Biomedical subjects

Ken Nakagawa

Publications and source records attributed to Ken Nakagawa.

At least 19 recordsLinked to original sources

PubMed2007

Recurrence patterns in patients with early stage non-small cell lung cancers undergoing positive pleural lavage cytology.

BACKGROUND: Cytologic approaches such as pleural lavage cytology (PLC) are considered as possible aids to assessing prognosis of lung cancers. However, there is some controversy whether radical surgery is warranted based on the positive PLC findings with stage I non-small cell lung cancers (NSCLCs). METHODS: From January 1991 to December 2002, PLC was performed before any manipulation or resection of the lung for 853 consecutive patients who had no macroscopic pleural effusion, dissemination, or diffuse adhesions and who subsequently underwent curative resection for NSCLCs. Results of PLC with reference to clinicopathologic characteristics, adjuvant therapy, 5-year survival, and recurrence patterns were analyzed. RESULTS: PLC findings were positive in 41 patients (4.8%), rates being most frequent with adenosquamous carcinomas and adenocarcinomas. In the positive group, distant metastases (72%) and pleural recurrence (25%) (p = 0.0011) were often observed, and the survival rate was significantly poorer (p < 0.002), even for patients with stage I disease (p = 0.009). As adjuvant therapies in the positive group after resection, 6 patients received hypotonic cisplatin and 15 received a distilled water infusion into the pleural space. Although only 2 patients had pleural recurrence, these therapies did not improve long-term outcome. CONCLUSIONS: PLC is a distinct prognostic factor for early stage lung carcinomas. Thus, we suggest that cytologic examination of PLC should be routine, even for patients with stage I NSCLCs before beginning lung resection. Moreover, curative resection, followed by adjuvant systemic therapy, could be necessary for improvement of outcome.

Adolescent↗

PubMed2006

Assessment of long-term quality of life using the FACT-BL questionnaire in patients with an ileal conduit, continent reservoir, or orthotopic neobladder.

OBJECTIVE: To assess and compare quality of life (QOL) of patients followed for a long time who underwent an ileal conduit (IC), continent reservoir (CR) or ileal neobladder (NB) using FACT-BL, a bladder-cancer-specific questionnaire. METHODS: One hundred and forty-seven patients underwent radical cystectomy and urinary diversion for bladder cancer from 1987 to 2002 at our institution. Of them, 79 (54%) patients were asked to participate in this study. Forty-nine patients (20 IC, 14 CR and 15 NB) returned the answered questionnaire for a survey response rate of 62%. Mean follow-up was 83.0 months. RESULTS: Four categories (physical, social/familial, emotional and functional well-being) in FACT-G were equally favorable in these groups. Patients with IC had less trouble controlling urine but had a worse image on altered body appearance compared with NB patients. Interest in sex was extremely low in all patients and capability of maintaining an erection was also low in 39 male patients. The mean total value of FACT-BL in IC, CR and NB patients was 106.3+/-16.4, 104.0+/-14.2, and 110.9+/-18.0, respectively, showing no significant difference. Ten (77%) of 13 IC, seven (78%) of nine CR and six (86%) of seven NB patients answered that they would choose the same type of diversion if they had the choice again. CONCLUSIONS: The type of urinary diversion does not appear to be associated with a different QOL by general cancer-related assessment. Urinary function and body image are affected and related to the method used to reconstruct the urinary system.

Aged↗

PubMed2006

p53 mutation spectra for squamous cell carcinomas at different levels of human bronchial branches.

The question of whether squamous cell carcinomas (SCCs) arising in different sites of lung are caused by different etiological factors is of obvious importance for prevention, early detection and effective treatment. We here subclassified a large series of resected SCCs (74 cases) into 3 tumor-sites, central (main to segmental bronchi), intermediate (subsegmental to sub-subsegmental) and peripheral (distal to sub-subsegmental bronchi), and examined relationships with p53 mutational spectra and smoking history to provide clues to etiological factors. The rate for G-->A transitions at CpG sites considered to be caused by endogenous mechanism was higher in central (40%) than in intermediate (0%) and peripheral (14%) lesions, in spite of highest percentage of heavy smokers. In contrast, G-->T transversions associated with tobacco smoke carcinogens were most frequent (50%) in the intermediate location, although proportions of heavy smoker's ratio were the same among the locations when confined to p53 mutation cases. In the periphery, other mutations were highest (67%) compared with 33 and 50% in the central and intermediate regions, respectively. Thus, different etiological factors may be playing causal roles in the development of SCCs in different locations of bronchial tree. Furthermore, the results suggest that more extensive study of the influence of tobacco smoke carcinogens on endogenous mechanisms is warranted.

Adult↗

PubMed2006

Postoperative ischemic change in bronchial stumps after primary lung cancer resection.

BACKGROUND: The bronchopleural fistula (BPF) is a major complication after lung surgery. We have reviewed our experience with ischemic changes in bronchial stumps, some of which resulted in BPFs (we term this postoperative ischemic bronchitis (POIB)) and studied predisposing factors. METHODS: A total of 1015 patients undergoing curative resection of lung cancers between 1991 and 2002 were reviewed. Details regarding bronchofiberscopic findings within the first 15 postoperative days were carefully reviewed with particular attention to factors possibly affecting the occurrence of POIB: the techniques for bronchial closure and mediastinal lymph node dissection (LND). Information about clinical profiles and histologic status was also analyzed. RESULTS: The incidence of POIB was 2.5% (29/1015), affecting 26 males and 3 females. The most common site was the right intermediate trunk stump (n=4; 7.1%), followed by the left upper (n=8; 3.4%), right lower (n=5; 3.4%), right middle (n=2; 3.3%), and left lower (n=4; 3.2%) lobar bronchial stumps. BPFs eventually resulted in 3 patients (10%) out of 29 with POIB and in 4 (0.4%) out of 986 without it (p<0.0001). Being male, a smoker, having diabetes mellitus, having postoperative respiratory complications and subcarinal LND proved to exert a significant impact with regard to POIB. CONCLUSIONS: Surgeons must bear in mind the possibility of POIB occurrence, especially in cases undergoing particular types of lobectomy (right middle and lower, left upper, right lower or right middle) accompanied by subcarinal LND and having postoperative respiratory complications. Moreover, in appropriate groups with tumors of the right upper lobe or left upper segment, limited mediastinal LND might allow avoidance of POIB.

Aged↗

PubMed2006

Neuroendocrine neoplasms of the lung: a prognostic spectrum.

PURPOSE: Neuroendocrine (NE) tumors of the lung include typical carcinoid (TC), atypical carcinoid (AC), large-cell NE carcinoma (LCNEC), and small-cell lung carcinoma (SCLC). Their clinicopathologic profiles and relative grade of malignancy have not been defined. PATIENTS AND METHODS: From 10 Japanese institutes, 383 surgically resected pulmonary NE tumors were collected. The histologic diagnosis was determined by the consensus of a pathology panel consisting of six expert pathologists as TC, AC, LCNEC, or SCLC on the basis of the WHO classification, and its relationship to clinicopathologic profiles was analyzed. RESULTS: Of the 383 tumors, 18 were excluded because of an improper specimen. The pathology panel reviewed the remaining 366 tumors, and a diagnosis of NE tumor was made in 318 patients (87.4%); 55 patients had TC, nine had AC, 141 had LCNEC, and 113 had SCLC. The 5-year survival rates of patients with all stages were as follows: 96.2% for TC, 77.8% for AC, 40.3% for LCNEC, and 35.7% for SCLC. There was significant prognostic difference between TC and AC as well as between AC and LCNEC+SCLC. However, there was no difference between LCNEC and SCLC, and their survival curves were superimposed. The multivariate analysis indicated that histologic type, completeness of resection, symptoms, nodal involvement, and age were significantly prognostic. CONCLUSION: The grade of malignancy of NE tumors was upgraded in the following order: TC, AC, LCNEC, and SCLC. No prognostic difference was noted between LCNEC and SCLC. The high-grade NE histology uniformly indicated poor prognosis regardless of its histologic type.

Carcinoma, Small Cell↗

PubMed2006

Preoperative nomograms for predicting stone-free rate after extracorporeal shock wave lithotripsy.

PURPOSE: Extracorporeal shock wave lithotripsy is currently accepted as a first line treatment modality for urolithiasis. In obtaining informed consent it is important to inform patients of the stone-free rate with extracorporeal shock wave lithotripsy before surgery. The present study was performed to develop preoperative nomograms for predicting stone-free rates after extracorporeal shock wave lithotripsy. MATERIALS AND METHODS: A total of 435 patients with 507 urinary stones were treated with extracorporeal shock wave lithotripsy with a Dornier Lithotripter D. Patient age, sex, body mass index, number of stone(s) in each treatment, stone length, side and location were evaluated before extracorporeal shock wave lithotripsy, and treatment efficacies were evaluated at 3 months after each session. The treated stones were divided into 2 groups, those in cases that were stone-free with a single extracorporeal shock wave lithotripsy session and those in all other cases. Multivariate analysis was performed using a logistic regression model. The nomograms were developed by repeating the analysis on 200 bootstrap samples. RESULTS: Stone length, location and number were identified as significant variables on multivariate analysis, and a logistic regression model was developed using these variables. The nomograms predicting stone-free rate at 3 months after single extracorporeal shock wave lithotripsy treatment were finally developed from 200 bootstrap samples. In these nomograms the stone-free probability was highest for solitary proximal ureteral stones less than 5 mm in size (93.8%) and lowest for multiple caliceal stones greater than 21 mm (10.5%). CONCLUSIONS: This study demonstrated that stone size, location and number are significant predictors of extracorporeal shock wave lithotripsy outcome. We have developed nomograms for predicting the stone-free rate of extracorporeal shock wave lithotripsy, which is useful for counseling patients with urolithiasis before surgery.

Female↗

PubMed2006

Usefulness of alpha1-antichymotrypsin-PSA complex for predicting bone metastases of prostate cancer.

OBJECTIVES: To determine the usefulness of alpha1-antichymotrypsin-prostate-specific antigen (PSA) complex (PSA-ACT)-based parameters in predicting bone metastasis in patients with prostate cancer. METHODS: PSA-ACT, total PSA, free PSA, their volume-adjusted values, and alkaline phosphatase were evaluated in 220 consecutive patients with newly diagnosed prostate cancer. RESULTS: Bone metastases were detected by bone scan in 27 (12.3%) of the 220 patients. The serum levels of PSA-ACT, total PSA, free PSA, PSA density, PSA adjusted for transition zone volume, PSA-ACT density, PSA-ACT adjusted for transition zone volume, alkaline phosphatase, PSA-ACT/PSA ratio, and Gleason score in patients with bone metastases were each significantly greater than in those without bone metastases. On receiver operating characteristic analyses, PSA-ACT had the greatest area under the curve (0.88), but the receiver operating characteristic curve demonstrated that the sensitivity and specificity of PSA-ACT were marginally better than those of total PSA at only a few selected cutoff points. At a sensitivity of 93% (2 patients with bone metastasis missed), unnecessary bone scans would have been avoided in 107 and 102 patients using a PSA-ACT cutoff value of 10 ng/mL and total PSA cutoff value of 11.5 ng/mL, respectively. Multivariate logistic regression analysis demonstrated that PSA-ACT and Gleason score were significant independent predictors of bone metastasis. CONCLUSIONS: PSA-ACT is as useful as total PSA for identifying patients with a low probability of having bone metastasis. PSA-ACT could replace PSA for predicting negative bone scans in a clinical setting in which PSA-ACT is used for monitoring and screening patients for prostate cancer.

Aged↗

PubMed2006

Maximum tumor diameter is a simple and valuable index associated with the local extent of disease in clinically localized prostate cancer.

BACKGROUND: The present study was undertaken to investigate the association of pathological features, including the total tumor volume (TTV), maximum tumor area (MTA), and maximum tumor diameter (MTD), with the local extent of disease in clinically localized prostate cancer. METHODS: Serial whole sections of the prostate from 164 patients who underwent radical prostatectomy for localized prostate cancer were investigated. The correlations between the indicators of tumor size, including the TTV, MTA, and MTD, and other pathological parameters were evaluated. RESULTS: The MTD, MTA, and TTV were significantly correlated with each other. Multivariate stepwise logistic regression analysis indicated that the Gleason score, perineural invasion, microvascular invasion, and MTD were significant independent parameters associated with extraprostatic disease. CONCLUSION: The histological tumor grade, perineural invasion, microvascular invasion, and tumor size were correlated with the local extent of disease. The MTD, a simple, easy, and inexpensive parameter, is a more significant pathological feature associated with the local extent of disease than the MTA or TTV.

Aged↗

PubMed2005

Two subclasses of lung squamous cell carcinoma with different gene expression profiles and prognosis identified by hierarchical clustering and non-negative matrix factorization.

Current clinical and histopathological criteria used to define lung squamous cell carcinomas (SCCs) are insufficient to predict clinical outcome. To make a clinically useful classification by gene expression profiling, we used a 40 386 element cDNA microarray to analyse 48 SCC, nine adenocarcinoma, and 30 normal lung samples. Initial analysis by hierarchical clustering (HC) allowed division of SCCs into two distinct subclasses. An additional independent round of HC induced a similar partition and consensus clustering with the non-negative matrix factorization approach indicated the robustness of this classification. Kaplan-Meier analysis with the log-rank test pointed to a nonsignificant difference in survival (P = 0.071), but the likelihood of survival to 6 years was significantly different between the two groups (40.5 vs 81.8%, P = 0.014, Z-test). Biological process categories characteristic for each subclass were identified statistically and upregulation of cell-proliferation-related genes was evident in the subclass with poor prognosis. In the subclass with better survival, genes involved in differentiated intracellular functions, such as the MAPKKK cascade, ceramide metabolism, or regulation of transcription, were upregulated. This work represents an important step toward the identification of clinically useful classification for lung SCC.

Biomarkers, Tumor↗

PubMed2005

Classification of parietal pleural invasion at adhesion sites with surgical specimens of lung cancer and implications for prognosis.

Parietal pleural invasion of non-small cell lung cancer (NSCLC) is a factor for poor prognosis, and a tumor of any size that invades the parietal pleura is classified as T3. However, with microscopic invasion beyond elastic fibers of the visceral pleura but no penetration to the parietal pleura at tight adhesion sites (we term this p1-3), classification as to the T factor is unclear. Among 1,179 consecutive patients with NSCLCs who underwent curative surgery between 1980 and 2002, 20 were in this category. Here, a comparison was made with subgroups of p stages IB, II, and IIIA with regard to histology, pleural invasion, and survival rates. To maximize the power of assessing prognostic potential, we set the significance level at 0.10, one-sided. The p1-3 condition sites of the 20 cases were the parietal pleura for 17 cases and the pericardium, diaphragm, and chest wall for one each of the remainder. The 5-year survival rate for these p1-3 patients was 71.6%. Significant differences were observed between p1-3 and IIIA groups. Although the 5-year survival rates did not significantly differ between p1-3 and T3N0 or unequivocal T3 subgroups, the prognosis of p1-3 patients was rather better than that of T3 and identical to T2. It was demonstrated that p1-3 status is not a factor warranting T3 classification for NSCLCs. Considering the prognosis, pathologic p1-3 tumors should be managed as a T2 disease for the present.

Aged↗

PubMed2005

Refractory ulcerative colitis accompanied with cytomegalovirus colitis and multiple liver abscesses: a case report.

Various hepato-biliary complications are an increased incidence in patients with inflammatory bowel disease, and portal bacteremia is well documented in patients with ulcerative colitis (UC). However, few reports mention UC in association with liver abscesses. Recently, there are several reports describing cytomegalovirus (CMV) infection in association with disease exacerbation and steroid refractoriness in patients with UC. Here we present a case of refractory UC accompanied with multiple liver abscesses and CMV colitis. The patient, a 72-year-old male, with a five-year history of repeated admissions to our hospital for UC, presented with an exacerbation of his UC. Sigmoidoscopy performed on admission suggested that his UC was exacerbated, then he was given prednisolone and mesalazine orally, and betamethasone enemas. However, he had exacerbated symptoms. Repeat sigmoidoscopy revealed multiple longitudinal ulcers and pseudopolyps in the rectosigmoid colon. Although immunohistochemical staining of biopsy specimens and the serum testing for antigenemia were negative on admission and after the repeat sigmoidoscopy, they became histologically positive for CMV. Nonetheless, the patient developed spiking fevers, soon after ganciclovir was administered. Laboratory studies revealed an increased white cell count with left shift, and Enterococcus fecalis grew in blood cultures. An abdominal computed tomography (CT) scan was obtained and the diagnosis of liver abscesses associated with UC was made, based on CT results. The hepatic abscesses were successfully treated with intravenous meropenem for 6 wk, without further percutaneous drainage. To our knowledge, this is the first reported case of multiple liver abscesses that develop during UC exacerbation complicated by CMV colitis.

Aged↗

PubMed2005

Phase I study of combination chemotherapy with gemcitabine and irinotecan for non-small cell lung cancer.

UNLABELLED: A phase I study combining a fixed dose of gemcitabine with differing doses of CPT-11 every two weeks for previously treated non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: A total of 21 patients with previously treated non-small cell lung cancer were treated every two weeks with CPT-11 followed by gemcitabine. The gemcitabine dose was fixed at 1000 mg/m2. The starting dose of CPT-11 (50 mg/m2) was then escalated different patients in 25 mg/m2 increments until 150 mg/m2 (level 5), the recommended dose as a single agent in Japan. RESULTS: Dose-limiting toxicity was only observed at level 5, in three of nine patients receiving the highest dose of CPT-11. One patient had grade 3 diarrhea, and two could not continue chemotherapy with grade 1 diarrhea or grade 1 neutropenia on day 15. Hematologic toxicity with this combination regimen, however, was generally mild. No grade 4 neutropenia, and only one case of grade 3 leukopenia was noted at level 5. Compliance with the combination regimen was good and there was no cumulative toxicity with the subsequent courses. Twenty-five courses of therapy were given at level 5 and the percentage of actual delivered doses/planned doses was 82%. CONCLUSIONS: The combination chemotherapy has only very mild toxicity and dose which can be recommended with this regimen are 1000 mg/m2 for gemcitabine and 150 mg/m2 for CPT-11 every two weeks.

Adult↗

PubMed2005

Antipyrine test predicts pharmacodynamics in docetaxel and cisplatin combination chemotherapy.

To clarify the role of cytochrome P450 in docetaxel and cisplatin combination chemotherapy, cytochrome P450 activity was measured by simple antipyrine test, and its correlation with the drugs' pharmacodynamics was assessed. Twenty-five patients with advanced non-small cell lung cancer received an antipyrine test and were treated with docetaxel and cisplatin. Plasma antipyrine concentration (C) was measured 4 and 24h after oral administration of 500 mg antipyrine. Antipyrine disappearance rate (ADR) was calculated by: [(C(4h)-C(24h))/C(4h)]x100. ADR correlated significantly with neutropenia nadir. ADR and alpha(1)-acid glycoprotein were selected for independent predictors of neutropenia by multiple regression analysis. In addition, 25 patients were separated into "low ADR" (<40%) and "high ADR" groups (>40%). Grade 3--4 neutropenia was observed in 7/9 "low ADR" patients (77%), whereas grade 3--4 neutropenia was observed in 5/16 "high ADR" patients (31%). We concluded that antipyrine test and cytochrome P450 play an important role in predicting toxicities of docetaxel and cisplatin combination chemotherapy.

Adenocarcinoma↗

PubMed2005

Prostate specific antigen adjusted for transition zone epithelial volume: the powerful predictor for the detection of prostate cancer on repeat biopsy.

PURPOSE: The indications for repeat prostate biopsy for persistently increased prostate specific antigen (PSA) in men with prostate cancer never detected on previous biopsy are not clear. In this study we determined that PSA adjusted for transition zone (TZ) epithelial volume is the most powerful predictor for detecting prostate cancer on repeat biopsy. MATERIALS AND METHODS: Repeat prostate biopsies including additional TZ cores were performed in 75 men with PSA between 4.0 and 10.0 ng/ml. TZ epithelial volume was calculated by multiplying TZ volume by the percent of epithelium, which was measured by morphometric analysis using image analysis computer software. RESULTS: Prostate cancer was detected on repeat biopsy in 19 of the 75 patients. Patients with prostate cancer had a significant smaller percent area of epithelium or glandular lumen than those without cancer. In patients without prostate cancer TZ epithelial volume significantly correlated with total PSA. According to ROC analysis PSA adjusted for TZ epithelial volume had the greatest AUC for cancer detection (0.879). This parameter was able to avoid more than 90% of unnecessary repeat biopsies with 90% sensitivity. Multiple logistic regression analysis showed that PSA complex adjusted for TZ epithelial volume was the significant independent predictor of cancer. CONCLUSIONS: PSA adjusted for TZ epithelial volume is the most powerful predictor of cancer in men who have undergone previous negative prostate biopsies and in whom PSA remains between 4.0 and 10.0 ng/ml.

Aged↗

PubMed2005

Pulmonary adenocarcinomas with enteric differentiation: histologic and immunohistochemical characteristics compared with metastatic colorectal cancers and usual pulmonary adenocarcinomas.

Primary pulmonary adenocarcinomas with enteric differentiation (PAED) are mainly composed of tall-columnar cells that show similarity to intestinal epithelia and colorectal carcinomas. In this study, we analyzed the immunostaining profiles of 7 PAEDs in comparison with 14 metastatic colorectal carcinomas (MCRs) and 30 usual pulmonary adenocarcinomas (PACs), using antibodies against CDX-2, cytokeratin 7 (CK7), cytokeratin 20 (CK20), TTF-1, surfactant apoprotein-A (SP-A), Napsin A, and MUC2. The positive rates for CDX-2, CK7, CK20, TTF-1, SP-A, Napsin A, and MUC2 were 71%, 100%, 43%, 43%, 14%, 0%, and 43%, respectively, in the PAEDs; 100%, 0%, 86%, 0%, 0%, 0%, and 57% in the MCRs; 3%, 100%, 0%, 93%, 73%, 90%, and 0% in PACs. As expected, immunoreactivity of CDX-2, CK20, and MUC2 was detected in PAEDs. The observed decrease or loss of immunoreactivity for TTF-1, SP-A, and Napsin A indicates that these lesions demonstrate a shift away from their pulmonary phenotype, although CK7 expression was retained. The results indicate that CK7 and CK20 may be useful markers for distinction of PAEDs from MCRs.

Adenocarcinoma↗

PubMed2005

Successful treatment of chemo-refractory pulmonary metastases of renal pelvic cancer by second-line chemotherapy including gemcitabine followed by salvage surgery.

A 51-year-old woman developed multiple pulmonary metastases after receiving nephroureterectomy and two cycles of adjuvant chemotherapy for the treatment of renal pelvic transitional cell carcinoma. All metastases disappeared after four cycles of methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) chemotherapy followed by radiotherapy; however, 8 months later two pulmonary metastases recurred. The patient was entered into a phase I study of combination chemotherapy with gemcitabine, etoposide and cisplatin, designed for chemorefractory urothelial cancer. The lung masses showed significant reduction after two cycles of this chemotherapy; following salvage surgery, the patient has been well with no evidence of recurrence for more than 3 years.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Testicular seminoma after the complete remission of extragonadal yolk sac tumor : a case report.

BACKGROUND: Between 2% and 5% of malignant germ-cell tumors in men arise at extragonadal sites. Of extragonadal germ cell tumors, testicular carcinoma in situ (CIS) are present in 31-42% of cases, and CIS are reported to have low sensitivity to chemotherapy in spite of the various morphology and to have a high likelihood of developing into testicular tumors. A testicular biopsy may thus be highly advisable when evaluating an extragonadal germ cell tumor. CASE PRESENTATION: A 36-year-old man was diagnosed as having an extragonadal non-seminomatous germ cell tumor, that was treated by cisplatin-based chemotherapy, leading to a complete remission. In the meantime, testicular tumors were not detected by means of ultrasonography. About 4 years later, a right testicular tumor was found, and orchiectomy was carried out. Microscopically, the tumor was composed of seminoma. CONCLUSIONS: We herein report a case of metachronous occurrence of an extragonadal and gonadal germ cell tumor. In the evaluation of an extragonadal germ cell tumor, a histological examination should be included since ultrasonography is not sufficient to detect CIS or minute lesions of the testis.

Adult↗

PubMed2004

Two prognostically significant subtypes of high-grade lung neuroendocrine tumours independent of small-cell and large-cell neuroendocrine carcinomas identified by gene expression profiles.

BACKGROUND: Classification of high-grade neuroendocrine tumours (HGNT) of the lung currently recognises large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung carcinoma (SCLC) as distinct groups. However, a similarity in histology for these two carcinomas and uncertain clinical course have led to suggestions that a single HGNT classification would be more appropriate. Gene expression profiling, which can reproduce histopathological classification, and often defines new subclasses with prognostic significance, can be used to resolve HGNT classification. METHODS: We used cDNA microarrays with 40?386 elements to analyse the gene expression profiles of 38 surgically resected samples of lung neuroendocrine tumours and 11 SCLC cell lines. Samples of large-cell carcinoma, adenocarcinoma, and normal lung were also included to give a total of 105 samples analysed. The data were subjected to filtering to yield informative genes before unsupervised hierarchical clustering that identified relatedness of tumour samples. FINDINGS: Distinct groups for carcinoids, large-cell carcinoma, adenocarcinoma, and normal lung were readily identified. However, we were unable to distinguish LCNEC from SCLC by gene expression profiling. Three independent rounds of unsupervised hierarchical clustering consistently divided SCLC samples into two main groups with LCNEC samples largely integrated with these groups. Furthermore, patients in one of the groups identified by clustering had a significantly better clinical outcome than the other (83% vs 12% survived for 5 years; p=0.0094. None of the highly proliferative SCLC cell lines subsequently analysed clustered with this good-prognosis group. INTERPRETATION: Our findings show that HGNT of the lung can be classified into two groups independent of SCLC and LCNEC. To this end, we have identified many genes, some of which encode well-characterised markers of cancer that distinguish the HGNT groups. These results have implications for the diagnosis, classification, and treatment of lung neuroendocrine tumours, and provide important insights into their underlying biology.

Biomarkers, Tumor↗