viability in vitro, by inducing double-strand break DNA damage, leading to mitotic arrest and apoptotic cell death. Importantly, SMO inhibition resulted in the activation of the G2-M checkpoint and DNA damage kinase WEE1, increasing the vulnerability to WEE1 inhibition. Hence, the combination of MRT-92 with the WEE1 inhibitor AZD-1775 showed increased antitumor activity in vitro and in iCCA xenografts compared with single treatments. These data indicate that combined inhibition of SMO and WEE1 reduces tumor burden and may represent a strategy for the clinical development of novel therapeutic approaches in iCCA.

Tryptophan degradation enzymes and Angiotensin (1-7) expression in human placenta.

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are key enzymes for tryptophan degradation, regulating immune tolerance during pregnancy. The intrauterine renin-angiotensin system is also involved in the progression of a healthy pregnancy. Angiotensin(1-7) maintains the integrity of fetal membranes via counteracting the pro-inflammatory actions of Angiotensin II. No data are available on placental Angiotensin(1-7) co-expression with TDO. We aimed to characterize TDO mRNA expression and its localization in different areas of the placenta of physiological pregnancies delivered at term; its co-expression with Angiotensin(1-7) and its correlation with the plasma kynurenine/tryptophan (Kyn/Trp) ratio was investigated. This prospective observational study included a nonconsecutive series of 20 singleton uncomplicated pregnancies delivered vaginally. TDO mRNA was expressed in both maternal and fetal sides of the placentas and TDO protein also in the villi and it was co-expressed with IDO1 in almost half of the placental cells at these sites. The percentage of TDO+ and IDO1+ cells appeared to be influenced by maternal pre-gestational smoking and newborn weight. A strong correlation was found between the percentage of TDO+ and IDO1+ cells in the villi. TDO+ cells also expressed Angiotensin(1-7), with a higher percentage on the fetal side and in the villi compared to the maternal one. Kyn/Trp plasma ratio was not correlated with IDO and TDO expression nor with the patient's characteristics. Collectively, our data indicate that TDO is detectable in placental tissue and is co-expressed with IDO and with Angiotensin(1-7)+ on the fetal side and in the villi.

Ultrasonographic Intraparenchymal Renal Resistive Index Variation for Assessing Renal Functional Reserve in Patients Scheduled for Cardiac Surgery: A Pilot Study.

INTRODUCTION: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication in patients undergoing cardiac surgery. Preoperative renal functional reserve (RFR) has been demonstrated to be highly predictive of CSA-AKI. We have previously demonstrated that intraparenchymal renal resistive index variation (IRRIV) measured by ultrasound (US) can identify the presence of RFR in healthy individuals. This study aimed (1) to examine the correlation between the US IRRIV test and RFR measured through the protein loading test in patients undergoing elective cardiac surgery and (2) to determine the value of the 2 methods for predicting occurrence of AKI or subclinical AKI after cardiac surgery. METHODS: Consecutive patients scheduled for cardiac surgery were enrolled for this pilot study. The protein loading test and the IRRIV test were performed in all patients 2 days before cardiac surgery. Correlation between IRRIV and RFR was tested using Pearson correlation analysis. Association between presence of RFR and positive IRRIV test, presence of RFR and AKI and subclinical AKI, and positive IRRIV test and AKI and subclinical AKI was evaluated using logistic regression analysis. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the values of IRRIV for predicting RFR, RFR for predicting AKI and subclinical AKI, and IRRIV for predicting AKI and subclinical AKI. RESULTS: Among the 31 patients enrolled, significant association was found between IRRIV and RFR (r = 0.81; 95% CI: 0.63-0.90; p < 0.01). The association between RFR and IRRIV was described in 27/31 (87.1%) patients. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the IRRIV test were 100, 84, 60, and 100%, respectively. In ROC curve analysis, the area under the curve (AUC) was 0.80 (95% CI: 0.64-0.96). After cardiac surgery, 1/31 (3.2%) patient had AKI and 12/31 (38.7%) had subclinical AKI. RFR predicted subclinical AKI (odds ratio [OR] = 0.93; 95% CI: 0.87-0.98; p = 0.02). The sensitivity, specificity, PPV, and NPV of the RFR were 61, 88.8, 80, and 76%, respectively; the AUC was 0.75 (95% CI: 0.59-0.91). IRRIV predicts subclinical AKI (OR = 0.79; 95% CI: 0.67-0.93; p = 0.005). The sensitivity, specificity, PPV, and NPV of the IRRIV test were 46.1, 100, 100, and 72%, respectively; the AUC was 0.73 (95% CI: 0.58-0.87). CONCLUSION: This pilot study suggests that a positive IRRIV test can significantly predict the presence of RFR in patients scheduled for cardiac surgery. RFR measured by the protein loading test or by the US IRRIV test can predict the occurrence of subclinical postoperative AKI. The findings of this study need to be confirmed in large patient cohorts.

Risk factors for difficult Laryngeal Mask Airway LMA-Supreme™ (LMAS) placement in adults: a multicentric prospective observational study in an Italian population.

BACKGROUND: Supraglottic airway devices (SADs) are precious tools for airway management in both routine and rescue situations; few studies have analyzed the risk factors for their difficult insertion. METHODS: The aim of this study was to identify the risk factors for difficult insertion for a specific SAD, the Laryngeal Mask Airway LMA-Supreme™ (LMAS). This was a prospective multicentric observational study on a cohort of Italian adult patients receiving general anesthesia for elective surgery. The possible causes of difficulty in LMAS placement (difficulty in insertion or unsatisfactory ventilation) were identified based on literature and on the opinion of international airway management experts. A dedicated datasheet was prepared to collect patients' data, including anthropometric-parameters and parameters for the prediction of difficult airway management, as well as technical choices for the use of LMAS. Data were analyzed to discover the risk factors for difficult LMAS placement and the association between each risk factor and the proportion of incorrect positioning was evaluated through the relative risk and its confidence interval. RESULTS: Four hundred thirty-two patients were enrolled; seventy required two or more attempts to insert the LMAS; nine required a change of strategy. At multivariate analysis, the following factors were significantly associated with difficult LMAS placement: Mallampati III-IV with either phonation or not; inter-incisor distance < 3 cm; reduced neck mobility; no administration of neuromuscular blocking agents (NMBAs). CONCLUSIONS: The alignment of the laryngeal and pharyngeal axes seems to facilitate the procedure, together with NMBA administration; on the contrary, Mallampati grade III-IV are associated with difficult LMAS placement.

The relationship between intra-parenchymal renal resistive index variation and renal functional reserve in healthy subjects.

BACKGROUND: Renal functional reserve can be used as a clinical tool for risk stratification of patients undergoing potentially nephrotoxic procedures. Ultrasound assessment of intra-parenchymal renal resistive index variation-IRRIV test-has been recently proposed as a safe, reproducible, inexpensive and easy to perform technique to identify the presence of renal functional reserve. The present study has been designed to externally validate the IRRIV test in a validation cohort of healthy subjects. METHODS: We examined data from a group of 47 healthy subjects undergoing protein loading and IRRIV testing. The correlation between IRRIV and renal functional reserve was tested using Pearson correlation analysis. Concordance between presence of renal functional reserve (i.e. a value of renal functional reserve ≥ 15 ml/min/1.73 m2) and IRRIV was evaluated using logistic regression analysis. RESULTS: We found a significant correlation between IRRIV and renal functional reserve (Pearson correlation coefficient = 0.83 [95% confidence interval (CI) 0.71-0.90; p < 0.01]). Concordance between the presence of renal functional reserve and the IRRIV test was described in 45 (95.7%) subjects. In particular, a negative IRRIV test correctly predicted the absence of renal functional reserve in 5 subjects, while a positive IRRIV test correctly predicted the presence of renal functional reserve in 40 subjects. Only two subjects were incorrectly classified by the IRRIV test. IRRIV predicts renal functional reserve with a ROC-AUC of 0.86 [CI 95% 0.68-1]. CONCLUSIONS: The IRRIV test is an ultrasound technique that significantly predicts the presence and the degree of renal functional reserve in healthy subjects.

Efficacy and safety of switching from reference adalimumab to SB5 in a real-life cohort of inflammatory rheumatic joint diseases.

OBJECTIVE: SB5 showed comparable efficacy and safety profile in respect to adalimumab originator (ADA) in randomized clinical trials of rheumatoid arthritis (RA) and psoriasis. We aimed to describe the efficacy and safety of SB5 after switching from ADA in RA, axial spondyloarthritis (axSpA), psoriatic arthritis (PsA) and juvenile idiopathic arthritis (JIA) patients. METHOD: Adult RA, PsA, axSpA, JIA patients treated with ADA for at least 6 months, switched to SB5 in stable clinical conditions, were eligible. Data on safety, activity indexes and patient-reported outcomes were collected at baseline, 3 and 6 months after switching. RESULTS: Eighty-two patients (19 RA, 28 PsA, 32 axSpA and 3 JIA; 45 females, mean age 54 ± 14 years, disease duration 13 ± 7 years, ADA duration 6 ± 3 years) were enrolled. RA patients showed stable conditions, while PsA patients showed an increase in both HAQ, DAS28(CRP) and DAPSA and axSpA patients an increase in VAS pain, VAS patient disease activity and ASDAS, both at 3 months. There were changes in the concomitant medications profile, with regression of activity indexes increases at 6 months. Adverse events were reported by 33.7% patients at 3 months and 16.6% patients at 6 months, mostly disease flares and infectious events. Two patients stopped SB5. CONCLUSIONS: Despite temporary changes in the concomitant medication profile for mild disease flares, our real-life data replicate the safety profile of switching from ADA to SB5 in RA, with additional data for its applicability in PsA and axSpA patients, further supporting switching to biosimilars in treating inflammatory rheumatic conditions. Key Points • Switching from adalimumab originator to SB5 is feasible in real life rheumatic inflammatory joint diseases. • Mild disease flares can present after switching from originator adalimumab to SB5, in particular in axial spondyloarthritis and psoriatic arthritis. • Changes in concomitant medications profile allows the control of minor disease flares presenting after switching from adalimumab originator to SB5.

The switch from etanercept originator to SB4: data from a real-life experience on tolerability and persistence on treatment in joint inflammatory diseases.

AIMS: Switching from originator to biosimilar is part of current practice in inflammatory rheumatic musculoskeletal diseases (iRMDs) such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondylarthritis (axSpA), with evidences derived from both etanercept (ETN) to SB4-switching randomized controlled trials and real-life registries. We investigated the safety and treatment persistence of ETN/SB4 in a multi-iRMD cohort derived from two rheumatology departments in our region. METHODS: Adult patients with iRMDs, treated with ETN for at least 6 months and switched to SB4 in stable clinical condition, were eligible for this retrospective evaluation. Retrospective data on adverse events, loss of efficacy and persistence on treatment were collected until latest available follow-up. RESULTS: A total of 220 patients (85 RA, 81 PsA, 33 axSpA, 14 juvenile idiopathic arthritis and seven other conditions; 142 females, mean age 58 ± 7 years, disease duration 12 ± 4 years, ETN duration 7 ± 4 years) were enrolled, with median follow-up of 12.1 (9.7-15.8) months. A total of 50 patients (22.7%) presented with at least one adverse event, with 36 (16.4%) disease flares and 30 (13.6%: 11 for safety and 19 loss of efficacy) SB4 withdrawals. Cumulative SB4 treatment persistence was 99.1%, 88.6% and 64.6% at 6, 12 and 18 months respectively. Back-switch to ETN was performed in 17/30 cases, the remaining cases were managed with change of biologic disease modifying or conventional synthetic anti-rheumatic drug. Age was the only significant predictor of SB4 interruption at 6 months. CONCLUSION: Our real-life data confirm the safety profile of switching from ETN to SB4, with slightly higher treatment persistence rates compared with other real-life registries.

ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL.

Understanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Here we report a mechanism regulated by the oncogenic SOX2-GLI1 transcriptional complex driving melanoma invasion through the induction of the sialyltransferase ST3GAL1. Using in vitro and in vivo studies, we demonstrate that ST3GAL1 drives melanoma metastasis. Silencing of this enzyme suppresses melanoma invasion and significantly reduces the ability of aggressive melanoma cells to enter the blood stream, colonize distal organs, seed and survive in the metastatic environment. Analysis of glycosylated proteins reveals that the receptor tyrosine kinase AXL is a major effector of ST3GAL1 pro-invasive function. ST3GAL1 induces AXL dimerization and activation that, in turn, promotes melanoma invasion. Our data support a key role of the ST3GAL1-AXL axis as driver of melanoma metastasis, and highlight the therapeutic potential of targeting this axis to treat metastatic melanoma.

Phase 2 study of NAB-paclitaxel in SensiTivE and refractory relapsed small cell lung cancer (SCLC) (NABSTER TRIAL).

BACKGROUND: Despite sensitivity to first-line chemotherapy, most small-cell lung cancer (SCLC) patients relapse. In this setting, topotecan demonstrated modest activity with significant toxicity. Paclitaxel was also active. This study was designed to evaluate activity and safety of nab-paclitaxel in relapsed SCLC. METHODS: In this multicentre prospective Phase 2 trial, patients with refractory or sensitive SCLC progressed to first-line platinum-based chemotherapy received nab-paclitaxel 100 mg/smq on days 1, 8, 15 every 4 weeks up to six cycles, progressive disease or intolerable toxicity. Primary endpoint was investigator-assessed objective tumour response. Secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). RESULTS: Of the 68 patients treated, partial response was 8% in the refractory cohort and 14% in the sensitive cohort. Most common toxicities of any grade were fatigue (54%), anaemia (38%), neutropenia (29%), leukopenia (26%) and diarrhoea (21%). Median PFS was similar in both refractory (1.8 months) and sensitive cohorts (1.9 months), while median OS was longer in sensitive one (6.6 versus 3.6 months). CONCLUSIONS: Although nab-paclitaxel has shown some modest anti-tumour activity in relapsed SCLC, associated with a favourable toxicity profile, the primary end-point of the study was not met. CLINICAL TRIAL REGISTRATION: Clinical Trial registration number is ClinicalTrials.gov Identifier: NCT03219762.

Neuroprotection induced by dexpramipexole delays disease progression in a mouse model of progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Drugs able to counteract progressive multiple sclerosis (MS) represent a largely unmet therapeutic need. Even though the pathogenesis of disease evolution is still obscure, accumulating evidence indicates that mitochondrial dysfunction plays a causative role in neurodegeneration and axonopathy in progressive MS patients. Here, we investigated the effects of dexpramipexole, a compound with a good safety profile in humans and able to sustain mitochondria functioning and energy production, in a mouse model of progressive MS. EXPERIMENTAL APPROACH: Female non-obese diabetic mice were immunized with MOG35-55 . Functional, immune and neuropathological parameters were analysed during disease evolution in animals treated or not with dexpramipexole. The compound's effects on bioenergetics and neuroprotection were also evaluated in vitro. KEY RESULTS: We found that oral treatment with dexpramipexole at a dose consistent with that well tolerated in humans delayed disability progression, extended survival, counteracted reduction of spinal cord mitochondrial DNA content and reduced spinal cord axonal loss of mice. Accordingly, the drug sustained in vitro bioenergetics of mouse optic nerve and dorsal root ganglia and counteracted neurodegeneration of organotypic mouse cortical cultures exposed to the adenosine triphosphate-depleting agents oligomycin or veratridine. Dexpramipexole, however, was unable to affect the adaptive and innate immune responses both in vivo and in vitro. CONCLUSION AND IMPLICATION: The present findings corroborate the hypothesis that neuroprotective agents may be of relevance to counteract MS progression and disclose the translational potential of dexpramipexole to treatment of progressive MS patients as a stand-alone or adjunctive therapy.

hERG1 and HIF-2α Behave as Biomarkers of Positive Response to Bevacizumab in Metastatic Colorectal Cancer Patients.

BACKGROUND: In search of novel biomarkers of response to bevacizumab in metastatic colorectal cancer (mCRC), we analyzed the expression and prognostic role of several proteins related to angiogenesis. METHODS: A retrospective, multicenter study on 80 surgical samples from mCRC patients treated in first line with bevacizumab plus chemotherapy was accomplished. The following proteins were analyzed by immunohistochemistry: hERG1 potassium channel, ß1-integrin, pAKT, NFkB, HIF-1α, HIF-2α, p53, VEGF-A, GLUT-1, and CA-IX. Data were analyzed in conjunction with the clinicopathological characteristics of the patients, KRAS status, response to bevacizumab, and follow-up. RESULTS: (1) All the proteins were expressed in the samples, with statistically significant associations between HIF-1α and gender, HIF-2α and left colon, hERG1 and VEGF-A, ß1-integrin and HIF-2α, GLUT-1 and both HIF-1α and HIF-2α, and CA-IX and VEGF-A. (2) At the univariate analysis, positivity for hERG1, VEGF-A, and the active form of HIF-2α (aHIF-2α), and the G3 histological grade showed a positive impact on progression-free survival (PFS). (3) hERG1 and aHIF-2α maintained their positive impact on PFS at the multivariate analysis. (4) hERG1 behaved as a protective factor for PFS independently on KRAS status. CONCLUSIONS: hERG1 and aHIF-2α might help to identify patients who would benefit from bevacizumab treatment.

Intraoperative core temperature monitoring: accuracy and precision of zero-heat flux heated controlled servo sensor compared with esophageal temperature during major surgery; the ESOSPOT study.

Monitoring of intraoperative core temperature is strongly recommended to reduce the risk of perioperative thermic imbalance and related complications. The zero-heat-flux sensor (3M Bair Hugger Temperature monitoring system, ZHF), measures core temperature in a non-invasive manner. This study was aimed at comparing accuracy and precision of the ZHF sensor compared to the esophageal thermometer. Patients scheduled for major elective abdominal or urologic surgery were considered eligible for enrollment. Core body temperature was measured using both an esophageal probe (TESO) and a ZHF sensor (TZHF) every 15 min from induction until the end of general anaesthesia. A Bland-Altman plot for repeated measures was performed. The proportion of measurements within ± 0.5 °C was estimated; from a clinical point of view, a proportion greater than 90% was considered sufficiently accurate. Lin's concordance correlation coefficient (CCC) for repeated measures were calculated. To evaluate association between the two methods, a generalized estimating equation (GEE) simple linear regression model, was elaborated. A GEE multiple regression model was also performed in order to adjust the estimate of the association between measurements from surgical and patient's features. Ninety-nine patients were enrolled. Bland-Altman plot bias was 0.005 °C with upper and lower limits of agreement for repeated measures of 0.50 °C and - 0.49 °C. The percentage of measurements within 0.5 °C of the reference value was 97.98% (95% confidence interval 92.89-99.75%), indicating a clinically sufficient agreement between the two methods. This was also confirmed by a CCC for repeated measures of 0.89 (95% CI 0.80 to 0.94). The GEE simple regression model (slope value of 0.77) was not significantly influenced by any patient or surgical variables. According to GEE multiple regression model results, the explored patient- and surgery-related variables did not influence the association between methods. ZHF sensor has shown a clinically acceptable accuracy and precision for body core temperature monitoring during elective major surgery. CLINICAL TRIALS: Clinical trial number: NCT03820232.

Comparison of neostigmine vs. sugammadex for recovery of muscle function after neuromuscular block by means of diaphragm ultrasonography in microlaryngeal surgery: A randomised controlled trial.

BACKGROUND: Postoperative residual curarisation (PORC) is a risk directly related to the use of neuromuscular blocking agents during surgical procedures. Acceleromyography is distressing for conscious patients when assessing PORC. Diaphragm ultrasonography could be a valid alternative. OBJECTIVES: The primary objective was to achieve a 28% lower incidence of PORC in patients who, after rocuronium administration, received neostigmine or sugammadex at 30 min after surgery. To assess PORC, diaphragm ultrasonography was used, and thickening fractioning [the difference of thickness at the end of inspiration (TEI) and at the end of expiration (TEE), normalised for TEE (TEI - TEE/TEE)] was measured. PORC was defined as thickening fractioning of 0.36 or less. The secondary object was the comparison, in the two treatment groups, of the return to baseline thickening fractioning at 30 min after surgery (ΔTF30). DESIGN: Randomised, double-blind, single-centre study. SETTING: University Hospital Careggi, Florence, Italy. PATIENTS: Patients of American Society Anesthesiologists' physical status 1 or 2, 18 to 80 years, receiving rocuronium during microlaryngeal surgery. INTERVENTIONS: At the end of surgery participants were randomised to receive neostigmine (NEO group) or sugammadex (SUG group) as the reversal drug. Thickening fractioning and ΔTF30 were evaluated at baseline and at 0, 10 and 30 min after surgery. MAIN OUTCOME MEASURES: TEE and TEI at each time point. RESULTS: A total of 59 patients with similar demographic characteristics were enrolled. An association between lack of recovery (thickening fractioning ≤0.36) and drug treatment was only observed at 0 min (SUG vs. NEO, P < 0.05). Concerning ΔTF, at 30 min more patients in the SUG group returned to baseline than those in the NEO group (P < 0.001), after adjusting for side (P = 0.52), baseline thickening fractioning (P < 0.0001) and time of measurement (P < 0.01). CONCLUSION: We found an early (0 min) but not long-lasting (30 min) association between diaphragm failure and treatment allocation; a full recovery in baseline diaphragm function was observed only in patients receiving sugammadex. We cannot exclude that further differences have not been found due to interpatients variability in assessing diaphragm contractility by ultrasonography. TRIAL REGISTRATION: EudraCT Identifier: 2013-004787-62, Clinicaltrials.gov Identifier: NCT02698969.