Search Results (198)

Background: Locally advanced rectal cancer (LARC) has high recurrence rates despite aggressive multimodal treatment with neoadjuvant chemoradiotherapy (CRT) followed by surgery. Electrochemotherapy (ECT), combining electroporation with chemotherapy, has shown safety and feasibility in other malignancies, but its role as an additive neoadjuvant treatment in rectal cancer remains unexplored. Methods: In this parallel-group, randomised safety and feasibility trial, patients with histologically verified LARC who completed neoadjuvant CRT were randomised 1:1 to a single ECT treatment with bleomycin before surgery (n = 8) or standard therapy (n = 8). The primary outcome was safety (amended from the protocol-specified efficacy endpoint after early study termination). Follow-up was scheduled before surgery and at 6 and 12 weeks post-surgery, including adverse events, clinical examination, and patient-reported quality of life, bowel, urinary, and sexual function. Results: ECT was successfully delivered in all treated patients. Median procedure time was 23.5 min. Adverse events occurred in all ECT patients, predominantly rectal pain (86%), with one patient hospitalised for pain management. No procedure-related complications were observed. Two ECT patients had R1 resections due to intraoperative perforations. Tumour response was heterogeneous: two patients achieved complete response (TRG1), three achieved partial response (TRG2–3), and one achieved no response; corresponding numbers in the control group were 2, 4, and 2. One ECT patient achieved clinical complete response and entered a watch-and-wait programme. Patient-reported pain worsened transiently after ECT but returned to baseline by 12 weeks post-surgery. Conclusions: ECT is a technically feasible adjunct to neoadjuvant CRT for LARC. However, its efficacy and safety, particularly regarding surgical complications, remain unclear. Larger trials are needed to determine the role of ECT in multimodal neoadjuvant treatment. Full article

Background: Persistent human papillomavirus (HPV) can cause low- or high-grade cervical lesions, which may progress to cervical cancer. This prospective, multicenter, real-world study assessed the effectiveness, tolerability and safety of a Coriolus versicolor-based vaginal gel for the regression of HPV-related low-grade cervical lesions in routine Greek practice. Methods: PAPILOBS-GR is a multicenter, open-label, non-interventional, prospective observational, non-comparative study conducted across 45 sites in Greece. Women aged ≥18 years with ASCUS/LSIL cytology and concordant colposcopy were enrolled. Participants received Coriolus versicolor-based vaginal gel for six months. A second 6-month cycle was offered if needed. The primary endpoint was lesion regression. Secondary endpoints included HPV clearance, patient satisfaction, biopsy evolution, tolerability, and safety. Results: Of 524 enrolled patients (mean age: 34.4 ± 10.0 years; 40.5% HR-HPV), 494 (94.3%) completed the study. Overall, 75.9% achieved lesion regression (72.1% at 6 months and 34.0% at 12 months). HPV clearance occurred in 72.0% overall (68.1% at 6 months and 50.0% at 12 months). Exploratory comparisons showed generally consistent effectiveness across subgroups, including women with HR-HPV, those aged >40 years, and vaccinated participants. No significant differences in clinical endpoints were observed in association with age or vaccination status. Among 22 patients with baseline and 12-month biopsies, 59.1% showed histological improvement. Satisfaction scores exceeded 8/10 at 6- and 12-month follow-ups. Only two non-serious possibly product-related adverse events were reported. Conclusions: Coriolus versicolor-based vaginal gel was associated with high rates of lesion regression and excellent tolerability, reinforcing previous clinical findings and supporting its potential role as an adjunctive approach during watchful waiting for HPV-positive low-grade cervical lesions. Full article

Perioperative treatment for colorectal cancer (CRC) is undergoing a paradigm shift from uniform cytotoxic regimens toward strategies guided by tumor location, microsatellite instability (MSI)/mismatch repair (MMR) status, and recurrence risk. Four clinically relevant subgroups now shape decision-making: microsatellite stable (MSS)/proficient MMR (pMMR) colon cancer, microsatellite instability-high (MSI-H)/deficient MMR (dMMR) colon cancer, MSS/pMMR rectal cancer, and MSI-H/dMMR rectal cancer. In MSS/pMMR colon cancer, adjuvant therapy is being refined through risk-adapted treatment duration and selective use of neoadjuvant chemotherapy. In MSS/pMMR rectal cancer, total neoadjuvant therapy, selective omission of pelvic radiotherapy, and watch-and-wait strategies are redefining treatment sequencing and organ preservation. In MSI-H/dMMR colon cancer, immune checkpoint inhibitor (ICI) therapy has shown marked activity in both adjuvant and neoadjuvant settings. In MSI-H/dMMR rectal cancer, neoadjuvant ICI therapy is being explored as a non-operative organ preservation strategy. In parallel, circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) assessment is emerging as a tool for postoperative escalation, de-escalation, and surveillance. Across these settings, the maturity of the evidence varies widely, ranging from established phase III standards to guideline-endorsed but still single-arm approaches and investigational strategies that require prospective validation before routine adoption. This review summarizes the current evidence and remaining challenges in biology-, site-, and risk-adapted perioperative management of CRC. Full article

Background and Clinical Significance: Skin-limited Langerhans cell histiocytosis (LCH) is a clinically heterogeneous disease, ranging from self-healing forms to fulminant multi-organ failure, the latter being more often described in infants, especially preterm neonates. The optimal therapy for cutaneous LCH remains controversial; the possibilities vary from a watchful waiting approach to systemic chemotherapy. Case Presentation: This case report describes an exceptionally rare and clinically challenging course of skin-limited LCH in a prematurely born infant treated at the Department of Oncology and Hematology, Children’s Hospital Zagreb, Croatia. At presentation, the patient exhibited several features suggestive of aggressive disease biology. However, therapeutic decision-making was complicated by extreme prematurity and young age, both of which significantly increased vulnerability to treatment-related toxicity. Following failure of topical therapy, systemic treatment was initiated according to the LCH-IV trial, primarily due to concerns regarding potential evolution into multisystem LCH. During treatment, the patient developed multiple life-threatening complications, namely severe infections (Staphylococcus aureus endocarditis, Pneumocystis jirovecii pneumonia, and Enterobacter cloacae sepsis), aggravated by secondary hypogammaglobulinemia, neutropenia, and iatrogenic adrenal insufficiency. Conclusions: The varied nature of cutaneous LCH underscores the necessity for a tailored treatment approach. When deciding on the treatment modality, clinicians should weigh the benefits of aggressive therapies, ensuring better disease control, against the potential for severe adverse effects, particularly in young, fragile infants with immature immunity. Full article

Therapeutic inertia has been extensively examined in chronic medical conditions but remains insufficiently conceptualized and empirically studied in psychiatry. This structured narrative review examines therapeutic inertia as a multilevel and potentially bidirectional phenomenon arising when clinically relevant care is not reconsidered or modified despite unmet therapeutic goals and the availability of a reasonable and feasible alternative. A targeted PubMed search was supplemented by backward and forward citation searching, prioritizing psychiatric evidence and foundational literature on clinical decision-making under uncertainty. The review distinguishes therapeutic inertia from appropriate caution, watchful waiting, informed refusal, structural non-access, therapeutic nihilism, medical futility, therapeutic obstinacy, and evidence-based deprescribing. Potential determinants include cognitive and emotional mechanisms, diagnostic and prognostic uncertainty, adverse-effect concerns, patient preferences and previous experiences, therapeutic relationships, resource constraints, fragmented care, guideline structures, workload, and medicolegal culture. Clozapine underutilization in treatment-resistant schizophrenia represents the most compelling psychiatric example, while direct but more limited evidence is available in major depressive and bipolar disorders; applications to anxiety, obsessive-compulsive, substance-use, and non-pharmacological care remain largely hypothesis-generating. Strategies include explicit therapeutic goals, planned reassessment, measurement-based and guideline-informed care, shared decision-making, multidisciplinary review, improved access, clinical decision support, and audit and feedback. Future research should use operational definitions, experimental and observational designs, patient-centered outcomes, and real-world data to determine when treatment non-modification is inappropriate and whether corrective interventions improve care without promoting indiscriminate escalation, coercion, polypharmacy, or premature discontinuation. Full article

Background: The RAPIDO trial demonstrated that short-course radiotherapy (5 × 5 Gy) followed by chemotherapy and surgery decreased disease-related treatment failure compared to long-course chemoradiotherapy. However, at 5-year follow-up, an increase in locoregional recurrence was observed. A strategy to improve local control is to increase radiotherapy dose. We present a retrospective analysis of a patient cohort treated with intensified MRI-guided radiotherapy. Methods: Between November 2021 and January 2024, 28 patients with cT3-4 N0-2 rectal cancer were included. Treatment consisted of adaptive MRI-guided external beam radiotherapy 5 × 5 Gy on the mesorectum with a simultaneous integrated boost (SIB) of 5 × 6 Gy on the gross tumor volume (GTV) followed by chemotherapy consisting of 18 weeks of CAPOX or FOLFOX. In case of a complete clinical response (cCR) following neoadjuvant treatment, a watchful-waiting approach was considered. The primary outcome was local and distant recurrence. Results: 27 patients were included in the analysis, with a median follow-up of 39 months. One patient was excluded due to loss to follow-up. Six patients had a pathological complete response (pCR) on surgery, and seven in the watch-and-wait protocol had persistent cCR. Locoregional failure was observed in one patient and four patients developed distant metastasis, leading to death in one patient. Conclusions: Total neoadjuvant treatment (TNT) in locally advanced rectal cancer using an MRI-guided integrated boost on the GTV is tolerable and resulted in a high rate of pCR (22%) and persistent cCR (26%), with limited locoregional failure (4%) and distant relapse (15%). Full article

Background: Locally advanced rectal cancer (LARC) management has evolved, but surgery (total mesorectal excision, TME) remains the curative cornerstone. Total neoadjuvant therapy (TNT) and organ preservation (OP) have emerged as response-adaptive strategies. We conducted a state-of-the-art systematic review to critically appraise TNT efficacy, trade-offs, OP feasibility, and emerging biomarkers. Methods: Following PRISMA 2020 guidelines, we searched PubMed, MEDLINE, Scopus, and EMBASE (1990–March 2026) plus ASCO/ESMO abstracts (2020–2026). We included phase II/III randomised controlled trials and major prospective studies evaluating neoadjuvant strategies in non-metastatic LARC. Risk of bias was assessed using RoB 2. Given heterogeneity, a narrative synthesis was performed (PROSPERO: CRD420251252675). Results: From 2847 records, 45 publications (30 trials) were included. For high-risk LARC (cT4, cN2, EMVI+, MRF+, tumour deposits), TNT improves disease-free survival and reduces distant metastases versus standard chemoradiotherapy (RAPIDO, PRODIGE 23, STELLAR, TNTCRT). However, TNT increases locoregional recurrence risk with short-course radiotherapy (RAPIDO: 10% vs. 6%; Polish II: no sustained overall survival benefit). Organ preservation is achievable in expert centres (OPRA: 54% 5-year TME-free survival; OPERA; CAO/ARO/AIO-16), but surgery remains the durable standard for most patients. De-escalation (PROSPECT, CONVERT, FOWARC, OCUM) avoids radiotherapy in low-risk (mrMRF−) patients without compromising local control. Lateral pelvic lymph node involvement (LPLN+) remains a negative prognostic factor even after TNT. Immunotherapy added to TNT (UNION, STELLAR II, SPRING-01, PRECAM) increases pCR rates (40–60%) but remains investigational. ctDNA-guided adaptation (CINTS-R) is feasible but requires mature data. Conclusions: Surgery (TME) is the definitive curative treatment for LARC. TNT is a preferred intensification strategy for high-risk patients, but trade-offs between systemic and local control must be individualised. Organ preservation is safe only for selected patients in expert centres. Immunotherapy-TNT combinations and ctDNA guidance are promising but not yet standard. This review provides an evidence-based roadmap for integrating these advances without losing sight of surgery’s central role. Full article

Background: Although less frequently encountered, aortic valve stenosis is associated with complications separate from its hemodynamic burdens, such as infective endocarditis. Case Summary: We report the case of a 77-year-old female patient with regular cardiac follow-up in the setting of an asymptomatic severe aortic stenosis, who presented to the emergency department with signs and symptoms of sepsis and acute decompensated heart failure. Echocardiography revealed two vegetations attached to the tricuspid valve, an abscess of the anterior aortic ring, and a high-velocity ventricular septal defect. The patient was started on adequate antibiotic therapy. Surgical treatment in an urgent manner (within a few days) was decided by the Heart Team, in accordance with the ESC guidelines on the management of infective endocarditis. Whilst awaiting surgery, the patient presented with a sudden hemodynamic deterioration a few days after diagnosis, with cardiopulmonary arrest and subsequent death. Discussion: We hypothesize that the patient developed an infective endocarditis of the degenerated stenotic aortic valve with extension from left to right via a ventricular septal defect, the development of which was facilitated by the high trans-aortic valve gradient. Some reported cases describe a ventricular septal defect as a complication of native aortic valve endocarditis, though not all involve concomitant aortic stenosis. In conclusion, our case illustrates a very rare scenario of infective endocarditis complicating aortic stenosis with fulminant development. This case highlights a rare, albeit severe complication associated with aortic stenosis and therapeutic challenges in managing the dismal evolution of endocarditis in this setting. Full article

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive myeloproliferative neoplasm of early childhood characterized by constitutive activation of the RAS-MAPK signaling pathway. RASopathies are a heterogeneous group of complex genetic disorders arising from germline mutations that dysregulate RAS-MAPK signaling. Noonan syndrome, CBL syndrome, and neurofibromatosis type 1 (NF1) are the three major RASopathies predisposing to JMML. More than 90% of JMML cases harbor germline or somatic mutations in one of five canonical driver genes—PTPN11, NRAS, KRAS, NF1, or CBL—establishing JMML as the prototypical malignant manifestation of RASopathy biology. The fifth edition of the World Health Organization Classification of Tumours reclassified JMML as a myeloproliferative neoplasm while the International Consensus Classification adopted JMML under pediatric and/or germline mutation-associated disorders, introducing a JMML-like category for cases lacking five canonical mutations but harboring emerging drivers such as SH2B3::LNK alterations and ALK::ROS1 fusions. The distinction between germline and somatic mutations profoundly influences prognosis: e.g., germline PTPN11-associated myeloproliferations and many germline CBL cases undergo spontaneous resolution, whereas somatic PTPN11- and NF1-mutated JMML is more aggressive and requires prompt allogeneic hematopoietic stem cell transplantation. DNA methylation profiling has emerged as the most robust prognostic framework, with consensus defining high-, intermediate-, and low-methylation subgroups that independently predict outcome. Both genotype and DNA methylation subclassification have been integrated into clinical decision-making, incorporating pretransplant azacitidine, watch-and-wait approaches for favorable-risk patients, and emerging targeted therapies including MEK inhibitors. This review synthesizes recent advances in understanding JMML as a bona fide RASopathy; provides a diagnostic algorithm, molecular landscapes, and prognostic models; and highlights opportunities for molecularly targeted therapeutic intervention. Full article

Background/Objectives: WHO grade II meningiomas show highly variable growth rates that are difficult to predict using conventional histology. We investigated relationships between immune components within the tumor immune microenvironment (TIME) and explored their association with tumor growth kinetics. Methods: We retrospectively evaluated a small, preselected cohort of 15 patients with WHO grade II meningiomas who underwent initial “watch-and-wait” observation with serial preoperative MRI. Notably, this cohort represents a specific clinical subset—tumors deemed initially observable—and may not be representative of all WHO grade II meningiomas. Densities of Iba1-positive macrophages (TAMs) and B7-H3-positive tumor cells were quantified by digital pathology. The relative growth rate (RGR) was calculated from serial MRI. Results: A strong inverse correlation was observed between TAM density and B7-H3-positive tumor cell density (Spearman’s R = −0.921, p < 0.001). Individual immune components did not show significant linear correlations with RGR; on median-split stratification, high B7-H3-positive tumor cell density was associated with a nominally significant difference in RGR (p = 0.0428, unadjusted). Low TAM density showed a non-significant trend in the same direction. Conclusions: Our findings generate the hypothesis that WHO grade II meningiomas exhibit an inverse relationship between TAMs and B7-H3 and that macrophage-poor/B7-H3-high and macrophage-rich/B7-H3-low patterns may differ in preoperative growth behavior. These observations are derived from a small, preselected cohort of tumors managed with an initial “watch-and-wait” strategy and require validation in broader populations. Full article

Background and purpose: Organ-preservation strategies are increasingly being incorporated into rectal cancer management, but the role of HDR endorectal/endoluminal brachytherapy boost remains less well defined than that of broader non-operative treatment pathways. Existing literature is frequently mixed with contact X-ray brachytherapy series, neoadjuvant protocols with planned surgery, or heterogeneous watch-and-wait cohorts, limiting the interpretation of this specific strategy. Materials and methods: We performed a PROSPERO-registered systematic review and meta-analysis of studies evaluating definitive-intent external beam radiotherapy (EBRT), with or without chemotherapy, followed by HDR endorectal/endoluminal brachytherapy boost in histologically confirmed rectal adenocarcinoma managed without planned surgery. Pooled analyses were performed for clinical complete response (cCR) and late grade ≥3 gastrointestinal (GI) toxicity. Regrowth/local failure outcomes were synthesized descriptively because of heterogeneity in endpoint definitions, denominator selection, and follow-up structure. Results: Six studies were included in the quantitative evidence base, with one additional small feasibility report summarized narratively. The pooled cCR proportion was 69.2% (95% confidence interval [CI], 43.7–86.6). The pooled proportion of late grade ≥3 GI toxicity was 18.1% (95% CI, 10.9–28.6). Reported regrowth/local failure outcomes were not suitable for formal pooling because of inconsistent definitions, differing denominator structures, and non-uniform follow-up frameworks across studies. Conclusion: Current evidence suggests that EBRT plus HDR endorectal/endoluminal brachytherapy boost may represent a selective organ-preservation strategy for carefully chosen patients with rectal adenocarcinoma, particularly where surgery is not feasible or not desired. Its broader clinical use remains limited not only by the small size of the evidence base, but also by fragmented endpoint definitions, inconsistent denominator reporting, and insufficiently standardized durable local-control outcomes. These findings support cautious interpretation of the current evidence and highlight priorities for future prospective studies in rectal cancer management. Full article

Background/Objectives: The NETest is a blood-based, machine learning-enhanced multigene transcript assay designed to detect and monitor neuroendocrine tumors (NETs). This study evaluated the accuracy of the recently validated NETest2.0^® (2025) to (1) detect the presence of disease and (2) assess its utility as a clinically meaningful tool for monitoring NET status across diverse patient cohorts, including post-surgical surveillance, observation (“watch-and-wait”), and treatment settings. Methods: This registry study (NCT02270567) evaluated two objectives. For Objective 1, 1290 samples from 886 patients, of which 404 had paired follow-up samples, were analyzed for concordance between NETest2.0^® and imaging-detectable disease. For Objective 2, paired blood samples (n = 404; median interval 7 months [IQR 4–13.8]) from NET patients across specialized centers were assessed. NETest2.0^® scores were correlated with clinically adjudicated disease status using imaging as the comparator. Cohorts included post-surgical residual disease detection (n = 71), post-surgical recurrence monitoring (n = 44), observation (n = 72), and treatment monitoring (n = 217; somatostatin analogs, PRRT, and other therapies). Analyses were performed by cohort and in aggregate. Results: For Objective 1, NETest2.0^® (cut-off ≥ 50) demonstrated an AUC of 0.96, sensitivity of 91.9%, specificity of 94.9%, PPV of 98.4%, NPV of 77.1%, and overall accuracy of 92.5%. Performance was consistent across tumor grades and sites. For Objective 2, 286 patients (70.8%) were stable, and 118 (29.2%) had progression or recurrence. NETest2.0^® score changes correlated significantly with outcomes: scores decreased in stable patients (median −14.6%) and increased in progressive disease (median + 15.4%; p < 0.0001). Any increase (>0%) in score was associated with progression. Diagnostic performance for detecting progression reached a sensitivity of 78.0%, specificity of 98.3%, PPV of 91.1%, NPV of 90.2%, and accuracy of 83.9%. Conclusions: NETest2.0^® accurately detects disease and provides a clinically actionable tool for monitoring NETs. Its high specificity and predictive performance support risk-adapted surveillance, potentially reducing unnecessary imaging while identifying early progression across diverse clinical settings. Full article

Asymptomatic severe aortic stenosis (AS) is characterized by a prolonged latent phase during which progressive valvular obstruction and myocardial remodeling may occur despite preserved left ventricular ejection fraction and the absence of overt clinical symptoms. Historically, management has favored watchful waiting until symptom onset or guideline-defined triggers emerge; however, recent randomized data challenge this conservative paradigm. This review summarizes the natural history, risk stratification, and contemporary management of asymptomatic severe AS, with a focus on emerging insights that inform the timing of intervention. We propose an individualized, contemporary framework for managing asymptomatic severe AS that integrates multimodal risk assessment, procedural risk, and shared decision-making, and we outline future directions aimed at refining patient selection and optimizing the personalized timing of intervention. Full article

Background/Objectives: In our previous systematic review, we found no convincing evidence to support rapid maxillary expansion (RME) as a treatment for pediatric obstructive sleep apnea (OSA). Subsequent clinical guidelines and expert opinion have continued to recommend this orthodontic treatment. We aimed to update our search to determine whether new controlled prospective evidence alters this conclusion. Methods: We updated our previous systematic review, searching for controlled prospective studies on RME efficacy for pediatric OSA published up to 1st February 2026. Results: Three new randomized clinical trials (RCTs) were identified in addition to the five original studies. Critically, none of the new RCTs included a watchful waiting or supportive care control arm, leaving the sole available comparison against watchful waiting unchanged: a single RCT that found no significant difference in AHI change between RME and observation. Of the remaining new RCTs, two found marginal AHI improvement with RME and one found no significant AHI reduction. Conclusions: The observed AHI improvements in studies lacking an untreated comparator cannot be distinguished from the known potential for spontaneous improvement in growing children. Extreme caution is warranted before recommending RME as a treatment for pediatric OSA. Full article

Background/Objectives: Total neoadjuvant therapy (TNT), integrating systemic chemotherapy and radiotherapy before surgery or surveillance, has become a standard approach for locally advanced rectal cancer (LARC). However, optimal sequencing strategies and long-term outcomes of watch-and-wait (W&W) following sandwich TNT remain insufficiently characterized. We evaluated oncologic outcomes and treatment response in patients treated with an institutional sandwich TNT protocol. Methods: We conducted a retrospective cohort study of consecutive patients with LARC treated with sandwich TNT (induction chemotherapy followed by hypofractionated intensity-modulated radiotherapy with simultaneous integrated boost [IMRT-SIB] chemoradiotherapy and consolidation chemotherapy) at the Institute of Oncology Ljubljana between 2016 and 2023. The primary endpoint was an overall complete response (CR; pathological [pCR] and clinical [cCR]). Secondary endpoints included tumor regression grade (TRG), major pathological response (MPR), R0 resection rate, organ preservation, overall survival (OS), and disease-free survival (DFS). Results: Among 205 patients (median age 61 years), overall CR was 29.5% (pCR 19.3% and cCR 10.2%). Major pathological response (TRG 3–4) occurred in 37.6%. R0 resection was achieved in 94.5%. In the W&W cohort (n = 21), local regrowth occurred in 33.3% (95% CI, 14.6–57.0%) over a median follow-up of 4.96 years. Total mesorectal excision (TME)-free survival at 5 years was 73.1% (95% CI, 55.0–97.2%). Estimated 5-year OS was 81.1% (95% CI, 75.5–87.2%) and 5-year DFS was 75.2% (95% CI, 69.0–82.0). In multivariable analysis, non-R0 resection (HR 6.06, 95% CI, 1.99–18.42), MRI circumferential resection margin positivity (HR 3.11, 95% CI, 1.53–6.33), and MRI extramural vascular invasion positivity (HR 1.97, 95% CI, 1.05–3.91) remained independent predictors of DFS. Conclusions: Institutional sandwich TNT yields meaningful tumor response and durable survival in MRI-defined high-risk LARC. Structured W&W offers organ preservation with acceptable oncologic control under intensive surveillance. Full article