Search Results (1,120)

Background/Objectives: OrganoHIPEC is a phase-II, two-stage, open-label clinical trial that investigates if cytoreductive surgery (CRS) and patient-tailored HIPEC, based on a preclinical platform using patient-derived organoids, can improve disease control in peritoneal metastases from colorectal cancer (CRC-PM). Methods: Adults with limited CRC-PM and no distant metastases were included. CRC-PM were sampled for organoid development during diagnostic laparoscopy. These organoids were used in an in vitro HIPEC model to test various drugs suitable for intraperitoneal administration. After 3–6 months of systemic chemotherapy, patients without progression underwent CRS/HIPEC with personalized regimens based on organoid drug response. To detect an increase in 12-month peritoneal disease-free survival from 40% to 60%, 24 patients are needed. According to the two-stage design, if <7 of 10 patients in Stage-1 remain PM-free at 12 months, the trial is terminated. Results: Forty-seven patients were enrolled. Among 31 patients with available organoid data, the most active drugs were mitomycin-C (n = 14), cisplatin/mitomycin-C (n = 12), and low-dose (120 min) oxaliplatin (n = 4). No patient was sensitive to high-dose oxaliplatin (30 min) and cisplatin/doxorubicin. Ten patients had a potential follow-up >12 months. Peritoneal relapse occurred at 8 months in two patients, and one died of liver metastases at 7 months. Seven patients remained PM-free for >12 months (median 16.4, range 12.6–28.4). Conclusions: A comprehensive precision approach using patient-derived organoids to guide personalized HIPEC is feasible and shows promising early results. High-dose oxaliplatin is poorly active. As 7/10 patients achieved the endpoint of 12-month PM-free survival, Stage-1 was successfully completed. The trial is proceeding to Stage-2. Full article

Objectives: The aim of this study was to evaluate the reliability, accuracy, and morbidity of dynamic sentinel lymph node biopsy (DSNB) in patients with intermediate- and high-risk penile cancer who had clinically negative lymph nodes, with a focus on long-term follow-up outcomes. Methods: Between January 2005 and January 2024, 287 patients with histologically confirmed penile cancer underwent radioisotope-guided DSNB at the Department of Urology, University of Pécs. Patients lost to follow-up within 24 months were excluded. Of the remaining patients, 211 underwent primary DSNB and 37 secondary DSNB. Thirty-nine patients in the primary DSNB group with Tis, T1a, or G1 tumours were additionally excluded, leaving 209 patients for analysis. Variables included tumour stage and grade, sentinel lymph node (SLN) yield and histology, complications, inguinal progression, false-negative rate, and radical lymphadenectomy findings. Results: A total of 573 SLNs were removed from 209 patients, with a median of 2.7 nodes per patient. SLN metastases were identified in 31 patients, involving 37 groins. Among 178 patients with negative SLNs, three developed inguinal metastases. Sensitivity was 91% per patient and 92.5% per groin, with false-negative rates of 8% and 7.5%, respectively. All false-negative cases occurred within two years, with no later inguinal recurrences. DSNB-related complications occurred in 24 patients (11.4%); most were mild or moderate and managed on an outpatient basis. Two patients required surgery and one required hospital readmission. Conclusions: In a high-volume centre, DSNB is a safe and reliable staging procedure with low morbidity in clinically node-negative intermediate- and high-risk penile cancer. Further studies should assess radiotracer injection sites and compare one-day versus two-day protocols. Full article

Background/Objectives: Prostate cancer is biologically heterogeneous, and prognostic stratification informs the choice between definitive treatment and conservative management. Most evidence on the Gleason score addresses prostate cancer-specific mortality rather than survival from any cause. We assessed the association between Gleason score category and overall survival in a contemporary population-based cohort. Methods: Using Surveillance, Epidemiology, and End Results (SEER) Research Data from 17 registries (November 2024 submission), we included men aged 40 years and older with a first primary malignant prostate cancer and a recorded Gleason Score Clinical Recode (2010+). Because this recode is undefined before 2010, the analytic period was 2010–2019. Gleason score was categorized as ≤6, 7, and ≥8. Overall survival was estimated by Kaplan–Meier methods and compared by log-rank test; multivariable Cox regression adjusted for age, race and ethnicity, marital status, summary stage, surgery at the primary site, radiation therapy, and chemotherapy, with localized disease as the stage reference. Results: Among 374,763 men, 145,668 (38.9%) had Gleason ≤ 6, 148,773 (39.7%) Gleason 7, and 80,322 (21.4%) Gleason ≥ 8, with mortality during follow-up of 11.3%, 14.6% and 36.6% respectively (log-rank p < 0.0001). Adjusted hazards of death were higher for Gleason 7 (HR 1.53, 95% CI 1.50–1.57) and Gleason ≥ 8 (HR 2.89, 95% CI 2.82–2.95) relative to Gleason ≤ 6. Advancing age, regional disease (HR 1.47, 95% CI 1.43–1.51) and distant disease (HR 3.74, 95% CI 3.65–3.84) were also associated with increased mortality. The grade association attenuated over follow-up, the hazard ratio for Gleason ≥ 8 falling from 4.12 within two years to 2.17 beyond five years. Conclusions: Gleason score category is independently associated with overall survival and retains prognostic value on the all-cause mortality scale, with greatest discrimination in the years immediately following diagnosis. Full article

Background/Objectives: Histopathology-correlated evidence for preoperative magnetic resonance imaging (MRI) in penile cancer remains limited. We evaluated multiparametric MRI with artificially induced erection for local and nodal staging in surgically treated penile cancer. Methods: This prospective, single-centre diagnostic accuracy study included consecutive patients who underwent preoperative multiparametric MRI between 2017 and 2024, with postoperative histopathology as the reference standard. The primary endpoint was binary local T-staging (≤T1 vs. ≥T2). Secondary endpoints were three-category T-staging (≤T1/T2/≥T3) and binary nodal staging (N0 vs. N+) in patients with pathological nodal verification. Two radiologists independently reassessed all 38 examinations in a post hoc reproducibility analysis. Results: Thirty-eight patients were included; all tumours were glans-based and treated with organ-sparing surgery. Binary local staging showed 68.4% accuracy (95% CI, 52.5–80.9%), 88.2% sensitivity, 52.4% specificity, 60.0% positive predictive value, 84.6% negative predictive value, and balanced accuracy of 0.703 (95% CI, 0.568–0.838). Overstaging predominated (10 false-positive vs. 2 false-negative classifications; p = 0.043). Three-category exact agreement was 52.6% (κ = 0.257). In the pathologically verified nodal subset (n = 30), accuracy was 83.3% (95% CI, 66.4–92.7%), sensitivity 78.6%, specificity 87.5%, and balanced accuracy 0.830 (95% CI, 0.691–0.970). Inter-reader agreement was 92.1% for binary T staging (κ = 0.837) and 97.4% for binary N staging (κ = 0.943). Conclusions: mpMRI was sensitive but insufficiently specific for ≥T2 disease and should not independently trigger treatment escalation. Nodal performance was encouraging but arose from a guideline-selected verified subset. These findings apply primarily to glans-based, organ-preserving cohorts and do not establish an incremental benefit of erection induction. Full article

The aorta is a single arterial organ, yet the clinical response to its diseases is fragmented across specialties, institutions, and nations. Acute aortic syndromes remain lethal at every stage of the care continuum: a large share of patients with type A dissection die before reaching any hospital, roughly half die before reaching a specialist centre, a substantial proportion are misdiagnosed at first medical contact, and untreated mortality has historically been estimated at approximately one to two percent per hour. Reported 30-day mortality differs across surgical registry cohorts—for example, 7.6% in the Japan Cardiovascular Surgery Database and 16.9% in the cited GERAADA cohort—but such ecological comparisons are descriptive and cannot identify the contribution of organisational, biological, clinical, or ascertainment differences. This review synthesises registry, population, and health-services data from Europe, Japan, North America, and low- and middle-income settings to characterise where the pathway fails and what each system has already demonstrated. We argue that the next material advance in aortic care will come not from any single innovation in isolation but from the architecture that connects prevention, diagnosis, treatment, and follow-up and that system redesign and technological progress are complementary rather than competing; we propose a five-pillar framework (Prevention, Presentation, Pathway, Person, and Learning) mapped throughout to published exemplars and future research priorities. Full article

Objective: The aim of this study was to evaluate the efficacy and safety of endovascular and hybrid treatment approaches in patients with aortic arch aneurysms. Materials and Methods. This retrospective study included 68 male and female patients with a confirmed diagnosis of either an aortic arch aneurysm or a descending thoracic aortic aneurysm with a short proximal landing zone (<1.5 cm) who underwent either hybrid or endovascular treatment at the Department of Vascular Surgery between January 2017 and December 2024. Study outcomes included a composite measure of technical success, a composite measure of in-hospital clinical success, and a composite measure of long-term treatment outcomes, including stroke, myocardial infarction, and aortic-related mortality. Results. All 68 patients were divided into two groups: Group I comprised patients who underwent endovascular treatment, whereas Group II included patients who underwent hybrid surgical treatment. The groups were comparable with regard to demographic and anatomical characteristics, clinical presentation, and comorbidities. The composite technical success rate (defined as successful target stent-graft deployment without conversion to open surgery and absence of type I or type III endoleaks) was comparable between the groups at the intraoperative stage (p = 1.000). The composite measure of in-hospital clinical success was achieved in 33 patients (94%) in Group I and 22 patients (67%) in Group II and was significantly higher in the endovascular group (adjusted p = 0.005). This difference was primarily attributable to a higher incidence of complications in the hybrid treatment group, including stroke (9%) and peripheral nerve injury (9%), associated with the open surgical component of the procedure. The mean follow-up duration was shorter in Group I (19.3 ± 10.4 months) than in Group II (63.9 ± 29.5 months), reflecting the fact that most patients in Group I underwent treatment during the later years of the study period. Although a difference in the composite long-term outcome measure was observed before adjustment (p = 0.031), this finding did not remain statistically significant after correction for multiple testing (adjusted p = 1.000). Conclusions. In this preliminary single-centre study, endovascular and hybrid approaches showed comparable technical efficacy in the early postoperative period. However, hybrid surgical treatment was associated with a less favourable safety profile during the early postoperative period, as reflected by the significantly lower in-hospital composite clinical success rate and longer hospital stay than in the endovascular group. These findings remained robust after correction for multiple testing. Long-term results should be interpreted with caution and require confirmation in larger prospective studies with longer and balanced follow-up periods. Full article

Background: Emergency surgery for complicated colorectal cancer (CRC) presenting with obstruction, perforation, or uncontrolled bleeding has high postoperative mortality, especially in older patients. However, age-related risk and the roles of radical versus palliative treatment are not fully understood. This study aimed to measure 90-day and 36-month mortality after emergency CRC surgery and to analyze whether the relationship between age and mortality is nonlinear and influenced by operative intent. Methods: Retrospective cohort of consecutive adults undergoing emergency surgery for complicated CRC (2015–2024). The outcome was 90-day and 36-month all-cause mortality. Cox regression provided adjusted hazard ratios (HR) using two models: a primary whole-cohort model omitting pathological T/N stage, and a secondary resection-only model including pathological stage. Age was modeled with restricted cubic splines and predicted 90-day and 36-month mortality were plotted by operative intent. Results: In 496 patients, 90-day mortality was 19.7% (98/496), while 36-month mortality was 37.3% (185/496). In the primary whole-cohort Cox model, independent predictors of 36-month mortality included age ≥75 years (HR 2.09, 95% CI 1.48–2.95, p < 0.001), Charlson Comorbidity Index (HR 1.02, 95% CI 0.98–1.06, p = 0.31), obstruction (HR 1.69, 95% CI 1.18–2.42, p = 0.004), perforation (HR 2.05, 95% CI 1.24–3.39, p = 0.005), and metastatic disease (HR 2.30, 95% CI 1.62–3.27, p < 0.001); radical operative intent was independently associated with lower 36-month mortality (HR 0.461, 95% CI 0.30–0.71, p = 0.001). In a secondary resection-only model additionally adjusting for pathological T/N stage (n = 426 with available pathology), the association for radical intent was attenuated and no longer statistically significant (HR 0.67, 95% CI 0.43–1.03, p = 0.067). The 36-month mortality spline estimate indicated an increasing risk with advancing age; a likelihood-ratio test did not show that the spline model fit significantly better than a linear age term (χ² = 1.43, df = 1, p = 0.233), so this pattern is interpreted descriptively rather than as formal evidence of nonlinearity, and no formal interaction between age and operative intent was demonstrated. Conclusions: Ninety-day mortality after emergency colon cancer surgery remains significant. Age-related risk shows a predominantly monotonic, descriptive pattern and should not be assumed to vary by operative intent without formal interaction testing, emphasizing individualized risk assessment and shared decision-making. Full article

Background and Clinical Significance: Solitary fibrous tumor (SFT), historically termed hemangiopericytoma (HPC), is a rare fibroblastic mesenchymal neoplasm with variable biological behavior. Pulmonary involvement is uncommon and may represent either a primary thoracic tumor or metastatic disease from an extrapulmonary site. Its clinical course ranges from indolent, surgically curable disease to aggressive malignancy with local recurrence and distant dissemination. In this retrospective case, confirmatory STAT6 immunohistochemistry was unavailable; therefore, the tumor is described as a hemangiopericytoma/solitary fibrous tumor spectrum neoplasm. Case Presentation: We report the case of a 33-year-old woman who presented with sudden-onset hemoptysis and was found to have two large, well-defined bilateral pulmonary masses. Initial clinical and radiological evaluation raised suspicion of primary pulmonary tumors or other benign lesions. Because both lesions were considered resectable, staged pulmonary resections were performed. Subsequent reassessment of the patient’s medical history revealed previous surgeries for a poorly documented recurrent thigh tumor, later confirmed to represent the primary malignant hemangiopericytoma/solitary fibrous tumor spectrum neoplasm. Despite staged pulmonary resections, systemic chemotherapy, and further oncologic management, the disease progressed rapidly, with cerebral, bilateral pulmonary, mediastinal, and subcutaneous metastases. The patient died within 18 months of the initial pulmonary diagnosis. Conclusions: This case highlights the diagnostic difficulty of metastatic pulmonary hemangiopericytoma, particularly when the primary soft tissue tumor is inadequately documented. It emphasizes the importance of detailed clinical history, retrieval of previous histopathological reports, and long-term surveillance in patients with soft tissue tumors, even when initially considered benign. Full article

Background: This paper aims to investigate the effect of short-term cast immobilization on the prognosis of ankle fractures. Methods: A total of 60 patients who underwent ankle fracture surgery in our hospital from September 2021 to September 2022 were included and divided into a cast immobilization group (n = 30) and a control group (n = 30). Both groups were given open reduction and internal fixation. After the operation, the immobilization group used a plaster cast bandage to fix the ankle joint of the affected side in the functional position for 2 weeks; the control group did not receive cast immobilization and was only bandaged with routine wound dressings. The visual analog scale (VAS) score, ankle joint range of motion (ROM), lower extremity deep venous thrombosis rate, and ankle joint function score were followed up in the two groups. Results: All patients were followed up for 6 months. The VAS scores of the cast immobilization group were lower than the control group at 1, 3 and 7 days post-operation (p < 0.05). At 1, 2 and 3 months post-operation, the dorsiflexion ROM of the ankle joint in the cast immobilization group was larger than control group (p < 0.05). The ankle plantarflexion ROM at postoperative 1 and 2 months were larger than the control group (p < 0.05). The AOFAS of cast immobilization group was larger than the control group at 3 months post-operation (p = 0.002). The postoperative deep venous thrombosis rate was 1/30 (3.3%) in the cast immobilization group and 3/30 (10%) in the control group (p = 0.605). Conclusions: Short-term cast immobilization after ankle fracture surgery can significantly reduce postoperative pain in the early stage, without increasing the recovery and the incidence of deep venous thrombosis. Full article

Background and Clinical Significance: Oropharyngeal squamous cell carcinoma (OPSCC) and small-cell neuroendocrine carcinoma (SCNEC) are biologically distinct entities with markedly different prognostic and therapeutic implications. While HPV-negative OPSCC carries worse outcomes than HPV-positive disease, SCNEC is exceedingly rare, highly aggressive, and prone to early systemic dissemination. Their synchronous occurrence in the head and neck (HN) is exceptional and poses major diagnostic and therapeutic challenges. Case Presentation: A 54-year-old male, smoker and alcohol consumer, presented with a left tonsillar lesion and cervical lymphadenopathy. Biopsy confirmed p16-negative OPSCC. He underwent transoral robotic surgery with modified radical neck dissection. Histopathology unexpectedly revealed two distinct malignancies: keratinizing OPSCC in the tonsil and high-grade SCNEC in a cervical lymph node, confirmed by immunohistochemistry (synaptophysin, CD56, Ki-67 80%). Postoperative FDG-PET/CT performed within two months showed rapid systemic spread, including paravertebral, pulmonary, and pelvic nodal metastases. Despite recommendation for systemic therapy, the patient deteriorated quickly and died shortly thereafter. Conclusions: This study reports coexistence of p16-negative OPSCC and high-grade SCNEC in the HN. It highlights the diagnostic complexity, staging limitations, and therapeutic dilemmas of discordant histologies, while illustrating the fulminant clinical course typical of SCNEC of unknown origin. Early recognition, comprehensive pathology, and multidisciplinary management are essential, although prognosis remains dominated by the aggressive neuroendocrine component. Full article

Background/Objectives: Robotic-assisted thoracic surgery continues to spread internationally for anatomical lung resection, yet evidence on learning curve dynamics and conversion behaviour remains limited beyond the da Vinci system. The published clinical experience on the Versius CMR Surgical System does not yet match that of the da Vinci system. This study examines the learning curve and conversion pattern of a mature Versius programme using cumulative sum (CUSUM) analysis. Methods: Single-centre retrospective cohort study encompassing 206 consecutive anatomical lung resections (154 lobectomies, 52 segmentectomies) undertaken using the Versius CMR platform between April 2023 and February 2026. CUSUM analysis was applied at programme and individual surgeon level. Logistic regression was performed to identify independent predictors of conversion. Operative time and post-operative length of stay were examined, along with a comparative sub-analysis between converted and pure robotic cases, stratified by surgeon. Results: The programme-level CUSUM inflection point occurred at case 49 (7.3 months), with mean operative time falling from 250.9 ± 65.4 min in the early phase to 215.5 ± 46.8 min in the late phase (p = 0.001). Post-operative LOS improved from 5.8 to 4.7 days (p = 0.031). Forty-six cases (22.3%) required conversion, 87% of which were elective, with no significant change across programme phases (p = 1.00). A six-fold difference in conversion rate existed between the two main surgeons (35.4% vs. 6.1%). Surgeon-1’s conversions carried no operative time penalty (225.2 vs. 223.3 min, p = 0.96) or LOS penalty (3.9 vs. 5.0 days, p = 0.83), whereas Surgeon-2’s converted cases were significantly longer (333.3 vs. 216.9 min, p = 0.004) and associated with longer hospital stay (8.8 vs. 4.7 days, p = 0.004). On multivariable analysis, surgeon identity (aOR 5.39, 95% CI 2.25–12.92, p < 0.001), intra-operative adhesions (aOR 3.41, 95% CI 1.53–7.64, p = 0.003) and clinical stage II or higher (aOR 3.55, 95% CI 1.43–8.79, p = 0.006) were each independently associated with conversion. Conclusions: The Versius CMR system supports a definable and reproducible learning curve in anatomical lung resection. Conversion was determined both by operative difficulty and by individual surgeon decision-making philosophy, the latter accounting for the greater share of the programme’s conversion burden. Early elective conversion, when indicated, preserves operative efficiency and post-operative recovery, and should be viewed as wise surgical judgement, not a marker of programme immaturity. Full article

Background: Simultaneous pancreas–kidney transplantation (SPKT) restores both renal function and endogenous insulin secretion in selected patients with type 1 diabetes mellitus (T1DM) and end-stage renal disease (ESRD). Whether SPKT provides superior patient survival, kidney graft outcomes and cardiovascular benefit compared with kidney transplantation alone (KTA) remains debated, particularly when KTA is performed from a living donor. Methods: A systematic review was conducted according to PRISMA 2020 guidelines. PubMed/MEDLINE was searched using a predefined strategy including terms related to pancreas transplantation, kidney transplantation alone, T1DM, and ESRD/chronic kidney disease. Eligible studies included adult T1DM/ESRD populations comparing SPKT with KTA, including living-donor kidney transplantation (LDKT) and deceased-donor kidney transplantation (DDKT) and reporting clinically relevant outcomes. Full texts were reviewed and categorized as core comparative evidence, secondary/supportive evidence or excluded records. A quantitative synthesis was additionally performed for studies reporting directly comparable adjusted hazard ratios for patient mortality and kidney graft failure in the SPKT versus LDKT comparison. Results: Nineteen observational studies met the inclusion criteria and were included in the qualitative synthesis. SPKT consistently provided superior metabolic control and insulin independence when pancreas graft function was maintained. Compared with deceased-donor or mixed KTA cohorts, SPKT was frequently associated with more favorable long-term patient survival and cardiovascular outcomes in selected recipients. However, comparisons with LDKT yielded less consistent results, with several registry-based analyses reporting equivalent or superior kidney graft and survival outcomes after living-donor transplantation. Quantitative synthesis of the two studies providing directly comparable adjusted hazard ratios demonstrated a higher risk of patient mortality (HR 1.30, 95% CI 1.10–1.54) and kidney graft failure (HR 1.43, 95% CI 1.24–1.66) following SPKT compared with LDKT. Formal meta-analysis of SPKT versus DDKT was not feasible because of substantial heterogeneity in outcome definitions, statistical reporting methods and follow-up duration across studies. Conclusions: In adults with T1DM and ESRD, successful SPKT provides a durable metabolic advantage and may improve long-term outcomes compared with deceased-donor KTA in selected patients. Across analyses that included all transplanted recipients from the time of surgery (intent-to-treat), early perioperative risk is higher after SPKT but may be offset over time when pancreas graft function is maintained. Evidence does not support a universal survival superiority of SPKT over living-donor kidney transplantation. Our quantitative synthesis of intent-to-treat, transplant-date analyses indicates that LDKT is associated with lower risks of patient mortality and kidney graft failure compared with SPKT when a suitable living donor is available. Treatment decisions should be individualized, considering living-donor availability, anticipated waiting time and dialysis exposure, cardiovascular and surgical risk, and the likelihood of durable pancreas graft function, with greater weight given to contemporary cohorts. Full article

Background/Objectives: First-line therapy for advanced gastric cancer (AGC) has evolved from cytotoxic chemotherapy to HER2-targeted and immune checkpoint inhibitor (ICI)-based regimens, yet conversion surgery (CS) outcomes across these strategies remain poorly characterized. We describe CS outcomes and prognostic factors by first-line strategy at a single center. Methods: We retrospectively reviewed 187 patients with AGC who began first-line therapy from 2011, grouped as cytotoxic (CTX, n = 127), HER2-targeted (trastuzumab, n = 21), or ICI (n = 39). CS was defined as resection after response, including an extended oligometastatic definition (n = 74). Overall survival (OS) was measured from chemotherapy initiation, and prognostic factors were assessed by Cox regression. Results: Median OS was 14.8, 18.9, and 20.9 months for CTX, trastuzumab, and ICI, respectively (p = 0.048). CS rates were comparable (41%, 33%, and 38%; p = 0.794). Pathological response was more pronounced after trastuzumab/ICI (grade 3 and ypStage 0/1; both p < 0.001). Among CS cases, R0 resection (hazard ratio [HR] 0.31) and trastuzumab/ICI therapy (HR 0.37) were independent favorable factors, whereas high inflammatory–nutritional indices (NLR, CAR) were independent poor prognostic factors. OS was comparable between oligometastatic and conventional CS (p = 0.324). Conclusions: In this hypothesis-generating study, response depth tracked tumor biology, whereas survival was determined by R0 resection, targeted/ICI therapy, and host inflammatory–nutritional status—two largely dissociable axes informing biology- and host-based selection of CS candidates for prospective testing. Full article

Background/Objectives: To identify independent predictors of major amputation using adjusted effect estimates. Methods: PubMed, Scopus, Web of Science, and Cochrane Library were searched from inception to 1 March 2024, alongside grey literature. Studies reporting adjusted predictors of major amputation (at or proximal to the wrist or ankle) were eligible. Adjusted odds ratios (aORs) reported by ≥2 studies were pooled using random-effects models. Results: Forty-two studies were pooled. Markers of clinical severity showed the strongest associations: critical limb ischemia (aOR = 4.60, 95% CI 4.20–5.00), leukocytosis (aOR = 3.42, 1.72–5.13), end-stage renal disease (aOR = 3.19, 2.94–3.44), and Rutherford class ≥ IIb (aOR = 3.16, 1.87–4.45). Moderate associations included chronic kidney disease (aOR = 2.22, 1.68–2.76), current smoking (aOR = 2.21, 2.13–2.28), and several comorbidities (prior bypass surgery, chronic obstructive pulmonary disease, peripheral vascular disease; aORs 1.82–1.92). Sociodemographic factors and diabetes mellitus showed smaller but consistent effects (aORs 1.19–1.64). Lower serum albumin (aOR = 0.58, 0.45–0.70) and statin use (aOR = 0.71, 0.66–0.75) reduced odds. Hemoglobin, modelled per unit increase rather than dichotomised, was unexpectedly associated with increased odds (aOR = 1.59, 1.55–1.63), most plausibly reflecting residual confounding. Heterogeneity was substantial for most predictors (I² frequently > 80%). Conclusions: To our knowledge, this is the first meta-analysis of major amputation restricted to adjusted estimates across diverse populations and both amputation levels. Ischemic burden and systemic disease severity dominate the risk profile, whereas diabetic foot ulcer, wound depth, wound infection, coronary artery disease, and neuropathy did not retain independent significance after adjustment. Given the observational evidence base and substantial heterogeneity, these findings should inform risk stratification rather than causal inference. Full article

Background: Germline PALB2 variants are associated with hereditary breast cancer risk, but their clinical impact in Central Asian populations remains largely uncharacterized. This case study aims to evaluate the clinical significance of PALB2 variants in two Kazakh women with early-onset breast cancer. Methods: Molecular genetic testing identified germline PALB2 pathogenic variants (NM_024675.4:c.18_22delGAAGC and NM_024675.4:c.1034T>G) in two Kazakh women with early-onset invasive ductal carcinoma. Clinical courses, treatment responses, and outcomes were followed. Results: Neither patient had a reported family history of breast or other malignancies. Patient 1, a 26-year-old pregnant woman, was diagnosed with stage IIIB luminal B, HER2-negative invasive ductal carcinoma and received neoadjuvant chemotherapy, radical surgery, radiotherapy, endocrine therapy, and subsequent treatment for metastatic disease. Despite an initial response, she developed extensive skeletal metastases and died from metastatic breast cancer. Patient 2, a 33-year-old woman, presented with de novo stage IV luminal B, HER2-negative invasive ductal carcinoma with hepatic metastases. Following multimodal treatment, including chemotherapy, surgery, radiotherapy, endocrine suppression, and systemic therapy for disease progression, she experienced further metastatic spread and ultimately died from breast cancer-related complications. Conclusions: Both patients exhibited aggressive clinical courses characterized by early disease onset, metastatic progression, and poor outcomes despite comprehensive treatment. These cases highlight the potential clinical significance of germline PALB2 variants in apparently sporadic breast cancer and underscore the importance of genetic testing, risk assessment, and genetic counselling in young breast cancer patients, particularly in underrepresented. Full article