Haruhiko Nakayama

Pulmonary resection for metastatic colorectal cancer: Experiences with 159 patients ☆ ☆☆ ★ ★★

We reviewed the clinical courses of 159 patients between February 1967 and May 1995 for the purpose of examining the survival of patients who had pulmonary resection for metastatic colorectal cancer. The cumulative survivals at 5 years and 10 years were 40.5% and 27.7%, respectively. Fifteen patients (10%) were alive more than 10 years after the thoracotomy without any evidence of recurrence. The cumulative survival at 5 years for 39 patients who had hepatic metastases before thoracotomy was 33%. There was a statistically significant difference in survival between patients with extrapulmonary metastases and those with only intrapulmonary metastases before thoracotomy. The number of pulmonary metastases and the presence of hilar or mediastinal lymph node metastases affected postthoracotomy survival. There was no significant difference in survival on the basis of sex, age, location of the primary cancer, size of the pulmonary tumors, mode of operation, or disease-free interval. Surgical treatment for pulmonary metastases from colorectal cancer in selected patients, even those who had hepatic metastases before thoracotomy, might improve prognosis.

Lobe-specific extent of systematic lymph node dissection for non-small cell lung carcinomas according to a retrospective study of metastasis and prognosis.

BACKGROUND Complete lymphadenectomy of the mediastinum is advised for patients with lung cancer to provide prognostic information and possible survival benefit. The proper extent of dissection should be further defined. METHOD The lymphatic metastatic patterns according to the primary site and prognoses were retrospectively analyzed in 166 patients with non-small cell carcinoma who underwent at least lobectomy with hilar and mediastinal lymphadenectomy. All patients had histologically proven mediastinal metastasis (pN2). RESULTS Among 54 right upper lobe tumors the most common site of metastasis was the lower pretracheal station (74%), whereas metastases to the subcarinal station were seen only in 13%. Among 8 patients with right middle lobe tumors and 41 patients with right lower lobe tumors, both superior mediastinal and subcarinal stations were involved. The 34 left upper segment tumors metastasized to the aorticopulmonary window most commonly (71%) and to the subcarina only in 12% of cases. Inversely, the 10 left lingular tumors metastasized to the subcarina most commonly (50%) and to the aorticopulmonary window only in 20% of cases. Among 44 left lower lobe tumors the subcarinal station was most common for metastasis (58%), with infrequent metastases to the aorticopulmonary window. The 5-year survival for all 166 patients was 35%. Patients with single-station and single-node metastases had a significantly better prognosis than those with more extensive metastases. Right lower lobe tumors with superior mediastinal metastasis carried a particularly poor 5-year survival of only 4.1%. COMMENT Subcarinal lymphadenectomy is not always necessary for tumors of the right upper lobe and left upper segment. For tumors of other lobes both superior mediastinal dissection and subcarinal dissection are advised. However, superior mediastinal metastasis should be recognized as an indicator of poor prognosis in tumors of both lower lobes.

Dikkopf-1 as a Novel Serologic and Prognostic Biomarker for Lung and Esophageal Carcinomas

Gene expression profile analysis of lung and esophageal carcinomas revealed that Dikkopf-1 (DKK1) was highly transactivated in the great majority of lung cancers and esophageal squamous cell carcinomas (ESCC). Immunohistochemical staining using tumor tissue microarrays consisting of 279 archived non-small cell lung cancers (NSCLC) and 280 ESCC specimens showed that a high level of DKK1 expression was associated with poor prognosis of patients with NSCLC as well as ESCC, and multivariate analysis confirmed its independent prognostic value for NSCLC. In addition, we identified that exogenous expression of DKK1 increased the migratory activity of mammalian cells, suggesting that DKK1 may play a significant role in progression of human cancer. We established an ELISA system to measure serum levels of DKK1 and found that serum DKK1 levels were significantly higher in lung and esophageal cancer patients than in healthy controls. The proportion of the DKK1-positive cases was 126 of 180 (70.0%) NSCLC, 59 of 85 (69.4%) SCLC, and 51 of 81 (63.0%) ESCC patients, whereas only 10 of 207 (4.8%) healthy volunteers were falsely diagnosed as positive. A combined ELISA assays for both DKK1 and carcinoembryonic antigen increased sensitivity and classified 82.2% of the NSCLC patients as positive whereas only 7.7% of healthy volunteers were falsely diagnosed to be positive. The use of both DKK1 and ProGRP increased sensitivity to detect SCLCs up to 89.4%, whereas false-positive rate in healthy donors was only 6.3%. Our data imply that DKK1 should be useful as a novel diagnostic/prognostic biomarker in clinic and probably as a therapeutic target for lung and esophageal cancer.

Lymph node sampling in lung cancer: how should it be done?

OBJECTIVES Systematic lymph node dissection in radical operation for lung cancer is recognized as an operative procedure which is expected to improve local control. We investigate the most effective method of lymph node dissection or sampling. METHODS A retrospectrive study was carried out on 1815 patients who underwent systematic lymph node dissection and complete resection. The lymphatic route of metastatis from each lobe was investigated by examining which nodes had the most likelihood of metastasis, or to find out which is the sentinel lymph node in the case of small sized tumor, suitable for the video assisted thoracic surgery (VATS) approach. RESULTS At N2 level, distribution of major metastases from each lobe are as follows: right upper lobe tumor, #3 - 12.3% (80/648) and/or #4 - 8% (52/648); right middle lobe tumor, #3 and/or #7 - 16.4% (13/79); right lower lobe tumor, #7 - 13.7% (52/380); left upper lobe tumor, #5 - 12.3% (60/489) and/or #6 - 6.7% (33/489); and left lower lobe tumor, #7 - 11.9% (26/219). Small sized tumor requires lymph node sampling upon staging, and the lymph node most likely to become the first metastasis, i.e. sentinel node, are as follows: regardless of the location of tumor, #12, #11, and/or #10 in N1 level, which means dissection or sampling within these locations of lymph nodes are prerequisite. In N2 level, #3 and/or #4 in right upper lobe tumor, #3 and/or #7 in right middle lobe tumor, #7 in right lower lobe tumor, #5 and/or #6 in left upper lobe tumor, and, #7 in left lower lobe tumor. CONCLUSIONS In clinical T1NO lung cancer, sentinel lymph node sampling should be done first, if the nodes are negative, complete mediastinal lymph node dissection might be omitted. On the other hand, if the sentinel nodes are positive for pathology, complete medistinal lymph node dissection is required for curative resection.

Distinctive evaluation of nonmucinous and mucinous subtypes of bronchioloalveolar carcinomas in EGFR and K-ras gene-mutation analyses for Japanese lung adenocarcinomas: confirmation of the correlations with histologic subtypes and gene mutations.

Although adenocarcinomas of the lung are associated with epidermal growth factor receptor (EGFR) gene mutations and sensitivity to EGFR tyrosine kinase inhibitors, it remains unclear whether bronchioloalveolar carcinoma (BAC) components and/or subtypes affect these associations. We aimed to clarify correlations between EGFR gene mutations and BAC components and to establish the histologic features as reliable predictors for the mutations. We examined 141 non-small cell lung cancers (NSCLCs), including 118 adenocarcinomas, for mutations in exons 19 and 21 of the EGFR gene together with mutations in codon 12 of the K-ras gene using loop-hybrid mobility shift assays, a highly sensitive polymerase chain reaction-based method. Adenocarcinomas were subdivided into subtypes with a nonmucinous or mucinous BAC component and those without BAC components. In NSCLCs, EGFR mutations were detected in 75 cases (53.2%) and were significantly associated with adenocarcinoma, female sex, and never smoking. Among adenocarcinomas, nonmucinous and mucinous BAC components were significantly associated with EGFR and K-ras gene mutations, respectively. Because EGFR mutations were detected even in most pure nonmucinous BACs, ie, lung adenocarcinoma in situ, EGFR mutation is considered a critical event in the pathogenesis of nonmucinous BAC tumors.

Identification of Nectin-4 Oncoprotein as a Diagnostic and Therapeutic Target for Lung Cancer

Gene expression profile analysis of lung cancers revealed the transactivation of an immunoglobulin-like molecule Nectin-4 in the majority of non-small cell lung cancers (NSCLC). Immunohistochemical staining of 422 NSCLCs showed that a high level of Nectin-4 expression was associated with poor prognosis for NSCLC patients (P < 0.0001), and multivariate analysis confirmed its independent prognostic value (P < 0.0001). We established an ELISA to measure serum Nectin-4 and found that serum Nectin-4 levels were significantly higher in NSCLC patients than in healthy volunteers. The proportion of the serum Nectin-4-positive cases was 88 of 164 (53.7%) NSCLCs, whereas only 3 of 131 (2.3%) healthy volunteers were falsely diagnosed as positive, which was superior to carcinoembryonic antigen (CEA) and cytokeratin 19-fragment (CYFRA21-1) in sensitivity and specificity. A combined ELISA for both Nectin-4 and CEA increased sensitivity and classified 65.0% of lung adenocarcinomas as positive with false-positive rate of 4.6%. The use of both Nectin-4 and CYFRA21-1 classified 68.3% of lung squamous cell carcinomas as positive with false-positive rate of 6.1%. Treatment of lung cancer cells with small interfering RNAs against Nectin-4 suppressed its expression and cell growth. In addition, exogenous expression of Nectin-4 increased the lamellipodia formation and the invasive ability of mammalian cells through activation of small GTPase Rac1. Nectin-4 might play a significant role in lung carcinogenesis, and it should be a new candidate serum and tissue biomarker, as well as a therapeutic target.

Wnt Inhibitor Dickkopf-1 as a Target for Passive Cancer Immunotherapy

Dickkopf-1 (DKK1) is an inhibitor of Wnt/beta-catenin signaling that is overexpressed in most lung and esophageal cancers. Here, we show its utility as a serum biomarker for a wide range of human cancers, and we offer evidence favoring the potential application of anti-DKK1 antibodies for cancer treatment. Using an original ELISA system, high levels of DKK1 protein were found in serologic samples from 906 patients with cancers of the pancreas, stomach, liver, bile duct, breast, and cervix, which also showed elevated expression levels of DKK1. Additionally, anti-DKK1 antibody inhibited the invasive activity and the growth of cancer cells in vitro and suppressed the growth of engrafted tumors in vivo. Tumor tissues treated with anti-DKK1 displayed significant fibrotic changes and a decrease in viable cancer cells without apparent toxicity in mice. Our findings suggest DKK1 as a serum biomarker for screening against a variety of cancers, and anti-DKK1 antibodies as potential theranostic tools for diagnosis and treatment of cancer.

Adenocarcinoma arising from a gastric duplication cyst with invasion to the stomach: a case report with literature review

This report describes a rare case of adenocarcinoma arising from a gastric duplication cyst, with invasion to the stomach wall, in a 40 year old Japanese man. A cystic lesion was found between the stomach and the spleen. The cyst had a well circumscribed smooth muscle layer, corresponding to the muscularis propria of the stomach and the mucosa of the alimentary tract. A well differentiated adenocarcinoma was found within the duplication cyst, invading its serosa. Well differentiated adenocarcinoma was independently found in the fundus of the stomach; the tumour of the cyst was connected by fibrous tissue. Microscopically, there was neither adenocarcinoma in situ nor precancerous lesions, such as epithelial dysplasia, suggesting that the carcinoma derived from a gastric duplication cyst that invaded the stomach. Duplication cysts should be included in the differential diagnosis of cystic masses of the gastrointestinal tract, and the possibility of malignancy within these cysts should be considered.

Appropriate Sublobar Resection Choice for Ground Glass Opacity-Dominant Clinical Stage IA Lung Adenocarcinoma: Wedge Resection or Segmentectomy

BACKGROUND The purpose of this multicenter study was to characterize ground glass opacity (GGO)-dominant clinical stage IA lung adenocarcinomas and evaluate prognosis of these tumors after sublobar resection, such as segmentectomy and wedge resection. METHODS We evaluated 610 consecutive patients with clinical stage IA lung adenocarcinoma who underwent complete resection after preoperative high-resolution CT scanning and 18 F-fl uorodeoxyglucose PET/CT scanning and revealed 239 (39.2%) that had a . 50% GGO component. RESULTS GGO-dominant tumors rarely exhibited pathologic invasiveness, including lymphatic, vascular, or pleural invasion and lymph node metastasis. There was no significant difference in 3-year recurrence-free survival (RFS) among patients who underwent lobectomy (96.4%), segmentectomy (96.1%), and wedge resection (98.7%) of GGO-dominant tumors ( P = .44). Furthermore, for GGO-dominant T1b tumors, 3-year RFS was similar in patients who underwent lobectomy (93.7%), segmentectomy (92.9%), and wedge resection (100%, P = .66). Two of 84 patients (2.4%) with GGO-dominant T1b tumors had lymph node metastasis. Multivariate Cox analysis showed that tumor size, maximum standardized uptake value on 18 F-fl uorodeoxyglucose PET/CT scan, and surgical procedure did not affect RFS in GGO-dominant tumors. CONCLUSIONS GGO-dominant clinical stage IA lung adenocarcinomas are a uniform group of tumors that exhibit low-grade malignancy and have an extremely favorable prognosis. Patients with GGOdominant clinical stage IA adenocarcinomas can be successfully treated with wedge resection of a T1a tumor and segmentectomy of a T1b tumor.

Cancer-Testis Antigen Lymphocyte Antigen 6 Complex Locus K Is a Serologic Biomarker and a Therapeutic Target for Lung and Esophageal Carcinomas

Gene expression profile analyses of non-small cell lung carcinomas (NSCLC) and esophageal squamous cell carcinomas (ESCC) revealed that lymphocyte antigen 6 complex locus K (LY6K) was specifically expressed in testis and transactivated in a majority of NSCLCs and ESCCs. Immunohistochemical staining using 406 NSCLC and 265 ESCC specimens confirmed that LY6K overexpression was associated with poor prognosis for patients with NSCLC (P = 0.0003), as well as ESCC (P = 0.0278), and multivariate analysis confirmed its independent prognostic value for NSCLC (P = 0.0035). We established an ELISA to measure serum LY6K and found that the proportion of the serum LY6K-positive cases was 38 of 112 (33.9%) NSCLC and 26 of 81 (32.1%) ESCC, whereas only 3 of 74 (4.1%) healthy volunteers were falsely diagnosed. In most cases, there was no correlation between serum LY6K and conventional tumor markers of carcinoembryonic antigen (CEA) and cytokeratin 19-fragment (CYFRA 21-1) values. A combined ELISA for both LY6K and CEA classified 64.7% of lung adenocarcinoma patients as positive, and the use of both LY6K and CYFRA 21-1 increased sensitivity in the detection of lung squamous cell carcinomas and ESCCs up to 70.4% and 52.5%, respectively, whereas the false positive rate was 6.8% to 9.5%. In addition, knocked down of LY6K expression with small interfering RNAs resulted in growth suppression of the lung and esophageal cancer cells. Our data imply that a cancer-testis antigen, LY6K, should be useful as a new type of tumor biomarker and probably as a target for the development of new molecular therapies for cancer treatment.