Significance of ZO-1, an Intercellular Adhesion Molecule, as a Prognostic Marker in Lung Adenocarcinoma.

In epithelial tissues, intercellular adhesion structures are formed between adjacent cells via intercellular adhesion factors, such as zonula occludens (ZO-1), to maintain the structure and function of tissues and organs, thereby contributing to homeostasis. Epithelial cells are polarized into apical and basal regions by tight junctions (TJs), a type of intercellular adhesion structure, and thus, their intracellular organelles are asymmetrically distributed. Normal epithelial cells maintain their cellular function by controlling cytoskeletal reorganization, motility, and division by maintaining asymmetry in their intracellular organelles. Among the features common to many cancer tissues are abnormalities in cell polarity and intercellular adhesion. Lung adenocarcinoma consists of a mixture of five different histologic types that can be distinguished in the same section: lepidic, papillary, acinar, micropapillary, and solid patterns. Therefore, it is often difficult to accurately assess histological images because the staining differs according to the histological types. In the present study, we evaluated ZO-1 staining based on histological features observed in a single section and examined its relationship to clinicopathological features. In non-tumor areas, ZO-1 was expressed on the plasma membrane and in the cytoplasm of normal alveolar epithelial cells. However, in tumor areas, ZO-1 staining was mainly localized in the cytoplasm and on the plasma membrane only in a few cells. ZO-1-negative cases tended to have poorer prognoses in all histological types, with a poorer prognosis in the solid pattern. These results suggest that ZO-1 expression in solid-pattern lung adenocarcinoma may be a useful prognostic marker.

Protective effect of ebselen on bleomycin-induced lung fibrosis: analysis of the molecular mechanism of lung fibrosis mediated by oxidized diacylglycerol.

The molecular mechanisms underlying the development of pulmonary fibrosis remain unknown, and effective treatments have not yet been developed. It has been shown that oxidative stress is involved in lung fibrosis. Oxidized diacylglycerol (DAG) produced by oxidative stress is thought to play an important role in lung fibrosis. This study assessed the effect of oxidized DAG in an animal model of pulmonary fibrosis induced by aspiration of bleomycin (BLM) into the lungs. The inhibitory effect of ebselen on pulmonary fibrosis was also investigated. In lung fibrotic tissue induced by BLM, an increase in lipid peroxides and collagen accumulation was observed. Moreover, the levels of oxidized DAG, which has strong protein kinase C (PKC) activation activity, were significantly increased over time following the administration of BLM. Western blotting showed that phosphorylation of PKCα and δ isoforms was increased by BLM. Oral administration of ebselen significantly suppressed the increase in oxidized DAG induced by BLM and improved lung fibrosis. PKCα and δ phosphorylation were also significantly inhibited. The mRNA expression of α-smooth muscle actin and collagen I (marker molecules for fibrosis), as well as the production of transforming growth factor-ß and tumor necrosis factor-α(a potentially important factor in the fibrotic process), were increased by BLM and significantly decreased by ebselen. The administration of BLM may induce lipid peroxidation in lung tissue, while the oxidized DAG produced by BLM may induce overactivation of PKCα and δ, resulting in the induction of lung fibrosis.

Laparoscopic repair of diaphragmatic hernia associating with radiofrequency ablation for hepatocellular carcinoma: A case report.

BACKGROUND: Radiofrequency ablation (RFA) is an effective treatment for early-stage hepatocellular carcinoma (HCC). Although RFA is a relatively safe technique compared with surgery, several complications have been reported to be following/accompanying this treatment. Delayed diaphragmatic hernia caused by RFA is rare; however, the best surgical approach for its treatment is uncertain. We present a case of laparoscopic repair of diaphragmatic hernia due to RFA. CASE SUMMARY: An 80-year-old woman with segment VIII HCC was treated twice in 5 years with RFA; 28 mo after the second RFA, the patient complained of right hypochondriac pain. Computed tomography revealed that the small intestine was incarcerated in the right thorax. The patient was diagnosed with diaphragmatic hernia and underwent laparoscopic repair by non-absorbable running sutures. The patient's postoperative course was favorable, and the patient was discharged on postoperative day 12. The diaphragmatic hernia has not recurred 24 mo after surgery. CONCLUSION: Laparoscopic treatment of iatrogenic diaphragmatic hernia is effective and minimally invasive.

Par3 and ZO-1 Membrane Clustering is an Indicator of Poor Prognosis in Lung Squamous Cell Carcinoma.

Epithelial cells form epithelial tissue structures by joining together via intercellular adhesion structures composed of intercellular adhesion factors such as zona occludins-1 (ZO-1). Epithelial cells are polarized at the apical and basal regions, and are bordered by intercellular adhesion structures called tight junctions; the organelles within epithelial cells are distributed asymmetrically. Maintenance of this asymmetry in normal epithelial cells is essential for normal cytoskeletal remodeling, movement, and cell division. The key factor regulating cell polarity is called partitioning-defective protein 3 (Par3). Abnormalities in cell polarity and intercellular adhesion are common features of many cancer tissues. Mutation and loss of cell polarity regulators contributes to the immortalization of normal cells and to the malignant transformation of cancer cells. In this study, we investigated the relationship between the subcellular localization of Par3 and ZO-1 and clinicopathological features of lung squamous cell carcinoma (lung SqCC). Both molecules were localized to the cell membrane in normal lung tissue, but the levels were lower at this location in pulmonary tumor tissue compared with normal lung tissue. Both Par3 and ZO-1 accumulated in clusters on the cell membrane (hereinafter, "foci"). Tumor size, recurrence rate, and mortality rate were significantly higher in patients with Par3 foci compared to those without Par3 foci. Rates of lymph node metastasis, recurrence, and mortality were significantly higher in patients with ZO-1 foci than in those without ZO-1 foci. The expression of Par3 and ZO-1 mRNA was not s ignificantly different in s amples from p atients with foci versus those without. These results strongly suggest that the presence of Par3 and ZO-1 foci on the membrane may be a useful prognostic marker for lung SqCC.

A case of lung adenocarcinoma with a novel CD74-ROS1 fusion variant identified by comprehensive genomic profiling that responded to crizotinib and entrectinib.

ROS1 rearrangements are found in 1-2% of patients with non-small-cell lung cancer. The detection of the rearrangements is crucial since clinically effective molecular targeted drugs are available for them. We present a case of lung adenocarcinoma with a previously unknown ROS1-CD74 fusion variant, CD74 exon 3 fused to ROS1 exon 34, which was not detected by a conventional RT-PCR-based test for ROS1 fusion gene detection but identified by hybrid capture-based next-generation sequencing. This tumor responded to crizotinib initially and to entrectinib after relapse with brain metastasis, indicating the oncogenic activity of this novel fusion variant.

Inflammatory breast cancer associated with amyopathic dermatomyositis: a case report.

BACKGROUND: Dermatomyositis is associated with malignant tumors including breast cancer, and inflammatory breast cancer is considered to have a poorer prognosis than most breast cancers. CASE PRESENTATION: A 74-year-old Asian woman, developed erythema on her face, back, and the back of her hands, 3 weeks before attending our department. At the same time, she had noticed a right breast mass and redness of the skin of the breast. The clinical findings and vacuum aspiration biopsy diagnosed inflammatory breast cancer and neoadjuvant chemotherapy was performed. The mass and enlarged axillary lymph nodes had shrunk, therefore a total mastectomy was performed. The sentinel lymph node biopsy was negative. She was discharged 7 days after surgery without any complications. She has received a postoperative aromatase inhibitor and is alive without recurrence. The dermatomyositis also began to improve with the start of her chemotherapy and has not recurred since the surgery. CONCLUSIONS: Neoadjuvant chemotherapy was performed for inflammatory breast cancer with dermatomyositis, and tumor shrinkage was confirmed. A total mastectomy without axillary lymph node dissection was performed. Dermatomyositis and breast cancer have not recurred. Dermatomyositis may have been a paraneoplastic syndrome due to breast cancer.

A surgical case of methotrexate-associated lymphomatoid granuloma.

We reported a surgical case of methotrexate-associated lymphomatoid granuloma. A 69-year-old female had been treated with methotrexate for rheumatoid arthritis for 35 months. The patient underwent partial resection of the right upper pulmonary lobe for lung cancer when she was 67 years old. A nodule was detected in the left lung field on a chest radiograph performed during the postoperative follow-up period. Computed tomography revealed a 28-mm nodule in the lower left pulmonary lobe. A transbronchial biopsy examination did not lead to a diagnosis. The pulmonary nodule subsequently increased in size. We suspected a malignant tumor and performed lower left lobectomy. A pathological examination revealed lymphomatoid granuloma. Finally, the patient was diagnosed with methotrexate-associated lymphomatoid granuloma based on her history of oral methotrexate treatment.

Acute Cerebellar Ataxia Induced by Nivolumab.

A 54-year-old woman with adenocarcinoma of the lung and lymph node metastasis experienced nystagmus and cerebellar ataxia 2 weeks after initiating nivolumab therapy. An evaluation for several autoimmune-related antibodies and paraneoplastic syndrome yielded negative results. We eventually diagnosed the patient with nivolumab-induced acute cerebellar ataxia, after excluding other potential conditions. Her ataxic gait and nystagmus resolved shortly after intravenous steroid pulse therapy followed by the administration of decreasing doses of oral steroids. Nivolumab, an immune checkpoint inhibitor, is known to induce various neurological adverse events. However, this is the first report of acute cerebellar ataxia associated with nivolumab treatment.

Lymphatic invasion is a significant indicator of poor patient prognosis in lung squamous cell carcinoma.

Pathological stage is the most important prognostic factor in patients with lung cancer, and is defined according to the tumor node metastasis classification system. The present study aimed to investigate the clinicopathological significance of lymphatic invasion in 103 patients who underwent surgical resection of lung squamous cell carcinoma (SqCC). The patients were divided into two groups, according to the degree of lymphatic invasion: Those with no or mild lymphatic invasion (ly0­1) and those with moderate or severe lymphatic invasion (ly2­3). Ly2­3 was associated with tumor size (P=0.028), lymph node metastasis (P<0.001), venous invasion (P=0.001) and histological differentiation (P=0.047). Statistical analysis using the Kaplan­Meier method and the log­rank test indicated that overall survival was significantly reduced in patients with ly2­3 compared with those with ly0­1 (P<0.001). Multivariate analysis identified ly2­3 as an independent predictor of mortality (hazard ratio, 2.580; 95% confidence interval, 1.376­4.839). In conclusion, moderate or severe lymphatic invasion (ly2­3) indicated a high malignant potential and may be considered an independent predictor of poor prognosis in patients with SqCC of the lung.

Body mass index, C-reactive protein and survival in smokers undergoing lobectomy for lung cancer†.

OBJECTIVES: Cachexia has been shown to be related to mortality in patients with advanced cancers and chronic obstructive pulmonary disease. Smokers receiving surgery for lung cancer are thought to be at risk of developing cachexia postoperatively. We aimed to investigate whether 2 surrogate variables for cachexia, body mass index (BMI) and C-reactive protein (CRP) level, are predictive of mortality in smokers after complete resection of non-small-cell lung cancer. METHODS: We retrospectively examined 678 patients who underwent curative lobar resection for non-small-cell lung cancer at our hospital. Associations between clinicopathological factors and overall survival were assessed in smokers ( N = 421) and never smokers ( N = 257). RESULTS: Multivariate analysis of the smokers group showed that preoperative BMI ≤ 20.6 kg/m 2 and CRP ≥ 0.13 ng/ml were risk factors for poorer prognosis, independent of age and pathological stage. In never smokers, BMI and CRP were not significantly associated with survival. Smokers in the high-risk group, defined based on preoperative BMI and CRP, had shorter survival after recurrence, although they did not have an elevated recurrence rate. Despite the absence of recurrence, they died more frequently of pneumonia or other cancers. These observations are consistent with the idea that the poor postoperative prognosis could have resulted from the progression of cachexia. CONCLUSIONS: In smokers with non-small-cell lung cancer, preoperative low BMI and elevated CRP are predictive factors for poor prognosis after complete resection, probably as a result of cachexia progression. The effective treatment of cachexia might improve postoperative prognosis.

Epidermal Growth Factor Receptor Mutations and Prognosis in Pathologic N1-N2 Pulmonary Adenocarcinoma.

BACKGROUND: Advanced unresectable pulmonary adenocarcinoma with the epidermal growth factor receptor (EGFR) exon 21 L858R point mutation (Ex21) is associated with a poor prognosis. However, for early-stage resectable adenocarcinoma, Ex21 tumors have a lower-grade malignancy than exon 19 deleted (Ex19) tumors. We therefore investigated the effect of EGFR mutations on the prognosis in patients with completely resected pN1-N2 adenocarcinoma. METHODS: Five-year disease-free survival (DFS) and overall survival (OS) were analyzed in 202 pN1-N2 pulmonary adenocarcinoma patients, 100 of whom had EGFR mutations, comprising Ex21 in 41 (20.3%), Ex19 in 55 (27.2%), and Ex18 in 4 (2%). RESULTS: Patients with and without EGFR mutations had similar DFS (26.2% vs 24.6%, respectively; p = 0.280) and OS (64.9% vs 54.2%, respectively; p = 0.564). Patients with Ex19 tumors had significantly better DFS (38.8% vs 11.8%, p = 0.001) and tended to have better OS (78.3% vs 48.3%, p = 0.123) than those with Ex21 tumors. For pN1, patients with Ex19 tumors had a longer disease-free interval (54.0 vs 22.3 months, p = 0.003) and median survival time (81.0 vs 50.6 months, p = 0.022) than those with Ex21 tumors. For pN2, patients with Ex19 tumors had longer disease-free interval than those with Ex21 tumors (43.6 vs 30.1 months, p = 0.109). Multivariate analysis showed Ex21 was a prognosticator of poor DFS (hazard ratio, 2.25; 95% confidence interval, 1.21 to 4.20). CONCLUSIONS: For pN1-N2 pulmonary adenocarcinoma, Ex21 mutation was associated with poorer prognosis than Ex19 mutation. Thus, EGFR mutation status should be considered when predicting prognosis.

Suspected Aerogenous Lung Metastases From Nasopharyngeal Cancer.

A 44-year-old man experiencing repeated episodes of epistaxis and respiratory aspiration was diagnosed with nasopharyngeal cancer. Although the tumor completely disappeared after chemoradiation, six pulmonary nodules developed in the right lower lobe within a year. Right lower lobectomy was performed. All nodules were metastases of the nasopharyngeal cancer. Surgery was performed despite a poor prognosis, and there has been no recurrence 12 years postoperatively. Aerogenous metastases were suggested owing to right lower lobe localization and the patient's symptoms and prolonged survival. The possibility of aerogenous spread and the efficacy of local therapy should be further studied.

Use of a titanium alloy (Chest Way) in the surgical stabilization of flail chest.

To avoid the complications of internal pneumatic stabilization for flail chest, we performed stabilization of the chest wall with a metal bar using the Nuss procedure. Here, we used a highly elastic lightweight biocompatible titanium alloy Chest Way (Solve Corporation, Kanagawa, Japan), enabling magnetic resonance imaging. The patient was a 37-year-old man who sustained injuries in a car crash. Gradually increasing subcutaneous emphysema was present. Bilateral pleural drainage and tracheal intubation were conducted on the scene, and a peripheral venous line was established. The patient was then transferred to our hospital by helicopter. A titanium alloy Chest Way was inserted to manage his flail chest accompanied by multiple rib fractures on the left side. Two days later, artificial respiration was no longer required.

Reduced Expression of Hugl 1 Contributes to the Progression of Lung Squamous Cell Carcinoma.

Cell polarity and cell-cell adhesion play a critical role in the regulation of normal tissue architecture and function. Disruption of cell adhesion and cell polarity is often associated with neoplastic tumors. Loss of apical-basal polarity in epithelial cells is one of the hallmarks of aggressive and invasive cancers. Several polarity proteins including atypical protein kinase C (aPKC), Par 6, Par 3, and Lethal giant larvae (Lgl, the human homologues of which are called Hugl 1 and Hugl 2) are localized at the leading edge of migrating cells, and play critical roles during directional migration. Herein, we investigated the expression of aPKC, Par 6, Par 3, Hugl 1, and Hugl 2 in lung squamous cell carcinoma (SqCC). An inverse correlation was observed between the expression of Hugl 1 and lung SqCC progression. Results of immunohistochemistry and real-time RT-PCR analyses showed that reduced expression of Hugl 1 predicts poor survival in lung SqCC patients. The expression of Hugl 1 was inversely correlated with both overall survival rate and tumor stage. On the other hand, no associations were observed between the expressions of Hugl 2, Par 6, and Par 3 and lung SqCC progression. These findings indicate that the reduced expression of Hugl 1 could be considered as a poor prognostic factor in human lung cancers.

Ki-67 labeling index affects tumor infiltration patterns of lung squamous cell carcinoma.

Ki-67 is a nuclear protein that is expressed during the G1, S, G2 and M phases of the mitotic cell cycle. A previous study categorized tumor infiltration patterns (INF), of which INFc indicated cancer nests exhibiting infiltrative growth and an unclear boundary between tumor tissue and surrounding healthy tissue. The present study used the Ki­67 labeling index (Ki­67 LI) as an indicator of cell proliferation, in order to examine the factors affecting INF in lung squamous cell carcinoma (SqCC). SqCC specimens (89) were classified into two groups: High­grade cell proliferation (Ki­67 LI ≥30%) and low­grade cell proliferation (Ki­67 LI <30%). However, a high Ki­67 LI was significantly associated with cases that had an INFc component [INFc(+); P=0.03]. Univariate analyses indicated that INFc(+) was a predictor of venous invasion [P=0.032; odds ratio (OR), 2.615; 95% confidence interval (95% CI), 1.085­6.305], scirrhous stromal type (P<0.001; OR, 6.462; 95% CI, 2.483­16.817) and high Ki­67 LI (P=0.018; OR, 12.543; 95% CI, 1.531­102.777). Multivariate logistic analyses indicated that high Ki­67 LI was the strongest predictor of INFc(+) (P=0.028; OR, 8.027; 95% CI, 1.248­51.624). In conclusion, high­grade cell proliferation activity may contribute to aggressive infiltrative growth of lung SqCC.

Plexiform schwannoma involving the trachea and recurrent laryngeal nerve: a case report.

Plexiform schwannoma is an infrequent variant of schwannoma characterized grossly and microscopically by multi-nodular growth. Although plexiform schwannoma has such growth patterns, it is a benign tumor as well as a conventional schwannoma. It rarely infiltrates adjacent organs or arises from the organ itself. In this report, we describe a case in which plexiform schwannoma involved the tracheal wall and left recurrent laryngeal nerve to a great extent. As it was expected to be difficult to achieve complete resection even if the longer tracheal resection were performed, we preserved the trachea and resected as much of the tumor as possible. This report is thought to be the first to describe plexiform schwannoma infiltrating or growing from the trachea. Although the treatment decisions we made might be controversial, we believed we could make an accurate diagnosis and adequate treatment decision through surgery.

Localization of aPKC lambda/iota and its interacting protein, Lgl2, is significantly associated with lung adenocarcinoma progression.

Atypical protein kinase C lambda/iota (aPKC λ/ι) is expressed in several human cancers; however, the correlation between aPKC λ/ι localization and cancer progression in human lung adenocarcinoma (LAC) remains to be clarified. We found that patients with a high level of aPKC λ/ι expression in LAC had significantly shorter overall survival than those with a low level of aPKC λ/ι expression. In addition, localization of aPKC λ/ι in the apical membrane or at the cell-cell contact was associated with both lymphatic invasion and metastasis. The intercellular adhesion molecule, E-cadherin, was decreased in LACs with highly expressed aPKC λ/ι at the invasion site of tumor cells. This result suggested that the expression levels of aPKC λ/ι and E-cadherin reflect the progression of LAC. On double-immunohistochemical analysis, aPKC λ/ι and Lgl2, a protein that interacts with aPKC λ/ι, were co-localized within LACs. Furthermore, we found that Lgl2 bound the aPKC λ/ι-Par6 complex in tumor tissue by immune-cosedimentation analysis. Apical membrane localization of Lgl2 was correlated with lymphatic invasion and lymph node metastasis. These results thus indicate that aPKC λ/ι expression is altered upon the progression of LAC. This is also the first evidence to show aPKC λ/ι overexpression in LAC and demonstrates that aPKC λ/ι localization at the apical membrane or cell-cell contact is associated with lymphatic invasion and metastasis of the tumor.

Long-term functional changes after low anterior resection for rectal cancer compared between a colonic J-pouch and a straight anastomosis.

BACKGROUND/AIMS: We prospectively compared changes in function between colonic J-pouch and straight anastomoses from 1 to 5 years after low anterior resection for rectal cancer. METHODOLOGY: At 1, 3, and 5 years after surgery, functional outcome was compared between 48 patients with J-pouch reconstruction (J group) and 51 with straight anastomosis (S group), using a 17-item questionnaire (overall best, 0; overall worst, 26). Reservoir function was evaluated manovolumetrically. RESULTS: At 5 years, patients with ultralow anastomoses (< or =4 cm from anal verge) had fewer bowel movements during day or night, and less urgency and soiling in the J than S group. At that time, patients with low anastomoses (5 to 8 cm above the verge), had fewer bowel movements at night and less urgency in the J than S group. Manovolumetric results were better in the J than S group for both anastomotic levels. Functional scores improved significantly over time for both anastomotic levels, especially in the S group. Mean scores with ultralow anastomoses were J-group, 5.6 at 1 year vs. 5.3 at 3 years (P = 0.0304) vs. 3.7 at 5 years (P < 0.0001); and S group, 10.2 at 1 year vs. 9.6 at 3 years (P = 0.0063) vs. 7.3 at 5 years (P < 0.0001). Mean scores with low anastomoses were J group, 3.4 at 1 year vs. 3.1 at 3 years (P = 0.0052) vs. 2.1 at 5 years (P = 0.0003); and S group, 5.2 at 1 year vs. 3.8 at 3 years (P < 0.0001) vs. 2.7 at 5 years (P < 0.0001). Manovolumetric results improved overtime in both groups. CONCLUSIONS: Functional outcome improved in the J and especially the S group over 5 years. However, function was better in the J than S group at all time points.

Long-term functional outcome of colonic J-pouch reconstruction after low anterior resection for rectal cancer.

PURPOSE: To evaluate the long-term functional outcome of colonic J-pouch reconstruction after low anterior resection (LAR) for rectal cancer in a prospective study. METHODS: We compared the functional outcome of 46 patients who underwent J-pouch reconstruction (J-group) and 49 patients who underwent straight anastomosis (S-group) after LAR for rectal cancer. We evaluated clinical function using a 17-item questionnaire about different aspects of bowel function. Physiologic reservoir function was evaluated by manovolumetry. RESULTS: Among the patients with an ultralow anastomosis (

[Intracellular glutathione (GSH) of monocytes (Mo) directs the development of peritumoral stroma in patients with colon carcinoma].

BACKGROUND: One of the unresolved issues related to immunotherapy for cancers is how to predict the degree of growth of tumor stroma at the periphery of the tumor. We examined the feasibility of predicting stromal growth by measuring the glutathione (GSH) level in monocytes as an indicator of the local redox state of cancer, reflecting anti-tumor immune responses. METHODS: Blood was drawn preoperatively from 21 patients with colorectal cancer. Monocytes were isolated from each blood sample and observed under a fluorescent microscope after fluorescent dye staining. The chromatic responses were rated on a three-grade scale: strongly positive, moderately positive and weakly positive. The monocytes were counted in each grade, and the GSH score was calculated. After surgery, pathology specimens of resected tissue were observed under a microscope to measure the percentage of the surface area of stroma in a given visual field at a magnification of x200. The percentage of stromal surface area was measured for three visual fields (near the deepest area of the tumor) to calculate the stroma score. RESULTS: The mean GSH score was 290.2. The mean stroma score was 60.8. There was a significant correlation between the GSH score and the stroma score (r = 0.421, p < 0.05). CONCLUSION: The monocyte GSH level may serve as a predictor of stromal growth.