Surgical treatment of metastatic lung tumors — Recent changes in techniques and indications

Between 1969 and 1995, 180 patients underwent complete resection of lung metastases during initial thoracotomy at our institute, involving the resection of 917 pulmonary nodules at 202 thoracotomy procedures. The overall postmetastasectomy 5- and 10-year survival rates were 46% and 30%, respectively. Of 111 patients who underwent segmentectomy and/or local excision, 57 had multiple metastases, 39 of whom were treated by Nd:YAG laser after 1986, and 18 by conventional procedures before 1985. The average number of tumors resected per patient treated with the Nd:YAG laser was significantly greater than that of those treated with conventional procedures. However, the survival curve of the laser-treated group was better than that of the laser-nontreated group. Moreover, slightly better survival was achieved in patients operated on after 1992 compared with those operated on before 1991. We conclude that the laser technique may be warranted to afford complete resection of metastases and adequate pulmonary reservation in combination with a selected approach for thoracotomy under the exact detection of tumor localization using the most recent high-quality computed tomography (CT) scan. Furthermore, a one-stage operation to control synchronous intra- and extrapulmonary malignamcies may become a possible option in combination with selective adjunctive therapy.     

Identification and viability assessment of dermatophytes infecting nail based on quantitative PCR of dermatophyte actin (ACT) mRNA]

The diagnosis and choice of treatment for dermatophytoses are usually based on the result of microscopic observation of hyphal elements and culture. However, false negative cultures have sometimes been encountered and appropriate timing of discontinuation of treatment has not been formulated. In this study, we attempted the identification and viability assessment of dermatophytes based on the quantitative measurement of dermatophyte actin (ACT) mRNA. An internal fragment of the ACT, 725 to 762 bp, was isolated by PCR from the genomic DNA of dermatophytes and sequenced. ACT intron-based primers were dermatophyte species-specific and primer pairs crossing the intron were dermatophyte genus-specific. The LightCycler (LC) instrument, employing the two-step RT-PCR/fluorescent hybridization system, was used to quantify the actin mRNA (ACT) of dermatophytes. A 669 bp ACT cDNA fragment was used as a quantification standard. Several mg of samples were collected from skin scales or nail plates before and after the treatment using oral terbinafine. The results indicated that quantification of ACT mRNA correlated with the results of culture and KOH examination and that copy numbers of dermatophyte ACT mRNA per mg sample decreased with progression of the therapy. This method comprises a sensitive (1 fg), specific, rapid (< 4 h) and quantitative assessment of the viability and identification of dermatophytes in skin tissue.     

FGF signaling segregates biliary cell-lineage from chick hepatoblasts cooperatively with BMP4 and ECM components in vitro.

Intrahepatic bile ducts (IHBDs) are indispensable for transporting bile secreted from hepatocytes to the hepatic duct. The biliary epithelial cells (BECs) of the IHBD arise from bipotent hepatoblasts around the portal vein, suggesting the portal mesenchyme is essential for their development. However, except for Notch or Activin/TGF-beta signaling molecules, it is not known which molecules regulate IHBD development. Here, we found that FGF receptors and BMP4 are specifically expressed in the developing IHBD and the hepatic mesenchyme, respectively. Using a mesenchyme-free culture of liver bud, we showed that bFGF and FGF7 induce the hepatoblasts to differentiate into BECs, and that BMP4 enhances bFGF-induced BEC differentiation. The extracellular matrix (ECM) components in the hepatic mesenchyme induced BEC differentiation. Forced expression of a constitutively active form of the FGF receptor partially induced BEC differentiation markers in vivo. These data strongly suggest that bFGF and FGF7 promote BEC differentiation cooperatively with BMP4 and ECMs in vivo.     

Preferential expression of T(h)2-type chemokine and its receptor in atopic dermatitis

Lesional skin of patients with atopic dermatitis (AD) is histologically characterized by hypertrophy of the skin, and the infiltration of a large number of eosinophils and T cells into the dermis. Recent studies have indicated that Th2 cells play a crucial role in the pathogenesis of AD skin. Chemokines and their receptors are implicated in the development of symptoms of various skin diseases such as AD and psoriasis vulgaris (psoriasis). We have examined the in situ expression of a typical Th2-type chemokine, thymus- and activation-regulated chemokine (TARC), and its receptor (CCR4) using immunohistochemical techniques. TARC was found to be highly expressed in the basal epidermis of the lesional skin of AD patients and only slightly in the non-lesional skin. On the other hand, no positive cells were seen in the lesional skin of psoriasis. Consistently, CCR4+ cells were present predominantly in the lesional skin of AD patients, but not in the non-lesional skin. In contrast, in the lesional skin of psoriasis patients, cells positive for CCR5, which is expressed on Th1 cells, were abundantly present. Interestingly, psoralen plus ultraviolet A therapy reduced the number of CCR4+ cells in the AD skin lesions. These results suggest that Th2-type cytokines such as TARC are involved in the pathogenesis of skin lesions in AD patients through the preferential recruitment of Th2 cells.     

Immune responses against a single CD8+-T-cell epitope induced by virus vector vaccination can successfully control Trypanosoma cruzi infection

In order to develop CD8+-T-cell-mediated immunotherapy against intracellular infectious agents, vaccination using recombinant virus vectors has become a promising strategy. In this study, we generated recombinant adenoviral and vaccinia virus vectors expressing a single CD8+-T-cell epitope, ANYNFTLV, which is derived from a Trypanosoma cruzi antigen. Immunogenicity of these two recombinant virus vectors was confirmed by the detection of ANYNFTLV-specific CD8+ T cells in the spleens of immunized mice. Priming/boosting immunization using combinations of these two recombinant virus vectors revealed that the adenovirus vector was efficient for priming and the vaccinia virus vector was effective for boosting the CD8+-T-cell responses. Moreover, we also demonstrated that the ANYNFTLV-specific CD8+-T-cell responses were further augmented by coadministration of recombinant vaccinia virus vector expressing the receptor activator of NFkappaB (RANK) ligand as an adjuvant. By priming with the adenovirus vector expressing ANYNFTLV and boosting with the vaccinia virus vectors expressing ANYNFTLV and RANK ligand, the immunized mice were efficiently protected from subsequent challenge with lethal doses of T. cruzi. These results indicated, for the first time, that the induction of immune responses against a single CD8+-T-cell epitope derived from an intrinsic T. cruzi antigen was sufficient to control lethal T. cruzi infection.     

Stoichiometry of the Reaction Catalyzed by Skin Sulfhydryl Oxidase

The stoichiometry of the reaction catalyzed by skin sulfhydryl oxidase was investigated. Dithiothreitol (DTT) was used as the substrate for skin sulfhydryl oxidase. The consumption of DTT, consumption of oxygen, and production of hydrogen peroxide were measured during the enzyme reaction. The molar ratio of DTT:O₂:H₂O₂ in the enzyme reaction was 1:1.02:0.89. Correspondingly, the stoichiometry of the enzyme reaction was calculated to be R(SH)₂ + O₂ → + H₂O₂.     

Indications for intentionally limited resection for non-small-cell lung cancer

Radiographically, there have been new advances in spiral computed tomography (CT) scanning are currently being studied as a screening tools. As a result, many cases of small-sized lung cancer have been discovered. Some are noninvasive or minimally invasive bronchioloalveolar carcinoma, which is characterized by a the unique sign of ground-glass opacity (GGO) on high-resolution CT (HRCT) scanning. In such cases, lymph node metastases are extremely rare. However, there is currently no definitive surgical modality for such lesions. To clarify the indications of limited resection (segmentectomy or wedge resection), preoperative tumor diameter, location, and, GGO area on HRCT were estimated in patients with clinical T1N0 disease. In patients whose tumor included > or = 50% GGO area and was 15 mm or less in diameter, or patients with pure GGO regardless of tumor size, wedge resection without lymph node dissection should be considered as an acceptable treatment. Video-assisted thoracic surgery is a useful approach for selected patients. On the other hand, in patients with tumors < 50% GGO area in the range of 10-15 mm in diameter, segmentectomy with systematic lymph node dissection or diligent lymph node sampling should be considered.     

Kawasaki disease: basic and pathological findings

Kawasaki disease (KD) is considered to be a kind of systemic vasculitis syndrome. It most frequently affects infants and young children and primarily invades medium-sized muscular arteries, including the coronary arteries. The etiology of KD is unknown, but epidemiological data suggest involvement of infectious agents, such as bacteria and viruses, in the onset of KD. In addition, host genetics underlie the disease’s pathogenesis. Histologically, coronary arteritis begins 6–8 days after KD onset, and inflammation of all layers of the artery rapidly ensues. The inflammation spreads completely around the artery, resulting in severe damage to structural components. Then, the artery begins to dilate. KD arteritis is characterized by inflammation consisting of marked accumulation of monocytes/macrophages. Aberrant activation of monocytes/macrophages is thought to be involved in the formation of vascular lesions. Inflammatory-cell infiltration persists until about the 25th day of the disease, after which the inflammatory cells gradually decrease in number. Lesions in all arteries are relatively synchronous, as they evolve from acute to chronic injury. If a giant aneurysm remains or vessel recanalization occurs after thrombotic occlusion of an aneurysm, remodeling of the vascular structure, sometimes including even reocclusion, continues even in the remote stage.     

Combination tumor immunotherapy with radiotherapy and Th1 cell therapy against murine lung carcinoma

Mice bearing established Lewis lung carcinoma (LLC) expressing model tumor antigen, ovalbumin (OVA) (LLC-OVA) marginally responded to local radiotherapy, but none of the mice was cured. In contrast, treatment of the tumor-bearing mice with intratumoral injection of tumor-specific T helper type 1 (Th1) cells and tumor antigen (OVA) after radiotherapy dramatically prolonged the survival days and induced complete cure of the mice at high frequency (80%). Radiation therapy combined with Th1 cells or OVA alone showed no significant therapeutic activity against LLC-OVA. Such a strong therapeutic activity was not induced by intratumoral injection of Th1 cells plus OVA. Compared with other treatment, radiation therapy combined with Th1 cells and OVA was superior to induce the generation of OVA/H-2^b tetramer⁺ tumor-specific cytotoxic T lymphocyte (CTL) with a strong cytotoxicity against LLC-OVA in draining lymph node (DLN). Moreover, the combined therapy is demonstrated to inhibit the growth of tumor mass, which grew at contralateral side. These results indicated that radiotherapy combined with Th1 cell/vaccine therapy induced a systemic antitumor immunity. These findings suggested that combination therapy with radiotherapy and Th1 cell/vaccine therapy may become a practical strategy for cancer treatment. Hiroshi Yokouchi and Kenji Chamoto are equally contributed.