Psychospiritual distress (PSD) causes profound suffering in people with serious illness, yet treatment options are few and evidence of their efficacy is modest. Although high-level evidence is limited, decades of preliminary research suggest that psychedelic-assisted psychotherapy (PAP), including ketamine-assisted psychotherapy (KAP), may alleviate the anxiety, depression, and existential distress associated with PSD. However, clinical examples and published implementation frameworks for integrating these interventions into palliative care are scarce. To help bridge this gap, we describe the development and delivery of a palliative care-embedded KAP program at an academic medical center. To describe the design, implementation, and clinical experience of Pal-KAP, a safety-centered and equitably accessible KAP program embedded in outpatient palliative care. We detail the program's origins, team composition and training, operational model, patient selection and consent process, session structure, safety protocols, and financial model. We summarize patient characteristics and treatment patterns and share illustrative clinical vignettes from the program's first 28 months. Between May 2023 and September 2025, 59 patients were referred for Pal-KAP screening; 43 met the eligibility criteria, and 30 elected to participate. Patients (age 19-76, mean 53) completed a median of 1.5 medicine sessions (range 1-5). Most had cancer (80%) or neurological disease (13.3%). Ketamine dose averaged 0.93 mg/kg intramuscularly, with minor adverse effects (anxiety, headache, nausea, insomnia, dizziness) and no serious adverse events. To our knowledge, this is the largest published cohort of KAP in an academic palliative care context. Our Pal-KAP experience suggests that KAP can be delivered safely and ethically, providing a practical blueprint for programs exploring innovative ways to address PSD.

Neoadjuvant immune checkpoint blockade (ICB) and radiation therapy (RT) improve disease-free survival in select patients with soft tissue sarcoma (STS). However, most STS are myeloid-rich and lack pre-existing T cells associated with ICB response. In preclinical models, we observed that intratumoral BO-112 (nanoplexed polyinosinic: polycytidylic acid (poly I:C)) engages myeloid cells that persist after RT, ultimately enhancing T cell-dependent tumor control. We evaluated BO-112 and hypofractionated RT, with or without nivolumab, in fourteen patients with high-risk STS in a phase 1 neoadjuvant trial. Consistent with its immunologic potency, the triple combination induced rare immune-related adverse events (myositis-myocarditis-myasthenia gravis spectrum), mitigated by BO-112 and nivolumab dose adjustment. BO-112 and RT reprogrammed tumor-associated myeloid cells toward antigen-presenting states, promoted clonal replacement by less exhausted T cells, and enhanced malignant cell depletion compared to standard RT. These immunologic changes coincided with encouraging disease control in a small, high-risk cohort, supporting further clinical development.

Inflammatory bowel disease (IBD) management has evolved with the advent of Janus kinase inhibitors (JAKi), oral small molecules that modulate cytokine-driven inflammation via the Janus kinase-signal transducer and activator of transcription pathway. This narrative review synthesizes current evidence for JAKi in ulcerative colitis (UC) and Crohn’s disease (CD), detailing their efficacy, safety, positioning, and special contexts. Tofacitinib has demonstrated robust induction and maintenance efficacy in moderate-to-severe UC, including steroid-refractory and acute severe cases, while failing to meet endpoints in CD. Upadacitinib shows high rates of clinical, endoscopic, and durable remission in both UC and CD across pivotal trials, and emerging real-world data support its superiority in certain refractory settings. Filgotinib is effective in UC, with more limited but promising data in CD. Safety concerns span infectious complications (notably herpes zoster), cytopenias, dyslipidemia, thromboembolic risk, and potential impacts on pregnancy and lactation; long-term data remain largely extrapolated from rheumatologic cohorts. Combination regimens with other biologics have been explored but warrant caution due to additive immunosuppression. Data on pediatric IBD and extraintestinal manifestations are nascent. Limitations include sparse long-term safety data specific to IBD, unclear carcinogenesis implications, and reliance on indirect comparisons for positioning. Despite these gaps, JAKi - particularly tofacitinib and upadacitinib - offer effective alternatives in biologic-experienced and refractory IBD, with careful patient selection, screening, and monitoring essential to mitigate risks. Future prospective studies should clarify optimal sequencing, long-term safety, and gut-selective strategies.

This post hoc analysis of the phase 2b/3 SELECTION (NCT02914522) study and its long-term extension (SELECTIONLTE; NCT02914535) evaluated the impact of filgotinib 200 mg (FIL200) on health-related quality of life (HRQoL) and work productivity in Japanese patients with ulcerative colitis over 3 years. Patients in SELECTION were randomized to FIL200, filgotinib 100 mg, or placebo (PBO) during the induction phase. Week-10 responders were re-randomized to continue assigned treatment or PBO in the 47-week maintenance phase. Patients who completed the SELECTION induction and maintenance phases (completers) and week-10 non-responders could enter SELECTIONLTE. HRQoL and work productivity were assessed using EQ 5-dimension (EQ-5D), EQ visual analog scale, Inflammatory Bowel Disease Questionnaire (IBDQ), 36-item Short Form Health Survey (SF-36), and Work Productivity and Activity Impairment (WPAI) questionnaires at week 10 (FIL200 vs. PBO), and at week 10 and years 1-3 (completers and non-responders who received only FIL200 in SELECTION+SELECTIONLTE). Proportions of patients with minimal clinically important differences (MCIDs) at week 10 were higher with FIL200 versus PBO for IBDQ total score (77% vs. 54%), SF-36 mental component summary (58% vs. 21%), and SF-36 physical component summary (54% vs. 36%). All measures (except WPAI absenteeism) showed mean score changes from baseline at week 10 in the direction of improved HRQoL with FIL200 versus PBO. MCID rates were maintained in completers up to 3 years and increased notably in non-responders (except WPAI absenteeism and EQ-5D) from week 10 to years 1-3. FIL200 treatment was associated with sustained improvements in HRQoL and work productivity over 3 years in Japanese patients with ulcerative colitis, consistent with the overall SELECTION and SELECTIONLTE trial populations.

Background and Objectives: Porcelain aorta is an anatomy-driven high-risk phenotype characterized by extensive calcification of the ascending aorta, which complicates surgical aortic valve replacement by increasing embolic and technical hazards during cannulation and cross-clamping. As transcatheter aortic valve implantation (TAVI) expands into younger and low-surgical-risk populations, porcelain aorta creates a distinct clinical dilemma: optimizing short-term procedural safety while ensuring durable long-term outcomes and preserving future treatment options. Materials and Methods: We performed a targeted literature search of MEDLINE/PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL), with the last search conducted on 31 January 2026. We synthesized contemporary clinical evidence on TAVI in patients with imaging-defined porcelain aorta, focusing on neurological outcomes, procedural strategies to reduce embolic risk, access considerations, valve performance, cerebral embolic protection, and implications for lifetime valve management (including coronary access and feasibility of future valve-in-valve interventions). Results: The evidence base specific to porcelain aorta in the contemporary TAVI era is limited and largely observational. Across published cohorts, TAVI avoids direct ascending aortic cannulation and cross-clamping and is generally associated with favorable early safety, with a recurring directional signal toward lower neurological risk compared with surgical strategies that require manipulation of a severely calcified ascending aorta. Interpretation is constrained by heterogeneity in porcelain-aorta definitions, patient selection, valve platforms and access routes, as well as, variability in neurological endpoint definitions and adjudication. Conclusions: In patients with porcelain aorta, TAVI is frequently favored because it minimizes ascending aortic manipulation and may mitigate neurological and procedural hazards. In younger and low-risk patients, Heart Team decision-making should incorporate lifetime management principles, including access planning, preservation of future coronary access, and procedural strategies to reduce embolic risk (with consideration of cerebral embolic protection when appropriate).

Ramicotomy is a surgical approach that focuses on dividing the rami communicantes of the sympathetic chain and has been introduced as a treatment for palmar and axillary hyperhidrosis with the goal of reducing the incidence of compensatory sweating. Evidence from recent randomized controlled studies and meta-analyses suggests that this technique effectively reduces localized excessive sweating while resulting in lower rates of compensatory hyperhidrosis and less postoperative hand dryness compared with traditional sympathetic chain interruption. Despite these advantages, ramicotomy has been linked to a greater likelihood of symptom recurrence, underscoring the importance of thorough patient selection and detailed preoperative counseling about potential long-term outcomes. Overall quality of life improvements and patient satisfaction appear similar between ramicotomy and conventional sympathicotomy, although ramicotomy may provide benefits in decreasing the severity or extent of compensatory sweating. In cases of axillary hyperhidrosis, combining ramicotomy with endoscopic sympathetic blockade does not seem to significantly change patient satisfaction or overall rates of compensatory sweating compared with blockade alone, though it may influence the pattern or distribution of compensatory symptoms. In summary, ramicotomy is a reasonable surgical option for carefully selected patients who prioritize a lower risk of compensatory hyperhidrosis, accepting the trade-off of a potentially higher recurrence rate.

Total knee arthroplasty (TKA) is one of the most performed surgical procedures in the United States and is often associated with moderate to severe postoperative pain. Multimodal postoperative analgesia following TKA is essential for optimizing postoperative recovery and enabling early postoperative mobilization. Regional anesthesia using ultrasound-guided peripheral nerve blocks plays an important part in perioperative pain management by targeting the femoral, obturator, and sciatic nerves of the knee joint. A variety of peripheral nerve block techniques have been described, which can be classified as either motor-blocking or motor-sparing techniques. Traditional motor-blocking regional anesthesia techniques, such as femoral and sciatic nerve blocks, provide excellent analgesia but can result in significant quadriceps weakness that delays ambulation after TKA. Motor-sparing regional anesthesia techniques, including the adductor canal block, iPACK block, and genicular nerve block, are becoming more widely used in enhanced postoperative recovery protocols for outpatient and short-stay inpatient TKAs. The peripheral nerve block technique can be selected according to the type of surgical procedure, the planned length of stay, rehabilitation goals, and patient comorbidities. Multiple peripheral nerve blocks provide better analgesia than single-injection blocks, and continuous catheter techniques are used for prolonging analgesia in select patients. An individualized multimodal regional anesthesia approach should be utilized to maximize analgesia after TKA to optimize postoperative outcomes. We present a narrative review of peripheral nerve block techniques and strategies for their use following inpatient or outpatient TKA.

Polycythemia vera (PV) is a myeloproliferative neoplasm that is treated according to the patient's thrombosis risk, including cytoreductive therapies for those at high-risk for thrombosis. Ropeginterferon alfa-2b, a mono-pegylated interferon α-2b, is a new cytoreductive therapy for PV. This expert consensus study, conducted before ropeginterferon alfa-2b recommendations were added to the Japanese guidelines, used a four-phase Delphi method to survey 18 Japanese hematology experts and develop suggestions for ropeginterferon alfa-2b use in Japan. Several scenarios where ropeginterferon alfa-2b treatment is considered appropriate for patients with PV were identified, including: 1) low-risk patients requiring cytoreductive therapy (excluding low-risk patients requiring cytoreductive therapy due to splenomegaly); 2) patients intolerant or resistant to hydroxyurea treatment; 3) high-risk patients aged ≤ 70years, even if hematocrit < 45% is achieved and maintained under hydroxyurea treatment; and 4) patients who wish to conceive or who are pregnant and require cytoreductive therapy. This is the first expert consensus study using the Delphi method to examine cytoreductive therapy for Japanese patients with PV and contributes to the appropriate selection of patients for ropeginterferon alfa-2b in clinical practice.

Introduction Immune checkpoint inhibitors (ICIs) have turned out to be a potent treatment of advanced solid tumor, but the issue of therapy discontinuation under the influence of the resistance, or immune-related adverse events (irAEs) is still a significant challenge. ICI rechallenge, which is a reintroduction of immunotherapy after initial failure is a favorable alternative whose guidelines are not standardized. Methods This narrative review was a literature synthesis of the existing evidence drawn from PubMed, Web of Science, Embase, and Cochrane Library as up to July 21, 2025. We assesed real-world studies, retrospective cohorts, and meta-analyses, which examined patient selection criteria, rechallenge strategies, efficacy results, and safety profile across different types of solid tumors. Findings The predictors of successful rechallenge include persistent initial response (progression-free survival ≥6 months), prolonged treatment-free interval (≥6 months), excellent performance status (ECOG-PS ≤1), and complete irAE resolution (Grade ≤1). The outcome of an after toxicity rechallage is superior to after progression (median PFS: 5.1 vs. 2.9 months). There is a better response to a combination of anti-angiogenics, chemotherapy, or radiotherapy strategies. However, the recurrence rate of irAE is 20%-60% and severe initial toxicities can be a reason to discontinue the drug permanently. Discussion ICI rechallenge benefits the right patients significantly. We propose a clinical decision model that might assist in integrating both biological and clinical variables to base individualized rechallenge, but the standard set of criteria and possibilities to validate biomarkers remains in urgent need.

Background/Objectives: Molecular subtyping of pediatric B-cell acute lymphoblastic leukemia (B-ALL) has improved patient outcomes through stratification and selection of targeted therapies. Despite extensive genomic and transcriptomic profiling of this cancer, few studies to date have characterized the proteomic landscape, although proteins are the direct targets of many therapeutic agents. Methods: In this study, we demonstrate the utility of multi-omic integration of global transcriptomic, proteomic, and phosphoproteomic profiles of samples from patients diagnosed with either of two B-ALL subtypes—Ph-like (BCR::ABL1-like) and ETV6::RUNX1. Through individual and multi-omic analysis, we recapitulate known transcriptomic findings and identify novel subtype-specific proteomic and phosphoproteomic biomarkers. Conclusions: Our findings suggest a previously undescribed role for calcium-dependent signaling processes in Ph-like B-ALL, which has the potential to serve as a novel avenue for targeted treatments. By integrating multiple -omics modalities, we identify not only features of interest but also begin to unravel the regulatory interactions driving subtype-specific mechanisms of leukemogenesis. This integrated analytic approach paves the way for enhanced precision medicine for precise subtyping and treatment selection for pediatric leukemia patients.

Background Autoimmune pancreatitis (AIP) is a distinct type of chronic pancreatitis that responds well to glucocorticoid therapy. However, some patients experience frequent relapses or become glucocorticoid-dependent. In Western countries, immunosuppressive agents such as azathioprine are widely used to maintain remission. In contrast, evidence for the use of immunosuppressive agents for AIP is limited in Japan and other Asian countries. Therefore, this study aimed to evaluate the efficacy and safety of immunosuppressive agents in patients with refractory AIP. Methods We retrospectively analyzed 12 Japanese patients with type 1 AIP who experienced two or more documented relapses and received immunosuppressive therapy. Clinical remission, adverse events, and the incidence of malignancy were assessed. Results Among 199 patients with AIP treated between 2006 and 2024, 12 (6.0%) with multiple relapses were administered immunosuppressive agents, including azathioprine (n=9), tacrolimus (n=2), and methotrexate (n=1). Nine patients continued therapy for at least two months; of these, eight (88.9%) maintained clinical remission without relapse during treatment. One patient relapsed. However, three patients (25.0%) were unable to continue therapy due to adverse events. Two patients developed malignancies during the long-term follow-up: one with malignant lymphoma and the other with small cell lung cancer. Conclusion Immunosuppressive therapy may contribute to the maintenance of remission in some AIP patients with glucocorticoid-dependent or repeated relapses, even among Japanese patients. However, adverse events led to treatment discontinuation in 25% of patients, and two developed malignancies during follow-up. These findings underscore the need for careful patient selection, individualized risk-benefit evaluation, and ongoing monitoring.

Immune checkpoint inhibitors (ICIs) have revolutionized the management of multiple malignancies, offering durable clinical benefit in a subset of patients. However, the emergence of distinct response patterns has revealed two major challenges: primary resistance, observed in patients who fail to respond from the outset, and acquired resistance, which develops after an initial period of disease control. These two resistance phenotypes likely arise from divergent biological mechanisms, involving both tumour-intrinsic and tumour-extrinsic factors. A comprehensive understanding of these processes is essential to optimize therapeutic strategies, particularly through rational combinations of ICIs with novel immunomodulators, targeted therapies, or conventional treatments. In this review, we provide an integrative overview of the key molecular and cellular mechanisms underlying both primary and acquired resistance to ICIs, encompassing alterations in antigen presentation, interferon signalling, oncogenic and metabolic pathways, as well as immune exclusion within the tumour microenvironment. We also highlight emerging predictive biomarkers of response and resistance—ranging from genomic and transcriptomic signatures to soluble immune checkpoints and non-immune circulating markers—aimed at refining patient selection and guiding personalized immunotherapy. Ultimately, deciphering these mechanisms will be pivotal for designing the next generation of immune-based combinations to overcome therapeutic resistance and expand the population of patients who can benefit from immune checkpoint blockade.

Biliary tract cancers, encompassing intrahepatic, perihilar and distal cholangiocarcinoma and gallbladder cancer, are a heterogeneous group of highly aggressive malignancies. Most patients have unresectable disease at first presentation, and even those who undergo surgery are likely to have disease recurrence. Newer approaches have included liver transplantation for selected patients, and the integration of locoregional and systemic therapies has expanded the number of patients who can benefit from surgery. The advent of immune-checkpoint inhibitors and targeted therapies for patients with advanced-stage disease has prompted the exploration of these agents in earlier-stage disease settings. Despite this progress, treatment algorithms remain complex, necessitating a multidisciplinary and individualized approach to patient management. Future research should focus on optimizing patient selection through biomarker-driven strategies, including the integration of molecular profiles to guide the selection of systemic therapy, as well as refining the criteria for surgery and transplantation. These improvements will require global collaboration and novel clinical trial designs. In this Review, we describe evolving perioperative strategies for the management of patients with biliary tract cancers and highlight emerging directions in the field.

Since its introduction in 1974, the artificial urinary sphincter (AUS) has been considered the gold standard for treatment of moderate to severe male stress urinary incontinence. This article provides an overview of perioperative management and long-term outcomes, offering an evidence-based foundation for clinical practice. Current evidence on patient selection, preoperative diagnostics, surgical techniques, long-term outcomes, and management of complications was reviewed, based on recent studies, multicenter cohorts, and registry data. The implantation of an AUS generally results in high continence rates and substantial improvement in quality of life. Perioperative risk factors, including prior radiotherapy, diabetes mellitus, or previous urethral procedures, increase the likelihood of postoperative complications such as infections, urethral erosions, or mechanical failure. Specialized centers with extensive experience achieve better functional outcomes and lower revision rates. Despite potential complications, most patients report sustained satisfaction and an improved quality of life following AUS implantation. The AUS is an effective treatment option for moderate to severe stress urinary incontinence. Perioperative risk assessment, specialized implantation techniques, and treatment in experienced centers are crucial for therapeutic success. Prospective registry and multicenter data provide valuable guidance for evidence-based patient selection, complication management, and of long-term outcome optimization.

Implications of Sarcopenia in Patients with Structural Valve Pathology.

Management of Post-Myocardial Infarction Ventricular Septal Defects.

Claudins (CLDNs) are transmembrane proteins that contribute to the epithelial cell polarity and integrity of tight junctions in healthy tissues. CLDNs are frequently overexpressed across different solid tumours, and expression correlates with tumour subtype, grade and prognosis. Dysregulated CLDN expression modulates oncogenic signalling and contributes to tumour proliferation, epithelial-mesenchymal transition, stemness, fibrosis, immune modulation and therapeutic resistance. Owing to their frequent overexpression and functional role in cancer biology, CLDNs have emerged as attractive therapeutic targets. Their surface expression can be exploited to guide therapies into tumours. For example, a monoclonal antibody targeting the CLDN18.2 isoform has reached clinical approval, validating the potential of CLDN-directed approaches. Additional strategies such as antibody-drug conjugates, bispecific and trispecific antibodies and chimeric antigen receptor(CAR)T cells are in development for several CLDN family members. Targeting intracellular CLDN domains or their downstream signalling to disrupt their biological function may offer further promise. Here, we review the functional role of CLDN biology in solid tumours, summarize the clinical development of therapeutic approaches and discuss opportunities for biomarker-enriched patient selection. Collectively, we highlight CLDN targeting as a precision oncology approach relevant to multiple solid tumours.

Minimally invasive surgery has emerged as a promising approach to the management of advanced-stage epithelial ovarian cancer, particularly in the setting of interval debulking surgery following neoadjuvant chemotherapy. Although primary cytoreduction has traditionally been performed via laparotomy, growing evidence supports the use of neoadjuvant chemotherapy to reduce surgical morbidity without compromising survival, creating new opportunities for minimally invasive surgery. Retrospective and prospective studies consistently report perioperative advantages with minimally invasive surgery, including less blood loss, shorter hospital stay, faster recovery, and earlier resumption of chemotherapy, when applied in carefully selected patients. Importantly, these benefits have yet to be supported by definitive data on long-term oncologic outcomes, underscoring the need for high-quality randomized trials of minimally invasive surgery, which are ongoing. Patient selection remains central to the safe application of minimally invasive surgery. Candidates are typically characterized by favorable response to chemotherapy, limited residual disease, and absence of extensive upper abdominal involvement, with pre-operative assessment supported by imaging, measurement biomarkers such as CA-125, and diagnostic laparoscopy. Despite encouraging feasibility data, adherence to oncologic principles and readiness to convert to laparotomy remain essential safeguards. Parallel technologic advances are expanding the scope of minimally invasive surgery. For example, robotic platforms improve dexterity and ergonomics, whereas intra-operative fluorescence imaging, ultrasound, and augmented-reality navigation offer new ways to identify residual disease and guide cytoreduction. Computational tools, including predictive models, artificial intelligence, and radiomic/pathomic integration, are emerging to refine triage and surgical planning. These innovations, although largely investigational, illustrate the potential of multi-modal integration to enhance both the precision and safety of minimally invasive surgery. Looking forward, the future of minimally invasive surgery will depend on maturation of evidence from randomized trials, broader incorporation of patient-centered outcomes, and integration with precision oncology and adjunct therapies. Minimally invasive surgery holds significant promise to reduce the morbidity of and improve recovery from advanced epithelial ovarian cancer, but its widespread adoption must await confirmation of oncologic equivalence to the open approach.

Thoracic endovascular aortic repair (TEVAR) has become the preferred treatment for most descending thoracic aortic pathologies. In Zone 2 procedures, intentional coverage of the left subclavian artery (LSA) is frequently required to achieve an adequate proximal seal, but this carries a risk of stroke, spinal cord ischemia, and upper extremity ischemia. Preventive LSA revascularization is therefore recommended in current guidelines, although the level of supporting evidence remains limited. This narrative review summarizes the indications, timing strategies, techniques, and outcomes of surgical LSA debranching in combination with Zone 2 TEVAR. Both carotid-subclavian bypass (CSB) and subclavian-carotid transposition (SCT) restore antegrade flow to the LSA. Patency rates are excellent for both techniques, with CSB being favored in many tertiary centers due to lower rates of local nerve injury. Timing remains debated: staged approaches are increasingly adopted in elective cases, as simultaneous debranching and TEVAR have been associated with higher perioperative stroke rates. However, overall stroke risk appears more strongly related to the TEVAR procedure itself than to the revascularization technique. Surgical debranching offers long-term durability and versatility, especially in complex arch anatomy, and avoids endoleak-related complications. Endovascular alternatives, however, reduce local surgical morbidity and allow minimally invasive management under sedation, with comparable long-term survival. In conclusion, surgical LSA debranching remains a cornerstone adjunct to Zone 2 TEVAR, balancing durability and neurological protection against higher local complication rates. Further studies are required to refine patient selection, compare surgical and endovascular strategies, and strengthen the evidence base for current recommendations.

Endoscopic follow-up of gastric ulcers is a complex and often debated issue. Current British Society of Gastroenterology guidelines recommend a repeat oesophagogastroduodenoscopy (OGD) 6–8 weeks after the index procedure in all patients diagnosed with a gastric ulcer. An increased risk of gastric cancer in gastric ulcers which initially appeared macroscopically and histologically benign is proposed as the rationale for endoscopic surveillance. Endoscopy services both nationally in the UK and internationally are under increasing pressure, and it is therefore essential to ensure for both services and for patients that all endoscopic procedures which are performed are appropriate. The purpose of this review is to consider the literature concerning follow-up OGDs for gastric ulcers. At present, no comprehensive review of the substantial volume of literature on this important and clinically relevant subject has previously been performed. Through consideration of nineteen published studies and six published abstracts, the review demonstrates that rates of gastric cancer at follow-up endoscopy were very low and that cases may have been suspected at the index procedure even when histology was negative. It also suggests that adequate biopsy sampling and a careful assessment of the endoscopic appearances of the ulcer are key in making the safest choices for patients and may inform patient selection for follow-up procedures. While the evidence strongly supports a tailored approach to follow-up endoscopy, clinical judgement of individual endoscopists should always remain central to any decision which is made to ensure that patient safety is paramount at all times.