Takashi Yoshimatsu

Prognostic value of the immunohistochemical detection of p16INK4 expression in nonsmall cell lung carcinoma

The product of the p16INK4/CDKN2/MTS1 (p16) controls the transition from the G1 phase to the S‐phase in the cell cycle by inhibiting the phosphorylation of the retinoblastoma gene product. A lack of p16 expression has been reported in various cancer cell lines and tumors; however, there have been only a few reports on the prognostic significance of p16 alteration. The authors studied p16 expression in nonsmall cell lung carcinoma (NSCLC) and also examined its correlation with clinicopathologic features and prognosis.

Postoperative complications after pneumonectomy for treatment of lung cancer : Multivariate analysis

The charts of 62 patients with primary lung cancer who underwent a pneumonectomy at our department from 1979 through 1992 were reviewed for the evaluation of postoperative morbidity and mortality. The 30‐day mortality was 3/62 or 4.8%. Postoperative complication occurred in 37 of 62 patients (60%). The most common complication was a supraventricular tachyarrythmia. A major complication, which was defined as one necessitating re‐thoracotomy or one which caused death, occurred in 19 patients (31%). We analyzed 43 perioperative variables for their predictive value of postoperative morbidity and mortality. Univariate analysis indicated that an elevated serum LDH, low predicted forced vital capacity, low predicted forced expiratory volume in 1 sec (FEV1) were significantly associated with the occurrence of a major complication. A multivariate logistic regression model indicated that a high LDH level, a low predicted FEV1 and no extubation following surgery were associated independently with a postoperative major complication. Since only the complete removal of a tumor offers a chance for cure for the treatment of non‐small cell lung cancer, it is sometimes necessary to perform a pneumonectomy for these high‐risk patients. Patients identified as being at high risk of a major complication should be candidates for intensive preoperative evaluation and perioperative care.

Expression of the melanoma antigen‐encoding gene in human lung cancer

Background and Objectives: We surveyed expression of melanoma antigen‐encoding genes in lung cancer because of promising implications for immunotherapy.

Prediction of pulmonary complications after a lobectomy in patients with non-small cell lung cancer.

BACKGROUND Although the preoperative prediction of pulmonary complications after lung major surgery has been reported in various papers, it still remains unclear. METHODS Eighty nine patients with stage I–IIIA non-small cell lung cancer (NSCLC) who underwent a complete resection at our institute from 1994–8 were evaluated for the feasibility of making a preoperative prediction of pulmonary complications. All had either a predicted postoperative forced vital capacity (FVC) of >800 ml/m2 or forced expiratory volume in one second (FEV1) of >600 ml/m2. RESULTS Postoperative complications occurred in 37 patients (41.2%) but no patients died during the 30 day period after the operation. Pulmonary complications occurred in 20 patients (22.5%). Univariate analysis indicated that the factors significantly related to pulmonary complications were FVC <80%, serum lactate dehydrogenase (LDH) level ⩾230 U/l, and arterial oxygen tension (Pao 2) <10.6 kPa (80 mm Hg). In a multivariate analysis the three independent predictors of pulmonary complications were serum LDH ⩾230 U/l (odds ratio (OR) 10.5, 95% CI 1.4 to 77.3), residual volume (RV)/total lung capacity (TLC) ⩾30% (OR 6.0, 95% CI 1.1 to 33.7), and Pao 2 <10.6 kPa (OR 5.6, 95% CI 1.4 to 22.2). CONCLUSIONS The above findings indicate that three factors (serum LDH levels of ⩾230 U/l, RV/TLC ⩾30%, and Pao 2 <10.6 kPa) may be associated with pulmonary complications in patients undergoing a lobectomy for NSCLC, even though the patient group was relatively small for statistical analysis of such a diverse subject as pulmonary complications.

Treatment strategy for patients with surgically discovered N2 stage IIIA non-small cell lung cancer

BACKGROUND The treatment strategy for patients with non-small cell lung cancer and clinically negative, but surgically detected mediastinal lymph node metastasis (surgically discovered N2 disease) is controversial. METHODS From August 1979 through December 1994, 53 patients with non-small cell lung cancer were found to have surgically discovered N2 disease. We retrospectively studied the clinical characteristics and the factors that influenced the prognosis in these patients. RESULTS The 3-year and 5-year survival rates and the median survival for the 53 patients with surgically discovered N2 disease were 44%, 21%, and 26 months. Two thirds of the patients had adenocarcinoma. Only complete resection affected long-term survival; adjuvant therapy had no effect on survival. In regard to lymph node status, a single metastatic focus in the aortic area was associated with long-term survival. CONCLUSIONS Patients with adenocarcinoma may require histologic determination of N2 disease. Complete resection, including extensive and complete mediastinal lymph node dissection, is warranted in patients with surgically discovered N2 disease. In particular, when the aortic lymph node (including stations 5 and 6) alone is involved, the patients should undergo as complete a resection as possible.

Postoperative Prognosis in Patients With Non–Small Cell Lung Cancer With Synchronous Ipsilateral Intrapulmonary Metastasis

BACKGROUND Non-small cell lung cancer with intrapulmonary metastasis (PM) was recently reclassified according to the revision of the TNM classification. To determine whether the new staging system is appropriate, we analyzed the postoperative prognosis of patients with synchronously detected and resected PM lesions. METHODS Of 509 patients with non-small cell lung cancer who underwent surgical resection, 42 patients were revealed to have synchronous and ipsilateral PM. Their survival was compared with that of matched stage groups (without PM) by Kaplan-Meier test and log rank test. RESULTS Two patients who were classified as stage I survived 40 and 30 months after operation, respectively. One patient was determined to be stage II, and survived 100 months postoperatively. Thirty-eight patients were classified as stage IIIA/IIIB (19 each) (90.5% of all cases with PM). There was no significant difference between 3- and 5-year survival rates of the PM stage IIIA group (34.2% and 34.2%) and those of the other IIIA (144 patients; 37.9% and 31.6%). Survival rates of such stage IIIA subgroups as PM, T3 and N2, were comparable. No significant differences were observed between the 3- and 5-year survival rates of the PM stage IIIB (16.6/16.6%) and those of the other stage IIIB (45 cases; 11.7% and 0.0%). The survival rates of such stage IIIB subgroups as PM, T4 and N3 were also similar. CONCLUSIONS The new staging system for patients with synchronous resectable PM appears to be reasonable regarding survival. Most cases of PM are categorized as locally advanced disease; however, stage IIIA/IIIB cases have become a more heterogeneous population.

Optimal dose of basic fibroblast growth factor for long-segment orthotopic tracheal autografts

When a primary anastomosis of the trachea is not feasible, extensive grafting is required. However, despite the use of omental wrapping for revascularization, long-segment tracheal grafts frequently do not maintain structural integrity because of insufficient blood supply. We examined the use of basic fibroblast growth factor for preservation of long-segment tracheal autografts after orthotopic transplantation with omental wrapping in 23 dogs. All animals received orthotopic tracheal transplantation, with 14-ring autografts that occupied a major part of the thoracic trachea, and omental wrapping. The 23 animals were classified randomly into six groups as follows: no treatment (group I, n = 3), topical administration of fibrin glue alone (group II, n = 4), fibrin glue enriched with 1 microg/cm2 basic fibroblast growth factor (group III, n = 4), fibrin glue enriched with 5 microg/cm2 basic fibroblast growth factor (group IV, n = 4), and fibrin glue enriched with 10 microg/cm2 basic fibroblast growth factor (groups V and VI, each n = 4). The omentum that was used to wrap the autografts was fed by the right gastroepiploic artery in groups I to V and by both the right gastroepiploic artery and splenic artery in group VI. All autografts in groups I and II showed dissolution. Ten of 12 autografts in groups III, V, and VI did not maintain long-term structural integrity. By contrast, all autografts in group IV showed long-term viability, as demonstrated by graft patency, epithelialization, cartilage morphology, and vascularity. We conclude that treatment with fibrin glue enriched with 5 microg/cm2 basic fibroblast growth factor in combination with omental wrapping may prolong the viability of long-segment tracheal autografts.

Autologous Tumor‐specific Cytotoxic T Lymphocytes in a Patient with Lung Adenocarcinoma: Implications of the Shared Antigens Expressed in HLA‐A24 Lung Cancer Cells

Human lung adenocarcinoma‐specific cytotoxic T lymphocytes (CTL) were generated by multiple stimulations with autologous tumor cells (named A110L) from regional lymph node lymphocytes and tumor‐infiltrating lymphocytes expanded by solid‐phase anti‐CD3 monoclonal antibody (mAb) and recombinant interleukin‐2. The CTL lysed A110L but failed to kill either autologous B lymphocytes immortalized by the Epstein‐Barr virus or K562. The killing activity of the CTL against autologous A110L was inhibited by anti‐MHC class I mAb (W6/32), but not by anti‐MHC class II mAb. The CTL produced interferon‐γ and GM‐CSF in response to A110L and the production was completely blocked by the addition of anti‐MHC class I mAb. The HLA type of the CTL was HLA‐A2/A24, B52/B54, Cw1/‐. Allele‐specific deletion of HLA‐A2 molecules was observed in A110L by staining with anti‐HLA‐A2 mAb. A partial blocking effect on the cytokine production from the CTL was also obtained with anti‐CD8, and anti‐HLA‐A24 mAbs, but not with anti‐MHC class II, anti‐CD4 and anti‐HLA‐A2 mAbs. To analyze further the mechanism of antigen recognition by the CTL, the cross reactivity of the CTL against several HLA‐A locus‐matched (HLA‐A24+) and mismatched allogeneic tumor cells (HLA‐A24‐) was investigated. The A110L‐specific CTL showed a weak but significant cytotoxicity against some HLA‐A24 positive lung cancer cell lines, such as Sq‐1 (HLA‐A11/A24, squamous cell carcinoma) and PC‐9 (HLA‐A2/A24, adenocarcinoma), but failed to kill HLA‐A locus‐mismatched allogeneic tumors. This cross reactivity of the CTL against Sq‐1 and PC‐9 was blocked by anti‐MHC class I mAb. These results thus demonstrate that shared common tumor antigens might exist among lung cancer cells in the context of HLA‐A24.

The induction of cytotoxic T lymphocytes against HLA-A locus-matched Lung adenocarcinoma in patients with non-small cell Lung cancer

To induce cytotoxic T lymphocytes (CTL) against non‐small cell lung cancer (NSCLC) efficiently, the induction of CTL was attempted using HLA‐A locus‐shared allogeneic NSCLC cells. T cells derived from either tumor tissue specimens or the regional lymph nodes of patients with NSCLC were stimulated twice or three times with an HLA‐A2/A24‐positive NSCLC cell line (PC‐9), and thereafter the cytotoxic activity was examined by 51Cr‐release assay. In patients with HLA‐A24/ adenocarcinoma, anti‐PC‐9 cytotoxicity was induced in all 6 patients tested. Anti‐PC‐9 cytotoxicity was induced in 2 out of 5 patients with HLA‐A2 (A24−)/adenocarcinoma, in 2 out of 4 patients with HLA‐A24/squamous cell carcinoma, and 1 of 2 patients with HLA‐A2/squamous cell carcinoma. The cytotoxic activity was observed to kill PC‐9 selectively, not other NSCLC lines, and the activity was substantially blocked by anti‐MHC class I antibody, but not by anti‐MHC class II antibody. The PC‐9‐specific CTL produced γ‐interferon in response to autologous tumor cells. These results indicated that the anti‐PC‐9 cytotoxicity was mediated by cytotoxic T lymphocytes that may recognize the T cell epitope(s) shared and presented by HLA‐A2 and/or HLA‐A24‐positive NSCLC.

Expression of aldehyde dehydrogenase 2 in the normal esophageal epithelium and alcohol consumption in patients with esophageal cancer.

Alcohol consumption is a risk factor for esophageal cancer. Acetaldehyde, a highly toxic intermediate produced from ethanol, is converted to acetic acid mainly by aldehyde dehydrogenase 2 (ALDH2) in the metabolic pathway of ethanol. Fifty percent of Japanese have inactive ALDH2 due to genetic polymorphism, which is considered to be a risk factor associated with esophageal cancer. In our previous study, we have demonstrated that ALDH2 is expressed in the esophagus with a considerable variation among individuals. In this study, we further investigated the expression of ALDH2 in esophagus and its relationship with risk factors of esophageal cancer. Tissue specimens resected from 51 patients with esophageal cancer were analyzed by immunohistochemistry using ALDH2-antibody. The immuno-staining of ALDH2 in the esophageal epithelium was compared with both the drinking habit and the occurrence of flushing that is closely associated with the ALDH2 deficiency. ALDH2 was not detectable in 8 (16%) among 51 specimens. All of the 8 patients were non- or light-drinkers but not heavy-drinkers. Among 18 patients showing the high level ALDH2 expression in the esophagus, 15 patients (83%) were heavy-drinkers. Although the relationship between the ALDH2 deficiency and drinking habit is not clear, the patients with ALDH2 deficiency tend to be non- or light drinkers while heavy-drinkers tend to have the active form of ALDH2. These results suggest that both inactive and active forms of ALDH2 are induced in the esophagus by heavy drinking and also support a hypothesis that ALDH2 deficiency might be a high-risk factor of esophageal cancer for the individuals having a heavy-drinking habit. To our knowledge, this is the first study demonstrating the induction of ALDH2 in the esophagus by ethanol consumption.