Correlation between TXNRD1/HO-1 expression and response to neoadjuvant chemoradiation therapy in patients with esophageal squamous cell carcinoma.

BACKGROUND: Thioredoxin reductase 1 (TXNRD1) and heme oxygenase-1 (HO-1) are both involved in the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and play key roles in antioxidant responses. In patients with esophageal squamous cell carcinoma (ESCC), the correlation between the expression of these two proteins and the therapeutic response to neoadjuvant chemoradiation therapy (NACRT), as well as the difference in their expression after chemoradiotherapy, remains unknown. METHODS: Proteins involved in the Nrf2 pathway were immunolocalized in carcinoma cells in ESCC patients on NACRT with 5-fluorouracil and cisplatin, followed by esophagectomy. The 8-hydroxydeoxyguanosine (8-OHdG) levels were used to quantify reactive oxygen species. The changes in immunoreactivity before and after NACRT (Δ) were assessed. RESULTS: Tumor reduction following NACRT was significantly attenuated in pre-therapeutic biopsy specimens associated with high HO-1 status. TXNRD1Δ, HO-1Δ, and 8-OHdGΔ were significantly different in the ineffective and effective groups. The overall survival was significantly lower in high Nrf2 and TXNRD1 groups. In addition, high TXNRD1 expression was an independent prognostic factor in the multivariate analysis of overall survival. CONCLUSIONS: The study findings indicate that HO-1 status in pre-therapeutic biopsy specimens could predict response to NACRT, and TXNRD1 status could predict overall survival of ESCC patients.

Cardiac Lymphatic Dysfunction Causes Drug-Eluting Stent-Induced Coronary Hyperconstricting Responses in Pigs In Vivo.

Objective- We have previously demonstrated that coronary adventitial inflammation plays important roles in the pathogenesis of coronary vasomotion abnormalities, including drug-eluting stent (DES)-induced coronary hyperconstricting responses. Importantly, the adventitia also harbors lymphatic vessels, which may prevent inflammation by transporting extravasated fluid and inflammatory cells. We thus aimed to examine the roles of coronary adventitial lymphatic vessels in the pathogenesis of DES-induced coronary hyperconstricting responses in a porcine model in vivo. Approach and Results- We performed 2 experimental studies. In protocol 1, 15 pigs were divided into 3 groups with or without DES and with bare metal stent. Nonstented sites 20 mm apart from stent implantation also were examined. In the protocol 2, 12 pigs were divided into 2 groups with or without lymphatic vessels ligation followed by DES implantation at 2 weeks later (n=6 each). We performed coronary angiography 4 weeks after DES implantation, followed by immunohistological analysis. In protocol 1, the number and the caliber of lymphatic vessels were greater at only the DES edges after 4 more weeks. In protocol 2, coronary hyperconstricting responses were further enhanced in the lymphatic vessels ligation group associated with adventitial inflammation, Rho-kinase activation, and less adventitial lymphatic vessels formation. Importantly, there were significant correlations among these inflammation-related changes and enhanced coronary vasoconstricting responses. Conclusions- These results provide evidence that cardiac lymphatic vessel dysfunction plays important roles in the pathogenesis of coronary vasoconstrictive responses in pigs in vivo.

Glucocorticoid receptor and serum- and glucocorticoid-induced kinase-1 in esophageal adenocarcinoma and adjacent Barrett's esophagus.

Barrett's esophagus (BE) is a consequence of gastroesophageal reflux disease and is predisposed to esophageal adenocarcinoma (EAC). EAC is an exemplar model of inflammation-associated cancer. Glucocorticoids suppress inflammation through glucocorticoid receptor (GR) and serum- and glucocorticoid-induced kinase-1 (Sgk1) expressions. Therefore, we immunolocalized GR and Sgk1 in EAC and the adjacent BE tissues and studied their association with clinical disease course in 87 patients with EAC who underwent surgical resection (N = 58) or endoscopic submucosal dissection (N = 29). Low GR and Sgk1 expressions in adjacent BE tissues were associated with adverse clinical outcomes (P = 0.0008 and 0.034, respectively). Patients with low Sgk1 expression in EAC cells exhibited worse overall survival (P = 0.0018). In multivariate Cox regression analysis, low GR expression in the adjacent nonmalignant BE tissues was significantly associated with worse overall survival (P = 0.023). The present study indicated that evaluation of GR and Sgk1 expressions in both the EAC cells and adjacent nonmalignant BE tissues could help to predict clinical outcomes following endoscopic and surgical treatments. In particular, the GR status in BE tissues adjacent to EAC was an independent prognostic factor.

Time to symptom onset and manual reduction outcomes as predictors of bowel viability in incarcerated obturator hernias.

The current study aimed to identify the indications for manual reduction in incarcerated obturator hernias (OH). Further, whether time to symptom onset and manual reduction outcomes can be predictors of bowel viability and the need for bowel resection in incarcerated OH were examined. This retrospective study included 26 patients with incarcerated OH who underwent surgery. All patients underwent manual reduction, and computed tomography scan after manual reduction confirmed hernia release. Multivariate analyses were performed to determine the predictors of bowel resection. The bowel resection group had a significantly longer average time to symptom onset than the nonbowel resection group (88 vs 36 h). Further, the bowel resection group was more likely to have failed manual reduction than the nonbowel resection group. A time to symptom onset of ≥ 72 h and failed manual reduction were significant predictors of bowel viability. Age, sex, hernia localization, American Society of Anesthesiologists physical status score, and laboratory findings did not differ significantly between the bowel resection and nonbowel resection groups. Time to symptom onset and manual reduction outcomes are significant predictors of bowel viability in incarcerated OH. Patients with a time to symptom onset of ≥ 72 h and failed manual reduction require surgical evaluation due to a high risk of bowel nonviability. Therefore, a cautious approach is required in the management of OH, and further research on optimized treatment protocols should be conducted.

Manual reduction for incarcerated obturator hernia.

Emergent surgery is a common approach for incarcerated obturator hernias, with high morbidity and mortality rates. Moreover, there have been reports of elective surgery cases after noninvasive manual reduction. For a decade, the initial approach in our institution is also manual reduction unless bowel viability is poor. This study aimed to clarify the efficacy and safety of manual reduction followed by elective surgery. We retrospectively reviewed 50 cases of incarcerated obturator hernia from 2010 to 2022 at Iwate Prefectural Iwai Hospital. Manual reduction was attempted in 31 (62%) patients. The reduction was successful in 21 (42%) patients, and most of them received mesh repair using the extraperitoneal approach as elective surgery. However, two patients underwent emergent surgery in the waiting period because of late-onset constriction and a small bowel perforation. Patients with irreducible hernia underwent emergent surgery, except for two patients who received the best supportive care. Postoperative complications were observed in 5% and 22% of reducible and irreducible cases, respectively. Postoperative mortality was zero in both groups. Manual reduction is useful in some cases, but careful observation is needed because late-onset constriction and perforation could occur.

HO-1 in lymph node metastasis predicted overall survival in patients with esophageal squamous cell carcinoma receiving neoadjuvant chemoradiation therapy.

BACKGROUND: Lymph node metastasis is one of the pivotal factors of the clinical outcomes of patients with esophageal cancer receiving neoadjuvant chemoradiation therapy (NACRT). Both the nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway and heme oxygenase-1 (HO-1) are frequently upregulated in various human malignancies and associated with resistance to chemoradiation therapy, subsequently resulting in adverse clinical outcomes. However, the Nrf2 and HO-1 status in lymph node metastasis and their differences between primary and metastatic lesions are unknown. AIMS: To examine the levels of Nrf2 signaling proteins and HO-1 in primary and metastatic lesions of patients with esophageal squamous cell carcinoma using immunohistochemistry. METHODS AND RESULTS: We immunolocalized Nrf2 signaling proteins in 69 patients with lymph node metastases, who received NACRT with 5-fluorouracil and cisplatin before esophagectomy. We also compared the findings between primary and metastatic lesions. Residual lymph node metastases were detected in 30 patients and among them, both primary and metastatic lesions were available for evaluation in 25 patients. Subsequently, we correlated the results with patients' survival. Nrf2, HO-1, and the Ki-67 labeling index were all significantly lower in the patients with lymph node metastases than in those with primary tumors. Carcinoma cells with high HO-1 levels were significantly associated with pathological resistance to NACRT. These results suggested that overall and disease-free survival of esophageal squamous cell carcinoma were significantly associated with both pN2 and high HO-1 levels, respectively. CONCLUSIONS: Protein expression in the Nrf2 pathway was significantly lower in patients with lymph node metastases than in those with primary lesions. HO-1 levels in lymph node metastases could be used to predict the eventual clinical outcome of patients with esophageal cancer receiving NACRT.

Thoracoscopic esophagectomy for esophageal carcinoma after peroral endoscopic myotomy for esophageal achalasia: a case report.

BACKGROUND: Esophageal achalasia causes dysphagia following impaired relaxation of the lower esophageal sphincter due to the degeneration of Auerbach's plexus in the esophageal smooth muscle. Recently, peroral endoscopic myotomy (POEM) has become one of the preferred treatment options for esophageal achalasia. However, pathomorphological changes after POEM have not been well examined. CASE PRESENTATION: A 65-year-old man with a history of POEM for esophageal achalasia was diagnosed with clinical stage II (cT2-N0-M0) thoracic esophageal squamous cell carcinoma and was consequently treated with neoadjuvant chemotherapy followed by thoracoscopic esophagectomy. Intraoperatively, the esophagus appeared dilated, reflecting esophageal achalasia; however, fairly slight fibrous adhesions were observed between the esophagus and the pericardial surface despite previously performed POEM via an anterior incision. Histopathological examination revealed esophageal wall thickening, edema, and fibrosis extending from the lamina propria to the submucosa. Besides, the majority of the inner layer and some proportion of the outer layer of the muscularis propria were found to be missing or atrophic at the esophagogastric junction (EGJ). No ganglion cells could be detected at the Auerbach's plexus. CONCLUSIONS: The previous history of POEM did not affect circumferential mediastinal periesophageal dissection during thoracoscopic esophagectomy. Nevertheless, a large proportion of the inner layer of the muscularis propria at the EGJ level seemed to have become lost or atrophic because of the POEM procedure.

Necroptosis in Esophageal Squamous Cell Carcinoma: An Independent Prognostic Factor and Its Correlation with Tumor-Infiltrating Lymphocytes.

Necroptosis is a pivotal process in cancer biology; however, the clinical significance of necroptosis in esophageal squamous cell carcinoma (ESCC) has remained unknown. Therefore, in this study, we aimed to verify the potential involvement of necroptosis in the clinical outcome, chemotherapeutic resistance, and tumor microenvironment of ESCC. Mixed lineage kinase domain-like protein (MLKL) and phosphorylated MLKL (pMLKL) were immunohistochemically examined in 88 surgically resected specimens following neoadjuvant chemotherapy (NAC) and 53 pre-therapeutic biopsy specimens, respectively. Tumor-infiltrating lymphocytes (TILs) were also evaluated by immunolocalizing CD3, CD8, and forkhead box protein 3 (FOXP3) in the residual tumors after NAC. High pMLKL status in the post-NAC resected specimens was significantly correlated with worse prognosis in ESCC patients. Multivariate analysis demonstrated that a high pMLKL status was an independent prognostic factor. In pre-NAC biopsy specimens, a high pMLKL status was significantly associated with a lower therapeutic efficacy. CD8+ TILs were significantly lower in the high-pMLKL group. FOXP3+ TILs were significantly higher in both high-MLKL and high-pMLKL groups. We first demonstrated pMLKL status as an independent prognostic factor in ESCC patients. Our study revealed the possible involvement of necroptosis in the immunosuppressive microenvironment, resulting in the attenuated therapeutic efficacy of NAC and eventual adverse clinical outcomes in ESCC.

Immune microenvironment in Barrett's esophagus adjacent to esophageal adenocarcinoma: possible influence of adjacent mucosa on cancer development and progression.

The immune microenvironment plays a pivotal role in cancer development and progression. Therefore, we studied the status of immune cells in esophageal adenocarcinoma (EAC) and adjacent Barrett's esophagus (BE) and their association with the clinical course of patients. We included 87 patients with EAC who underwent surgical resection or endoscopic submucosal dissection. CD3, CD8, Foxp3, p53, and Ki-67 were immunolocalized in EAC and adjacent BE (N = 87) and BE without EAC (N = 13). BE adjacent to EAC exhibited higher CD3+ lamina propria lymphocyte (LPL) numbers than BE without EAC. Abundant Foxp3+ LPLs in BE were associated with dysplasia and increased Ki-67 labeling index (LI) in BE glandular cells and tended to link to aberrant p53 expression. Abundant CD8+ LPLs in adjacent BE were associated with worse prognosis of EAC patients (P = 0.019). Results of our present study firstly revealed the potential influence of the tissue immune microenvironment of BE adjacent to EAC on cancer development and eventual clinical outcome of EAC patients. T cell infiltration could play pivotal roles in facilitating the dysplasia-adenocarcinoma sequence in BE. The number of Foxp3+ T cells is increased at the early stage of carcinogenesis and could help identify patients harboring dysplastic and highly proliferating cells. CD8+ T cells could reflect unfavorable inflammatory response in adjacent tissue microenvironment and help predict worse prognosis of EAC patients.

Curative resection of advanced esophageal cancer with metachronous stage IV breast cancer: A case report.

INTRODUCTION: Recent studies have shown the safety and efficacy of curative resection of esophageal cancer with multiple primary cancers. However, our literature search revealed no curative surgery cases for esophageal cancer in patients with multiple primary cancers with distant metastasis. CASE PRESENTATION: A 75-year-old woman visited our hospital with dysphagia. She had a history of breast cancer with multiple bone metastasis. Esophagogastroduodenoscopy revealed a circumferential mass in the upper intrathoracic esophagus. Histopathological examination of the biopsy showed squamous cell carcinoma. Other imaging findings revealed multiple nodules in the liver. The nodules were thought to have originated from the breast, but metastasis of esophageal cancer was considered a possibility. Intraoperative frozen sections of the liver and peritoneal nodules showed adenocarcinoma. Thoracoscopic esophagectomy was then performed. Following surgery, the patient received fulvestrant therapy, followed by capecitabine therapy, and the liver tumors decreased in size. She is currently alive after 1.5 years of the surgery without local recurrence of esophageal cancer. DISCUSSION: Although the patient had metastatic breast cancer, her relapse-free interval of 20 years and good response to hormone therapy for 15 years were favorable prognostic factors. Her life expectancy was estimated to be a few years and surgery was performed. CONCLUSION: Curative resection could be considered for patients with esophageal cancer who have an additional cancer with distant metastasis when the prognosis of the additional cancer is not poor.