Okayama University Hospital

BACKGROUNDImmune checkpoint inhibitors (ICIs) targeting the programmed cell death 1 axis have revolutionized metastatic non–small cell lung cancer (mNSCLC) treatment. However, disease progression remains a concern, and the role of the complex tumor microenvironment (TME) in treatment failure is not fully understood.METHODSIn this biomarker study involving 103 patients with mNSCLC, including 81 patients who received ICI treatment, we evaluated the association between heterogeneous immune cell subsets and ICI efficacy through single-cell spatial profiling of pretreatment tumor tissue, using a 29-marker multiplex IHC platform built for in-depth dissection of the TME.RESULTSAmong various types of intratumoral lymphocytes, including Th1, Treg, and NK cells, only CD8+ T cells (tumor-infiltrating lymphocytes [TILs]) were associated with ICI efficacy. Computational tissue segmentation underscored the importance of direct physical interactions between CD8+ TILs and cancer cells for ICI efficacy. TIL phenotyping identified CD39/CD103/Ki-67 positivity as a hallmark of exhausted yet functional tumor-reactive CD8+ TILs. Immunosuppressive tumor-associated macrophages (TAMs) and cancer-associated fibroblasts were independent unfavorable adversaries. High CD73 expression on cancer cells was suggested to confer tolerance to ICI in EGFR/ALK-oncogene+ NSCLC, potentially through M2-TAM accumulation and aberrant angiogenesis.CONCLUSIONOur study delineates the clinical relevance of heterogeneous immune cell subsets in ICI-treated mNSCLC, aiding the development of targeted therapeutic strategies.FUNDINGOsaka Cancer Society, KANAE Foundation for the Promotion of Medical Science, SGH Foundation, and YOKOYAMA Foundation for Clinical Pharmacology.

Post-transplant acute limbic encephalitis (PALE) has been reported, and human herpesvirus 6 (HHV-6) is one of the causes. Reports of PALE in children are still limited. In the present study, the detailed clinico-radiological findings of PALE and the neurological outcomes of four children are reported. Four patients aged three to twelve years of 142 patients who underwent allogeneic hematopoietic stem cell transplantation developed PALE. Underlying disorders were neuroblastoma in three patients and acute lymphoblastic leukemia in one. All four patients showed disorientation, behavioral changes, emotional dysregulation, anterograde amnesia, or decreased level of consciousness between 12 and 22days after transplantation. None had clinical seizures. In all patients, MRI showed hyperintense signals in unilateral or bilateral hippocampi, especially in the CA1 area, on diffusion-weighted imaging (DWI), with a decreased apparent diffusion coefficient. Though the hippocampi were also hyperintense on T2-weighted and fluid-attenuated inversion recovery imaging, signal intensity was higher on DWI by visual inspection. Electroencephalograms showed poorly organized posterior dominant rhythm in all patients and left occipito-centro-parietal slow waves in one without epileptiform discharges. HHV-6 DNA was positive in both cerebrospinal fluid and whole blood by polymerase chain reaction in three of the four patients. Two patients had pharmaco-resistant epilepsy and cognitive impairment three years after PALE, but the other two recovered neurologically from PALE. A DWI abnormality of the hippocampal CA1 area is a good biomarker for the diagnosis of HHV-6-positive or -negative PALE in children. Glutamatergic dysregulation and hippocampal cytotoxic edema may be involved in PALE.

Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system. Although immunotherapy with immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) has emerged as novel antitumor therapy, high-risk NB tumors are refractory to ICI therapy. Oncolytic virotherapy is expected to potentiate the antitumor immune response by inducing immunogenic cell death (ICD). In the present study, we assessed the therapeutic potential of OBP-301 and OBP-702, telomerase-specific oncolytic adenoviruses, for the induction of ICD and combined effect with PD-1 blockade against NB cells. The cytopathic activity of OBP-301 and OBP-702 was assessed using three human MYCN-amplified NB cell lines (IMR-32, LA-N-5, and NB-1) and a murine non-MYCN-amplified NB cell line (Neuro-2a). Virus-mediated antitumor effect was assessed by analyzing cell viability, secretion of extracellular adenosine triphosphate (ATP) and high-mobility group box protein B1 (HMGB1), apoptosis, autophagy, and PD-L1 levels. A subcutaneous Neuro-2a tumor model was used to evaluate the in vivo antitumor effect of combination therapy with OBP-702 and anti-PD-1 antibody. OBP-702 exhibited stronger cytopathic activity, inducing ICD with secretion of ATP and HMGB1, compared to OBP-301 in human and murine NB cells. OBP-301 and OBP-702 increased apoptosis, autophagy, and PD-L1 expression in murine NB cells. Moreover, OBP-702 significantly prolonged the survival of tumor-bearing mice compared to monotherapy with PD-1 blockade. OBP-702 is a promising antitumor strategy to promote the antitumor effect of ICIs by inducing ICD against NB tumors.

Diabetic polyneuropathy (DPN) decreases health-related quality of life (HRQOL) and physical function. Exercise therapy improves the physical function of patients with DPN; however, its effect on HRQOL remains unknown. Therefore, we subanalyzed the effect that teleguidance for exercise therapy by physiotherapists has on HRQOL in older patients with DPN by using our previously obtained data. The physiotherapist who participated in this study is a specialist in exercise therapy for diabetes. Participants with DPN were categorized into the teleguidance for exercise therapy by physiotherapists (TelePhysio) and control groups (n = 18 and 19, respectively). Both groups underwent the same moderate-intensity exercise therapy program. In the TelePhysio group, teleguidance for exercise therapy was provided for 30min once a week for six months. In the control group, no telephone intervention was provided, and patients were interviewed at the hospital only at 3 months after discharge. For the comparison between parameters at baseline and six months later, in the TelePhysio group, the EuroQol 5-dimensional (EQ-5D) score and knee extension force (KEF) did not decrease, whereas the Diabetes Treatment Satisfaction Questionnaire (DTSQ) score significantly improved (24.2 ± 5.7 to 26.7 ± 6.0; P < 0.05). In contrast, in the control group, the EQ-5D score and KEF were significantly decreased, whereas the DTSQ score remained unchanged. TelePhysio is effective in improving treatment satisfaction and may help prevent decline in HRQOL and physical function in older patients with DPN. Our findings suggest that TelePhysio may be a treatment option for older patients with DPN. The online version contains supplementary material available at 10.1007/s13340-026-00884-8.

Abstract Introduction Maintaining dose intensity is essential for the efficacy of adjuvant S-1 chemotherapy in gastric cancer. Although pharmacist interventions can reduce toxicity and improve adherence, multicenter evidence regarding their impact on dose maintenance is limited. Aim This study aimed to evaluate the impact of continuous pharmacist intervention on treatment completion and relative performance (RP) value in patients receiving adjuvant S-1 chemotherapy for gastric cancer. Methods This multicenter retrospective study analysed 225 patients across 12 institutions, categorised into continuous intervention (n=97) and non-continuous intervention (n=128) groups. Continuous intervention was defined as systematic monitoring and management for at least 50% of the treatment duration. Inverse probability of treatment weighting adjusted for baseline covariates. The primary and secondary endpoints were the eight-cycle completion rate and the RP value, respectively. Results Eight-cycle completion rate did not differ significantly between the continuous and non-continuous intervention groups (53.0% vs. 55.2%, p = 0.775), nor did the frequency of treatment modification events, including discontinuation or dose reduction. However, the RP value was significantly higher in the continuous intervention group than in the non-continuous intervention group (73.7% vs. 64.9%, p = 0.038), a finding robustly supported by sensitivity analysis between these two groups (75.1% vs. 61.1%, p = 0.0008). The continuous group maintained a high intervention rate (89.1%) throughout the final cycle, providing significantly more supportive care interventions than the non-continuous intervention group (53.2% vs. 4.9%, p &lt; 0.001). Conclusion Although continuous pharmacist intervention did not improve the binary completion rate, it was essential for maintaining RP values above the clinically essential 70% threshold through proactive toxicity management and dynamic dose optimization. These findings suggest that systematic pharmaceutical care contributes significantly to ensuring the quality and intensity of adjuvant chemotherapy.

Metastatic neuroendocrine tumors (NETs) typically involve the liver and lymph nodes. Metastases in the orbit, heart, and ovary are rare and present unique clinical challenges. We report a woman who was 70 years old at the time of initial presentation with liver metastases from a rectal neuroendocrine tumor. Following a right hepatectomy for liver metastases, she remained free of hepatic recurrence for 10 years. Notably, four years after the right hepatectomy, she developed new metastases in the left orbit, right ventricle, and left ovary, with diplopia as the sole clinical symptom. This clinical course suggests a distinct metastatic pathway associated with the lower rectum that bypasses the portal circulation, consistent with the dual drainage system of the rectal region. Management involved a strategic multimodal approach that includes systemic therapy with everolimus and lanreotide as well as targeted surgical resectioning of the cardiac and ovarian lesions. The orbital lesion achieved a complete response through systemic therapy alone, preserving visual function. Currently, 10 years after the initial treatment, the patient maintains an excellent performance status (ECOG PS 0) while receiving peptide receptor radionuclide therapy (PRRT). This case demonstrates that recognizing atypical metastatic pathways and employing strategic multimodal therapies can achieve long-term survival and functional preservation in rectal NETs.

In the field of team-based care, pharmacists are vital for optimizing medication therapy. However, many medical professionals lack the opportunity to learn how to propose prescription changes with precision. This study aimed to address this knowledge gap by developing and assessing a new educational program for pharmacy students focused on prescription support and interprofessional collaboration. We recruited 191 fifth-year pharmaceutical students during the 2022-2024 academic years. The program featured a 7-day intensive curriculum that included learning how to assist with prescriptions, analyzing clinical data, and engaging in role-playing exercises. A web-based questionnaire and a paper test were used to evaluate students' awareness and knowledge both before and after the program. Statistical analyses were performed to verify the significance of changes; we utilized the Wilcoxon signed-rank test for the ordinal data derived from the specific behavioral objectives and 2-tailed paired t tests for the interval data from the knowledge tests. The magnitude of change was quantified using r for Wilcoxon tests and Cohen dz for 2-tailed t tests, with 95% CI calculated to ensure the stability and reliability of the observed results. Analysis of the primary outcome specific behavioral objectives revealed statistically significant effects across all items (Wilcoxon signed-rank test; P<.001). Effect sizes (r=0.505-0.835) ranged from moderate to large, with particularly large effects observed in identifying contents issue (r=0.835, 95% CI 0.126-0.330; P<.001). Knowledge test scores showed significant improvement in the following 3 subjects: pharmacology (r=-0.504, 95% CI -0.215 to 0.127; P<.001), organic chemistry (r=0.254, 95% CI -0.148 to -0.193; P=.004), and communication (r=0.221, 95% CI -0.151 to -0.190; P=.01). No significant changes were observed in pathology or pharmacokinetics. This program provides strong evidence that practical, hands-on learning with hospital pharmacists helps improve pharmacy students' professional skills and optimize pharmaceutical therapies in interprofessional care. By teaching pharmacists to effectively propose prescription changes, the program equips them to become integral members of interprofessional care, ultimately leading to optimized pharmaceutical care for patients.