Comparative Analysis of COVID-19 Outcomes in Type 1 and Type 2 Diabetes: A Three-Year Retrospective Study.

Background and Objectives: This comprehensive retrospective study assesses COVID-19 outcomes in type 1 (T1D) and type 2 diabetes (T2D) patients across three years, focusing on how these outcomes varied with the evolving pandemic and changes in diabetes management. The study aims to determine if COVID-19 outcomes, including severity, intensive care unit (ICU) admission rates, duration of hospitalization, and mortality, are significantly different between these diabetes subtypes. Materials and Methods: The study analyzed data from patients admitted to the Victor Babes Hospital for Infectious Diseases and Pulmonology with confirmed COVID-19 and pre-existing diabetes, from the years 2020, 2021, and 2022. Results: Among 486 patients (200 without diabetes, 62 with T1D, 224 with T2D), T2D patients showed notably higher severity, with 33.5% experiencing severe cases, compared to 25.8% in T1D. Mortality rates were 11.6% in T2D and 8.1% in T1D. T2D patients had longer hospital stays (11.6 ± 7.0 days) compared to T1D (9.1 ± 5.8 days) and were more likely to require ICU admission (OR: 2.24) and mechanical ventilation (OR: 2.46). Hyperglycemia at admission was significantly higher in the diabetes groups, particularly in T2D (178.3 ± 34.7 mg/dL) compared to T1D (164.8 ± 39.6 mg/dL). Conclusions: The study reveals a discernible difference in COVID-19 outcomes between T1D and T2D, with T2D patients having longer hospital admissions, mechanical ventilation necessities, and mortality risks.

Clinical Implications of Diabetic Peripheral Neuropathy in Primary Infrapopliteal Angioplasty Approach for Neuro-Ischemic Foot Wounds.

BACKGROUND: To assess the clinical effects of diabetic peripheral neuropathy (DPN) in patients with chronic limb-threatening ischemia (CLTI) treated by primary infrapopliteal angioplasty for neuro-ischemic Rutherford 5, foot wounds. MATERIALS AND METHODS: Over a 10-year period (2009-2019), a series of 304 diabetic ischemic limbs adding or not evincible neuropathic affectation were treated by primary infrapopliteal angioplasty and their files were retrospectively reviewed. Mean length of treated arterial lesions was 6.1 cm (range 1-22 cm). Inferior limb vibration perception threshold diagnostic was performed for comparing and scoring detectable DPN in all studied diabetic patients (classed from 0 to 10 points). There were 19% limbs with normal (0-1 points) perception (group 1), 55% others with "mild" and "moderate" (2-6 points) neuropathic impairment (group 2), and 26% limbs showing "severe" (7-10 points) DPN (group 3). RESULTS: Primary infrapopliteal angioplasty succeeded in 89% cases in group 1, in 82% in group 2, and in 68% of limbs in group 3. This latest group assembled the heaviest neuropathic affectation and arterial calcifications and proved the lowest clinical benefit at 36 months: 35% (95% confidence interval [CI]=22% to 48%) of primary patency, 36% (95% CI=22% to 50%) wound healing, and 54% (95% CI=39% to 69%) limb preservation rates. A comparison between groups 1 vs 3 and 2 vs 3 of primary patency (p=0.014 and p=0.043), tissue healing (p=0.049 and p=0.01), and limb salvage (p=0.006 and p=0.023) proved significant, yet without statistical weight for group 1 vs 2 (p>0.05). Overall survival was not significantly affected between groups (p=0.34). CONCLUSION: The presence of severe DPN may jeopardize the results of infrapopliteal angioplasty in terms of patency, tissue cicatrization, and limb preservation, yet without significance on survival of these patients. When present, DPN requires appropriate stratification as specific indicator in CLTI treatment.

Metabolite Profiling of the Gut-Renal-Cerebral Axis Reveals a Particular Pattern in Early Diabetic Kidney Disease in T2DM Patients.

Type 2 diabetes mellitus (T2DM) represents an important microvascular disease concerning the kidney and the brain. Gut dysbiosis and microbiota-derived metabolites may be in relation with early pathophysiological changes in diabetic kidney disease (DKD). The aim of the study was to find new potential gut-derived biomarkers involved in the pathogenesis of early DKD, with a focus on the complex interconnection of these biomarkers with podocyte injury, proximal tubule dysfunction, renal and cerebrovascular endothelial dysfunction. The study design consisted of metabolite profiling of serum and urine of 90 T2DM patients (subgroups P1-normoalbuminuria, P2-microalbuminuria, P3-macroalbuminuria) and 20 healthy controls (group C), based on ultra-high-performance liquid chromatography coupled with electrospray ionization-quadrupole-time of flight-mass spectrometry analysis (UHPLC-QTOF-ESI+-MS). By multivariate and univariate analyses of serum and urine, which included Partial Least Squares Discriminant Analysis (PLSDA), Variable Importance Plots (VIP), Random Forest scores, One Way ANOVA and Biomarker analysis, there were discovered metabolites belonging to nitrogen metabolic pathway and retinoic acid signaling pathway which differentiate P1 group from P2, P3, C groups. Tyrosine, phenylalanine, indoxyl sulfate, serotonin sulfate, and all-trans retinoic acid express the metabolic fingerprint of P1 group vs. P2, P3, C groups, revealing a particular pattern in early DKD in T2DM patients.

Mitochondrial DNA Changes in Blood and Urine Display a Specific Signature in Relation to Inflammation in Normoalbuminuric Diabetic Kidney Disease in Type 2 Diabetes Mellitus Patients.

Mitochondrial dysfunction is an important mechanism contributing to the development and progression of diabetic kidney disease (DKD). Mitochondrial DNA (mtDNA) levels in blood and urine were evaluated in relation to podocyte injury and proximal tubule (PT) dysfunction, as well as to a specific inflammatory response in normoalbuminuric DKD. A total of 150 type 2 diabetes mellitus (DM) patients (52 normoalbuminuric, 48 microalbuminuric, and 50 macroalbuminuric ones, respectively) and 30 healthy controls were assessed concerning the urinary albumin/creatinine ratio (UACR), biomarkers of podocyte damage (synaptopodin and podocalyxin), PT dysfunction (kidney injury molecule-1 (KIM-1) and N-acetyl-ß-(D)-glucosaminidase (NAG)), and inflammation (serum and urinary interleukins (IL-17A, IL-18, and IL-10)). MtDNA-CN and nuclear DNA (nDNA) were quantified in peripheral blood and urine via qRT-PCR. MtDNA-CN was defined as the ratio of the number of mtDNA/nDNA copies via analysis of the CYTB/B2M and ND2/B2M ratio. Multivariable regression analysis provided models in which serum mtDNA directly correlated with IL-10 and indirectly correlated with UACR, IL-17A, and KIM-1 (R2 = 0.626; p < 0.0001). Urinary mtDNA directly correlated with UACR, podocalyxin, IL-18, and NAG, and negatively correlated with eGFR and IL-10 (R2 = 0.631; p < 0.0001). Mitochondrial DNA changes in serum and urine display a specific signature in relation to inflammation both at the podocyte and tubular levels in normoalbuminuric type 2 DM patients.

Clinical, Pathological and Molecular Insights on KRAS, NRAS, BRAF, PIK3CA and TP53 Mutations in Metastatic Colorectal Cancer Patients from Northeastern Romania.

Mutations in RAS, BRAF, PIK3CA, and TP53 are well-established genetic abnormalities in metastatic colorectal cancer (mCRC). However, limited information is available for patients from Eastern Europe, including Romania. In this retrospective analysis, we investigated 104 mCRC patients from the Northeastern region of Romania to determine the frequency, distribution, coexistence, and clinicopathological and molecular correlations of these mutations. TP53 was the most frequently mutated gene (73.1%), followed by KRAS (45.2%) and PIK3CA (6.7%). Patients with KRAS mutant tumors and wild-type TP53 genotype were found to have no personal history of gastrointestinal cancer (p = 0.02, p = 0.007). KRAS mutations in exon 3 were associated with the female gender (p = 0.02) and the absence of lymph node invasion (p = 0.02). PIK3CA mutations were linked to the absence of lymph node invasion (p = 0.006). TP53 mutations were associated with KRAS mutations in exon 2 (p = 0.006), ulcerated histopathologic type (p = 0.04), and G2 differentiation (p = 0.01). It provides novel insights into genetic variations specific to the population from Northeastern Romania, which has been underrepresented in previous studies within Eastern Europe. Furthermore, our findings enable the development of genetic profiles in a developing country with limited access to specialized genetic tests and facilitate comparisons with other populations.

The Experience of a Single Tertiary Center Regarding Benign and Malignant Tumors in Acromegalic Patients.

Background and Objectives: Acromegaly is a rare disease associated with increased levels of growth hormones (GHs) that stimulates the hepatic production of insulin growth factor-1 (IGF-1). Increased secretion of both GH and IGF-1 activates pathways, such as Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5), and mitogen-activated protein kinase (MAPK), involved in the development of tumors. Materials and Methods: Given the disputed nature of the topic, we decided to study the prevalence of benign and malignant tumors in our cohort of acromegalic patients. In addition, we aimed to identify risk factors or laboratory parameters associated with the occurrence of tumors in these patients. Results: The study group included 34 patients (9 men (25.7%) and 25 women (74.3%)). No clear relationship between the levels of IGF-1 or GH and tumor development could be demonstrated, but certain risk factors, such as diabetes mellitus (DM) and obesity, were more frequent in patients with tumors. In total, 34 benign tumoral proliferations were identified, the most common being multinodular goiter. Malignant tumors were present only in women (14.70%) and the most frequent type was thyroid carcinoma. Conclusions: DM and obesity might be associated with tumoral proliferation in patients with acromegaly, and findings also present in the general population. In our study we did not find a direct link between acromegaly and tumoral proliferations.

Grades of Below-the-Ankle Arterial Occlusive Disease following the Angiosome Perfusion: A New Morphological Assessment and Correlations with the Inframalleolar GVG Stratification in CLTI Patients.

PURPOSE: To assess a specific classification of the foot atherosclerotic disease concerning the angiosomal source arteries, the connected foot arches and attached collaterals for Rutherford 5, CLTI patients. To compare eventual analogies of this novel grading system with previously reported GLASS/GVG inframalleolar patterns of occlusive disease (P0-P2). MATERIALS AND METHODS: A series of 336 ischemic feet (221 diabetics) were selected and retrospectively analyzed. For each angiographic pattern of inframalleolar atherosclerotic disease, 4 severity classes of targeted angiosomal artery path (TAAP), associating 4 other classes concerning linked foot arches (LFA) and collaterals occlusive disease were described. By associating the 4 TAAP with the 4 others parallel LFA and collaterals classes, 4 novel anatomical "Grades" (A-D) of occlusive disease were described. Limb salvage was studied between groups of diabetic and non-diabetic patients. RESULTS: Using a primary endovascular approach, limb preservation comparison of grade A/B proved without significance for diabetics (P = 0.032) and non-diabetics (P = 0.226). Comparison in diabetics and/or non-diabetics between A/C (P = 0.045 and 0.046), A/D (P = 0.027 and 0.030,B/C (P = 0.009 and 0.038), and B/D (P = 0.006 and P = 0.042), as well as C/D groups (P = 0.048 and P = 0.034) proved ponderous. Parallel analysis of similar grades (A/A, B/B, etc.) with, or without diabetes appeared without significance (P > 0.05). Further comparison between grades A+B (assigned as P0/GVG), versus C (P1), and D (P2), proved significant (P < 0.0001). CONCLUSION: The present grading system proposes a useful correlation between the severity of foot angiosomal arteries, arches, and collaterals disease and limb salvage, confirming the clinical significance of P0-P2 GVG severity score. This analysis also points the limits of EVT to be probably avoided in grade D patients.

High-Resolution Tandem Mass Spectrometry Identifies a Particular Ganglioside Pattern in Early Diabetic Kidney Disease of Type 2 Diabetes Mellitus Patients.

Considering the valuable information provided by glycosphingolipids as molecular markers and the limited data available for their detection and characterization in patients suffering from Type 2 diabetic kidney disease (DKD), we developed and implemented a superior method based on high-resolution (HR) mass spectrometry (MS) and tandem MS (MS/MS) for the determination of gangliosides in the urine of DKD patients. This study was focused on: (i) testing of the HR MS and MS/MS feasibility and performances in mapping and sequencing of renal gangliosides in Type 2 DM patients; (ii) determination of the changes in the urine gangliosidome of DKD patients in different stages of the disease-normo-, micro-, and macroalbuminuria-in a comparative assay with healthy controls. Due to the high resolution and mass accuracy, the comparative MS screening revealed that the sialylation status of the ganglioside components; their modification by O-acetyl, CH3COO-, O-fucosyl, and O-GalNAc; as well as the composition of the ceramide represent possible markers for early DKD detection, the assessment of disease progression, and follow-up treatment. Moreover, structural investigation by MS/MS demonstrated that GQ1d(d18:1/18:0), GT1α(d18:1/18:0) and GT1b(d18:1/18:0) isomers are associated with macroalbuminuria, meriting further investigation in relation to their role in DKD.

Practical Applicability of the ISARIC-4C Score on Severity and Mortality due to SARS-CoV-2 Infection in Patients with Type 2 Diabetes.

Background and objectives. There is a bidirectional relationship between SARS-CoV-2 infection and diabetes mellitus (DM), as people with DM are more vulnerable, and SARS-CoV-2 infections worsen the prognosis in these patients. The main purpose of the study was to evaluate the application validity of the ISARIC-4C score in patients confirmed with SARS-CoV-2 infection. Materials and Methods. The study included 159 patients previously known to have type 2 DM and confirmed positive for SARS-CoV-2 infection. We analyzed the concordance between the clinical evaluation of the patients and the ISARIC-4C score. Results. The mortality rate in hospitalized patients was 25.15%. The mortality risk was higher for ISARIC-4C values >14 than in the opposite group (63.93% vs. 31.24%; p < 0.001). The area under the curve (AUC) of the mortality score was 0.875 (95% CI: 0.820−0.930; p < 0.001), correctly classifying 77.36% of the cohort. A cut-off value of >14 had a sensitivity of 87.80% (95% CI: 87.66−87.93), specificity 73.72% (95% CI: 73.48−73.96), positive predictive value 53.73% (95% CI: 53.41−54.04), and negative predictive value 94.56% (95% CI: 94.5−94.62). The Cox regression model showed that the length of hospitalization (LH) was significantly influenced by body mass index, lung impairment, and aspartate aminotransferase, increasing the hazards, while lower HbA1c and lower SatO2 significantly decreased the hazards. Conclusions. ISARIC-4C score estimates the likelihood of clinical deterioration and the mortality risk in patients hospitalized with type 2 DM and positive for SARS-CoV-2, being useful in assessing the prognosis from the onset, as well as in developing therapeutic strategies.

Long noncoding RNAs may impact podocytes and proximal tubule function through modulating miRNAs expression in Early Diabetic Kidney Disease of Type 2 Diabetes Mellitus patients.

Aims: Long noncoding RNAs (lncRNAs) play key roles in the pathophysiology of DKD involving actions of microRNAs (miRNAs). The aims of the study were to establish the involvement of selected lncRNAs in the epigenetic mechanisms of podocyte damage and tubular injury in DKD of type 2 diabetes mellitus (DM) patients in relation to a particular miRNAs profile. Methods: A total of 136 patients with type 2 DM and 25 healthy subjects were assessed in a cross-sectional study concerning urinary albumin: creatinine ratio (UACR), eGFR, biomarkers of podocyte damage (synaptopodin, podocalyxin) and of proximal tubule (PT) dysfunction (Kidney injury molecule-1-KIM-1, N-acetyl-D-glucosaminidase-NAG), urinary lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), nuclear-enriched abundant transcript 1 (NEAT1), myocardial infarction-associated transcript (MIAT), taurine-upregulated gene 1 (TUG1), urinary miRNA21, 124, 93, 29a. Results: Multivariable regression analysis showed that urinary lncMALAT1 correlated directly with urinary synaptopodin, podocalyxin, KIM-1, NAG, miRNA21, 124, UACR, and negatively with eGFR, miRNA93, 29a (p<0.0001; R2=0.727); urinary lncNEAT1 correlated directly with synaptopodin, KIM-1, NAG, miRNA21, 124, and negatively with eGFR, miRNA93, 29a (p<0.0001; R2=0.702); urinary lncMIAT correlated directly with miRNA93 and 29a, eGFR (p<0.0001; R2=0.671) and negatively with synaptopodin, KIM-1, NAG, UACR, miRNA21, 124 (p<0.0001; R2=0.654); urinary lncTUG1 correlated directly with eGFR, miRNA93, 29a, and negatively with synaptopodin, podocalyxin, NAG, miRNA21, 124 (p<0.0001; R2=0.748). Conclusions: In patients with type 2 DM lncRNAs exert either deleterious or protective functions within glomeruli and PT. LncRNAs may contribute to DKD through modulating miRNAs expression and activities. This observation holds true independently of albuminuria and DKD stage.

Increased Incidence of Type 1 Diabetes during the COVID-19 Pandemic in Romanian Children.

Background and Objective: It is known that several viruses are involved in the pathogenesis of type 1 diabetes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new worldwide spread virus that may act as a trigger for the autoimmune destruction of the ß-cells, as well, and thus lead to an increase in the incidence of type 1 diabetes. Material and Methods: The Romanian National Organization for the Protection of Children and Adolescents with Diabetes (ONROCAD) has collected information regarding new cases of type 1 diabetes in children aged 0 to 14 years from all over the country since 1996 and has computed the incidence of type 1 diabetes in this age group. Results: We observed a marked increase in the incidence of type 1 diabetes in the first year of the COVID-19 pandemic, with 16.9%, from 11.4/100,000 in 2019 to 13.3/100,000 in 2020, much higher compared to previous years (mean yearly increase was 5.1% in the period 1996-2015 and 0.8% in the interval 2015-2019). The proportion of newly diagnosed cases was significantly higher in the second half of 2020 compared to the second half of the previous years (57.8 vs. 51%, p < 0.0001). Conclusions: All these aspects suggest the role that SARS-CoV-2 could have in triggering pancreatic autoimmunity. To confirm this, however, collecting information from larger populations from different geographical regions, monitoring the incidence curves over a period of several years, and gathering background information on COVID-19 and/or data on COVID-19 specific antibodies are needed.

Healing of Diabetic Neuroischemic Foot Wounds With vs Without Wound-Targeted Revascularization: Preliminary Observations From an 8-Year Prospective Dual-Center Registry.

Purpose: To assess the clinical efficacy of endovascular angiosome-oriented wound-targeted revascularization (WTR) vs indirect (wound-indifferent) revascularization (IR) in diabetic patients with neuroischemic foot ulcers. Materials and Methods: Between April 2009 and July 2017, 167 diabetic patients (mean age 72.8 years; 137 men) with chronic limb-threatening ischemia (Rutherford category 5) and foot wounds (Wagner 2-4) in 194 limbs were prospectively registered and scheduled for primary infragenicular endovascular treatment. Specific angiosome source artery reperfusion sustained by patent foot arches or arterial-arterial connections was attempted initially. If this approach failed, topographic revascularization via available collaterals (WTRc) and IR were sequentially attempted. Results: Reperfusion was successful in 176 (91%) of 194 limbs (113 with WTR, 28 with WTRc, and 35 with IR); the global angiosome-oriented technical success (WTR and WTRc) was 73% (141/194). The mean follow-up was 10.9±0.7 months (range 3-12.5). Over 1 year, 102 (58%) of the 176 successfully treated limbs experienced wound healing [79/113 (70%) in the WTR group, 15/28 (54%) in the WTRc group, and 7/35 (20%) in the IR group; p=0.011]. The mean time to healing was 6.8±0.4 months in the WTR group, 7.9±0.6 months in the WTRc group, and 9.8±0.7 months in the IR group (p=0.001). Relapses were noted in 18 (16%) WTR limbs, 5 (18%) WTRc limbs, and 6 (17%) IR limbs. Comparison between WTR and IR and WTRc vs IR showed improved cicatrization in the angiosome-oriented groups (p<0.05). Major adverse limb events (MALE) and limb salvage were different between WTR and WTRc and between WTR and IR groups (p<0.05), while WTRc vs IR was not. Amputation-free survival was not influenced by the revascularization strategy (p=0.093). Conclusion: Wound healing in diabetic patients with chronic limb-threatening ischemia appeared to be improved by intentional wound-targeted revascularization, but no uniform benefit concerning MALE or limb preservation was observed. IR still represents an alternative for limb salvage in cases in which angiosome-guided revascularization fails.

MiRNA Expression is Associated with Clinical Variables Related to Vascular Remodeling in the Kidney and the Brain in Type 2 Diabetes Mellitus Patients.

Background: The association of vascular remodeling in the kidney and the brain with a particular microRNAs (miRNA) profile is not well studied.Methods: Seventy-six patients with Type 2 diabetes and 11 healthy subjects were assessed concerning urine albumin: creatinine ratio (UACR), biomarkers of podocyte injury and of proximal tubule (PT) dysfunction. MiRNA were quantified in blood and urine by a real-time PCR System. Cerebrovascular ultrasound measurements were performed in the carotid and middle cerebral arteries.Results: MiRNA21 and miRNA124 correlated positively with nephrin, podocalyxin, synaptopodin, urinary N-acetyl-D-glucosaminidase (NAG), urinary kidney-injury molecule-1 (KIM-1), UACR, and negatively with eGFR; miRNA125a, 126, 146a, 192 correlated negatively with nephrin, podocalyxin, synaptopodin, urinary NAG, urinary KIM-1, UACR, and directly with eGFR. Plasma miRNA-21 and miRNA192 correlated directly with cerebral hemodynamics parameters of atherosclerosis and arteriosclerosis. MiRNA-124, 125a, 126, 146a showed negative correlations with the same parameters.Conclusions: In Type 2 diabetes patients there is an association of vascular remodeling in the brain and the kidney with a specific miRNAs pattern. Cerebrovascular changes occur even in normoalbuminuric patients, with 'high-to-normal' levels of podocyte injury and PT dysfunction biomarkers. These phenomena may be explained by the variability of miRNA expression within the two organs in early DKD.

Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia.

GUIDELINE SUMMARY: Chronic limb-threatening ischemia (CLTI) is associated with mortality, amputation, and impaired quality of life. These Global Vascular Guidelines (GVG) are focused on definition, evaluation, and management of CLTI with the goals of improving evidence-based care and highlighting critical research needs. The term CLTI is preferred over critical limb ischemia, as the latter implies threshold values of impaired perfusion rather than a continuum. CLTI is a clinical syndrome defined by the presence of peripheral artery disease (PAD) in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration. Venous, traumatic, embolic, and nonatherosclerotic etiologies are excluded. All patients with suspected CLTI should be referred urgently to a vascular specialist. Accurately staging the severity of limb threat is fundamental, and the Society for Vascular Surgery Threatened Limb Classification system, based on grading of Wounds, Ischemia, and foot Infection (WIfI) is endorsed. Objective hemodynamic testing, including toe pressures as the preferred measure, is required to assess CLTI. Evidence-based revascularization (EBR) hinges on three independent axes: Patient risk, Limb severity, and ANatomic complexity (PLAN). Average-risk and high-risk patients are defined by estimated procedural and 2-year all-cause mortality. The GVG proposes a new Global Anatomic Staging System (GLASS), which involves defining a preferred target artery path (TAP) and then estimating limb-based patency (LBP), resulting in three stages of complexity for intervention. The optimal revascularization strategy is also influenced by the availability of autogenous vein for open bypass surgery. Recommendations for EBR are based on best available data, pending level 1 evidence from ongoing trials. Vein bypass may be preferred for average-risk patients with advanced limb threat and high complexity disease, while those with less complex anatomy, intermediate severity limb threat, or high patient risk may be favored for endovascular intervention. All patients with CLTI should be afforded best medical therapy including the use of antithrombotic, lipid-lowering, antihypertensive, and glycemic control agents, as well as counseling on smoking cessation, diet, exercise, and preventive foot care. Following EBR, long-term limb surveillance is advised. The effectiveness of nonrevascularization therapies (eg, spinal stimulation, pneumatic compression, prostanoids, and hyperbaric oxygen) has not been established. Regenerative medicine approaches (eg, cell, gene therapies) for CLTI should be restricted to rigorously conducted randomizsed clinical trials. The GVG promotes standardization of study designs and end points for clinical trials in CLTI. The importance of multidisciplinary teams and centers of excellence for amputation prevention is stressed as a key health system initiative.

Midterm Outcomes From a Pilot Study of Percutaneous Deep Vein Arterialization for the Treatment of No-Option Critical Limb Ischemia.

PURPOSE: To report the initial clinical experience with percutaneous deep vein arterialization (PDVA) to treat critical limb ischemia (CLI) via the creation of an arteriovenous fistula. METHODS: Seven patients (median age 85 years; 5 women) with CLI and no traditional endovascular or surgical revascularization options (no-option CLI) were recruited in a pilot study to determine the safety of PDVA. All patients were diabetic; 4 had Rutherford category 6 ischemia. Six were classified at high risk of amputation based on the Society for Vascular Surgery WIfI (wound, ischemia, and foot infection) classification. The primary safety endpoints were major adverse limb events and major adverse coronary events through 30 days and serious adverse events through 6 months. Secondary objectives included clinical efficacy based on outcome measures including thermal measurement, transcutaneous partial pressure of oxygen (TcPO2), clinical improvement at 6 months, and wound healing. RESULTS: The primary safety endpoints were achieved in 100% of patients, with no deaths, above-the-ankle amputations, or major reinterventions at 30 days. The technical success rate was 100%. Two myocardial infarctions occurred within 30 days, each with minor clinical consequences. All patients demonstrated symptomatic improvement with formation of granulation tissue, resolution of rest pain, or both. Complete wound healing was achieved in 4 of 7 patients and 5 of 7 patients at 6 and 12 months, respectively, with a median healing time of 4.6 months (95% confidence interval 84-192). Median postprocedure peak TcPO2 was 61 mm Hg compared to a preprocedure level of 8 mm Hg (p=0.046). At the time of wound healing, 4 of 5 of patients achieved TcPO2 levels of >40 mm Hg. There were 2 major amputations, 1 above the knee after PDVA thrombosis and 1 below the knee for infection. Three patients died of causes unrelated to the procedure or study device at 6, 7, and 8 months, respectively. Limb salvage was 71% at 12 months. CONCLUSION: PDVA is an innovative approach for treating no-option CLI and represents an alternative option for the "desert foot," potentially avoiding major amputation. Our results demonstrate its safety and feasibility, with promising early clinical results in this small cohort.

Therapy with atorvastatin versus rosuvastatin reduces urinary podocytes, podocyte-associated molecules, and proximal tubule dysfunction biomarkers in patients with type 2 diabetes mellitus: a pilot study.

BACKGROUND: Diabetic nephropathy is a severe complication of Type 2 diabetes. Tubular lesions may play an important role in its early stages. The aim of our study was to determine if atorvastatin protects the podocytes and the proximal tubule in patients with Type 2 diabetes. METHODS: A total of 63 patients with Type 2 diabetes completed this 6-months prospective pilot study. They were randomized to continue rosuvastatin therapy (control group) or to be administered an equipotent dose of atorvastatin (intervention group), and were assessed regarding urinary podocytes, podocyte-associated molecules, and biomarkers of proximal tubule dysfunction. RESULTS: The patients from the intervention group presented a significant reduction in podocyturia (from 7.0 to 4.0 cells/ml, p < .05), urinary nephrin (from 1.7 to 1.3 mg/g, p < .001), urinary vascular endothelial growth factor (from 262.8 to 256.9, p < .01), urinary alpha1-microglobulin (from 10.0 to 8.3 mg/g, p < .01), urinary kidney injury molecule-1 (from 139.5 to 136.3 ng/g, p < .001), and urinary advanced glycation end-products (from 112.6 to 101.3 pg/ml, p < .001). Podocyturia correlated directly with the podocyte damage biomarkers, proximal tubule dysfunction biomarkers, albumin to creatinine ratio, and advanced glycation end-products, and inversely with the glomerular filtration rate. CONCLUSIONS: In patients with Type 2 diabetes, atorvastatin exerts favorable effects on the kidney. There is a correlation between the evolution of the podocytes and of the proximal tubule biomarkers, supporting the hypothesis that the glomerular changes parallel proximal tubule dysfunction in the early stages of diabetic nephropathy.

New developments and standard of care in the management of advanced gastric cancer.

Advanced gastric adenocarcinoma is a common disease with a poor prognosis whose treatment has for decades been based on cytotoxic chemotherapy, including platinum salts in first-line, and taxane or irinotecan in second or later line. Recent years have seen the emergence of new drugs that have improved patient survival, such as trastuzumab in first-line for HER2-positive tumors, ramucirumab alone or in combination with paclitaxel in second-line, and trifluridine-tipiracil beyond the second-line treatment. More recently, two monoclonal antibodies have demonstrated their efficacy in combination with oxaliplatin-based first-line chemotherapy, nivolumab (anti-PD1) for PD-L1 CPS ≥5 tumors, and zolbetuximab for tumors overexpressing Claudin 18.2. In addition, regorafenib has been also showed effective in phase 3 trial for heavily pretreated patients. Based on phase 2 studies, trastuzumab-deruxtecan was approved in 2022 by the EMA for HER2-positive pretreated patients. This agent is currently evaluated in phase 3 study (DESTINY-Gastric04 trial), as are several other anti-HER2 (zanidatamab, margetuximab, tucatinib), immune checkpoint inhibitors, or targeted therapies (anti-FGFR2b).