To evaluate outcomes of a multimodal prehabilitation service for cancer surgery patients delivered through three pathways (Specialised, Targeted, Universal) within routine NHS care at Nottingham University Hospitals NHS Trust.

This was a retrospective observational service evaluation of routine care data collected between 2022 and 2025. Of 1961 referred patients, 1720 were analysed: Specialised (n = 329), Targeted (n = 943), and Universal (n = 448). Multimodal prehabilitation included exercise, nutrition, and psychological support, stratified by risk. Functional capacity was assessed using the Incremental Shuttle Walk Test (ISWT), 60-s Sit-to-Stand (STS), and grip strength. Psychological well-being was measured using the Generalised Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-9 (PHQ-9). Physical activity behaviour was also recorded.

All pathways showed significant within-group improvements. ISWT increased by 57 m (p < 0.001, d = 0.6) and STS by 6 repetitions (p < 0.001, d = 0.9). Anxiety (Δ -1.9) and depression (Δ -2.0) scores decreased (both p < 0.001, d ≈ -0.5). Weekly physical activity rose by 142 min (d = 1.07), and strength sessions increased by 2.4 per week (d = 1.1). Between-group differences were limited: PHQ-9 improved more in Specialised versus Targeted, and strength sessions increased more in Universal versus Targeted.

A tiered, multimodal prehabilitation service integrated into cancer pathways produced meaningful functional, psychological, and behavioural benefits, supporting broader implementation and improved patient access.

Although older adults (≥ 75 years) constitute a large proportion of patients with unresectable pancreatic cancer (PC), they remain underrepresented in clinical trials. Biweekly gemcitabine plus nab-paclitaxel (GnP) has been evaluated in retrospective studies as an alternative dosing schedule, whereas prospective evidence remains limited.

This single-center, prospective Phase II trial aimed to evaluate the efficacy and safety of biweekly GnP as a first-line therapy in older adults with unresectable PC.

Eligible patients aged ≥ 75 years with histologically or cytologically confirmed unresectable pancreatic adenocarcinoma received GnP (1000 mg/m² gemcitabine; 125 mg/m² nab-paclitaxel) on days 1 and 15 of each 28-day cycle. The primary endpoint was the overall response rate (ORR). Key secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. A total of 17 patients were enrolled between August 2019 and March 2021 (median age, 77 years; 13 metastatic, 4 locally advanced). The ORR was 47.1% (8/17; 95% confidence interval [CI], 23.0%-72.2%), and the disease control rate was 82.4% (14/17). The median OS and PFS were 16.8 (95% CI, 5.9-24.6) and 8.3 (95% CI, 4.9-10.1) months, respectively. The 1- and 2-year survival rates were 58.8% and 29.4%, respectively. Grade ≥ 3 hematologic adverse events occurred in 17.6% of patients. Treatment-related adverse events led to treatment discontinuation in three patients: one case of interstitial pneumonia and two cases of peripheral sensory neuropathy. No treatment-related deaths occurred.

Biweekly GnP showed promising antitumor activity in a selected population of patients aged ≥ 75 years with unresectable PC. Because enrollment ended before the planned sample size was reached, the study findings should be interpreted cautiously.

jRCTs051190038.

Anastomotic leakage (AL) after esophagectomy increases morbidity and mortality. Although mediastinal anatomy has been implicated in AL, no prior study has evaluated this issue in transcervical-hiatal subtotal esophagectomy (closed mediastinum). We investigated whether the scaled upper mediastinal anteroposterior diameter (sAPD) and anastomotic height (AH) influence AL.

We retrospectively studied 224 patients who underwent transcervical-hiatal subtotal esophagectomy with mediastinoscopy-assisted mediastinal lymphadenectomy and posterior mediastinal reconstruction using a subtotal gastric conduit; the pleura was preserved (closed mediastinum). sAPD was measured on preoperative CT and AH on the first postoperative CT obtained 3-6 months postoperatively. Associations with AL were assessed by logistic regression, and receiver operating characteristic (ROC)-derived cutoffs defined four sAPD × AH risk groups. Two comparison cohorts (transthoracic, n = 91; narrow gastric conduit, n = 20) were also analyzed.

AL occurred in 31/224 (13.8%). Narrower sAPD and higher AH were independently associated with AL (odds ratio [OR] 0.86, p = 0.002; OR 1.15, p = 0.049); risk was highest in the narrow-sAPD/high-AH group (35.9%; OR 12.32). Airway-gastric fistula occurred in five patients (2.2%), all with a narrow sAPD. AH alone was associated with AL in the transthoracic cohort; AL was 5.0% in the narrow gastric conduit cohort.

sAPD and AH are practical, imaging-based predictors of AL after transcervical-hiatal subtotal esophagectomy. The association between narrow sAPD and airway-gastric fistula supports conduit-space mismatch as a mechanism. Combined assessment stratifies risk and may guide conduit design and anastomotic level.

Stomach adenocarcinoma (STAD) is a highly prevalent malignancy. YTH domain family protein 3 (YTHDF3), an m⁶A reader, correlates with worse survival outcomes in STAD. The aim was to study the impact of YTHDF3 on STAD cells and its underlying regulatory mechanisms.

Epidemiologically, the GEPIA and Kaplan-Meier Plotter databases were used to examine YTHDF3 expression in STAD and to assess its association with prognosis, with poor prognosis defined by overall survival (OS). Clinical parameters were also analyzed to validate the prognostic value of YTHDF3. Experimentally, STAD patients were selected as the study objects. Immunofluorescence was used to confirm YTHDF3 expression in STAD tissues. In vitro assays examined YTHDF3/Adenomatous polyposis coli (APC) regulation of Wnt signaling.

Epidemiologically, YTHDF3 elevation in STAD (p < 0.05) predicted poorer OS (hazard ratio [HR] = 1.46, 95% confidence interval [95% CI]: 1.17-1.81, p = 0.00066). High YTHDF3 expression was also significantly associated with advanced T stage (p = 0.0069), N stage (p = 0.0088), and positive distant metastasis (p = 0.0076). Experimentally, elevated YTHDF3 expression was observed in STAD tissues and cells (all p < 0.001). Silencing YTHDF3 suppresses AGS malignancy and promotes apoptosis. Conversely, YTHDF3 overexpression aggravated the malignant phenotype of STAD (all p < 0.001). Mechanistically, silencing YTHDF3 promoted APC expression (p < 0.001) in an m⁶A-dependent manner. Rescue experiments proved silencing APC reversed YTHDF3-knockdown-mediated repression of Wnt/β-catenin signaling and AGS cell malignancy (all p < 0.001).

YTHDF3 promoted STAD progression by regulating APC mRNA degradation.

Multiple myeloma is a systemic and spatially heterogeneous cancer of plasma cells. Available methods for diagnosing and monitoring disease do not fully capture its heterogeneity. For instance, bone marrow sampling is anatomically limited and [18F]FDG PET/CT reflects glucose metabolism rather than a specific target. In this issue of JCI, Gu et al. reported a prospective phase I study of [68Ga]Ga-PFBC01, a nanobody tracer targeting B cell maturation antigen (BCMA). The study presents a coherent translational pathway for [68Ga]Ga-PFBC01 PET and demonstrates high sensitivity, associations with tissue and circulating disease measures, and clinical management impact. By shifting myeloma imaging from metabolic assessment toward target biology, [68Ga]Ga-PFBC01 PET may visualize whole-body disease distribution and actionable target expression, while blood-pool activity may reflect systemic antigen biology (Figure 1).

Intraductal tubulopapillary neoplasm (ITPN) is a rare intraductal pancreatic tumor, accounting for approximately 3% of all intraductal neoplasms. ITPN is characteristically paucimucinous and lacks low-grade (adenomatous) components. Since reported cases of ITPN remain limited, its prognosis, prognostic factors, and role of perioperative chemotherapy are not well defined.

A 64-year-old man presented with loss of appetite and abdominal pain in year X-1. Endoscopic US-guided fine-needle aspiration (EUS-FNA) was performed, and the findings showed atypical epithelial cells suspicious for adenocarcinoma. The lesion was radiologically assessed as borderline-resectable pancreatic head cancer with portal venous involvement. Curative-intent resection was attempted at the referring hospital; however, the tumor was judged intraoperatively to be locally unresectable because safe vascular dissection around the superior mesenteric vein (SMV) was difficult. Choledochojejunostomy, cholecystectomy, and gastrojejunostomy were performed for obstructive jaundice and duodenal stenosis. From October X-1, the patient received gemcitabine plus nab-paclitaxel, followed by tegafur/gimeracil/oteracil. The maximum tumor diameter decreased from 60 to 50 mm, and the imaging response to systemic chemotherapy was classified as stable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, without distant progression. In May X, the patient was referred to our department for consideration of surgical treatment. Repeat EUS-FNA strongly suggested ITPN. Subtotal stomach-preserving pancreatoduodenectomy with SMV-portal vein (PV) axis resection and reconstruction was performed using a right common femoral vein graft. Postoperative right deep femoral vein thrombosis was managed with anticoagulation. The patient was discharged on POD 16, and follow-up CT 1 year after surgery confirmed thrombus resolution. Histopathological examination confirmed invasive ITPN without lymph node metastasis or vascular invasion. The histological treatment effect was classified as grade 1a according to the Japanese classification of pancreatic carcinoma by the Japan Pancreas Society, eighth edition, and as grade I according to the Evans classification. Adjuvant chemotherapy was not administered. The patient remained disease-free 29 months after surgery.

This case highlights the importance of multidisciplinary re-evaluation in pancreatic tumors initially managed as pancreatic ductal adenocarcinoma, particularly when an unusual histology such as ITPN is suspected.

Epidermal growth factor receptor inhibitors (EGFRIs) -related rash is prevalent, and honeysuckle therapy (HT) has been extensively utilized for skin rash. However, high-quality clinical evidence supporting the use of HT for EGFRIs-related rash remains scarce. This study aims to systematically assess the prophylactic and therapeutic effectiveness and safety of HT in managing EGFRIs-related rash.

A systematic literature search was performed in six electronic databases from their inception to 25 March 2025 to identify eligible randomized controlled trials (RCTs). Methodological risk of bias was evaluated using the Cochrane RoB 1.0 tool, and the certainty of evidence was graded using the GRADE approach. Meta-analyses were implemented using RevMan 5.4 software.

Seven RCTs with a total of 534 participants were enrolled. Prophylactically, HT significantly reduced ≥ Grade 2 rash incidence (RR = 0.43, 95% CI: 0.29-0.65, P < 0.001; 2 RCTs) and delayed time to rash onset (MD = 8.87 days, 95% CI: 5.30-12.44 days, P < 0.001; 1 RCT). No significant differences were detected in overall rash incidence (RR = 0.84, 95% CI: 0.69-1.01, P = 0.07; 2 RCTs) or rash duration (MD = -4.43 days, 95% CI: -9.69 to 0.83 days, P = 0.10; 1 RCT). For therapeutic use, HT significantly improved the clinical effective rate of rash management (RR = 1.35, 95% CI: 1.13-1.62, P = 0.001; 5 RCTs). Subgroup analyses confirmed consistent efficacy across single-botanical drug/compound formulations and topical/combined oral-topical administration routes. HT also improved quality of life. No severe HT-related adverse events were documented among studies that reported safety outcomes. Evidence certainty was low to very low.

Due to the low certainty and very low certainty of evidence, HT may alleviate severe EGFRIs-related rash and improve therapeutic response. High-quality, large-scale, multicenter RCTs with standardized honeysuckle botanical drug formulations, dosages, and outcome measures are urgently needed to validate these preliminary findings and improve clinical generalizability.

https://www.crd.york.ac.uk/PROSPERO/, Identifier CRD420251035535.

Toripalimab, an anti-programmed cell death protein 1 (PD-1) monoclonal antibody developed in China, is increasingly used in the treatment of solid tumors. Although immune checkpoint inhibitors improve antitumor immunity, they may also cause immune-related adverse events involving the nervous system. We report a 60-year-old woman with triple-negative right breast cancer who developed bilateral ptosis and mild limitation of horizontal eye movements approximately 2 weeks after receiving nab-paclitaxel, carboplatin, and toripalimab. Serological testing showed positivity for anti-ryanodine receptor antibody (RYR-IgG, 1:100) and anti-titin antibody (Titin-IgG, 1:320), whereas acetylcholine receptor, muscle-specific kinase, and low-density lipoprotein receptor-related protein 4 antibodies were negative. The neostigmine test was negative. Routine nerve conduction studies were largely normal, and repetitive nerve stimulation showed no low-frequency decrement. After symptom onset, CK-MB mass was markedly elevated despite a normal hs-cTnI level, and AST and ALT were also increased. Because simultaneous total CK and myoglobin measurements were unavailable, the tissue source of the CK-MB elevation could not be determined, and the result was considered uninterpretable in isolation. Possible skeletal-muscle involvement, including ocular myositis, therefore remained in the differential diagnosis. Brain MRI showed chronic ischemic changes without an acute explanatory lesion. No bulbar, respiratory, limb, or cardiac symptoms were documented. After differential assessment, a probable toripalimab-associated ocular myasthenia gravis-like presentation was considered. Toripalimab was discontinued, and oral methylprednisolone 20 mg once daily was administered for 6 days from January 17 to January 22, 2026, beginning the day after discharge. Ptosis improved during early follow-up and remained improved at the subsequent visit. This case illustrates that ocular symptoms after PD-1 inhibitor therapy may represent a neuromuscular immune-related adverse event even when conventional myasthenia gravis antibodies and repetitive nerve stimulation are negative. The significance of RYR-IgG and Titin-IgG positivity in this patient remains uncertain because the assay platform and laboratory cut-offs were unavailable. Their detection should not be regarded as confirmation of ocular myasthenia gravis.

Ovarian cancer (OC) is a biologically heterogeneous malignancy associated with poor clinical outcomes. Oncolytic viruses (OVs) have emerged as a promising immunotherapeutic strategy; however, optimal approaches to maximize their antitumor efficacy-especially in combinatorial or sequential settings-remain insufficiently defined. To determine how the sequence of administration of two clinically relevant, stem cell-delivered OV platforms influences tumor control and immune remodeling in an immunocompetent OC model.

We investigated the sequence of two clinically relevant products: neural stem cell delivered conditionally replication competent adenovirus (NSC.CRAd-S-pk7; NNV24) and a mesenchymal stem cell delivered vaccinia virus (MSC.VP001; SNV1). Female C57BL/6 mice were randomized into three groups: untreated tumor-bearing controls, NNV24 followed by SNV1 (NNV24+SNV1), or SNV1 followed by NNV24 (SNV1+NNV24). Therapeutic efficacy and immune responses were assessed by overall survival, histopathological evaluation, flow cytometric analysis of dendritic cell (DC) subsets and cytotoxic T lymphocytes (CTLs), and bulk RNA sequencing.

Treatment regimens initiated with NNV24 significantly prolonged survival compared with SNV1-first sequences. NNV24+SNV1 treatment resulted in enhanced intratumoral viral localization, increased infiltration of CTLs, mature DCs, and concomitant with a reduction in tolerogenic DC populations. Transcriptomic profiling corroborated these findings through revealing suppression of immunoregulatory and tolerogenic pathways signaling in comparison to SNV1+NNV24 group.

The treatment sequence of heterologous OV has a significant effect on the tumor microenvironment. NNV24+SNV1 promotes robust antitumor immunity and improved survival, whereas the reverse sequence compromises immune activation and therapeutic response. These findings establish a mechanistic framework for rational sequencing of OV-based immunotherapies.

Methotrexate (MTX) resistance limits its clinical efficacy in gestational trophoblastic neoplasia (GTN). To develop safer treatment strategies for patients of reproductive age, this study aims to investigate whether anti-trophoblast cell surface antigen 2 (Anti-Trop2) facilitates the tumor-targeted delivery of MTX-loaded liposomes, thereby enhancing drug sensitivity in chemoresistant GTN.

Clinical samples were collected to detect trophoblast cell surface antigen 2 (Trop2) in MTX-resistant GTN. A methotrexate-loaded targeted liposome (A-Lipo@MTX) was designed and fully characterized. In vitro experiments were performed to evaluate the cellular uptake efficiency and cytotoxicity of the liposomes in MTX-resistant JEG3 cells (JEG3R), and to explore the underlying mechanism. The antitumor efficacy against drug-resistant tumors and initial biosafety of A-Lipo@MTX were further assessed in animal models.

Clinical specimens revealed that Trop2 was significantly upregulated in chemoresistant GTN tissues. Trop2 could serve as a potential therapeutic target for drug-resistant tumors. The designed A-Lipo@MTX exhibited a uniform nanoscale size (~210 nm), high encapsulation efficiency (~85%), and favorable stability. In vitro, Anti-Trop2 functionalization significantly increased liposomal endocytosis within MTX-resistant GTN cells; the resulting intracellular MTX accumulation inhibited PI3K-AKT-mTOR signaling and triggered tumor cell apoptosis. In vivo imaging results confirmed its increased tumor accumulation, which translated into superior antitumor efficacy. Importantly, A-Lipo@MTX improved biosafety during medication, as indicated by stable body weight, normal serum biochemical parameters, and minimal organ damage.

This study identifies Trop2 as an effective target to promote liposome specific uptake, elevates intratumoral MTX accumulation at tumor sites, and suppress the activation of drug-resistant signaling pathways. This strategy provides a clinically relevant and safer approach for overcoming chemoresistance in GTN.