Severe disseminated infection by hypermucoviscous Klebsiella pneumoniae successfully treated by intensive therapy with continuous hemodiafiltration using AN69ST: A case report and review of the literature.

Klebsiella pneumoniae (Kpn) is one of the most common gram-negative bacilli causing lung, urinary tract, and biliary tract infections. However, as a distinct entity from classic Kpn, hypervirulent Kpn causing liver abscess, endophthalmitis, and lung abscess with poor prognoses has been reported mainly in East and Southeast Asia since the mid-1980s. Although the definition of hypervirulent Kpn is unclear, the hypermucoviscosity of Kpn is considered an important feature of hypervirulence. We present a case of emphysematous pyelonephritis accompanied by septic shock and acute kidney injury caused by hypermucoviscous Kpn infection that was successfully treated by intensive treatment. A 70-year-old woman with type 2 diabetes mellitus was diagnosed with emphysematous pyelonephritis, and string test-positive Kpn was detected in blood and urine cultures and percutaneous catheter drainage fluid from the renal pelvis. The patient was treated with intensive therapies including antibiotics, ventilator management, and continuous hemodiafiltration (CHDF) using AN69ST, which can absorb cytokines. During the course of treatment, the infection was complicated by pyogenic spondylitis, which was cured by antimicrobial therapy, and the patient was transferred to another hospital for rehabilitation on day 119 after admission. Hypermucoviscous Kpn infection often has a severe course, and it is important to initiate multidisciplinary treatment at an early stage, including rifampicin, which is expected to inhibit the viscosity of hypermucoviscous Kpn. In the current case, immediate CHDF using AN69ST was also considered a life-saving treatment because it improved both volume overload and neutrophil-activated hypercytokinemia.

Chest wall tuberculosis: precision surgery with indigo carmine in limited cases for safe and intuitive lesion excision.

In addition to treatment with antituberculosis drugs, complete surgical excision is important for the cure of chest wall tuberculosis. However, surgery is often challenging to perform due to different factors such as the strong adhesion of tuberculous lesions to the surrounding normal tissue, growth of neovascularization and presence of fragile necrotic tissues. Firm adhesions, bleeding and fragile tissue make it difficult to determine the boundary with normal tissue and completely excide the lesion. Moreover, ingenuity is required. Herein, we report the identification of the boundary between the lesion and normal tissue by injecting indigo carmine into the abscess to completely excide the lesion, which is considered an intuitive and safe method.

Association between the expression of chemokine receptors CCR7 and CXCR3, and lymph node metastatic potential in lung adenocarcinoma.

Chemokines and their receptors are essential for leukocyte trafficking, and are also involved in cancer metastasis to specific organs. Although the migration of tumor cells into the lymph nodes is an important aspect of cancer, the processes involved are poorly understood. Chemokine receptors CCR7 and CXCR3 have been shown to play an important role in tumor cell migration and lymph node metastasis. Therefore, the assessment of chemokine receptor expression on lung adenocarcinomas may improve the prediction of the spread of this carcinoma to the lymph nodes. In this study, we examined the expression and function of these two chemokine receptors (CCR7 and CXCR3) in lung adenocarcinoma. By using flow cytometry, they were detected in all of the lung adenocarcinoma cell lines examined. In the chemotaxis assays, A549 cells exhibited CCL21-induced migration, which was significantly suppressed by neutralizing anti-CCR7 antibody. The CXCL10-induced migration of A549 cells was also significantly suppressed by neutralizing anti-CXCR3 antibody. In clinical lung adenocarcinoma samples, we found the expression of CCR7 and CXCR3 in 65 and 90% cases, respectively, most of which had lymph node metastasis. Importantly, the expression of CCR7 was significantly associated with lymph node metastasis, although the expression of CXCR3 was not. These results suggest that the activation of CCR7 and CXCR3 with their ligands preferentially stimulates lung adenocarcinoma metastasis to the draining lymph nodes.

Gastric Volvulus After Left Lower Lobectomy.

Gastric volvulus is a rare complication after pulmonary resection. To date, only eight cases of postpulmonary resection gastric volvulus have been reported in the English literature, and several of these patients underwent left pneumonectomy or had hiatal hernia. This report describes a case of postlobectomy gastric volvulus in a 73-year-old woman without hiatal hernia.

Correlation between lymph node metastasis and the expression of VEGF-C, VEGF-D and VEGFR-3 in T1 lung adenocarcinoma.

Vascular endothelial growth factor (VEGF)-C and VEGF-D influence lymphangiogenesis through the activation of the vascular endothelial growth factor receptor (VEGFR)-3. They have been implicated in lymphatic tumor spread, which is an important prognostic factor in patients with non-small cell lung carcinoma (NSCLC). Whether or not the expression of VEGF-C, -D, and VEGFR-3 correlates with clinicopathological factors in patients with T1 lung adenocarcinoma was analysed. The tumor specimens were homogenized to determine the protein expression of VEGF-C, -D, and VEGFR-3 by enzyme-linked immunosorbent assay (ELISA). RNA fractions extracted from the tumor tissues were subjected to real-time reverse transcription-polymerase chain reaction (RT-PCR) to assess the mRNA levels of VEGF-C, -D, and VEGFR-3. The expression of VEGF-D protein and mRNA levels in patients without lymph node metastasis were significantly higher than those with metastasis (p=0.013, p=0.0494, respectively). However, the protein and mRNA levels of VEGF-C and VEGFR-3 were not significantly different in patients with or without metastasis. The 5-year survival rates of the patients with high VEGF-D levels were significantly higher than those of patients with low levels (p =0.0221). No significant difference in the survival rates was observed for VEGF-C and VEGFR-3. VEGF-D may be downregulated in NSCLC tissues in comparison to adjacent normal tissue, resulting in lymph node metastasis and poor prognosis.

Sonodynamic therapy of cancer using novel sonosensitizers.

Sonodynamic therapy (SDT) of cancer is based on preferential uptake and/or retention of a sonosensitizing drug (sonosensitizer) in tumor tissues and subsequent activation of the drug by ultrasound irradiation. Ultrasound can penetrate deeply into tissues and can be focused into a small region of a tumor to activate a sonosensitizer. This is a unique advantage in the non-invasive treatment of nonsuperficial tumors when compared to laser light used for photodynamic therapy. Recently, it has been found that photochemically active porphyrins also show significant antitumor effects when activated with ultrasound. The mechanism of sonodynamic action has been suggested to involve photoexcitation of the sensitizer by sonoluminescent light, with subsequent formation of singlet oxygen. This mini-review provides a brief overview of the following four sonosensitizers useful in SDT: i) a homogeneous complex of oligomers of hematoporphyrin, Photofrin II; ii) a gallium porphyrin complex, ATX-70; iii) a hydrophilic chlorin derivative, A7X-S10, and iv) a novel porphyrin derivative devoid of photosensitivity, DCPH-P-Na (I).

Selective up-regulation of claudin-1 and claudin-2 in colorectal cancer.

BACKGROUND: To understand the molecular and morphological alterations in the tight junction in colorectal cancer (CRC) tissues, the expression of eight tight junction proteins in normal and cancer colorectal tissues were compared. PATIENTS AND METHODS: Adenocarcinoma tissues and paired normal mucosa were resected from surgical specimens of CRC patients. The expression of occludin, ZO-1, ZO-2, and claudin-1 -5 was analyzed at the mRNA level by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and at the protein level by immunohistochemistry. RESULTS: The expression of claudin-1 and claudin-2 in cancer tissues was upregulated 40- and 49.2-fold, respectively, at the mRNA level, as compared with that in normal tissues. The up-regulation of these two claudins was also observed at the protein level and it appeared to depend on the depth of tumor invasion. CONCLUSION: Claudin-1 and claudin-2 were found to be overexpressed in CRC tissues. They may be useful as tumor markers and targets for the treatment of colorectal cancer.

Significance of platelet counts in patients who underwent surgical treatment for lung metastasis.

Many studies have asserted that thrombocytosis has a prognostic impact in various malignancies. To date, there has been no report of platelet value in patients with pulmonary metastasis. We retrospectively reviewed the medical charts of 143 patients with resection for lung metastasis. The thrombocyte cut-off was 22 x 10(4) /ml, which was the average count in this study, and we separated patients into two groups (high group versus low group). Cases of larger-size (>2-0.5 cm) pulmonary metastasis showed a significant increase compared with cases of smaller size (-2 cm; P = 0.0040). In univariate analysis, location in the bilateral lung and higher platelet count were significantly associated with prognosis. Multivariate analysis showed that only the high platelet group (P = 0.0334) showed significant independent prognostic factors. Platelet count may be a valuable marker in patients with pulmonary metastasis and for surgical indication with higher count.

Possible applications of antibodies or their genes in cancer therapy.

In this review article the possible applications of anti-tumor-associated antigen (TAA) antibodies in the therapy of cancer have been summarized. First, recombinant monoclonal antibodies (MAbs) are increasingly being used as therapeutic agents, especially in combination with anti-cancer drugs. Second, conjugation of antibody therapy with toxins or radioisotopes offers more therapeutic approaches. Third, development of cytotoxic T-lymphocyte (CTL) or natural killer (NK)-cell populations with anti-TAA antibody activity may be important for the success of cancer immunotherapy because the downregulated HLA class I molecules and the non-ubiquitous expression of NK receptor ligands in tumor tissues constitute the major tumor escape mechanism facing tumor-specific CTL- and/or NK-cell-mediated responses. Finally, in cancer gene therapy, the strategies to target viral vectors carrying therapeutic genes to tumor tissues by modifying the tropisms with MAbs or their genes against TAAs are also very promising.

Primary osteosarcoma of the lung: a case report.

We report a rare case of primary osteosarcoma of the lung. A 73-year-old Japanese man with a productive cough and hemosputum was referred to us for further evaluation of a huge cavitating mass in the left upper lobe, shown on a radiograph of his chest. The result of a tumor biopsy, via fiberoptic bronchoscope, raised a strong suspicion of sarcoma. Therefore a left upper lobectomy was performed without any adjuvant therapy. The tumor, which measured 72 x 70 x 62 mm, was well-defined, whitish-yellow in color and soft in consistency. Histological examination of the tumor showed a dense proliferation of spindle cells and the presence of many collagen fibers. Eosinophilic osteoid, with no epithelial structures, were noted in the stroma. Immunohistochemically, the tumor cells were positive for mesenchymal, but negative for epithelial markers. These pathological features suggested the tumor was an osteosarcoma. A general inspection of other organs did not reveal any more tumorous lesions, therefore, the final diagnosis of the tumor was primary osteosarcoma of the lung.

Re-targeting of cytotoxic T lymphocytes and/or natural killer cells to CEA-expressing tumor cells with anti-CEA antibody activity.

Cellular immunity, in which cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are main effector cells, plays an important role in the antitumor defense mechanism. T cell immunotherapy is based on the assumption that tumor antigen (TA) peptides are correctly presented by HLA class I molecules on target tumor cells, while NK cell immunotherapy is based on the hypothesis that cell surface TAs or ligands for NK receptors are widely expressed in tumor cells. However, human tumor cells are well known to often lose HLA class 1 molecules, and target cell ligands for NK receptors are not always expressed in human tumor cells. This altered HLA class 1 expression and non-ubiquitous distribution of NK receptor ligands constitute the major tumor escape mechanism facing tumor-specific CTL and/or NK cell-mediated responses. These facts also indicate that it is not easy to eliminate the target tumors only by activating tumor-specific CTLs or NK cells. On the other hand, although the protective role of humoral immunity in cancer seems not to be imperative, it is easily confirmed by immunostaining whether or not antibody-recognized TAs such as carcinoembryonic antigen (CEA) exist on the cell surface of target tumor cells. Therefore, endowing CTLs or NK cells with antigen-binding specificity of anti-TA antibody is promising for re-targeting the activities of these effector cells to tumor cells in an HLA-independent manner. This mini-review provides a brief overview of the following four technologies for re-targeting CTLs or NK cells to CEA-expressing tumor cells with anti-CEA antibody activity: i) bispecific antibody technology, ii) antibody-cytokine fusion protein technology, iii) chimeric immune receptor technology, and iv) antibody-HLA/peptide complex technology.

Clinical evaluation of systemic inflammatory response syndrome (SIRS) in advanced lung cancer (T3 and T4) with surgical resection.

OBJECTIVES: The systemic inflammatory response syndrome (SIRS) is well known to occur in patients who have suffered organ damage or trauma, or undergone surgery. SIRS provides useful information in patients with morbidity after surgery. To date, there has been no report of SIRS after surgery in patients with lung cancer. Therefore, based on this new concept of the syndrome, we review here a series of T3 and T4 NSCLC patients who underwent extended resection at our hospital, and attempt to identify the value and correlation of SIRS in predicting the morbidity of such patients. METHODS: We retrospectively reviewed the patients with NSCLC treated at our hospital between January 1994 and August 2003. Among these 720 patients, a curative approach was attempted in 144 with advanced stage (T3, 100; T4, 44) cancer. The patients were consequently divided into three groups (G1, negative or less than 3 days in SIRS following surgery; G2, less than 7 days; G3, continued over 7 days). Pre- or peri-operative factors were evaluated, and the 5-year survival rates were analyzed. Post-operative morbidity was also compared between the three groups in association with SIRS. RESULTS: Pre-operative counts of WBC were 8848.28+/-3879.21/microl in G3 compared with 7383.33+/-3132.98/microl in G2 and 6778.31+/-3184.89/microl in G1. Values in G3 were significantly higher than those in the other groups (P<0.001). Predicted %FEV1 in G3 was significantly lower than those in the other groups. Duration of SIRS after lung surgery was associated with high levels in WBC and low %FEV1. Post-operative morbidity such as bronchial fistula or ARDS were more frequent in the G3 and G2 groups than in G1. The 1-year survival was as follows; G1, 75.4%; G2, 47.9%; G3, 38.1%. Overall 5-year survival rate for NSCLC with T3 and T4 was 32.2%, and the difference between G3 and the other groups in terms of survival was statistically significant (P<0.0001). CONCLUSIONS: The concept of SIRS have been associated with post-operative complications and survival in NSCLC. Surgical candidates should be carefully according to the predicting factor of SIRS.

PPARalpha ligand WY14643 reduced acute rejection after rat lung transplantation with the upregulation of IL-4, IL-10 and TGFbeta mRNA expression.

BACKGROUND: The peroxisome proliferators-activated receptor-alpha (PPARalpha) is important in lipid metabolism and regulation of inflammation. Recent studies have demonstrated the immunoregulatory effects of PPARalpha. This investigated the immunosuppressive effects of PPARalpha using its ligand, WY14643, on acute lung allograft rejection in a rat model and its mechanism of action. METHOD: The left lungs were transplanted orthotopically from Brown-Norway donors to F344 recipients. The recipients were then divided into control and WY14643 treatment groups. The allograft rejection was evaluated by daily chest X-ray imaging and was evaluated histologically on Day 7 after transplantation. The cytokine messenger RNA (mRNA) expression at Days 3 and 5 were also evaluated in allografts and recipient spleens. RESULTS: The radiologic and histologic findings indicated that treatment with the WY14643 reduced acute allograft rejection. WY14643 also significantly extended the allograft survival time. This amelioration of acute rejection by WY14643 was also associated with up-regulated interleukin (IL)-4, IL-10, and transforming growth factor-beta (TGFbeta) mRNA expression in the lung allografts and spleens. CONCLUSION: This study demonstrated that the administration of the PPARa ligand, WY14643, ameliorates acute lung allograft rejection in rats. Treatment with WY14643 reduced histopathologic scores, prolonged graft survival, and up-regulated the expression of anti-inflammatory cytokine IL-4, IL-10, and TGFbeta mRNA compared with the control.

Is T2 non-small cell lung cancer located in left lower lobe appropriate to upstage?

In the TNM classification, patients with T2 non-small cell lung cancer (NSCLC) have heterogeneous factors. The efficacy of surgery for T2 disease remains unsatisfactory. We retrospectively reviewed 268 T2 patients with non-small cell lung cancer for whom a curative approach had been attempted between January 1994 through December 2003. All patients were subjected to lobectomy, including dissection of hilar and mediastinal lymph nodes contained in pathologically proven adenocarcinoma or squamous cell carcinoma. The overall survival rates at 5 and 7 years were 58.4% and 48.5%, respectively. Five-year survival of patients with a tumor in the left lower lobe (LLL) was 38.8%; other lobe, 61.6%. Primary tumor distribution in the LLL was significantly associated with a poor survival in T2 NSCLC. In univariate analysis, tumors size less than 4 cm, tumor in the left lower lobe, histological differentiation, lymph node involvement were significantly associated with prognosis. Multivariate analysis showed that tumor in the left lower lobe (P=0.0159), histological differentiation (P=0.0071), and lymph node involvement (P=0.0266) were found to be independent prognostic factors in cases of T2 disease. In cases where the primary tumor without well differentiation is in the LLL, surgery for T2 NSCLC should be considered carefully.

T cell-specific disruption of arylhydrocarbon receptor nuclear translocator (Arnt) gene causes resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced thymic involution.

The arylhydrocarbon receptor nuclear translocator (ARNT) is a member of the basic helix-loop-helix, PER-ARNT-SIM family of heterodimeric transcription factors, and serves as a dimerization partner for arylhydrocarbon receptor (AHR) and hypoxia-inducible factor-1alpha. To assess the function of ARNT in T cells, we disrupted the Arnt gene specifically in T cells of mice by conditional gene targeting using T cell-specific p56(lck)-Cre (Lck-Cre) transgenic Arnt-floxed mice. Thus generated, T cell-specific Arnt-disrupted mice (Lck-Cre;Arnt(flox/Delta) transgenic mice) exhibited complete loss of the expression of ARNT protein only in T cells, and were viable and appeared normal. The Arnt-disrupted T cells in the thymus were phenotypically and histologically normal. The Arnt-deficient T cells in the spleen were capable of responding to TCR stimulation in vitro. However, unlike normal mice in which exposure to the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an AHR ligand, resulted in thymic involution, the thymus of Lck-Cre;Arnt(flox/Delta) mice were resistant to TCDD treatment in vivo. In contrast, benzo(a)pyrene, another AHR ligand, still caused thymic involution in Lck-Cre;Arnt(flox/Delta) mice. Finally, fetal thymus organ culture using Lck-Cre;Arnt(flox/Delta) and K5-Cre;Arnt(flox/Delta) (epithelial cell-specific Arnt-disrupted mice) showed that thymocytes rather than thymic epithelial cells are predominantly responsible for TCDD-induced thymic atrophy. Our results indicate that ARNT in T lineage cells is essential for TCDD-mediated thymic involution.