Robotic-assisted versus conventional laparoscopic ICG-fluorescence lymphatic-sparing palomo varicocelectomy: a comparative retrospective study of techniques and outcomes.

PURPOSE: This study aimed to compare techniques and outcomes of robotic-assisted varicocelectomy (RAV) and laparoscopic varicocelectomy (LV). METHODS: The medical records of 40 patients, who received RAV and LV over a 2-year period, were retrospectively analyzed. Palomo lymphatic-sparing varicocelectomy using ICG fluorescence was adopted in all cases. Three 5-mm trocars were placed in LV, whereas four ports, three 8-mm and one 5-mm, were placed in RAV. The spermatic vessels were ligated using clips in LV and ligatures in RAV. The two groups were compared regarding patient baseline and operative outcomes. RESULTS: All patients, with median age of 14 years (range 11-17), had left grade 3 varicocele according to Dubin-Amelar. All were symptomatic and 33/40 (82.5%) presented left testicular hypotrophy. All procedures were completed without conversion. The average operative time was significantly shorter in LV [20 min (range 11-30)] than in RAV [34.5 min (range 30-46)] (p = 0.001). No significant differences regarding analgesic requirement and hospitalization were observed (p = 0.55). At long-term follow-up (30 months), no complications occurred in both groups. The cosmetic outcome was significantly better in LV than RAV at 6-month and 12-month evaluations (p = 0.001). The total cost was significantly lower in LV (1.587,07 €) compared to RAV (5.650,31 €) (p = 0.001). CONCLUSION: RAV can be safely and effectively performed in pediatric patients, with the same excellent outcomes as conventional laparoscopic procedure. Laparoscopy has the advantages of faster surgery, smaller instruments, better cosmesis and lower cost than robotics. To date, laparoscopy remains preferable to robotics to treat pediatric varicocele.

Immediate or staged complete revascularisation in patients presenting with acute coronary syndrome by number of diseased vessels: a substudy of the BIOVASC randomised trial.

BACKGROUND: In patients presenting with acute coronary syndrome (ACS), the number of diseased vessels may affect the efficacy of a complete revascularisation strategy. AIMS: The authors sought to evaluate the safety and efficacy of immediate complete revascularisation (ICR) and staged complete revascularisation (SCR) in patients presenting with ACS stratified by the number of diseased vessels. METHODS: In this prespecified analysis of the BIOVASC trial, ICR was compared with SCR in patients with two-vessel disease (2VD) or three-vessel disease (3VD). The primary endpoint was a composite of all-cause mortality, myocardial infarction (MI), any unplanned ischaemia-driven revascularisation or cerebrovascular events at 1 year after the index procedure. Comparisons were performed using Cox regression. RESULTS: A total of 1,525 patients were enrolled in the BIOVASC trial, of whom 1,177 presented with 2VD and 265 with 3VD. In the 2VD group, 613 patients were assigned to ICR and 564 to SCR. In the 3VD group, 117 patients were assigned to ICR and 148 to SCR. ICR and SCR led to similar results in both the 2VD (hazard ratio [HR] 0.76, 95% confidence interval [CI]: 0.50-1.13; p=0.18) and 3VD groups (HR 0.79, 95% CI: 0.39-1.59; p=0.51) (pinteraction=0.91) in terms of the primary endpoint. ICR was associated with a lower rate of MI in patients with 3VD (HR 0.21, 95% CI: 0.046-0.93; p=0.04) (pinteraction=0.30). CONCLUSIONS: ICR might be an option in patients presenting with extensive 3VD and might be associated with a lower rate of myocardial infarction compared with SCR.

Kidney Injury After Minimal Radiographic Contrast Administration in Patients With Acute Coronary Syndromes.

BACKGROUND: Acute kidney injury (AKI) is common in patients with acute coronary syndromes (ACS) treated by percutaneous coronary intervention. OBJECTIVES: Contrast media (CM) volume minimization has been advocated for prevention of AKI. The DyeVert CM diversion system (Osprey Medical, Inc) is designed to reduce CM volume during coronary procedures. METHODS: In this randomized, single-blind, investigator-driven clinical trial conducted in 4 Italian centers from February 4, 2020 to September 13, 2022, 550 participants with ACS were randomly assigned in a 1:1 ratio to the following: 1) the contrast volume reduction (CVR) group (n = 276), in which CM injection was handled by the CM diversion system; and 2) the control group (n = 274), in which a conventional manual or automatic injection syringe was used. The primary endpoint was the rate of AKI, defined as a serum creatinine (sCr) increase ≥0.3 mg/dL within 48 hours after CM exposure. RESULTS: There were 412 of 550 (74.5%) participants with ST-segment elevation myocardial infarction (211 of 276 [76.4%] in the CVR group and 201 of 274 [73.3%] in the control group). The CM volume was lower in the CVR group (95 ± 30 mL vs 160 ± 23 mL; P < 0.001). Seven participants (1 in the CVR group and 6 in the control group) did not have postprocedural sCr values. AKI occurred in 44 of 275 (16%) participants in the CVR group and in 65 of 268 (24.3%) participants in the control group (relative risk: 0.66; 95% CI: 0.47-0.93; P = 0.018). CONCLUSIONS: CM volume reduction obtained using the CM diversion system is effective for prevention of AKI in patients with ACS undergoing invasive procedures. (REnal Insufficiency Following Contrast MEDIA Administration TriaL IV [REMEDIALIV]: NCT04714736).

Video-assisted anal fistula treatment (VAAFT) combined with ozonide oil dressing: standardization of technique in pediatric patients.

BACKGROUND: Anal fistula and perianal abscess are commonly acquired anorectal pathologies in children. Surgical treatment options commonly adopted are fistulotomy, fistulectomy, cutting seton placement, and more recently video-assisted anal fistula treatment (VAAFT). Optimal postoperative wound dressing remains debated. This study aimed to report our series of pediatric patients, who received VAAFT and postoperative wound dressing using ozonide oil. METHODS: All patients who underwent VAAFT between August 2018 and May 2023 were included in the study. Demographics, clinical features, pre-operative imaging, surgical details, outcome, and mid-term outcome data were retrospectively reviewed for each patient. All VAAFT procedures were performed under general anesthesia and using a 10-Ch fistuloscope. RESULTS: Thirty-three VAAFT procedures were performed in 30 patients over the study period. The median patient age was 5.7 years (range 1.75-14). Anal fistula was idiopathic in 26/30 (86.6%), iatrogenic in 2/30 (6.7%), and secondary to Crohn's disease in 2/30 (6.7%). The median duration of surgery was 23 min (range 18-40). All patients received ozonide oil dressing twice a day for 5 weeks postoperatively. The median hospital stay was 24 h (range 9-36). The median healing time was 28 days (range 17-39). With a median follow-up of 2 years (range 0.5-5), disease recurrence occurred in 3/30 (10%) patients with idiopathic fistula, who were re-operated using the same technique, with no further recurrence. No fecal incontinence or soiling was observed. CONCLUSION: Our series confirmed that VAAFT is a safe and effective technique to treat children with perianal fistula. The technique is versatile, allowing to treat fistulae of different etiologies. Postoperative course was painless and fast. Future comparative prospective studies are needed to better establish these conclusions.

Intranasal administration of Escherichia coli Nissle expressing the spike protein of SARS-CoV-2 induces long-term immunization and prevents spike protein-mediated lung injury in mice.

While current anti-Spike protein (SP) vaccines have been pivotal in managing the pandemic, their limitations in delivery, storage, and the inability to provide mucosal immunization (preventing infections) highlight the ongoing necessity for research and innovation. To tackle these constraints, our research group developed a bacterial-based vaccine using a non-pathogenic E. coli Nissle 1917 (EcN) strain genetically modified to express the SARS-CoV-2 spike protein on its surface (EcN-pAIDA1-SP). We intranasally delivered the EcN-pAIDA1-SP in two doses and checked specific IgG/IgA production as well as the key immune mediators involved in the process. Moreover, following the initial and booster vaccine doses, we exposed both immunized and non-immunized mice to intranasal delivery of SARS-CoV-2 SP to assess the effectiveness of EcN-pAIDA1-SP in protecting lung tissue from the inflammation damage. We observed detectable levels of anti-SARS-CoV-2 spike IgG in serum samples and IgA in bronchoalveolar lavage fluid two weeks after the initial treatment, with peak concentrations in the respective samples on the 35th day. Moreover, immunoglobulins displayed a progressively enhanced avidity index, suggesting a selective binding to the spike protein. Finally, the pre-immunized group displayed a decrease in proinflammatory markers (TLR4, NLRP3, ILs) following SP challenge, compared to the non-immunized groups, along with better preservation of tissue morphology. Our probiotic-based technology provides an effective immunobiotic tool to protect individuals against disease and control infection spread.

Cangrelor in contemporary patients with ST-segment elevation myocardial infarction pretreated with Ticagrelor: Pharmacodynamic data from the POMPEII study.

Background: There are limited data to assess pharmacodynamic (PD) profiles of patients with STEMI undergoing primary percutaneous coronary intervention (PCI) and receiving cangrelor after pretreatment with ticagrelor. Methods: The PharmacOdynaMic effects of cangrelor in PatiEnts wIth acute or chronIc coronary syndrome undergoing percutaneous coronary intervention (POMPEII) registry (NCT04790032) is a prospective study conducted at Federico II University of Naples enrolling all patients undergoing PCI receiving cangrelor at operator's discretion. PD assessments were performed with 3 assays: (1) the gold standard light transmittance aggregometry (LTA) (20- and 5-µM adenosine diphosphate [ADP] stimuli); (2) VerifyNow P2Y12-test; (3) Multiplate electrode aggregometry (MEA), ADP-test. Results: We analyzed 13 STEMI patients pretreated with ticagrelor within 1 h at the time they underwent primary PCI receiving cangrelor. All patients showed low maximal platelet aggregation at 30-minute during cangrelor infusion, as well as at 3 h and 4-6 h (corresponding to 1 h and 2-4 h after stopping cangrelor infusion) with no cases of high residual platelet reactivity. These results were consistent with all assays. Conclusions: PD data show that in contemporary real-world STEMI patients pretreated within 1 h with ticagrelor undergoing primary PCI, adding cangrelor resulted in fast and potent platelet inhibition, thus suggesting that cangrelor may bridge the gap until ticagrelor reaches its effect.

Cardiac rehabilitation and acute aortic dissection: understanding and addressing the evidence GAP a systematic review.

Despite guideline recommendations, strategies for implementing cardiac rehabilitation (CR) in patients with acute aortic dissection (AAD) are not well established with little evidence to risk stratify prudent and effective guidelines for the many required variables. We conducted a systematic review of studies (2004-2023) reporting CR following type A (TA) and type B (TB) AAD. Our review is limited to open surgical repair for TA and medical treatment for TB. A total of 5 studies were included (4 TA-AAD and 1 TB-AAD) in the qualitative analysis. In general, observational data included 311 patients who had an overall favorable effect of CR in AAD consisting of a modestly improved exercise capacity and work load during cycle cardiopulmonary exercise test (TB-AAD), and improved quality of life (QoL). No adverse events were reported during symptom limited pre-CR treadmill or cycle exercise VO2 max or CR. Given the overall potential in this high risk population without adequate evidence for important variables such as safe time from post-op to CR, intensity of training, duration and frequency of sessions and followup it is time for a moderate sized well designed safe trial for patients' post-op surgery for TA-AAD and medically treated TB-AAD who are treated with standardized evidence based medical therapy and physical therapy from discharge randomized to CR versus usual care. PROSPERO registry ID: CRD42023392896.

Health-related quality of life in patients with aortic dissection: An unmet need.

Knowledge about the Health-related Quality of Life (HR-QoL) after Type A (TA-AAD) and Type B acute aortic dissection (TB-AAD) is still insufficient. Through this systematic review, including 22 studies (16 for TA-AAD and 6 TB-AAD -1998-2023), the entire literature on HR-QoL after surgical and/or endovascular and/or medical interventions has been investigated. In TA-AAD patients, despite overall SF-36 score was similar to the standard population, with > 80 years patients displaying a better emotional domain, the SF-12 was significant lower to controls in physical and mental well-being domains. Exercise-based cardiac rehabilitation improved HR-QoL. In TB-AAD, vitality and mental health SF-36 scores improved after thoracic endovascular aortic repair (TEVAR); long-term QoL was similar in the open surgery group compared to TEVAR. Overall, HR-QoL after AAD seems adequate irrespective of age or sex, except for some specific domains. Physical exercise and cardiac rehabilitation may improve HR-QoL in these patients. PROSPERO registry ID: CRD42023421130.

Indocyanine green fluorescent cholangiography: The new standard practice to perform laparoscopic cholecystectomy in pediatric patients. A comparative study with conventional laparoscopic technique.

BACKGROUND: This study aimed to compare outcomes of standard laparoscopic cholecystectomy and indocyanine green fluorescent cholangiography laparoscopic cholecystectomy over a 10-year period. METHODS: From 2013 to 2023, 173 laparoscopic cholecystectomies were performed in 2 pediatric surgery units: 83 using standard technique (G1) and 90 using indocyanine green fluorescent cholangiography (G2). Patients included 96 girls and 77 boys, with a median age of 12.3 years (range 4-17) and a median weight of 51 kg (range 19-114). The 2 groups were compared regarding the following: (1) perioperative complications rate; (2) overall length of surgery (T1); (3) length of cystic duct isolation, clipping, and sectioning (T2); (4) time of gallbladder removal (T3); (5) degree of visualization of biliary tree; (6) safety and feasibility of indocyanine green fluorescent cholangiography; (7) incidence of anatomical anomalies detected intraoperatively. RESULTS: All laparoscopic cholecystectomies were accomplished without conversion to open. The perioperative complications rate was significantly higher in G1 compared with G2 (12% vs 0%; P = .0007). Median T1, T2, and T3 were significantly longer in G1 (90, 37, 35 minutes) compared with G2 (55, 17, 19 minutes) (P = .0001), respectively. The visualization rate of the complete biliary tree was significantly higher in G2 (98.8%) than in G1 (80.7%) (P = .0001). No adverse reactions to indocyanine green were recorded. The incidence of biliary anomalies detected intraoperatively was significantly higher in G2 (7.8%) than in G1 (1.2%) (P = .03). CONCLUSION: Indocyanine green fluorescent cholangiography can be considered the new standard practice to perform laparoscopic cholecystectomy in pediatrics. Indocyanine green fluorescence provided superior visualization of biliary anatomy, increased detection of anatomic variants, faster procedure, and fewer complications compared with conventional technique. Indocyanine green fluorescent cholangiography was safe, feasible, simple, inexpensive, and a timesaving tool.

Indocyanine green (ICG)-GUIDED lymphatic sparing laparoscopic varicocelectomy in children and adolescents. Is intratesticular injection of the dye safe? A mid-term follow-up study.

BACKGROUND: Laparoscopic Palomo varicocelectomy using indocyanine green (ICG) fluorescent lymphography (FL) is standardized technique to perform lymphatic sparing and avoid post-operative hydrocele. No data regarding the safety of intratesticular injection of ICG are currently available. OBJECTIVE: The study aimed to assess the safety and efficacy of this procedure at mid-term follow-up. STUDY DESIGN: Seventy-two patients (median age 14.5 years) undergoing laparoscopic Palomo varicocelectomy using ICG-FL from January 2019 to July 2022, were enrolled. Operative indication was high-grade varicocele in all patients, associated symptoms in 30/72 (41.7 %) and left testicular hypotrophy in 42/72 (58.3 %). Follow-up included clinical examination at 1, 6, 12 months and scrotal Doppler ultrasonography (US) at 12 months postoperatively to assess varicocele persistence, hydrocele, and injections-related complications. RESULTS: Lymphatic sparing was achieved using ICG-FL in all cases. No intra-operative complications or adverse reactions secondary to ICG occurred. The median follow-up was 22.8 months (range 11-49). Self-limited scrotal hematoma at the injection site occurred in 1/72 (1.4 %). Intratesticular hypoechoic millimetric area was detected at the injection site in 3/72 (4.2 %) on US. This finding disappeared after 1-year observation in 2/3 cases (66.7 %) (Figure). Persistent grade II varicocele was observed in 4/72 (5.5 %), not requiring re-intervention. No hydrocele occurred and 14/22 (63.6 %) with pre-operative hypotrophy showed catch-up growth. DISCUSSION: ICG-FL was clinically safe, with no allergy or systemic adverse reactions to the dye reported in this series. No injury directly related to the injection of the dye was clinically observed, except for self-limiting scrotal hematoma in one patient. A millimetric hypoechoic and avascular area in the body of the left testicle at the injection site was found on scrotal US at 1-year follow-up in 3 patients of our series. This finding does not seem to be clinically relevant as patients were asymptomatic and serum tumor markers were normal in all cases. Furthermore, the hypoechoic area with calcifications resolved 1 year later in 2/3 patients. The absence of evolution of this finding seems to exclude the heteroplastic nature. We hypothesized that this finding may be linked to elevated volume and/or pressure of intratesticular injection. Future prospective study with larger series and longer follow-up is needed to assess long-term testicular outcomes. CONCLUSION: Laparoscopic Palomo varicocelectomy using ICG-FL reported excellent outcomes with low incidence of varicocele persistence and no post-operative hydrocele. These preliminary data also confirmed safety of intratesticular injection of ICG at mid-term follow-up, without specific risks for both testis and patient.

Coronary calcification in patients presenting with acute coronary syndromes: insights from the MATRIX trial.

AIMS: The role of coronary calcification on clinical outcomes among different revascularization strategies in patients presenting with acute coronary syndromes (ACSs) has been rarely investigated. The aim of this investigation is to evaluate the role of coronary calcification, detected by coronary angiography, in the whole spectrum of patients presenting with acute ACS. METHODS AND RESULTS: The present study was a post hoc analysis of the MATRIX programme. The primary endpoint was major adverse cardiovascular events (MACE), defined as the composite of all-cause mortality, myocardial infarction (MI), or stroke up to 365 days. Among the 8404 patients randomized in the MATRIX trial, data about coronary calcification were available in 7446 (88.6%) and therefore were included in this post hoc analysis. Overall, 875 patients (11.7%) presented with severe coronary calcification, while 6571 patients (88.3%) did not present severe coronary calcification on coronary angiography. Fewer patients with severe coronary calcification underwent percutaneous coronary intervention whereas coronary artery bypass grafting or medical therapy-only was more frequent compared with patients without severe calcification. At 1-year follow-up, MACE occurred in 237 (27.1%) patients with severe calcified coronary lesions and 985 (15%) patients without severe coronary calcified lesions [hazard ratio (HR) 1.91; 95% confidence interval (CI) 1.66-2.20, P < 0.001]. All-cause mortality was 8.6% in patients presenting with and 3.7% in those without severe coronary calcification (HR 2.38, 1.84-3.09, P < 0.001). Patients with severe coronary calcification incurred higher rate of MI (20.1% vs. 11.5%, HR 1.81; 95% CI 1.53-2.1, P < 0.001) and similar rate of stroke (0.8% vs. 0.6%, HR 1.35; 95% CI 0.61-3.02, P = 0.46). CONCLUSION: Patients with ACS and severe coronary calcification, as compared to those without, are associated with worse clinical outcomes irrespective of the management strategy.

Applications of indocyanine green (ICG) fluorescence technology in open surgery: preliminary experience in pediatric surgery.

Background: Indocyanine green fluorescence technology (ICG) in pediatric minimally invasive surgery has undergone an important improvement in the last 5 years. However, its use in open surgery is still limited. In this paper, we aim to report our preliminary experience with Rubina® lens ICG fluorescence technology in combination with the IMAGE1 S™ system from KARL STORZ in open excision of masses in children. Methods: The records of 18 patients undergoing open surgery for head, neck and thorax masses between September and November 2022 were retrospectively reviewed. Rubina® lens ICG fluorescence technology system was used in all the cases. In 10 cases we adopted the holding arm system and in 8 cases the hand-held technique. Data about patients' demographics, surgery and outcomes were collected and analyzed through the following criteria: mass localization, intraoperative time (min), ICG administration (ml), intraoperative complications, postoperative complications. Results: A total of 18 patients were operated: 4 thyroglossal duct cysts, 3 supraorbital cysts, 2 neck masses, 2 pre-auricular and 2 scalp cysts, 2 gynecomastias, 2 lymphangiomas, 1 nose mass. In all the cases, intralesional injection of 0.5-1 ml of ICG solution was performed peri-operatively. Mean operative time was 58.4 min (35-134 min). Postoperative complications included seroma formation in 2 cases. Surgical pathology reports confirmed complete mass excision in all the cases. Conclusion: Based on our preliminary experience, ICG fluorescence guided surgery using Rubina® lens system was very helpful also in open surgery procedures. Rubina® lens system permits to have a very low complication rate, a time-saving surgery, a real time reliability of anatomic structures and an excellent clinical safety. In our experience, holding arm system seems more comfortable than hand-held system. However, further cases need to be performed to evaluate the exact role and to identify new indications of this technique in open pediatric surgical procedures.

Anti-VEGF therapy selects for clones resistant to glucose starvation in ovarian cancer xenografts.

BACKGROUND: Genetic and metabolic heterogeneity are well-known features of cancer and tumors can be viewed as an evolving mix of subclonal populations, subjected to selection driven by microenvironmental pressures or drug treatment. In previous studies, anti-VEGF therapy was found to elicit rewiring of tumor metabolism, causing marked alterations in glucose, lactate ad ATP levels in tumors. The aim of this study was to evaluate whether differences in the sensitivity to glucose starvation existed at the clonal level in ovarian cancer cells and to investigate the effects induced by anti-VEGF therapy on this phenotype by multi-omics analysis. METHODS: Clonal populations, obtained from both ovarian cancer cell lines (IGROV-1 and SKOV3) and tumor xenografts upon glucose deprivation, were defined as glucose deprivation resistant (GDR) or glucose deprivation sensitive (GDS) clones based on their in vitro behaviour. GDR and GDS clones were characterized using a multi-omics approach, including genetic, transcriptomic and metabolic analysis, and tested for their tumorigenic potential and reaction to anti-angiogenic therapy. RESULTS: Two clonal populations, GDR and GDS, with strikingly different viability following in vitro glucose starvation, were identified in ovarian cancer cell lines. GDR clones survived and overcame glucose starvation-induced stress by enhancing mitochondrial oxidative phosphorylation (OXPHOS) and both pyruvate and lipids uptake, whereas GDS clones were less able to adapt and died. Treatment of ovarian cancer xenografts with the anti-VEGF drug bevacizumab positively selected for GDR clones that disclosed increased tumorigenic properties in NOD/SCID mice. Remarkably, GDR clones were more sensitive than GDS clones to the mitochondrial respiratory chain complex I inhibitor metformin, thus suggesting a potential therapeutic strategy to target the OXPHOS-metabolic dependency of this subpopulation. CONCLUSION: A glucose-deprivation resistant population of ovarian cancer cells showing druggable OXPHOS-dependent metabolic traits is enriched in experimental tumors treated by anti-VEGF therapy.

Transcatheter interventions for left-sided valvular heart disease complicated by cardiogenic shock: a consensus statement from the European Association of Percutaneous Cardiovascular Interventions (EAPCI) in collaboration with the Association for Acute Cardiovascular Care (ACVC) and the ESC Working Group on Cardiovascular Surgery.

Valvular heart disease (VHD) is one of the most frequent causes of heart failure (HF) and is associated with poor prognosis, particularly among patients with conservative management. The development and improvement of catheter-based VHD interventions have broadened the indications for transcatheter valve interventions from inoperable/high-risk patients to younger/lower-risk patients. Cardiogenic shock (CS) associated with severe VHD is a clinical condition with a very high risk of mortality for which surgical treatment is often deemed a prohibitive risk. Transcatheter valve interventions might be a promising alternative in this setting given that they are less invasive. However, supportive scientific evidence is scarce and often limited to small case series. Current guidelines on VHD do not contain specific recommendations on how to manage patients with both VHD and CS. The purpose of this clinical consensus statement, developed by a group of international experts invited by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) Scientific Documents and Initiatives Committee, is to perform a review of the available scientific evidence on the management of CS associated with left-sided VHD and to provide a rationale and practical approach for the application of transcatheter valve interventions in this specific clinical setting.

Left Ventricular Mechano-Energetic Efficiency Identifies an Early Impairment of Myocardial Blood Flow in Arterial Hypertension.

BACKGROUND: Arterial hypertension causes cardiac functional and structural alterations. In hypertensive patients without flow-limiting epicardial coronary artery disease, we investigated possible relationships between positron emission tomography/computed tomography-derived myocardial blood flow (MBF) and echocardiographic parameters of left ventricular (LV) performance, including mechano-energetic efficiency indexed for myocardial mass (MEEi). METHODS: Seventy-eight hypertensive patients without flow-limiting epicardial coronary artery disease underwent echocardiography, including MEEi computation, and cardiac positron emission tomography/computed tomography with assessment of MBF/mass ratio at rest and after stress and myocardial flow reserve. The lowest MEEi tertile (MEEi<0.031 mL/s/g) was compared to the merged second and third tertiles (MEEi≥0.031). RESULTS: Patients in the lowest MEEi tertile were older, had higher systolic blood pressure and body mass index. They also had higher prevalence of LV hypertrophy, whereas lower resting and stress MBF/mass ratio. MEEi was significantly correlated with both resting (r=0.51; P<0.0001) and hyperemic (r=0.54; P<0.0001) MBF/mass ratios, whereas it was not related to myocardial flow reserve. Delta of MBF/mass ratio was lower in the lowest MEEi tertile than in the highest (P<0.0001). In separate multiple linear regression models, after adjusting for sex, systolic blood pressure, body mass index, prevalence of LV hypertrophy, left atrial volume index, and diuretic therapy, the association between LV MEEi and both hyperemic (beta coefficient=0.44; P=0.003) and resting (beta coefficient=0.35; P=0.008) MBF/mass ratio remained significant. CONCLUSIONS: In hypertensive patients without flow-limiting epicardial coronary artery disease, low values of MEEi could detect an early LV dysfunction involving an impairment of both resting and hyperemic MBF/mass ratios. MEEi has the advantage of simpler detection, cheaper costs than positron emission tomography/computed tomography, and a lack of radiation exposure. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02211365.

The Role of Postoperative Dressing in Hypospadias Surgery: A Systematic Review and Meta-analysis of the Pediatric Literature.

This study aimed to describe the available dressings and their management in patients undergoing hypospadias repair and compare postoperative outcomes with and without dressing and between the different dressing types. A comprehensive electronic literature search of PubMed, Embase, and Cochrane Library was conducted to obtain studies, published in the period 1990 to 2021, reporting on the dressing used following hypospadias surgery. All information regarding the dressing was considered as primary endpoints, whereas surgical outcomes were assessed as secondary outcomes. Thirty-one studies containing 1,790 subjects undergoing hypospadias repair were included. Dressings were divided into three categories: nonadherent to the wound, adherent to the wound, and glue-based dressings. Most authors preferred to remove/change the dressing in the ward and the median time of removal/change was 6.56 postoperative days. The dressing removal appeared as the most frequent factor generating parental anxiety. The median rate of wound-related complications was 8.18%, of urethroplasty complications 9.08% and of reoperations 8.18%. Meta-analysis of outcomes showed higher risk of reoperations using conventional dressing, with no differences in urethroplasty and wound-related complications rates between conventional and glue-based dressings. Furthermore, the use of dressing reported increased risk of wound-related complications compared with no dressing, without significant differences regarding occurrence of urethroplasty complications and reoperations. The current evidence confirmed that there is no difference in outcomes of hypospadias repair depending on a certain dressing type. To date, surgeon's preference remains the main factor determining the choice for a specific dressing or for no dressing at all.

signifinder enables the identification of tumor cell states and cancer expression signatures in bulk, single-cell and spatial transcriptomic data.

Over the last decade, many studies and some clinical trials have proposed gene expression signatures as a valuable tool for understanding cancer mechanisms, defining subtypes, monitoring patient prognosis, and therapy efficacy. However, technical and biological concerns about reproducibility have been raised. Technical reproducibility is a major concern: we currently lack a computational implementation of the proposed signatures, which would provide detailed signature definition and assure reproducibility, dissemination, and usability of the classifier. Another concern regards intratumor heterogeneity, which has never been addressed when studying these types of biomarkers using bulk transcriptomics. With the aim of providing a tool able to improve the reproducibility and usability of gene expression signatures, we propose signifinder, an R package that provides the infrastructure to collect, implement, and compare expression-based signatures from cancer literature. The included signatures cover a wide range of biological processes from metabolism and programmed cell death, to morphological changes, such as quantification of epithelial or mesenchymal-like status. Collected signatures can score tumor cell characteristics, such as the predicted response to therapy or the survival association, and can quantify microenvironmental information, including hypoxia and immune response activity. signifinder has been used to characterize tumor samples and to investigate intra-tumor heterogeneity, extending its application to single-cell and spatial transcriptomic data. Through these higher-resolution technologies, it has become increasingly apparent that the single-sample score assessment obtained by transcriptional signatures is conditioned by the phenotypic and genetic intratumor heterogeneity of tumor masses. Since the characteristics of the most abundant cell type or clone might not necessarily predict the properties of mixed populations, signature prediction efficacy is lowered, thus impeding effective clinical diagnostics. Through signifinder, we offer general principles for interpreting and comparing transcriptional signatures, as well as suggestions for additional signatures that would allow for more complete and robust data inferences. We consider signifinder a useful tool to pave the way for reproducibility and comparison of transcriptional signatures in oncology.

Metabolic classification of non-small cell lung cancer patient-derived xenografts by a digital pathology approach: A pilot study.

Introduction: Genetically characterized patient-derived tumor xenografts (PDX) are a valuable resource to understand the biological complexity of cancer and to investigate new therapeutic approaches. Previous studies, however, lack information about metabolic features of PDXs, which may limit testing of metabolism targeting drugs. Methods: In this pilot study, we investigated by immunohistochemistry (IHC) expression of five essential metabolism-associated markers in a set of lung adenocarcinoma PDX samples previously established and characterized. We exploited digital pathology to quantify expression of the markers and correlated results with tumor cell proliferation, angiogenesis and time of PDX growth in mice. Results: Our results indicate that the majority of the analyzed PDX models rely on oxidative phosphorylation (OXPHOS) metabolism, either alone or in combination with glucose metabolism. Double IHC enabled us to describe spatial expression of the glycolysis-associated monocarboxylate transporter 4 (MCT4) marker and the OXPHOS-associated glutaminase (GLS) marker. GLS expression was associated with cell proliferation and with expression of liver-kinase B1 (LKB1), a tumor suppressor involved in the regulation of multiple metabolic pathways. Acetyl CoA carboxylase (ACC) was associated with the kinetics of PDX growth. Conclusion: Albeit limited by the small number of samples and markers analyzed, metabolic classification of existing collections of PDX by this mini panel will be useful to inform pre-clinical testing of metabolism-targeting drugs.