Giustino Varrassi

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms. Complete surgical resection is the mainstay of treatment, yet recurrence remains common even after apparent complete resection. Gastrointestinal stromal tumors carry a notable long-term risk of recurrence even after surgery, underscoring the need for ongoing vigilance. We present a case of very late recurrence of gastric GIST 17 years after complete resection. This case highlights the limitations of current surveillance protocols and raises important questions about tumor biology, genetic risk stratification, and the need for long-term or even lifelong follow-up in selected patients.

Postoperative delirium (POD) is the most common neurologic complication after surgery, affecting 15-50% of adults ≥65 years and up to 80% of those admitted to intensive care units. Clinically, POD is characterized by an acute, fluctuating disturbance in attention, awareness, and cognition that typically arises within 72 hours of anesthesia. Its occurrence is associated with a threefold rise in 30-day mortality, prolonged mechanical ventilation, increased institutionalization, and long-term cognitive decline, underscoring its substantial human and financial burden. POD arises through a multifactorial pathogenesis that includes neuroinflammation, blood-brain‑barrier disruption, neurotransmitter imbalance, sleep fragmentation, and perioperative cerebral hypoperfusion. Patient-related risk factors (advanced age, pre-existing cognitive impairment, frailty, sensory deficits, alcohol misuse, and polypharmacy) intersect with surgical drivers such as operative duration, intraoperative hypotension, high opioid doses, benzodiazepine exposure, and postoperative infections. Prevention hinges on identifying at-risk patients and mitigating modifiable factors. High-quality evidence supports the use of multicomponent nonpharmacological bundles, including orientation protocols, early mobilization, sleep promotion, optimized pain control, and hearing and vision aids, which reduce delirium incidence by 30-40%. Among pharmacologic strategies, dexmedetomidine infusion during and after cardiac and major noncardiac surgery consistently lowers delirium rates, whereas routine prophylaxis with antipsychotics, melatonin agonists, or cholinesterase inhibitors remains unproven and is not currently recommended outside clinical trials. Management prioritizes rapid diagnosis using validated tools (e.g., confusion assessment method for the intensive care unit (CAM‑ICU)), correction of precipitating insults, and judicious symptom control with low-dose haloperidol or atypical antipsychotics when nonpharmacologic measures fail. Future research should clarify optimal hemodynamic targets, refine electroencephalogram (EEG)-guided anesthetic titration, evaluate peri‑operative neuro‑inflammation biomarkers, and develop personalized, risk-stratified prevention algorithms further to reduce POD's pervasive impact on older surgical patients.

Hypertensive nephrosclerosis (HN) and diabetic nephropathy (DN) are the leading global causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Both conditions share overlapping clinical and histopathological features, particularly in patients with concurrent hypertension and diabetes, making accurate differentiation challenging. This narrative review synthesizes current evidence on the pathophysiology, histopathology, diagnostic criteria, and therapeutic implications of HN and DN, with emphasis on areas of morphological and clinical overlap. HN is driven by chronic vascular injury from sustained hypertension, resulting in ischemic glomerulosclerosis, arteriolar hyalinosis, and interstitial fibrosis. DN, in contrast, is primarily mediated by hyperglycemia-induced metabolic and hemodynamic stressors, producing diffuse and nodular mesangial expansion, glomerular basement membrane thickening, and bilateral arteriolar hyalinosis. While certain histological features, such as Kimmelstiel-Wilson nodules and efferent arteriole involvement, favor DN, mixed lesions are common in long-standing type 2 diabetes with hypertension. Accurate differentiation is clinically significant, as it guides the application of disease-specific interventions such as intensive glycemic control and emerging pharmacotherapies for DN, versus targeted vascular risk reduction in HN. Future advances in biomarkers, imaging, and genomics hold promise for earlier, noninvasive diagnosis.

Diabetic nephropathy (DN) is a leading cause of chronic kidney disease and end-stage renal disease worldwide, characterized by progressive injury across all renal compartments. Traditionally considered a glomerular disorder marked by basement membrane thickening, mesangial expansion, and nodular sclerosis, DN is now recognized as a multifaceted process involving tubulointerstitial, vascular, and podocyte pathology. This narrative review integrates current histopathological insights, highlighting key glomerular lesions, tubular basement membrane thickening, interstitial fibrosis, arteriolar hyalinosis, and podocyte injury, as well as atypical and advanced patterns. The role of kidney biopsy in diagnosis, the application of the Renal Pathology Society classification, and differentiation from mimicking conditions such as amyloidosis and monoclonal deposition disease are discussed. Emerging biomarkers and advanced imaging modalities offer promise for earlier detection and risk stratification. Understanding the full histological spectrum of DN is critical for accurate diagnosis, prognostication, and the development of targeted therapies. Future directions include molecular classification, non-invasive diagnostics, and precision medicine approaches to improve patient outcomes.

Electron microscopy (EM) remains an indispensable tool in renal pathology, providing ultrastructural details that complement light microscopy (LM) and immunofluorescence (IF) in the diagnosis of glomerular diseases. This review outlines the diagnostic role of EM across major categories of glomerular pathology, emphasizing its value in confirming and refining histopathological diagnoses. In membranous nephropathy, EM visualizes subepithelial electron-dense deposits and tracks disease progression through glomerular basement membrane (GBM) remodeling. In immune complex-mediated glomerulonephritides, such as IgA nephropathy and lupus nephritis, EM localizes deposits to mesangial, subendothelial, or subepithelial regions, facilitating accurate classification. For C3 glomerulopathies, EM distinguishes dense deposit disease from C3 glomerulonephritis by revealing unique ribbon-like intramembranous densities. In hereditary nephritides like Alport syndrome and thin basement membrane nephropathy, EM provides pathognomonic findings of GBM lamellation and thinning that often precede or guide genetic testing. Additionally, EM identifies organized deposits in fibrillary and immunotactoid glomerulopathies and helps differentiate diabetic glomerulosclerosis from mimickers through assessment of GBM thickening and matrix expansion. Despite advances in molecular diagnostics, EM remains essential for identifying subtle ultrastructural changes, validating immunopathologic interpretations, and guiding clinical management. This article reinforces EM’s continued relevance in an era of expanding genetic and serologic tools.

The global rise in obesity has accelerated both clinical and pharmaceutical innovation in antiobesity pharmacotherapy. This narrative review synthesizes current evidence on Food and Drug Administration-approved medications and emerging investigational agents that are shaping clinical practice. We summarize mechanisms of action, pivotal efficacy data, safety profiles, indications, prescribing guidance, and key uncertainties. Approved long-term agents, orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide, and tirzepatide, differ in mechanism, weight-loss magnitude, and safety considerations. Semaglutide and tirzepatide have redefined expectations for pharmacological weight loss, while next-generation drugs, such as oral glucagon-like peptide 1 receptor agonists (e.g., orforglipron) and multireceptor agonists (e.g., retatrutide), show even greater efficacy in early studies. Common safety concerns include gastrointestinal effects, gallbladder events, pancreatitis risk, thyroid C-cell tumor warnings, teratogenicity, and cost barriers. Appropriate patient selection depends on body mass index, comorbidities, contraindications, and treatment goals, with close monitoring throughout therapy. Long-term data on cardiovascular outcomes and posttreatment weight durability are emerging. Future research should prioritize direct comparative trials, real-world effectiveness, long-term safety, and strategies to improve access and adherence. This review offers clinicians a concise, evidence-based guide for obesity pharmacotherapy and outlines key research priorities as the treatment landscape rapidly evolves.

Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by a cytosine-adenine-guanine trinucleotide repeat expansion in the huntingtin (HTT) gene. The symptoms of HD include severe motor dysfunction, cognitive issues, and emotional dysregulation. These combined issues are not only debilitating but also lead to depression/anxiety, increased suicide rates, and caregiver burnout. Our narrative review summarizes several recent studies examining the efficacy and differences among emerging treatment strategies for HD. A systematic search of peer-reviewed literature was conducted, focusing on recent studies that describe molecular genetic manipulation of the HTT gene/huntingtin protein. The results of our narrative review reveal potential benefits in slowing disease progression and enhancing symptomatic management through genetic silencing, gene editing using Clustered Regularly Interspaced Short Palindromic Repeats technology, antisense oligonucleotide-mediated protein suppression, RNA interference, sirtuin modulation, and ferroptosis inhibition. Future studies should aim to examine the disease progression of HD models using multimodal therapeutic options with efficient delivery methods to deep brain structures, as well as to develop biomarkers to track disease progression and treatment response.

Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus, often inadequately managed by conventional pharmacological therapies. Alternative interventions, including spinal cord stimulation (SCS), have garnered increasing attention for their potential effectiveness. This narrative review evaluates the efficacy, safety, mechanisms of action, and impact on quality of life of SCS in the management of PDN. A systematic search was conducted covering the last 15 years (from January 2010 to April 2025), using the keywords “diabetic neuropathy,” “spinal cord stimulation,” “neuropathic pain,” and “neuromodulation” with Boolean operators. Eligible studies included randomized controlled trials (RCTs), observational studies, systematic reviews, and meta-analyses involving adult populations and published in English. Study selection and data extraction were performed independently by two authors. Multiple RCTs and observational studies (involving over 500 patients) were identified. RCTs consistently demonstrated that SCS significantly reduces neuropathic pain intensity compared to conventional medical therapy (CMT). The most recent study, with the largest sample size (216 patients), reported that high-frequency SCS achieved ≥50% pain relief in 79% of patients at 6 months, compared to only 5% in the CMT group. Observational studies confirmed sustained pain relief (≥50% reduction) in approximately 55–80% of patients over 5–10 years. Significant improvements in sleep, neurological function, and quality of life were also consistently observed. The complication rate was low, with infections requiring explantation in approximately 2–3% of cases. Rare serious adverse events, such as spinal hematoma, were reported. Current evidence underlines the efficacy and safety of SCS, particularly newer waveform paradigms, for the treatment of PDN refractory to medical management. Given its durable effects on pain relief, functional improvement, and quality of life, SCS should be considered an option within the treatment algorithm for carefully selected patients with severe, refractory PDN.

Gastrointestinal neuroendocrine neoplasms (GI NENs) represent a heterogeneous group of tumors distinguished by variable morphology, proliferative behavior, and clinical outcomes. Their incidence continues to rise globally, driven by improved detection methods and increased understanding of neuroendocrine biology. This narrative review synthesizes current knowledge on the morphologic, immunohistochemical, and molecular features of GI NENs across anatomic sites, highlighting advances in diagnostic evaluation and the prognostic significance of the WHO 2022 grade. Key diagnostic challenges, including differentiating neuroendocrine tumor grade 3 (NET G3) from neuroendocrine carcinoma (NEC) and accurately assessing mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs), are examined alongside sources of variability such as Ki-67 interpretation and sampling limitations. Emerging prognostic biomarkers, digital pathology applications, and evolving therapeutic strategies, particularly somatostatin analogs, peptide receptor radionuclide therapy, and systemic chemotherapy, are reviewed in the context of precision oncology. Continued integration of molecular profiling, artificial intelligence, and standardized diagnostic approaches promises to refine prognostication and personalize management for patients with GI NENs.