Ten cases of resected solitary pulmonary metastases arising from gastric cancer.

BACKGROUND: Because carcinomatous lymphangitis and carcinomatous pleuritis are the usual forms of metastasis associated with gastric cancer, resection of solitary pulmonary metastases arising from gastric cancer is rarely performed. To clarify the characteristics of pulmonary metastases from gastric cancer, we investigated patients who underwent resection of metastatic solitary lung tumors arising from gastric cancer. METHODS: Between October 2003 and October 2012, 10 patients underwent pulmonary metastasectomy for metastatic gastric cancer at our institution. We retrospectively evaluated features of the primary gastric cancer and the clinicopathological features of the pulmonary metastases in these cases. RESULTS: 70% of the patients had stage II disease. Lymphatic invasion was observed in all cases of primary gastric cancer. The method of pulmonary resection was partial resection in 5 cases, segmentectomy in 1, and lobectomy in 4. On histopathological examination, immunohistochemical staining was negative for thyroid transcription factor-1 and napsin A in all cases. Patients who underwent resection of pulmonary metastases arising from gastric cancer had a good prognosis: the 4-year survival rate was 75%. CONCLUSIONS: Carefully chosen patients have a good opportunity to obtain benefits from resection of pulmonary metastases arising from gastric cancer.

Efficacy of arginine supplementation for the treatment of air leakage.

BACKGROUND: Recently, the role of the amino acid arginine in wound healing has been emphasized. We studied whether postoperative enteral arginine supplementation can contribute to the resolution of prolonged air leakage after lung resections. METHODS: 42 patients undergoing lung resection at our institutions from 2009 to 2012 were enrolled in this study. In these patients, continuous air leakage in the expiratory phase was identified on the day of surgery and on the following day. The patients were divided into 2 groups; the first group included 21 patients consuming 3 packs of an arginine supplement beverage daily postoperatively, and the second group (control) included 21 patients who did not consume any additional supplements. The durations of air leakage and chest tube drainage were compared between the two groups. RESULTS: The mean durations of air leakage and chest tube drainage were shorter in the arginine supplementation group (4.4 vs. 6.7 days, p = 0.010; 6.5 vs. 8.3 days, p = 0.042, respectively). CONCLUSION: Postoperative enteral arginine supplementation may contribute to stopping air leaks after lung surgery.

Outcomes of surgery in lung cancer patients with schizophrenia.

PURPOSE: There are very few reports regarding the outcome of lung cancer surgery in patients with schizophrenia, and the clinical features of such patients are still unclear. METHODS: From 2004 to 2012, 11 lung cancer patients (six male, five female; mean age, 62.7 years) with schizophrenia underwent lung resections at our institutions. All patients had been institutionalized because they were unable to live independently at home. We retrospectively evaluated their postoperative clinical outcomes and long-term results. RESULTS: Ten of the 11 patients had comorbidities, such as diabetes mellitus and chronic obstructive pulmonary disease. Preoperatively, two patients had a history of treatment for other primary cancers in other organs, and one was on hemodialysis. A lobectomy was performed in nine patients, a segmentectomy in one, and a partial resection in one. There were no hospital deaths. The postoperative morbidity included two cases of pneumonia, one of atelectasis, and one of prolonged air leakage lasting more than 7 days. Wandering was postoperatively observed in two patients; one of these fell and fractured the left femur. At the time of our investigation, two patients were deceased, and the overall 5-year survival rate was 74.1 %. CONCLUSIONS: The postoperative morbidity and long-term results of schizophrenic patients with lung cancer were acceptable. Therefore, even in patients with schizophrenia, surgical treatment for lung cancer should be recommended when deemed to be necessary.

Off-the-job training for VATS employing anatomically correct lung models.

We evaluated our simulated major lung resection employing anatomically correct lung models as "off-the-job training" for video-assisted thoracic surgery trainees. A total of 76 surgeons voluntarily participated in our study. They performed video-assisted thoracic surgical lobectomy employing anatomically correct lung models, which are made of sponges so that vessels and bronchi can be cut using usual surgical techniques with typical forceps. After the simulation surgery, participants answered questionnaires on a visual analogue scale, in terms of their level of interest and the reality of our training method as off-the-job training for trainees. We considered that the closer a score was to 10, the more useful our method would be for training new surgeons. Regarding the appeal or level of interest in this simulation surgery, the mean score was 8.3 of 10, and regarding reality, it was 7.0. The participants could feel some of the real sensations of the surgery and seemed to be satisfied to perform the simulation lobectomy. Our training method is considered to be suitable as an appropriate type of surgical off-the-job training.

Does pneumothorax occurrence correlate with a change in the weather?

PURPOSE: There has been speculation that weather changes correlate with the incidence of spontaneous pneumothorax, although this has not been verified. Moreover, there are no significant data available on the meteoropathic pneumothorax in Asia. The aim of this study was to investigate the possible correlation and to compare our results to those of the United States and Europe. METHODS: From January 2000 to December 2009, 317 spontaneous pneumothorax cases with clear dates of onset were treated in our institution. Using the meteorological data of Fukuoka, Japan, the days with and without an occurrence of pneumothorax were statistically compared in terms of atmospheric pressure, the amount of precipitation, temperature, humidity, hours of sunshine, and occurrence of a typhoon and lightning. RESULTS: Multivariate analysis revealed that a decrease in the hours of sunshine, an increase in mean temperatures 2 days before the incidence, and the days following a day with lightning were all significantly correlated with the occurrence of pneumothorax (P = 0.2 days before the incidence, and the days following a day with lightning were all significantly correlated with the occurrence of pneumothorax (P = 0.0083, 0.0032, 0.0351, respectively). However, typhoons, as an "unusual" weather condition, did not influence the incidence of pneumothorax (P = 0.983). CONCLUSIONS: Our results show strong similarities with reports from European countries despite the different climates. We conclude that the occurrence of pneumothorax appears to correlate with some weather conditions in Japan.

Left sleeve Basal segmentectomy for broncholithiasis.

Broncholithiasis is an uncommon pulmonary problem that may present with life-threatening complications. We report one case of broncholithiasis. A 49-year-old female presented with hemoptysis. Chest X-ray and computed tomography (CT) showed left interlobar lymph node calcification near the interlobar pulmonary artery, and calcification continued into the basal bronchus. Bronchoscopy demonstrated pedunculated granulation tissue in the left B8 bronchus obstructing the lumen. We did not recommend endobronchial removal because of the risk of bleeding, so we proposed surgical treatment. We performed left basal segmentectomy associated with bronchoplasty to preserve pulmonary function. It is important to gain proximal control of the pulmonary artery before dissection of its branches and to approach the pulmonary artery from the periphery to avoid massive intraoperative bleeding. The intrabroncholuminal stone was composed of 61% calcium carbonate and 39% calcium phosphate. The postoperative course was not eventful, and the bronchoscopical findings confirmed a good surgical outcome.

Thymidine phosphorylase levels and dihydropyrimidine dehydrogenase levels in non-small cell lung cancer tissues.

Thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) are the major catabolic enzymes of 5-FU. In this study, we analyzed the concentration of TP and DPD in non-small cell lung cancer tissue by enzyme-linked immunosorbent assay. We measured the TP and DPD levels in 25 adenocarcinoma tissues and 25 squamous cell carcinoma tissues. The mean TP concentration in non-small cell lung cancer tissue was statistically higher than that of normal lung tissue as was the mean DPD concentration. The ratio of the TP level to DPD level in tumor tissue was higher in squamous cell carcinoma than in adenocarcinoma. No significant difference could be detected between the TP level, DPD level, or TP/DPD level and the tumor size or lymph node metastasis. In conclusion, chemotherapy with 5-FU may be more effective in squamous cell lung cancer patients than lung adenocarcinoma patients from the result of the ratio of TP to DPD.

[Lung cancer combined with idiopathic interstitial pneumonias].

It is known that patients with idiopathic interstitial pneumonias (IIPs) have an increased incidence of lung cancer. The purpose of this study was to evaluate the outcome of surgical treatment and to establish the surgical strategy for lung cancer with IIPs. Twenty-five patients with lung cancer and IIPs who were admitted in our hospital from 1996 to 2004 were examined. Eight patients underwent lobectomy with mediastinal lymph node dissection, while 17 patients underwent limited resection. The actuarial 3-year survival rate was 43%. There were no postoperative acute exacerbation of IIPs. We considered most patients were in a stable state of IIPs preoperatively, and we made effort to treat IIPs with limited resection. The prognosis of IIPs was poor. It is difficult to decide whether to carry out limited resection.

Intentional limited resection for small peripheral lung cancer based on intraoperative pathologic exploration.

OBJECTIVE: The aim of this study was to assess the adequacy of our intentional limited resection for small peripheral lung cancer based on intraoperative pathologic exploration. METHODS: Patients who had stage IA non-small cell lung cancer (NSCLC) with a maximum tumor diameter of 2 cm or less were candidates for limited resection. If bronchioloalveolar carcinoma (BAC) was suspected on computed tomography and intraoperative pathologic exploration revealed the lesion as BAC without foci of active fibroblastic proliferation (Noguchi type A and B), wedge resection was performed. If the tumor was not suspected of being Noguchi type A or B, extended segmentectomy with intraoperative lymph node exploration was performed. RESULTS: Limited resection was performed in 34 patients, wedge resection in 14, and extended segmentectomy in 20. The median follow-up period after wedge resection was 36 months, and all patients are alive with no signs of recurrence. The median follow-up period after extended segmentectomy was 54 months. No local recurrences were found, but distant metastasis was diagnosed in one patient. The 5-year survival rate after extended segmentectomy was 93%. In the same period, lobectomy was performed in 57 patients with stage IA NSCLC with a maximum tumor diameter of 2 cm or less, and the 5-year survival rate was 84%. There were no significant differences in 5-year survival between extended segmentectomy and lobectomy. CONCLUSIONS: Careful selection of patients based on high-resolution computed tomography findings and intraoperative pathologic exploration makes intentional limited resection an acceptable option for the treatment of small peripheral NSCLC.

Generation, immunologic characterization and antitumor effects of human monoclonal antibodies for carcinoembryonic antigen.

We generated fully human mAbs (HmAbs) to carcinoembryonic antigen (CEA) using the KM mouse, which carries a human chromosome 14 fragment containing the entire Ig H chain loci and human kappa L chain segments in the mouse genome. Forty-six hybridoma clones producing HmAbs to CEA were thus obtained by fusing the P3-U1 mouse myeloma cells with splenocytes of the KM mice immunized with CEA. Among them, 22 clones produced HmAbs that reacted with CEA but not with 3 other CEA-related cell adhesion molecule (CEACAM) family members, CEACAM1, CEACAM6 and CEACAM8. In 12 HmAbs examined, 8 were IgG4, 2 were IgG3, 1 was IgG2, and the other was IgG1. The affinity constants for CEA of these HmAbs were comparable to those of the previously prepared mouse anti-CEA mAbs (MmAbs). BIAcore analyses revealed that 1 and 2 of the 22 HmAbs react with 2 epitopes defined by MmAbs on the domain N and the domain A1 or B1 of CEA, respectively. In the presence of human complement in vitro, 2 HmAbs tested showed substantial cytotoxicity, namely, 50-65%, against CEA-expressing tumor cells. With human lymphokine-activated killer cells in vitro, 3 HmAbs tested exhibited 40-65% Ab-dependent cell-mediated cytotoxicity against the tumor cells. Moreover, one of the HmAbs induced a significant inhibition of tumor growth when administered to mice xenografted with the CEA-expressing cells. Considering their lack of immunogenicity to humans, these CEA-specific HmAbs may be useful for immunotherapeutic approaches as well as for immunodiagnosis.

Immunotherapy and gene therapy of cancer using antibodies or their genes against tumor-associated antigens.

The purpose of this article is to review the current significance of anti-tumor-associated antigen (TAA) antibodies in the therapy of cancer. Current data suggest that antibodies or their genes against TAAs can be used in order to increase the tumor specificity of various therapeutic approaches against cancer, thereby enhancing the tumoricidal effect of each treatment while reducing the side-effects.

cDNA cloning and sequencing of a novel monoclonal antibody to carcinoembryonic antigen and construction of a mouse/human chimeric antibody.

BACKGROUND: Mouse monoclonal antibody F33-104 recognizes an epitope which is present on the carcinoembryonic antigen (CEA) molecule but not on the other CEA family member proteins, and which seems to be of potential value for immunotherapy of CEA-expressing cancers. However, an inherent problem in its in vivo application is the human anti-mouse antibody response. MATERIALS AND METHODS: To reduce its immunogenicity in humans, we cloned and sequenced the V region genes of heavy and light chains of F33-104 using the reverse transcription-polymerase chain reaction method, and then constructed a mouse/human chimeric antibody, designated Ch F33-104, by fusing the F33-104 VH and V kappa genes to human C gamma 1 and C kappa genes, respectively. The resulting Ch F33-104 was expressed in non-Ig-producing myeloma cells and characterized for its CEA binding specificity and the tumor cell killing activity. RESULTS: Ch F33-104 specifically bound to CEA-expressing tumor cells and revealed a potent antibody-dependent cell-mediated cytotoxicity with human lymphokine-activated killer cells as effectors against the CEA-expressing tumor cells. CONCLUSION: This mouse/human chimeric antibody could therefore be a candidate for cancer immunotherapy of CEA-positive cancers.

Preparation of recombinant MK-1/Ep-CAM and establishment of an ELISA system for determining soluble MK-1/Ep-CAM levels in sera of cancer patients.

The MK-1 antigen, also termed as Ep-CAM, is a membrane glycoprotein that is overexpressed on the majority of tumor cells of epithelial origin and thereby can be used as a target of immunodetection and immunotherapy of cancer. It has previously been shown that several type-I transmembrane proteins, including E-cadherin, ErbB-2 and intercellular adhesion molecule-1 (ICAM-1), may be useful as tumor markers because they are released into the circulation of many cancer patients. To address the question of whether MK-1, the same type-I membrane protein, is also released into the sera, we developed a sandwich-type enzyme-linked immunosorbent assay (ELISA) system by preparing a recombinant MK-1 protein and two anti-MK-1 monoclonal antibodies with different epitope specificities. Using this ELISA, we found that the MK-1 levels in serum samples from healthy volunteers were all less than 2 ng/ml, whereas the Mk-1 levels in sera of about 10% of patients with malignant tumors of various tissue origins were increased to 2-78 ng/ml, indicating that MK-1 is released from tumor cells into the circulation under certain conditions. These findings should be borne in mind when trying to perform passive antibody therapy for cancer using anti-MK-1 antibody.

Opposite effects of thrombospondin-1 via CD36 and CD47 on homotypic aggregation of monocytic cells.

Thrombospondin-1 (TSP-1), an extracellular matrix protein, has a multimodular structure and each domain specifies a distinct biological function through interaction with a specific ligand. In this study we found that exogenously added TSP-1 inhibits phorbol myristate acetate (PMA)/LPS-induced homotypic aggregation of human monocytic U937 cells, whereas the 70-kDa fragment of TSP-1 generated by the proteolytic cleavage of the intact molecule promotes the homotypic aggregation. The aggregation was also inhibited by anti-CD47 mAb or the 4N1K peptide, of which sequence is derived from the CD47-binding site of TSP-1 and absent in the 70-kDa fragment. In contrast, the augmented cell aggregation by the 70-kDa fragment was hampered by anti-CD36 mAb or antibody against the CD36-binding site of TSP-1. The cell aggregation of U937 cells was completely blocked, even in the presence of the 70-kDa fragment, by mAb against leukocyte function associated antigen-1 (LFA-1) or intercellular adhesion molecule-1 (ICAM-1). We therefore propose that TSP-1 may regulate LFA-1/ICAM-1-mediated cell adhesion of monocytes/macrophages by either the inhibitory effect through CD47 or the promoting effect through CD36 depending on which domain/fragment is functional in a given biological setting.

Targeted sonodynamic therapy of cancer using a photosensitizer conjugated with antibody against carcinoembryonic antigen.

The goal of this study was to develop a strategy for the selective destruction of cancer cells by ultrasonic irradiation in the presence of an antibody-conjugated photosensitizer. To this end, a photoimmunoconjugate (PIC) was prepared between ATX-70, a photosensitizer of a gallium-porphyrin analogue, and F11-39, a high affinity monoclonal antibody (MAb) against carcinoembryonic antigen (CEA), which is often overexpressed in various carcinoma cells. This conjugate, designated F39/ATX-70, retained immunoreactivity against purified CEA and CEA-expressing cells as determined by enzyme-linked immunosorbent assay, flow cytometry and immunofluorescence microscopic analysis. The cytotoxicity of F39/ATX-70 against CEA-expressing human gastric carcinoma cells in vitro was found to be greater than that of ATX-70 when applied in combination with ultrasound irradiation. When in vivo anti-tumor effects in a mouse xenograft model were assessed, intravenous administration of F39/ATX-70 followed by ultrasonic irradiation produced a marked growth inhibition of tumor compared with irradiation alone or irradiation after administration of ATX-70. These results suggest that the PIC between anti-CEA MAb and ATX-70 may have applications in sonodynamic therapy where destruction of CEA-expressing tumor is required.

Thrombospondin-1 differentially regulates release of IL-6 and IL-10 by human monocytic cell line U937.

We investigated possible regulatory effects of thrombospondin-1 (TSP-1), a multifunctional extracellular matrix protein, on cytokine release from macrophages. Immobilized TSP-1 enhanced IL-6 release from the human monocytic U937 cells stimulated with phorbol myristate acetate and LPS, whereas it inhibited IL-10 release. The 70-kDa fragment of TSP-1 containing the type 1 repeats showed the same regulatory effects. The enhanced IL-6 release by TSP-1 was inhibited by anti-CD36 antibody or antibody against the sequence of the binding site to CD36 in the type 1 repeats of TSP-1. Conversely, the decrease in IL-10 release by TSP-1 was strengthened by the blocking of the interaction between CD36 and TSP-1. Furthermore, the involvement of TGF-beta1 in the inhibition of IL-10 release by TSP-1 was indicated by the facts that (i) TSP-1 induced activation of TGF-beta1 produced by the U937 cells, (ii) exogenously added TGF-beta1 inhibited IL-10 release, and (iii) antibody against TGF-beta1 blocked the inhibition of IL-10 release by TSP-1. Together, the present findings suggest that TSP-1 enhances IL-6 release from macrophages by interaction with CD36, whereas IL-10 release is regulated by the balance between the enhancing effect of TSP-1 via CD36 and the suppressive effect by TSP-1-activated TGF-beta1.

Significance of tumor-associated antigens in the diagnosis and therapy of cancer: an overview.

An enormous effort using a wide variety of approaches has been undertaken over the last three decades to transform both basic and clinical research into improved diagnoses and therapies of cancer. This brief overview summarizes the significance of tumor-associated antigens (TAAs) in the diagnosis and therapy of cancer. Current data suggest that immunotherapy and gene therapy using antibody-recognized TAAs as their targets are promising, whereas those using T cell-recognized peptide epitopes of TAAs as their targets remain controversial regarding their efficacy, mainly due to general losses of HLA molecules in tumor cells.