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.

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.

Reconstruction of Multiple Facial Nerve Branches Using Skeletal Muscle-Derived Multipotent Stem Cell Sheet-Pellet Transplantation.

Head and neck cancer is often diagnosed at advanced stages, and surgical resection with wide margins is generally indicated, despite this treatment being associated with poor postoperative quality of life (QOL). We have previously reported on the therapeutic effects of skeletal muscle-derived multipotent stem cells (Sk-MSCs), which exert reconstitution capacity for muscle-nerve-blood vessel units. Recently, we further developed a 3D patch-transplantation system using Sk-MSC sheet-pellets. The aim of this study is the application of the 3D Sk-MSC transplantation system to the reconstitution of facial complex nerve-vascular networks after severe damage. Mouse experiments were performed for histological analysis and rats were used for functional examinations. The Sk-MSC sheet-pellets were prepared from GFP-Tg mice and SD rats, and were transplanted into the facial resection model (ST). Culture medium was transplanted as a control (NT). In the mouse experiment, facial-nerve-palsy (FNP) scoring was performed weekly during the recovery period, and immunohistochemistry was used for the evaluation of histological recovery after 8 weeks. In rats, contractility of facial muscles was measured via electrical stimulation of facial nerves root, as the marker of total functional recovery at 8 weeks after transplantation. The ST-group showed significantly higher FNP (about three fold) scores when compared to the NT-group after 2-8 weeks. Similarly, significant functional recovery of whisker movement muscles was confirmed in the ST-group at 8 weeks after transplantation. In addition, engrafted GFP+ cells formed complex branches of nerve-vascular networks, with differentiation into Schwann cells and perineurial/endoneurial cells, as well as vascular endothelial and smooth muscle cells. Thus, Sk-MSC sheet-pellet transplantation is potentially useful for functional reconstitution therapy of large defects in facial nerve-vascular networks.

Preferential and comprehensive reconstitution of severely damaged sciatic nerve using murine skeletal muscle-derived multipotent stem cells.

Loss of vital functions in the somatic motor and sensory nervous systems can be induced by severe peripheral nerve transection with a long gap following trauma. In such cases, autologous nerve grafts have been used as the gold standard, with the expectation of activation and proliferation of graft-concomitant Schwann cells associated with their paracrine effects. However, there are a limited number of suitable sites available for harvesting of nerve autografts due to the unavoidable sacrifice of other healthy functions. To overcome this problem, the potential of skeletal muscle-derived multipotent stem cells (Sk-MSCs) was examined as a novel alternative cell source for peripheral nerve regeneration. Cultured/expanded Sk-MSCs were injected into severely crushed sciatic nerve corresponding to serious neurotmesis. After 4 weeks, engrafted Sk-MSCs preferentially differentiated into not only Schwann cells, but also perineurial/endoneurial cells, and formed myelin sheath and perineurium/endoneurium, encircling the regenerated axons. Increased vascular formation was also observed, leading to a favorable blood supply and waste product excretion. In addition, engrafted cells expressed key neurotrophic and nerve/vascular growth factor mRNAs; thus, endocrine/paracrine effects for the donor/recipient cells were also expected. Interestingly, skeletal myogenic capacity of expanded Sk-MSCs was clearly diminished in peripheral nerve niche. The same differentiation and tissue reconstitution capacity of Sk-MSCs was sufficiently exerted in the long nerve gap bridging the acellular conduit, which facilitated nerve regeneration/reconnection. These effects represent favorable functional recovery in Sk-MSC-treated mice, as demonstrated by good corduroy walking. We also demonstrated that these differentiation characteristics of the Sk-MSCs were comparable to native peripheral nerve-derived cells, whereas the therapeutic capacities were largely superior in Sk-MSCs. Therefore, Sk-MSCs can be a novel/suitable alternative cell source for healthy nerve autografts.

Delayed hemothorax superimposed on extrapleural hematoma after blunt chest injury: a case report.

We report a case showing delayed hemothorax superimposed on extrapleural hematoma after blunt chest injury. The patient was a 56-year-old man with a medical history of alcoholic hepatopathy who presented with a chief complaint of dyspnea on exertion. One month prior to presentation, he had sustained a fall that had resulted in left simple rib fracture. A chest radiograph taken at the time of injury showed notable reduction in the permeability of the left lung field along with high pulmonary collapse as well as rightward deviation of the shadow of the inferior mediastinum. Chest CT images showed a region of low absorption in the thoracic cavity with septi. Thoracic drainage was performed (1,300 mL total) and hemothorax was diagnosed. Thoracoscopic examination was then performed. When the inside of the thorax was observed, what had been presumed to be the septi of a multilocular fluid collection was found to be actually the parietal pleura, and a hematoma was confirmed inside the extrapleural cavity. The hematoma inside the extrapleural cavity was managed with lavage and drainage, and drainage tubes were placed inside both the thoracic cavity and extrapleural cavity at the end of the procedure. The patient's postoperative course was uneventful, and he was discharged on postoperative day 4.

Case of adolescent lung cancer resectable by the microthoracoscopic one-port method.

An abnormal shadow was detected in a 15-year-old male adolescent by routine chest radiography during a school medical examination. Further detailed examination demonstrated stage IA primary lung adenocarcinoma in the right inferior lobe. The patient then underwent surgery. The right inferior lobe was resected, and the mediastinal lymph node was dissected by the microthoracoscopic one-port method. Thoracoscopic surgery for stage IA primary adult lung cancer has been established. However, no report has been published on thoracoscopic surgery, particularly the one-port method, for rare primary lung cancer in an adolescent, as demonstrated in this case.

Periodic appearance and disappearance of a chest wall (serratus anterior development) cavernous hemangioma that was finally resected in a child.

Primary chest wall tumors occur infrequently; in particular, cavernous hemangioma of the chest wall is an extremely rare disease. We report a case of child with cavernous hemangioma of the chest wall, which was successfully resected. Obvious enlargement of the tumor and the appearance of pain were observed during a 2-year follow-up. In the present case, transcutaneous ultrasonography showed the appearance and disappearance of the mass. This was considered to be caused by the transfer of contents between the shallow and deep parts of the tumor. This may have resulted from serratus anterior muscle movement between the two-layered tumor. Transcutaneous ultrasonography, as well as magnetic resonance imaging, was therefore extremely effective for preoperative diagnosis. Transcutaneous ultrasonography is easily performed, even in children, such as in the present case. Because of its simplicity and usefulness, transcutaneous ultrasonography may be considered as the first-line imaging modality for diagnosis.

[Rectal tenesmus due to tumor invasion into the pelvic cavity responding favorably to antiarrhythmic drug therapy].

We experienced 3 patients(Cases 1, 3, and 4)with pelvic tumor-related rectal tenesmus showing favorable responses to antiarrhythmic drugs. Based on this experience, we administered antiarrhythmic drugs preferentially to 2 others with tumor derived rectal tenesmus(Cases 2 and 5), and again obtained favorable responses. These 5 patients(1 man, 4 women)were 28-89(mean 58)years of age. The primary lesion was cervical cancer in 3 patients, ovarian cancer in 1, and bladder cancer in 1. In the 3 with cervical cancer, the tumor had directly infiltrated the rectum and vulva. The patient with ovarian cancer had a residual tumor in the Douglas pouch postoperatively. The patient with bladder cancer had undergone total cystectomy and urinary diversion using an ileal conduit at another institution. All 5 patients complained of a frequent desire to defecate without feces(rectal tenesmus). Their rectal tenesmus was attributed to pelvic neurological dysfunction around the rectum. Drug therapy was initiated with oral mexiletine hydrochloride(Mexitil)150 mg in 3 divided doses in 4 patients and with continuous infusion of intravenous lidocaine 2%(Xylocaine)500mg/day in the other(Case 2). None had adverse reactions; all 5 experienced palliation of symptoms and improved quality of life.

Laminin-5γ2 chain expression is associated with tumor cell invasiveness and prognosis of lung squamous cell carcinoma.

Our previous study showed that tumor budding is a significant indicator of a poor prognosis in lung squamous cell carcinoma patients. Tumor budding-positive (Bud(+)) cases of lung squamous cell carcinoma (SqCC) showed locally aggressive growth, and the positivity was a useful indicator of the lymph node status and prognosis. The present study focused on the clinicopathologic significance of laminin-5γ2 chain expression for local aggressiveness in lung SqCC. Laminin-5γ2 chain immunohistochemical stains in tissue samples were divided into three distinct types: basement membrane (B type; laminin-5γ2 present in basement membrane), cytoplasmic (C type; laminin- 5γ2 present in intracellular matrix), and invasive front (F type; laminin-5γ2 present in cytoplasm, and strongly in part of peripheral nest). The F type was more common in Bud(+) cases than tumor budding-negative (Bud(-)) cases; B and C types were less common in Bud(+) cases (P 〈 0.001). The F type was more closely associated with decreased overall survival than the B and C types (P 〈 0.001 for both). Univariate analysis showed that the F type could be used to predict tumor size, lymph node metastasis, lymphatic invasion, tumor infiltrative patterns, tumor budding, and laminin-5γ2 chain staining. Multivariate analysis showed that laminin-5γ2 chain staining and tumor budding could be used to predict patient mortality (P 〈 0.001 and P = 0.005, respectively). The overall survival rate after curative resection was lower in patients with the F/Bud(+) type than in those with B+C/Bud(-) and B+C/Bud(+) types (P < 0.001 for both, log-rank test), and also lower with the F/Bud(-) type than the B+C/Bud(-) type. On the other hand, there was no significant difference between the F/Bud(+) and F/Bud(-) types. In conclusion, both laminin- 5γ2 chain staining and tumor budding are associated with tumor cell invasiveness and are independent predictors of mortality in lung SqCC patients.

Localized malignant pleural mesothelioma.

Localized malignant pleural mesothelioma (LMPM) is a rare tumor; previously only 52 cases have been reported in the English literature. This type of tumor should be distinguished from diffuse malignant pleural mesothelioma, because a good outcome may be obtained by surgical resection. We report a case of LMPM which grew rapidly within 1 year. Surgical resection was performed, and at present, 6 months since the operation, the patient remains free of the disease.

[Surgical therapy focusing mainly on endoscopic treatment].

Endoscopic surgery was popularized at the beginning of the 1990s in Japan, along with the development of video optical instruments, and it was soon applied to the treatment of solid cancers. Less invasive surgical techniques were sought using various approaches in various fields in the 2000s, and now in 2010 three approaches are notable: (1) single incision laparoscopic surgery using a one window method, which is attracting considerable interest because of its low invasiveness; (2) natural orifice translumenal endoscopic surgery (NOTES); and (3) robotic surgery, which is being pursued as a new modality. Further improvements in all these methods are anticipated as a result of the development of new instruments and the mastery of surgical techniques. However, an assurance of the safety of surgical procedures and a good prognosis are requisites for all these methods, and a level of quality equivalent to that of surgical techniques such as traditional thoracic and abdominal surgery must be maintained. Although these methods seem to represent difference paths, investigations of the various surgical techniques pursued by surgeons reveal that the various paths merge to reach the same goal. Therefore, extensive studies of new surgical techniques in various fields are needed to ensure that these new techniques hold up to the expectations of surgeons.