Introduction: Metastases to oral and maxillofacial regions are uncommon and may mimic odontogenic infection or primary intraosseous malignancy. Mandibular involvement in patients with gastric cancer is particularly rare, and delayed recognition may postpone definitive diagnosis. Case Presentation: A 61-year-old man presented with numb-chin syndrome and a nonhealing mandibular extraction socket. Panoramic radiography and CT revealed an ill-defined osteolytic lesion in the left mandible with suspected extraosseous extension. Although primary intraosseous carcinoma was initially suspected, histopathological reevaluation of the mandibular biopsy specimen suggested metastatic adenocarcinoma. 18F-FDG PET/CT demonstrated uptake in the mandible and a suspected primary lesion extending from the lower thoracic esophagus to the stomach, with multiple nodal and distant metastases. Upper gastrointestinal endoscopy revealed an ulcerated, bleeding mass at the gastroesophageal junction, and biopsy demonstrated adenocarcinoma. Based on the combined clinicopathologic, radiologic, and endoscopic findings, the lesion was diagnosed as mandibular metastasis from an advanced upper gastrointestinal adenocarcinoma, clinically managed as gastric cancer. The patient received four cycles of FOLFOX chemotherapy and achieved a partial radiologic response, but treatment was discontinued because of gastrointestinal perforation. He was transitioned to best supportive care and died 7 months after the initial diagnosis. Conclusion: Metastatic disease should be considered for patients with ill-defined mandibular osteolysis accompanied by numb-chin syndrome and a nonhealing extraction socket, even in cases without a history of malignancy. To avoid diagnostic delay, early tissue diagnosis and prompt systemic evaluation are critical.

We report a rare case of actinomycosis arising in the tongue. A female patient in her 70s presented to our department with swelling of the tongue. Despite only minimal mucosal change, a submucosal indurated mass was observed. Contrast-enhanced magnetic resonance imaging revealed a well-circumscribed mass-like lesion within the tongue muscle. Ultrasonography showed punctate hyperechoic foci within a hypoechoic lesion. As there were few signs of infection, a benign tumorous lesion was suspected, and an excisional biopsy was performed. Histopathological examination indicated sulfur granules in the mass, and no neoplastic lesion was observed. The mass was ultimately diagnosed as tongue actinomycosis. Three years after surgery, there was no evidence of recurrence at the wound site. This case highlights the diagnostic difficulty of lingual actinomycosis and suggests that internal punctate hyperechoic foci on ultrasonography may provide a useful clue to the diagnosis.

Abstract Topic Esophageal Cancer: Esophageal Carcinogenesis Background Esophagogastric junction (EGJ) adenocarcinoma comprises tumors arising from distinct backgrounds, including Barrett’s esophageal adenocarcinoma and gastric cardia adenocarcinoma. Although CK7/CK20 expression patterns and CDX2 expression have been associated with intestinal differentiation and Barrett-related carcinogenesis, their relationships with tumor origin, lymphatic spread, and prognosis remain unclear. Methods A total of 82 patients who underwent curative surgery for EGJ adenocarcinoma were retrospectively analyzed. Immunohistochemical expression of CK7 and CK20 was evaluated using H-scores, and expression patterns were categorized by combined high/low profiles. CDX2 expression was classified as high or low using a predefined cutoff of 50% positive tumor cells. For tissue microarray (TMA) analysis, two cores per tumor were stained, and the mean expression value was used for analysis. Associations between marker expression, tumor origin estimated from pathological findings, mediastinal lymph node metastasis, and survival outcomes were investigated. Logistic regression adjusted for lymphadenectomy extent was used to estimate region-specific odds ratios for lymph node metastasis. Kaplan–Meier and Cox regression analyses were performed to evaluate overall survival (OS) and disease-free survival (DFS). Results Among the 82 patients, 60 were diagnosed with Barrett-related EGJ adenocarcinoma. CK7/CK20 expression patterns showed limited association with Barrett versus non-Barrett classification, although non-Barrett tumors tended to be more frequent in the CK7-high group (OR 2.33, p = 0.11) and the CK7/CK20 double-high group (OR 2.21, p = 0.33); however, these differences were not statistically significant. CDX2 expression was not associated with tumor origin. After adjustment for lymphadenectomy extent, high CDX2 expression (OR 1.38, p = 0.66) and high CK20 expression (OR 1.50, p = 0.77) tended to be associated with a higher frequency of mediastinal lymph node metastasis. In survival analyses, the CK7/CK20 double-high group demonstrated more favorable 5-year OS (p = 0.26) and DFS (p = 0.17) than the other CK7/CK20 expression groups. Furthermore, high CDX2 expression was associated with improved 5-year DFS (HR 0.62, p = 0.10), although the difference did not reach statistical significance. Conclusion In EGJ adenocarcinoma, CK7/CK20 expression patterns may partially reflect tumor phenotype, although they do not solely allow the accurate prediction of tumor origin. CDX2 expression does not appear to reflect tissue origin but may serve as a clinically useful biomarker for predicting mediastinal lymphatic spread and postoperative prognosis.

The prognostic significance of mitochondrial status after neoadjuvant chemotherapy (NAC) and its association with the tumor microenvironment (TME) in esophageal squamous cell carcinoma (ESCC) remains unclear. We analyzed 202 ESCC patients who underwent NAC followed by surgical resection. Mitochondrial status was quantified using an objective, immunohistochemistry-based scoring system (Mito-score). The optimal cut-off value was determined by receiver operating characteristic curve analysis. Clinicopathological features, TME parameters (T-cell density and programmed death ligand-1 [PD-L1] expression), and survival outcomes were compared between high and low Mito-score groups. Multivariate Cox regression identified independent prognostic factors for overall survival (OS) and cancer-specific survival (CSS). The high and low Mito-score groups comprised 140 (69.3%) and 62 (30.7%) patients, respectively. NAC response rates and ypStages III-IV frequencies were similar in the two groups. PD-L1 expression was significantly higher in high Mito-score tumors (p = 0.04), while T-cell densities did not differ. High Mito-score was associated with significantly worse OS (3-year OS: 51.9% vs. 72.6%, p = 0.001) across both ypStages I-II (p = 0.047) and ypStages III-IV (p = 0.01) subgroups. In ypStages III-IV, high Mito-score was also linked to poorer CSS (p = 0.01). Multivariate analysis confirmed high Mito-score to be an independent predictor of unfavorable OS and CSS. Overall, high Mito-score after NAC identifies ESCC patients with significantly poorer survival, particularly among those with advanced pathological stages, thereby possibly serving as an independent prognostic biomarker.

INTRODUCTION:The optimal follow-up period and appropriate examinations for patients with esophageal squamous cell carcinoma (ESCC) who have remained disease-free for 5 years remain controversial. CASE PRESENTATION:A 73-year-old man was diagnosed with ESCC and underwent curative esophagectomy. Pathological examination revealed a superficial tumor without lymph node metastases, despite lymphatic and vascular involvement. The patient underwent routine postoperative follow-up at our institution and showed no signs of recurrence until the 5th postoperative year. However, his serum p53 antibody titer increased 5 years postoperatively, and careful follow-up using imaging modalities, including CT, was scheduled. No lesions suspected of recurrence were noted over the next 2 years until bilateral pleural effusion was detected on CT in the 7th postoperative year. Cytological examination of the pleural effusion revealed pleural-seeded ESCC cells. CONCLUSIONS:Although several cases of late recurrence (>5 years) have been previously reported, most have a deeper infiltration depth than that of T2 or pathologically positive lymph nodes. However, patients with lymphatic/vascular involvement, even those with pT1bN0 ESCC, require careful surveillance using imaging modalities and laboratory tests, given the possibility of late recurrence occurring beyond 5 years.

Cellular senescence is deeply involved in physiological homeostasis, development, tissue repair, aging, and diseases. Senescent cells (SnCs) accumulate in aged tissues and exert deleterious effects by secreting proinflammatory molecules that contribute to chronic inflammation and aging-related diseases. We revealed that an aberrant interaction between glycolytic PGAM1 and Chk1 kinase is augmented in SnCs associated with increased glycolysis, whose byproduct, lactate, promotes this binding in a noncell autonomous manner. The pseudo-Warburg effect of SnCs with enhanced PPP (pentose phosphate pathway) activity is maintained by HIF-2α phosphorylation by Chk1 and subsequent upregulation of glycolytic enzymes, creating a vicious cycle reprogramming the glycolytic pathway in SnCs. HIF-2α also activates FoxM1 expression, which transcriptionally suppresses proapoptotic profiles, including BIM, and upregulates DNA repair machineries in SnCs. FoxM1 thus supports the genomic integrity and survival capacity of SnCs during their glycolytic changes. Chemical abrogation of PGAM1-Chk1 binding reverts these phenotypes and eliminates SnCs through senolysis. Inhibition of the PGAM1-Chk1 interaction improves physiological parameters during aging and inhibits lung fibrosis in mouse models. Our study highlights a novel pathway contributing to the metabolic reprogramming of SnCs and how the use of a new senolytic molecule that targets the PGAM-Chk1 interaction creates a specific vulnerability of those cells to potentially fight age-related diseases.

Background: Enterotoxigenic Bacteroides fragilis (ETBF) carries the bft toxin gene, which influences the host immune response and inflammatory pathways and promotes colorectal cancer (CRC). This study investigated the potential role of ETBF in CRC liver metastasis. Methods: We reviewed the records of 226 consecutive patients who underwent curative-intent (R0) resection of CRC liver metastases. ETBF DNA in fresh-frozen metastasis specimens was quantified using droplet digital PCR (ddPCR). Patients were grouped into very-low (≤80%; N = 178), low (80–90%; N = 24), and high (>90%; N = 24) ETBF-DNA groups. Three tissue cores per specimen were stained for CD8, CD4, CD20, FOXP3, CD68, and CD163, and immune-cell densities were measured digitally (cells/mm2). Results: ETBF DNA was detected in 219 of 226 lesions (96.9%). The densities of cytotoxic CD8+ T-cells, effector CD4+ T-cells, CD20+ B-cells, and CD163+ macrophages did not differ significantly by ETBF-DNA group (Ptrend all > 0.12). FOXP3+ regulatory T-cells (Tregs) decreased (Ptrend = 0.010), and CD68+ macrophages increased (Ptrend = 0.020) as ETBF-DNA levels increased. ETBF-DNA levels in CRC liver metastases were not associated with disease-free survival or overall survival or serum C-reactive protein levels. Conclusions: ETBF was present in almost all CRC liver metastases. Higher ETBF levels were associated with a tumor-immune microenvironment enriched in CD68+ macrophages and deficient in FOXP3+ Tregs, suggesting that ETBF facilitates immune evasion without loss of effector lymphocytes. Although ETBF-DNA levels did not predict survival in this single-center cohort, the potential role of ETBF in immune remodeling and as a candidate biomarker and therapeutic target in metastatic CRC warrants further study.

Central nervous system (CNS) involvement in plasma cell neoplasms is rare and associated with poor prognosis, and indications for cerebrospinal fluid (CSF) analysis remain undefined. We describe three cases: two with advanced-stage, high-risk cytogenetics, and one stage I case meeting criteria for plasma cell leukemia (PCL). In two patients, delayed CSF evaluation after neurological symptoms led to rapid deterioration, whereas early CSF analysis in an asymptomatic patient enabled timely diagnosis. One case worsened acutely after treatment with plerixafor. These findings suggest that CSF evaluation may merit consideration in high-risk patients, including those with PCL or before plerixafor administration.

OBJECTIVE:We retrospectively evaluated the efficacy and safety of Pola‒R‒mini‒CHP therapy administered to very elderly treatment‒naive patients with DLBCL at our institution and compared them with R‒mini‒CHOP therapy reported from previous prospective studies. MATERIALS AND METHODS:We retrospectively analyzed the data of 23 patients. The median age of the patients was 83 (range 80‒92) years. The median observation period was 8.9 (3‒22) months, and the median number of treatment cycles was 8 (2‒8). RESULTS:The treatment was completed in 15 of the 23 patients, discontinued in 3 (1 died), and was ongoing in 5. The complete response rate (CRR) was 100% and the cumulative survival rate was 94.7%. In regard to hematological adverse events (Hem‒AEs), ≥Grade (G) 3 events occurred in 12 (52.2%), including anemia in 4 (17.4%), neutropenia in 4 (17.4%), leukopenia in 3 (13.0%), and thrombocytopenia in 1 (4.3%). In regard to non‒Hem‒AEs, ≥G3 events occurred in 3 (13.0%), including G3 COVID‒19 (coronavirus infectious disease) pneumonia and G3 bacteremia in 1 (4.3%) each; other non‒Hem‒AEs were G5 interstitial pneumonia in 1 (4.3%), ≤G2 constipation in 5 (21.7%), and ≤G2 peripheral neuropathy and ≤G2 diarrhea in 1 (4.3%) each. CONCLUSION:The results suggest that Pola‒R‒mini‒CHP was more effective and safer than R‒mini‒CHOP therapy. Comparison of the adverse events revealed that the incidence of anemia was higher, incidence of infection was comparable, and the incidences of gastrointestinal toxicity and peripheral neuropathy were lower in the patients who received Pola‒R‒mini‒CHP therapy as compared with R‒mini‒CHOP therapy. It was possible to continue as an outpatient.

Urothelial carcinoma in situ (CIS) is a flat-type noninvasive urothelial carcinoma. Appropriate diagnosis of CIS is important because treatment options depend on the diagnosis. However, it is often difficult to differentiate CIS from benign lesions, especially reactive atypia. Enhancer of zeste homolog 2 (EZH2) is a component of the polycomb repressor complex 2 that is involved in carcinogenesis by epigenetically regulating gene expression levels. The protein is highly expressed in various malignancies, including urothelial carcinoma. We hypothesized that immunostaining for EZH2 is useful to differentiate urothelial CIS from benign lesions. In the first analysis, we performed immunostaining for EZH2 and existing CIS markers (CK20, p53, Ki67, and AMACR/P504S) using 22 surgical specimens that could be easily differentiated morphologically as CIS or reactive atypical epithelium, thereby not requiring immunohistochemistry. EZH2 showed higher sensitivity and equal or better specificity than the existing markers. In the second analysis, we used 42 transurethral resection of bladder tumor or biopsy specimens for which diagnoses were difficult to establish based on morphology alone and required immunostaining for CK20 and p53. EZH2 showed higher sensitivity but somewhat lower specificity than the existing markers. In the third analysis, immunostaining for EZH2 was performed using 27 specimens of benign lesions other than reactive atypical epithelium, including inverted papilloma, nephrogenic adenoma, and cystitis glandularis. These lesions also showed minimal EZH2 staining. These results suggest that immunostaining for EZH2 is useful in the diagnosis of urothelial CIS, particularly as a marker with superior sensitivity.

The presence of Fusobacterium nucleatum is associated with an immunosuppressive tumor immune microenvironment (TIM) in primary colorectal cancer (CRC), contributing to tumor progression. Its persistence in CRC liver metastasis tissues raises questions about its role in modulating local and systemic immune responses and influencing recurrence patterns. This retrospective cohort study of 218 patients with CRC liver metastasis investigated the association of F. nucleatum in CRC liver metastasis tissues with systemic inflammation, TIM alterations, and the number of metastatic organs involved in recurrence. Two-step polymerase chain reaction (PCR), including digital PCR, detected F. nucleatum in 42% (92/218) of fresh-frozen specimens of CRC liver metastases. Compared with the F. nucleatum-none group, the F. nucleatum-high group showed higher C-reactive protein levels (0.82 vs. 0.22 mg/dL; Ptrend = 0.02), lower numbers of CD8+ cells (33.2 vs. 65.3 cells/mm2; Ptrend = 0.04) and FOXP3+ cells (11.3 vs. 21.7 cells/mm2; Ptrend = 0.01) in the TIM, and a greater number of metastatic organs involved in recurrence (1.6 vs. 1.1; p < 0.001). The presence of F. nucleatum in CRC liver metastasis tissues was associated with increased systemic inflammation, TIM alterations, and a greater number of metastatic organs involved in recurrence. These findings suggest a potential contribution of F. nucleatum to the metastatic propensity of CRC cells and could inform future research to enhance understanding of the interaction between tumor, host, and microbes in the metastatic process.