Kindai 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.

Radiographic progression (RP) without prostate-specific antigen (PSA) elevation has emerged as a clinically important pattern in the androgen receptor pathway inhibitors (ARPI) era, but its prevalence and prognostic significance in real-world metastatic hormone-sensitive prostate cancer (mHSPC) cohorts remain unclear. To assess the prevalence and prognostic implications of RP alone progression in mHSPC patients treated with first-line ARPIs. We retrospectively analyzed 518 mHSPC patients treated with abiraterone acetate plus prednisolone, enzalutamide, or apalutamide. PSA progression was defined using PCWG3 criteria. Patients were categorized into PSA progression or RP alone progression groups, and clinical outcomes were compared. Among 169 patients who developed castration-resistant prostate cancer (CRPC), 34 (20.1%) experienced RP alone. RP alone patients had significantly worse overall survival compared to those with PSA progression (median 21 vs. 39 months, p = 0.007), despite exhibiting deeper biochemical responses-PSA nadir (0.055 vs. 0.86 ng/mL, p < 0.001) and a higher rate of PSA nadir < 0.2 ng/mL (61.8% vs. 27.4%, p < 0.001). The baseline characteristic differing between groups was CHAARTED volume classification; high volume disease was markedly more common in RP alone patients (94.1% vs. 77.8%). In univariate and multivariate analyses of the overall cohort, CHAARTED high volume disease was identified as an independent risk factor for RP alone (HR 10.3, 95% CI 1.20-89.3; p = 0.034). RP alone progression occurred in approximately one-fifth of patients and was associated with significantly poorer survival despite excellent PSA responses, underscoring the limitation of PSA-based monitoring and supporting routine imaging for early detection of PSA-incongruent disease progression in mHSPC.

The crystal structure of a one-dimensional anionic bis-muth(III) iodide coordination polymer, catena-poly[[tri-iodido-bis-muth(III)]-di-μ-iodido-[tri-iodido-bis-muth(III)]-μ-4,7-bis-(pyridin-4-yl)benzo[c][1,2,5]thia-diazole], {(C16H36N)2[Bi2I8(C16H10N4S)]} n , constructed from μ2-iodido-bridged dinuclear [Bi2I8]2- units and the π-conjugated N-donor ligand 4,7-bis-(pyridin-4-yl)benzo[c][1,2,5]thia-diazole (dpbt) is reported. Each BiIII centre adopts a distorted octa-hedral geometry with five iodido ligands and one nitro-gen donor atom. The dinuclear units are linked by dpbt to form infinite chains, with charge balance provided by tetra-n-butyl-ammonium cations. The crystal packing is governed by C-H⋯I hydrogen bonds and C-H⋯π inter-actions, while π-π stacking is suppressed by steric effects. Anionic iodido-bis-muth polymers of this type are rare.

ABSTRACTWe investigated immunologic biomarkers that predict outcomes of patients with previously treated metastatic non‐small cell lung cancer who were enrolled in the J‐TAIL study, a prospective, observational study of atezolizumab monotherapy. Of 262 patients participating in the J‐TAIL exploratory study, peripheral blood mononuclear cells were obtained from 51 patients and analyzed by T‐cell fractionation analysis using Helios mass cytometry and serum proteomics analysis. Following treatment with atezolizumab, an increase in programmed cell death‐1 (PD‐1)‐expressing CD8 and CD4 T‐cell populations was observed. A more pronounced increase in PD‐1 expression was seen in T cells from patients whose progression‐free survival (PFS) was 100 days or longer compared with those with shorter PFS. The proximity extension assay, which is highly sensitive multiplex analysis technology that combines antibody‐based affinity assays with next‐generation sequencing, showed a significant increase in FOXO1, possibly in response to precursor‐exhausted T‐cell population activation. Immune‐related adverse events were associated with a high percentage of PD‐1‐positive cells on effector memory CD8 T cells, which was thought to be accompanied by extremely high CD8 T‐cell activation. Further analysis distinguished poor prognosis populations with significant differences in CD62Lhigh Th7R and CXCR3+ component of Th7R (CXCR3+ Th7R) within the population with PFS < 50 days. Patients with low Th7R or CXCR3+ Th7R percentages prior to atezolizumab treatment had significantly poorer overall survival. These findings provide valuable insights regarding T‐cell kinetics and biomarkers in atezolizumab therapy and may offer promising directions for future research.Trial Registration: UMIN Clinical Trials Registry: UMIN000033133 and UMIN000035567; ClinicalTrials.gov: NCT03645330

Adjuvant immunotherapy improved patient outcomes in two trials in completely resected non-small cell lung cancer (NSCLC), but with conflicting primary end point results. The Canadian Cancer Trials Group BR.31 trial evaluated adjuvant durvalumab in completely resected early-stage NSCLC. Following resection of stage IB (≥4 cm) to IIIA NSCLC (American Joint Committee on Cancer 7th Edition) and optional adjuvant chemotherapy, patients were randomly assigned 2:1 to durvalumab 20 mg/kg or placebo 20 mg/kg once every 4 weeks for 12 cycles. Random assignment was stratified by stage, extent of nodal dissection, tumor cell (TC) PD-L1 expression, adjuvant chemotherapy use, and center. The primary end point was investigator-assessed disease-free survival (DFS). Secondary outcomes included overall survival (OS), adverse events, and quality of life. The primary analysis was in the subgroup with cancers that had a PD-L1 TC expression ≥25%, no common activating EGFR mutations (EGFR-), and no ALK gene rearrangements (ALK-). Secondary analyses in hierarchical order included DFS in the subgroup whose tumors were EGFR-/ALK- with PD-L1 TC ≥1%, followed by all patients whose tumors were EGFR-/ALK-, followed by OS in the same primary and secondary subgroups in the same hierarchical order. Of 1,415 patients randomly assigned, 1,219 (86%) had EGFR-/ALK- tumors: 815 randomly assigned to durvalumab and 404 to placebo. With a median follow-up of 60 months, there were no differences in DFS between patients assigned durvalumab (316) versus placebo (161) in the primary population (stratified hazard ratio [HR], 0.93 [95% CI, 0.71 to 1.25]; P = .64) or in the secondary populations. Grade 3 to 4 adverse events were higher in durvalumab-treated patients (D = 26% v P = 20%). Adjuvant durvalumab following complete resection was not associated with improvement in DFS compared with placebo in EGFR-/ALK- NSCLC, regardless of PD-L1 status.

We report a rare case of traumatic osteonecrosis of the femoral head, which was caused by rupture of the ligamentum teres, in which femoral varus osteotomy was performed and bone regeneration occurred at the necrotic area.BackgroundShe was a 20 years old female. She was a short-distance runner and got injured during competition at the age of 14. She was diagnosed as avulsion fracture of the attachment of the left ligamentum teres, and received conservative treatment. After the pain relieved, she continued running exercise. However, she began to feel left hip pain again from 10 months before, and was referred to our hospital.ResultsMRI and CT examination indicated the osteonecrosis of the medial side of left femoral head and bone defect of the medial weight bearing area. To address that, we performed femoral varus osteotomy using angular plate and screws. She was allowed 1/3 partial weight bearing at 6 weeks postoperatively, and full weight bearing at 18 weeks postoperatively. After confirmation of bone union at the osteotomy site at 10 months postoperatively, removal of the plate and screws concomitant to hip arthroscopy was performed. Hip arthroscopy showed a rupture of the ligamentum teres, but no apparent defect of the cartilage around necrotic area of the femoral head was detected. She was allowed full weight bearing at 2 months after hardware removal.At the time of 13 months after osteotomy, she was able to walk alone without claudication and have no limitation in hip range of motion. Plain radiography and CT indicated bone repair at the preoperative bone defect area.DiscussionIn this case, the interruption of the blood supply via ligamentum teres at the time of injury might result in the osteonecrosis of the femoral head which was limited to the medial side. Femoral varus osteotomy reduced the load on the necrotic area and probably induced angiogenesis followed by bone regeneration in the necrotic area.

Although pathologic stage I (pStage I) non–small cell lung cancer (NSCLC) has a good prognosis, some patients experience disease recurrence. Identification of prognostic markers for pStage I NSCLC may facilitate personalized perioperative treatment by expanding the candidates for adjuvant treatment. Patients with NSCLC with ground-glass opacity have excellent survival outcomes. Therefore, in this study, we explored prognostic biomarkers in pure solid nonsquamous NSCLC. We focused on nonsquamous NSCLC because the gene expression status is distinct from that of squamous cell carcinomas. RNA sequencing was performed on frozen tumor specimens from 33 patients with nonsquamous NSCLC with disease recurrence (recurrence group) and 33 counterparts (control group) extracted from patients without disease recurrence using propensity score matching (cohort 1). The candidate genes were further refined using an independent real-world cohort 2a (N = 125) and validated in The Cancer Genome Atlas cohort. Through the analysis of cohort 1 and cohort 2a, we found that low expression of six genes (BMP6, KCNK3, NFASC, OLFM1, PEG3, and TNXB) was associated with disease recurrence. The prognostic impact of the six genes was confirmed using The Cancer Genome Atlas lung adenocarcinoma database. Multivariable proportional hazard analysis using the cohort 2a dataset revealed that the combination of BMP6 and OLFM1 status predicted recurrence-free survival. In conclusion, we found that low BMP6/OLFM1 gene status is a potential biomarker to identify patients with high-risk pStage I pure solid nonsquamous NSCLC after pulmonary resection.Significance:The identification of subgroups with a high risk of disease recurrence among patients with NSCLC with pStage I is an important clinical issue. We explored genetic factors in patients with pStage I NSCLC with a high-risk clinical feature and identified low expression of OLFM1 and BMP6 genes as candidate biomarkers. Clinical application of these biomarkers, together with others, will open an opportunity to administer adequate adjuvant treatment for these high-risk patients.