Cyclic AMP is both a pro-apoptotic and anti-apoptotic second messenger.

The second messenger cyclic AMP (cAMP) can either stimulate or inhibit programmed cell death (apoptosis). Here, we review examples of cell types that show pro-apoptotic or anti-apoptotic responses to increases in cAMP. We also show that cells can have both such responses, although predominantly having one or the other. Protein kinase A (PKA)-promoted changes in phosphorylation and gene expression can mediate pro-apoptotic responses, such as in murine S49 lymphoma cells, based on evidence that mutants lacking PKA fail to undergo cAMP-promoted, mitochondria-dependent apoptosis. Mechanisms for the anti-apoptotic response to cAMP likely involve Epac (Exchange protein activated by cAMP), a cAMP-regulated effector that is a guanine nucleotide exchange factor (GEF) for the low molecular weight G-protein, Rap1. Therapeutic approaches that activate PKA-mediated pro-apoptosis or block Epac-mediated anti-apoptotisis may provide a means to enhance cell killing, such as in certain cancers. In contrast, efforts to block PKA or stimulate Epac have the potential to be useful in diseases settings (such as heart failure) associated with cAMP-promoted apoptosis.

A phase II study of amrubicin combined with carboplatin for elderly patients with small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0405.

BACKGROUND: Amrubicin, a new anthracycline agent, has shown high activity for small-cell lung cancer (SCLC) in previous studies. However, a combination regimen with amrubicin and platinum has been investigated little. On the basis of previous phase I study, we conducted this study to evaluate the efficacy and the safety of amrubicin and carboplatin for elderly patients with SCLC. METHODS: Chemotherapy-naive elderly patients with SCLC received amrubicin (35 mg/m(2), days 1-3) and carboplatin [area under the curve (AUC) 4.0, day1] every 3 weeks. The primary end point was overall response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival and toxicity profile. RESULTS: From January 2005 to November 2007, 36 patients were enrolled [median age 76 (range 70-83); ECOG performance status of zero and one in 17 and 19 patients, respectively]. One complete response and 31 partial responses were observed (ORR 89%). Median PFS was 5.8 months and median survival time was 18.6 months. Grade 3-4 neutropenia was observed in 97% of the patients and six patients (17%) suffered from grade 3-4 febrile neutropenia. Other toxic effects were moderate and treatment-related death was not observed. CONCLUSIONS: Amrubicin combined with carboplatin is quite effective for SCLC with acceptable toxic effects even for the elderly population. Further evaluation of this regimen is warranted.

A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations.

Retrospective analysis has shown that activating mutations in exons 18-21 of the epidermal growth factor receptor (EGFR) gene are a predictor of response to gefitinib. We conducted a phase II trial to evaluate the efficacy and safety of gefitinib as first-line therapy for advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Patients with stage IIIB or IV chemotherapy-naïve NSCLC with EGFR mutation were treated with 250 mg gefitinib daily. For mutational analysis, DNA was extracted from paraffin-embedded tissues and EGFR mutations were analysed by direct sequence of PCR products. Twenty (24%) of the 82 patients analysed had EGFR mutations (deletions in or near E746-A750, n=16; L858R, n=4). Sixteen patients were enrolled and treated with gefitinib. Twelve patients had objective response and response rate was 75% (95% CI, 48-93%). After a median follow-up of 12.7 months (range, 3.1-16.8 months), 10 patients demonstrated disease progression, with median progression-free survival of 8.9 months (95% CI, 6.7-11.1 months). The median overall survival time has not yet been reached. Most of the toxicities were mild. This study showed that gefitinib is very active and well tolerated as first-line therapy for advanced NSCLC with EGFR mutations.

Thymidylate synthase and dihydropyrimidine dehydrogenase activities in non-small cell lung cancer tissues: relationship with in vitro sensitivity to 5-fluorouracil.

We examined enzymatic activities of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in non-small cell lung cancer (NSCLC) tissues to determine the relationship to tumor sensitivity to 5-fluorouracil (5-FU). TS and DPD activities were measured in 60 surgically resected primary NSCLC tissues using a TS-binding assay and a radioenzyme assay, respectively. In vitro tumor sensitivity to 5-FU was assayed using a collagen gel droplet embedded culture drug test (CD-DST). DPD activities slightly correlated with in vitro sensitivity to 5-FU (r=0.402,P=0.013), such that tumors with higher DPD activity were more resistant to 5-FU. In contrast, no correlation was observed in TS activities. Thus, it was suggested that only DPD activity in NSCLC tissues is a potential indicator in predicting tumor sensitivity to 5-FU. Based on these results, further study is needed to evaluate the clinical significance of these enzymes in 5-FU-based chemotherapy for patients with NSCLC.

Interferon gamma-producing ability in blood lymphocytes of patients with lung cancer through activation of the innate immune system by BCG cell wall skeleton.

An in vitro assay system was developed to assess the potency of the human innate immune system by measurement of IL-12, IL-18, IL-10 and IFNgamma in the supernatants of bacillus Calmette-Guerin cell wall skeleton (BCG-CWS)-stimulated blood samples. BCG-CWS is a ligand for Toll-like receptor (TLR) 2 and 4, and activates monocytes to macrophages (Mphi), and immature dendritic cells to mature antigen-presenting cells (APC). This system was found to allow the discrimination of immune suppressive states in patients with lung cancer from normal immune states in light of the cytokine profile. The following results were deduced from analyses of BCG-CWS-stimulated blood samples of lung cancer patients with reference to normal subjects. (1) The levels of production of IFNgamma and IL-10 by lymphocytes were decreased. (2) IL-12 p40 production by monocytes/Mphi was upregulated, while that of IL-10 was downregulated. (3) IL-18 was detected in all patients in a range similar to normal subjects. (4) Responses of lymphocytes to IL-2 and IL- 18 in terms of IFNgamma production were diminished. (5) The upregulated IL-12 levels were recovered to within the normal range in most patients after tumor resection. (6) Male patients showed more severe suppression of IL-12/IL-18-mediated IFNgamma production than female patients. Thus, the lesser IFNgamma production observed in patients' blood with high IL-12 p40 levels in response to BCG-CWS may reflect the production of p40 dimers or IL-23 instead of p70, or the presence of some unknown pathways to prohibit the interface between the innate and acquired immune systems. BCG-CWS-mediated Toll signaling may participate in IFNgamma induction for lymphocytes through Mphi/APC IL-12/I-18 modulation.

Transmediastinal approach to exploring the lung contralateral to the thoracotomy site.

OBJECTIVE: The approach to contralateral lung through the mediastinum is assumed useful in managing oddly distributed bilateral lung tumors. SUBJECTS AND METHODS: To remove a tumor located in the contralateral lung, a transmediastinal approach from the thoracotomy site to the contralateral lung was used in 6 patients having oddly distributed bilateral lung tumors, 1 of which was located in the contralateral lung close to the anterior or posterior mediastinum. RESULTS: All cases were treated successfully. One patient required an additional small incision on the contralateral anterior chest wall to insert an endoscopic stapler without intraoperative postural change. The postoperative course was uneventful and, to date, no local recurrence has been seen at the resected margin of the contralateral lung. CONCLUSION: This novel approach is useful, offering the advantages of reduced invasiveness and pain, shorter surgical duration, and favorable cosmetic results for patients with a tumor close to the mediastinum in the contralateral lung.

Prognostic value of ground-glass opacity found in small lung adenocarcinoma on high-resolution CT scanning.

OBJECTIVE: This study was undertaken to investigate the value of the ground-glass opacity (GGO) area found on high-resolution computed tomography (HRCT) scanning as a preoperative prognostic indicator. PATIENTS AND METHODS: We studied 104 patients with small-sized lung adenocarcinoma, 20 mm or less in diameter, between 1995 and 1999. Three independent radiologists semi-quantitatively scored the extent of GGO on HRCT as greater than or less than 50%. Three independent pathologists semi-quantitatively scored the extent of the bronchioloalveolar carcinoma (BAC) component of the tumor on histologic examination as greater than or less than 50%. As no relapse occurred in patients with GGO greater than 50%, multivariate analysis of this prognostic factor was not possible. RESULTS: Fifty patients were scored as having both BAC and GGO greater than 50%, 36 as both BAC and GGO less than 50%, and 16 as BAC greater than 50% and GGO less than 50%. In only two patients (1.9%), BAC less than 50% was overestimated on HRCT as GGO greater than 50%. The sensitivity and specificity of GGO to BAC were 76 and 95%, respectively. The 3 year-relapse-free survival rates in each group of 52 patients with GGO greater than and less than 50% were 100 and 72%, respectively, after a median follow-up of 24 months. Univariate analysis indicated that both GGO and BAC areas were significantly correlated with cancer relapse (P=0.005 and P=0.002). The multivariate analysis revealed an independent prognostic influence of the BAC area on relapse-free survival (P=0.015, relative risk=0.07). CONCLUSIONS: To date there has been no relapse among the 52 patients with GGO greater than 50%. This novel classification based on the semiquantitative analysis of GGO area on HRCT should become an useful independent preoperative indicator when deciding on operative procedure, and to predict the potential of relapse in patients with small adenocarcinoma arising from the peripheral lung.

Isolation of a novel human lung-specific gene, LUNX, a potential molecular marker for detection of micrometastasis in non-small-cell lung cancer.

We have isolated a novel human lung-specific gene, LUNX (lung-specific X protein), by differential-display mRNA analysis. The full-length cDNA contained 1,015 nucleotides including an open reading frame of 768 nucleotides encoding 256 amino acids. We localized the gene to chromosomal region 20p11.1-q12 by radiation hybrid mapping. Using an RT-PCR assay specific for LUNX mRNA, 35 non-small-cell lung-cancer (NSCLC) tumors and 0 of 16 normal lymph nodes were positive. Furthermore, LUNX mRNA expression was enhanced in 26 (84%) of 31 NSCLC tumors vs. corresponding cancer-free lung tissues by semi-quantitative analyses with multiplex RT-PCR. We assessed the possibility of LUNX mRNA as a molecular marker for detection of micrometastasis in dissected lymph nodes obtained from 20 patients with NSCLC tumors. LUNX mRNA was detected in 16 (80%) of 20 histologically positive lymph nodes and 21 (25%) of 84 histologically negative lymph nodes. Comparative analyses of the conventional histological examination and the RT-PCR detection assay for LUNX mRNA showed that the detection rate of metastases in lymph nodes by the RT-PCR assay was higher in 12 and consistent in 6 of the total 20 NSCLC patients. We demonstrate that the LUNX RT-PCR assay is a potential diagnostic method for detection of micrometastases in lymph nodes of NSCLC patients.

Cisplatin-based chemotherapy for postoperative recurrence in non-small cell lung cancer patients: relation of the in vitro chemosensitive test to clinical response.

The usefulness of the in vitro chemosensitivity test, the collagen gel droplet embedded culture drug- sensitivity test (CD-DST, Int J Oncol 11: 449, 1997), in cisplatin-based combined chemotherapy for postoperative recurrent tumors in non-small cell lung cancer (NSCLC) patients was retrospectively analyzed. CD-DST data for cisplatin (or carboplatin), etoposide, 5-fluorouracil, mitomycin C, and vindesine were obtained in 311 surgically resected primary lesions. Of them, 25 patients were practically treated with first-line cisplatin- or carboplatin-based chemotherapy for postoperative initial recurrence. Nine (36%) of them responded to the combined chemotherapy for recurrent lesions, including one with complete remission, whereas 16 did not, with no change in 5 and progression in 11. Seven (70%) of 10 patients receiving combined chemotherapy using two or three in vitro sensitive chemoagents showed good responses, whereas there was no responder among the patients receiving chemotherapy including no in vitro sensitive chemoagents. In particular, of 11 patients showing good sensitivity to cisplatin or carboplatin on CD-DST, 8 (73%) responded to chemotherapy, whereas only one (7%) of 14 patients showing cisplatin- or carboplatin-resistance on CD-DST was a responder. Thus, CD-DST results for the chemoagents, especially cisplatin or carboplatin, correlated with chemotherapeutic response, indicating that the CD-DST analysis of surgically resected primary NSCLC tumors is a practically useful indicator of the clinical effect of first-line cisplatin-based combined chemotherapy for postoperative recurrence.

Examination of in vitro chemosensitivity test using collagen gel droplet culture method with colorimetric endpoint quantification.

To develop a simpler method of performing the collagen gel droplet-embedded culture drug sensitivity test (CD-DST), we examined the introduction of colorimetric quantitative determination of images for evaluation of anticancer effect against cancer cells alone in the presence of fibroblasts, based on differences in proliferative morphology and stainability with neutral red of cells within collagen gel drops determined using a video-microscope and NIH Image software. In examinations using a human cancer cell line and a fibroblast cell line, a high degree of linearity between number of cancer cells and image-optical density was found within the range of 10(2) - 10( 6) cells / droplet (r (2) = 0.933). Using NIH Image, fibroblast cells could be eliminated at a cut-off value of 128, and an immunocytochemical method demonstrated that the cells eliminated from the image were indeed fibroblasts, and those remaining were cancer cells. CD-DST was carried out with mixtures of cancer cells with fibroblasts at various ratios, and the feasibility of evaluating anticancer activity in cancer cells alone with no effect of fibroblasts at any mixing ratio was confirmed. In addition, for CD-DST of primary cell cultures of human lung cancers collected at the time of surgery, a high correlation between results obtained with the volume supplementation method, a current cell quantification method, and those with the imaging colorimetric quantification method was obtained (r = 0.933). These results indicate that introduction of imaging colorimetric quantification utilizing NIH Image makes CD-DST a quick and simple method that should be highly useful for clinical chemosensitivity testing using primary cell cultures of human cancers.

Clinical value of pleural lavage cytological positivity in lung cancer patients without intraoperative malignant pleuritis. Recurrent pattern based on semiquantitative analysis of tumor cells in pleural lavage.

OBJECTIVES: We recently developed pleural lavage cytology for lung cancer patients without intraoperative signs of malignant pleuritis (Ann Surg Oncol, 4: 409, 1997). We analyzed recurrent patterns in pleural lavage cytology-positive lung cancer patients without intraoperative signs of malignant pleuritis based on semiquantitative evaluation of tumor cell clusters in pleural lavage solution. METHODS: Between December 1987 and December 1998, pleural lavage cytology-positive results after thoracotomy were obtained in 97 cases of lung cancer despite the lack of evidence of malignant pleuritis. Based on semiquantitative evaluation of the mean number of tumor cell clusters per slide in pleural lavage solution, patients were classified as Type I, in whom the mean number of clusters was < 1; Type II, in whom clusters numbered 1-10; and Type III, in whom clusters exceeded 10. RESULTS: Type I patients numbered 37, Type II 40, and Type III 20. By September 1999, pleural recurrence had occurred in 17 patients (18%)--2(5%) Type I, 4 (10%) Type II, and 11 (55%) Type III. The incidence of pleural recurrence was significantly higher for Type III patients, i.e., 5 of 11 Type III patients with pleural recurrence showed no sign of distant metastasis. In contrast, the main recurrent patterns in the other 2 groups were extrathoracic, nodal, and/or intrapulmonary. CONCLUSIONS: The semiquantitative evaluation of tumor cell clusters in pleural lavage cytology-positive patients provided useful information on postoperative recurrence. Since Type III patients are at high-risk for pleural recurrence, postoperative therapy targeting local control should be conducted in such patients.

[Prognostic assessment of resected lung cancer based on the new international staging system: analysis by histologic types].

The purpose of this study is to assess the validity of the new international staging system for lung cancer revised in 1997 and to clarify the prognostic value of histologic type. Of 1,042 patients with primary lung cancer who underwent resection from 1982 to 1995, 549 patients with adenocarcinoma (AD) and 363 with squamous cell carcinoma (SQ) were included in this study. Overall deaths including operative deaths were treated as the terminal event. For patients with AD, 5-year survival rates were 83% in T1N0M0, 70% in T2N0M0, 46% in T2N1M0, 45% in T3N0M0, 43% in T1N2M0, 32% in T1N1M0, 27% in T2N2M0, 25% in T3N1M0, and 10% in T3N2M0, respectively. For patients with SQ, 5-year survival rates were 80% in T1N0M0, 78% in T1N1M0, 67% in T1N2M0, 60% in T3N0M0, 56% in T2N0M0, 47% in T2N1M0, 36% in T3N1M0, 26% in T2N2M0, and 10% in T3N2M0, respectively. Survival of T1N2M0 was significantly better than that of T2N2M0 and similar to that of T3N0M0 and T2N1M0 both in AD and SQ. In AD survival was dominantly affected by N factor, while in SQ survival was strongly correlated with T factor. In conclusion, we propose that T1N1M0, T2N1M0, T3N0M0 and T1N2M0 should be classified as stage II and T3N2M0 be included into stage IIIB for AD. The TNM grouping for SQ is same as that for AD except setting T1N1M0 as stage IB and T2N0M0 as stage II.

[Use of percutaneous cardiopulmonary support (PCPS) for extended surgery in patients with T4 tumor].

Since 1991, we have performed operations for tumors invading the upper airway, left atrium or main pulmonary artery with percutaneous cardiopulmonary support (PCPS) stand by support available. Of 15 cases with PCPS stand by, 6 patients actually underwent operation using PCPS. There were three esophageal cancers invading the carina, two lung neoplasms with left atrial invasion and one neoplasm extending to the main pulmonary artery. One of three patients with esophageal cancer had massive bleeding in the trachea resulting in airway obstruction. For this patient, emergency PCPS was carried out followed by the total removal of the thoracic esophagus and combined resection of membranous portion of the carina. As a result, a substantial amount of time (6 hours) was required. The two patients with reconstruction of the carina due to esophageal cancer were also successfully treated by using PCPS. Two patients with malignant pulmonary neoplasms invading the left atrium underwent combined resection of the lung and left atrium using a combination of PCPS and ventricular fibrillation under normothermia. In conclusion, PCPS should be accepted as a standard technique for patients with advanced thoracic malignancies in whom cardiac arrest or ventilation support is thought to be necessary for the complete removal of the tumor.

[Diagnosis and treatment of small peripheral lung cancer].

Recently, routine clinical use of CT scan has enabled the detection of many small pulmonary nodules. Concurrently, high-resolution CT(HRCT) has made great advances in the diagnosis of small peripheral lung cancer. In the tumor of adenocarcinoma, non-invasive bronchioloalveolar carcinoma(BAC) component having a replacement growth pattern of alveolar lining cells shows ground-glass opacity(GGO) on HRCT. On the basis of analysis of small peripheral adenocarcinoma (= < 2 cm), patients with tumors showing > = 50% GGO had no metastatic tendency. Therefore, simple wedge resection may be acceptable as a radical operation. On the other hand, since patients with tumors < 50% GGO had slight metastatic tendency depending upon the tumor size, segmentectomy with mediastinal lymph node sampling should be considered only for tumors = < 15 mm.

p53-regulated GML gene expression in non-small cell lung cancer. a promising relationship to cisplatin chemosensitivity.

The GML gene (glycosylphosphatidylinositol-anchored molecule-like protein gene) is a novel gene specifically induced by wild-type p53, which may participate in cell cycle control or the cell apoptotic pathway. Recent experiments suggest that the expression of this novel gene in cancer cells is closely associated with sensitivity to certain anticancer drugs. To elucidate the role of the gene expression in cisplatin (CDDP) chemosensitivity of non-small cell lung cancer (NSCLC), 30 surgically resected materials were examined by reverse transcriptase-polymerase chain reaction (RT-PCR). GML gene expression was detected in 9 (30%) samples. Its incidence was significantly higher in immunohistochemically p53-negative (P=0.040) or wild-type p53 tissues (P=0.041). On in vitro chemosensitivity testing using 29 primary tissues, six samples with GML gene expression showed good sensitivity to CDDP. In particular, in tissues with immunohistochemically p53-negative accumulation, those with GML gene expression showed significantly better in vitro sensitivity to CDDP (P=0.012). Clinically a good response to CDDP-based chemo(thermo)therapy for NSCLC patients with tumour residue or recurrence, was observed only in those with p53-negative accumulation and GML gene expression, in agreement with in vitro results. Thus, although the number of tested samples was small, GML gene expression is commonly detected in immunohistochemically p53-negative NSCLCs in close association with good sensitivity to CDDP. GML gene expression analysis may serve as a predictor of CDDP-based chemotherapy for patients with NSCLC.

Survival and postoperative complications after extended surgery for non-small-cell lung cancer. A retrospective study.

OBJECTIVE: We evaluated survival after extended surgery in patients with non-small-cell lung cancer and the effects of induction therapy on results and complications. SUBJECTS AND METHODS: Between April 1987 and March 1998, 127 patients with pathological T3 (pT3) or T4 (pT4) non-small-cell lung cancer underwent extended surgery combined with resection of neighboring organs. Of these, 35 received induction therapy. In the remaining 92, surgery preceded other therapy. Long-term results and postoperative respiratory complications were analyzed and compared between the patients with and without induction therapy. RESULTS: Overall 5-year survival after extended surgery was 37%. Five-year survival rates in the pT3 was 41% and that in the pT4 group 28% (p = 0.030). Five-year survival rate in the pN0-1 was 46% and that in the pN2-3 group 26% (p = 0.003). No significant difference was observed in survival curves between patients with and without induction therapy. Induction therapy responders showed better survival than nonresponders. To prevent postoperative fatal complications due to bronchopleural fistula, we prophylactically covered the bronchial stump using autologous tissue in 31 induction therapy patients, and no mortality due to complications was seen in this group. CONCLUSION: Long-term survival after extended surgery was observed in pT3 and pT4 patients, especially among those with a pN0-1 status. Induction therapy responders may be considered good candidates for extended surgery because of the favorable prognosis in contrast to that for nonresponders.

A novel sperm-specific hypomethylation sequence is a demethylation hotspot in human hepatocellular carcinomas.

Certain human DNA regions are strikingly undermethylated at CpG sites in sperm compared to adult somatic tissues. These sperm-specific hypomethylation sequences are thought to function early in embryogenesis or gametogenesis. By using the restriction landmark genomic scanning (RLGS) cloning method, we have isolated a novel sperm-specific hypomethylation sequence, the status of which changes during spermatogenesis, embryonal growth and differentiation. This sequence is a part of a new 'NotI repeat' consisting of a 1.4 kb repetitive unit sequence named DE-1. The sequence is GC-rich and has high homology to a CpG DNA clone that was isolated by a methyl CpG protein binding column, indicating that it was normally highly methylated. We investigated the methylation status of this sequence. In the normal genome the sequence was methylated, but in the human hepatocellular carcinoma (HCC) genome, the target sequence was demethylated at the cytosine residue of the CpG dinucleotides with high frequency (75% in the previous study). These data suggest that this regional DNA hypomethylation may play a role in both cell differentiation and hepatocarcinogenesis.

Successful removal of a primitive neuroectodermal tumor in the lung with gross extension into the left atrium.

We report here the successful multi-model treatment of a 31-year-old female demonstrating a primitive neuroectodermal tumor originating in the lower lobe of the right lung with gross extension into the left atrium via the inferior pulmonary vein. The tumor was markedly reduced by combination chemotherapy consisting of vincristine, doxorubicin, cyclophosphamide, and ifosfamide. The residual tumor was completely removed through a combined left atrial resection and right middle and lower lobectomy, using a percutaneous cardiopulmonary support system.

Mediastinal lymph node involvement as the initial manifestation of occult thyroid cancer in the surgical treatment of lung cancer: report of a case.

A 63-year-old man was referred to our institute for the treatment of squamous cell carcinoma of the upper lobe of his right lung. A right upper lobectomy of the lung was performed with a mediastinal lymph node dissection. The postoperative pathological examination of the dissected specimens revealed one of the superior mediastinal lymph nodes to be morbid with micrometastasis of occult thyroid cancer, while no node involvement was seen due to lung cancer. A right lobectomy of the thyroid gland with a modified radical neck dissection was done 4 years later after the confirmation of the absence of any recurrent sign of lung cancer. In the resected specimen, papillary thyroid microcarcinoma was observed with several intraglandular metastases and right regional lymph node involvement. Eight months later, a new primary lung cancer developed in the left lung, and a left upper lobectomy of the lung with a mediastinal lymph node dissection was performed. At that time, the absence of mediastinal lymph node metastasis from lung cancer or thyroid cancer was confirmed. Mediastinal lymph node involvement as the initial manifestation of occult thyroid cancer in surgical treatment for lung cancer is rare, but it is important to be aware of the possibility of incidentally detecting occult thyroid cancer in surgical dissections in this area for lung cancer. The appropriate surgical treatment should be determined while carefully considering the prognosis of the lung cancer as well as that of any coexisting malignancy.