ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer.

The European Society for Medical Oncology (ESMO) held a virtual consensus-building process on epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer in 2021. The consensus included a multidisciplinary panel of 34 leading experts in the management of lung cancer. The aim of the consensus was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where the available evidence is either limited or conflicting. The main topics identified for discussion were: (i) tissue and biomarkers analyses; (ii) early and locally advanced disease; (iii) metastatic disease and (iv) clinical trial design, patient's perspective and miscellaneous. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the recommendations developed, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation.

Final overall survival results of WJTOG3405, a randomized phase III trial comparing gefitinib versus cisplatin with docetaxel as the first-line treatment for patients with stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer.

BACKGROUND: Primary analysis of the phase III study WJTOG 3405 demonstrated superiority of progression-free survival (PFS) for gefitinib (G) in patients treated with the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) gefitinib compared with cisplatin plus docetaxel (CD) as the first-line treatment of stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. This report presents final overall survival (OS) data. PATIENTS AND METHODS: Patients were randomized between G (250 mg/day orally) and cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 i.v.), administered every 21 days for three to six cycles. After the exclusion of 5 patients, 172 patients (86 in each group, modified intention-to-treat population) were included in the survival analysis. OS was re-evaluated using updated data (data cutoff, 30 September 2013; median follow-up time 59.1 months). The Kaplan-Meier method and the log-rank test were used for analysis, and hazard ratios (HRs) for death were calculated using the Cox proportional hazards model. RESULTS: OS events in the G group and CD group were 68 (79.1%) out of 86 and 59 (68.6%) out of 86, respectively. Median survival time for G and CD were 34.9 and 37.3 months, respectively, with an HR of 1.252 [95% confidence interval (CI): 0.883-1.775, P = 0.2070]. Multivariate analysis identified postoperative recurrence and stage IIIB/IV disease as independent prognostic factors, with an HR of 0.459 (95% CI: 0.312-0.673, P < 0.001). Median survival time (postoperative recurrence versus stage IIIB/IV disease) were 44.5 and 27.5 months in the G group and 45.5 and 32.8 months in the CD group, respectively. CONCLUSION: G did not show OS benefits over CD as the first-line treatment. OS of patients with postoperative recurrence was better than that of stage IIIB/IV disease, even though both groups had metastatic disease.This study was registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.

Comparative evaluation of new and conventional classifications of magnifying endoscopy with narrow band imaging for invasion depth of superficial esophageal squamous cell carcinoma.

A new classification of magnifying endoscopy with narrow band imaging (ME-NBI) for diagnosing and staging superficial esophageal squamous cell carcinoma (SESCC) was proposed by the Japan Esophageal Society in 2011. This study aimed to compare the new classification with the conventional classifications (Inoue's classification and Arima's classification). This was a prospective analysis of data from a single cancer center involving 151 consecutive patients with 156 SESCCs that were endoscopically or surgically resected. Initially, only ME-NBI images were selected and reviewed independently by three experienced endoscopists. White light imaging (WLI) was then evaluated separately after an interval. The diagnostic performance of each classification and interobserver agreement were assessed, and the WLI findings that affect the diagnosis by the new classification were identified. The specificity for classifying invasive depth as epithelium (EP)/lamina propria mucosae (LPM) confined was higher with the new classification than with Inoue's classification (0.512 vs. 0.349; P = 0.02) and Arima's classification (0.512 vs. 0.279; P < 0.01). However, the sensitivity was lower (0.902 vs. 1.000; P < 0.01) compared with Arima's classification. The concordance rates of three evaluators (κ values) were 0.52 for the new classification, 0.50 for Inoue's classification, and 0.23 for Arima's classification. On multivariate analysis, thickness on WLI independently affected the accuracy of diagnosis with the new classification (OR 3.23; 95%CI, 1.30-8.03). The new classification is superior to conventional classifications with respect to specificity for diagnosing SESCC with depth EP/LPM. Thickness on WLI was a factor negatively affecting the diagnostic performance of the new classification.

Genetic features of pulmonary adenocarcinoma presenting with ground-glass nodules: the differences between nodules with and without growth.

BACKGROUND: Pulmonary ground-glass nodules (GGNs) include both malignant and benign lesions. Some GGNs become larger, whereas others remain unchanged for years. We have previously reported that smoking history and large diameters are predictors for growth. However, the genetic differences among GGNs remain unclear. PATIENTS AND METHODS: GGNs with ground-glass component of ≥50% on a thin-section computed tomography scan that were resected between 2012 and 2014 were evaluated for clinicopathological features and the presence of EGFR/KRAS/ALK/HER2 mutations. 'Incidence of 2-mm growth' and 'Time to 2-mm growth' were analyzed according to the mutational status. RESULTS: Among 104 GGNs in 96 patients, this study included 3 atypical adenomatous hyperplasia (AAH), 19 adenocarcinoma in situ (AIS), 27 minimally invasive adenocarcinoma (MIA), and 55 invasive adenocarcinoma (IA). Among the 71 lesions evaluable for growth, 30 GGNs exhibited growth and 5 lesions remained unchanged for ≥2 years before surgery was carried out. We identified mutations or rearrangements in 75% of GGNs (78/104). EGFR mutations were noted in 64% of samples, KRAS in 4%, ALK in 3%, and HER2 in 4%. The remaining 26 quadruple-negative tumors were significantly associated with AAH/AIS (P < 0.01) and no-growth (P < 0.01) compared with driver mutation-positive tumors, whereas EGFR mutation-positive tumors were correlated with MIA/IA (P < 0.01) and growth (P < 0.01) compared with EGFR-negative tumors. CONCLUSIONS: Three fourths of resected GGNs were positive for EGFR, KRAS, ALK, or HER2 mutations. Quadruple-negative tumors were associated with a lack of GGN growth, whereas EGFR mutation-positive tumors displayed a correlation with growth.

Inguinal hernia repair in patients with artificial urinary sphincter after radical prostatectomy.

PURPOSE: Stress urinary incontinence (UI) often develops after radical prostatectomy for prostate cancer, and in those patients with moderate-to-severe stress UI an artificial urinary sphincter (AUS) is implanted. Inguinal hernias (IHs) often occur after radical prostatectomy. As the prevalence of AUS implantation increases, it is possible to encounter patients with IHs undergoing AUS implantation (IHA). This study investigated our treatment and discussed an appropriate approach for IHAs. METHODS: We retrospectively investigated patients who underwent IH repair with AUS implantation at our hospital from January 2018 to March 2023. We classified IHAs into Types A-D based on the positions of the IHs and AUS devices (the positions of the control pump, pressure-regulating balloon, and connecting tube). The hernia and control pump were ipsilateral in Types A and B, whereas the hernia and pressure-regulating balloon were ipsilateral in Types A and C. RESULTS: This study included 12 IHs of 11 patients. The median patient age was 77 years. We conducted open repair in nine patients with all types and laparoscopic repair in two patients with Type B. The median operation times for unilateral and bilateral repairs were 96 and 182 min, respectively. There were no complications with AUS or hernia surgeries. CONCLUSION: IHA has its own characteristics, and multidisciplinary knowledge thereof will help surgeons safely perform IH surgery.

Time to first cigarette and lung cancer risk in Japan.

BACKGROUND: Cigarette smoking is the major cause of lung cancer (LC). Although the time to first cigarette (TTFC) of the day is a distinct indicator of nicotine dependence, little information is available on its possible relation to LC. PATIENTS AND METHODS: This case-control study includes a total of 1572 incident LC cases and 1572 non-cancer controls visiting for the first time the Aichi Cancer Center Hospital between 2001 and 2005. We estimated the odds ratio (OR) and 95% confidence interval (CI) for TTFC using a logistic regression model after adjustment for several potential confounders. RESULTS: TTFC was inversely associated with the risk of LC. This association was consistent across histological subtypes of LC. For all LCs considered among ever smokers and after accurate allowance for smoking quantity and duration, besides other relevant covariates, compared with TTFC >60 min, the adjusted ORs were 1.08 (95% CI, 0.73-1.61) for TTFC of 31-60 min, 1.40 (0.98-2.01) for 6-30 min and 1.86 (1.28-2.71) for within 5 min (Ptrend, < 0.001). Statistically marginally significant heterogeneity by histological subtype was observed (Pheterogeneity, 0.002). CONCLUSIONS: Nicotine dependence, as indicated by the TTFC, is associated with increased risk of LC and is therefore an independent marker of exposure to tobacco smoking.

Prevalence of delirium among outpatients with dementia.

BACKGROUND: Delirium and dementia are highly interrelated. However, few comprehensive epidemiological studies have examined this altered state of consciousness superimposed on dementia. We investigated the frequency of delirium in patients with dementia, its prevalence in patients with each dementia type, and its association with cerebrovascular disease (CVD) in patients with neurodegenerative dementias. METHODS: We studied 261 consecutive outpatients in the memory clinic of a psychiatric hospital between April 2010 and September 2011. All patients underwent routine laboratory tests and computed tomography (CT), and their Mini-Mental State Examination, Neuropsychiatric Inventory (NPI), Physical Self-Maintenance Scale (PSMS), and Delirium Rating Scale - Revised 98 scores were recorded. The diagnosis of delirium was based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision. CVD was detected by CT. RESULTS: Among the 206 patients with dementia, delirium was present in 40 (19.4%). The proportion of patients who experienced episodes of delirium was 14.7% in the Alzheimer's disease, 34.4% in the vascular dementia, 31.8% in the dementia with Lewy bodies, and none in frontotemporal lobar degeneration. Delirium was frequently observed in patients with dementia and CVD. The NPI total and agitation subscale scores were significantly higher in dementia patients with delirium than in those without delirium. PSMS scores were significantly lower for patients with delirium than for patients without delirium. CONCLUSIONS: The frequency of delirium varies with each dementia type. In addition, delirium decreases activities of daily living, exaggerates behavioral and psychological symptoms dementia, and is associated with CVD in patients with neurodegenerative dementias.

Association between dietary folate intake and clinical outcome in head and neck squamous cell carcinoma.

BACKGROUND: The association between dietary folate intake, two polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TYMS), and survival in head and neck squamous cell carcinoma (HNSCC) patients is not clarified. PATIENTS AND METHODS: We conducted a retrospective cohort study of 437 HNSCC patients treated at Aichi Cancer Center. We evaluated the survival impact of pretreatment dietary folate intake, which was estimated using a food-frequency questionnaire, and two polymorphisms, MTHFR C677T and a 6-bp insertion/deletion in the 3'-untranslated region of TYMS, using multivariate proportional hazard models. RESULTS: Patients with high folate intake (≥320 µg/day; n=144) had significantly higher survival than patients with low or medium folate intake (<320 µg/day; n=278; 79.1% versus 68.2%, respectively, P=0.020). This association was consistent with multivariate analyses adjusted for established prognostic factors (hazard ratio 0.56; 95% confidence interval 0.37-0.84). MTHFR and TYMS polymorphisms did not show significant association with survival, although the TYMS 6-bp insertion allele showed potential association with a reduced risk of death. Notably, no significant interaction was observed between folate intake and the two examined polymorphisms. CONCLUSIONS: High pretreatment dietary folate intake was identified as an independent prognostic factor associated with improved clinical outcomes in HNSCC patients. Further study is warranted.

BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer.

BACKGROUND: Activating mutation of KRAS and BRAF are focused on as potential prognostic and predictive biomarkers in patients with colorectal cancer (CRC) treated with anti-EGFR therapies. This study investigated the clinicopathological features and prognostic impact of KRAS/BRAF mutation in advanced and recurrent CRC patients. METHOD: Patients with advanced and recurrent CRC treated with systemic chemotherapy (n=229) were analysed for KRAS/BRAF genotypes by cycleave PCR. Prognostic factors associated with survival were identified by univariate and multivariate analyses using the Cox proportional hazards model. RESULTS: KRAS and BRAF mutations were present in 34.5% and 6.5% of patients, respectively. BRAF mutated tumours were more likely to develop on the right of the colon, and to be of the poorly differentiated adenocarcinoma or mucinous carcinoma, and peritoneal metastasis. The median overall survival (OS) for BRAF mutation-positive and KRAS 13 mutation-positive patients was 11.0 and 27.7 months, respectively, which was significantly worse than that for patients with wild-type (wt) KRAS and BRAF (40.6 months) (BRAF; HR=4.25, P<0.001, KRAS13; HR=2.03, P=0.024). After adjustment for significant features by multivariate Cox regression analysis, BRAF mutation was associated with poor OS (HR=4.23, P=0.019). CONCLUSION: Presence of mutated BRAF is one of the most powerful prognostic factors for advanced and recurrent CRC. The KRAS13 mutation showed a trend towards poor OS in patients with advanced and recurrent CRC.

Role of endoscopic ultrasound and endoscopic ultrasound-guided fine-needle aspiration in diagnosing metastasis to the pancreas: a tertiary center experience.

BACKGROUND: Metastasis to the pancreas (MP) is a rare entity that is difficult to identify by imaging alone. Few reports have described endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (FNA) findings. Herein, we try to describe the EUS and EUS-FNA characteristics of MP. METHODS: This retrospective study compared 28 patients with MP (13 males; mean age: 60.1 ± 12.6 years) and 60 control patients (30 males; 62.7 ± 11.5 years) with pancreatic ductal adenocarcinoma (PDAC). All lesions were characterized by EUS, and MP was diagnosed by EUS-FNA (n = 16), surgery (n = 6) or both (n = 6). RESULTS: Multivariate logistic regression revealed that the presence of regular borders (p = 0.004; OR: 8.81, 95% CI: 1.97-39.4), the absence of retention cysts (p = 0.045; OR: 12.5, 95% CI: 1.06-147.0), and the absence of main pancreatic duct (MPD) dilation (p = 0.003; OR: 8.18, 95% CI: 2.04-32.8) were predictors of MP rather than PDAC. The EUS-FNA sampling adequacy was 95.4% (21/22), and the correct diagnosis was obtained in 95.2% (20/21) of cases when K-ras mutation analysis and/or immunostaining were added. CONCLUSION: The presence of regular borders, the absence of retention cysts and the presence of nondilated MPD on EUS indicate MP rather than PDAC. This diagnosis can be accurately confirmed by EUS-FNA with immunostaining and/or K-ras analysis.

Development of pancreatic cancers during long-term follow-up of side-branch intraductal papillary mucinous neoplasms.

BACKGROUND AND STUDY AIMS: Side-branch intraductal papillary mucinous neoplasms (SB-IPMNs), and associated synchronous and metachronous pancreatic cancers are increasingly detected as imaging modalities become more sensitive. We investigated the natural history of SB-IPMN, and the incidence and characteristics of pancreatic cancers among patients undergoing long-term follow-up. PATIENTS AND METHODS: We reviewed the clinical, imaging, and pathological features in 103 patients, diagnosed at the Aichi Cancer Center between September 1988 and September 2006 as having SB-IPMN, and conservatively followed up for ≥ 2 years (median 59 months) based on an endoscopic ultrasonography (EUS) database. RESULTS: 74 (71.8 %) patients had nonprogressive lesions. Overall, six patients (5.8 %) developed pancreatic cancers during follow-up, with intraductal papillary mucinous (IPM) carcinoma in four, and ductal carcinoma of pancreas that was not IPMN in two patients. Of the six pancreatic cancers, five were diagnosed at a resectable stage. The 5-year and 10-year actuarial rates of development of pancreatic cancer were 2.4 % and 20.0 %, respectively. Although, at the last follow-up, cyst size, main pancreatic duct (MPD) diameter, mural nodule size, and frequency of metachronous and/or synchronous cancers of other organs were significantly higher in patients who developed IPM carcinoma, resected SB-IPMNs without mural nodules and dilated MPDs had no IPM carcinomas. CONCLUSIONS: The frequency of pancreatic cancers is high on long-term follow-up of SB-IPMN. Although conservative management is appropriate for selected patients, regular and long-term imaging, especially by EUS is essential, even if SB-IPMN remains unchanged for 2 years. Presence of mural nodule and dilated MPD seem to be more appropriate indicators for resection than cyst size alone for SB-IPMNs.

Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach.

Although widespread metastasis is the major cause of human lung cancer-related deaths, its underlying mechanism remains largely unclear. Our genome-wide comparison of the expression profiles of a highly metastatic lung cancer cell line, NCI-H460-LNM35 (LNM35), and its parental clone, NCI-H460-N15 (N15), resulted in the identification of a cancer metastasis signature composed of 45 genes. Through gene ontology analysis, our study also provided insights into how this 45-gene metastasis signature may contribute to the acquisition of metastatic potential. By applying the signature to datasets of human cancer cases, we could demonstrate significant associations with a subset of cases with poor prognosis not only for the two datasets of cancers of the lung but also for cancers of the breast. Furthermore, we were able to show that enforced expression of the DLX4 homeobox gene, which was identified as a gene with significant downregulation in LNM35 as well as with significant association with favorable prognosis for lung cancer patients, markedly inhibited in vitro motility and invasion as well as in vivo metastasis via both hematogenous and lymphogenous routes. Taken together, these findings indicate that our combined transcriptome analysis is an efficient approach in the search for genes possessing both clinical usefulness in terms of prognostic prediction in human cancer cases and clear functional relevance for studying cancer biology in relation to metastasis.

Site-specific Chemotherapy Based on Predicted Primary Site by Pathological Profile for Carcinoma of Unknown Primary Site.

AIMS: Although platinum-based combination chemotherapies are commonly used for unfavourable subsets of cancer of unknown primary (CUP), the prognosis remains poor. Several studies have suggested that gene expression profiling or immunohistochemistry was useful for the prediction of primary sites in CUP, and site-specific therapy based on predicted primary sites might improve overall outcomes. In Japan, to identify primary sites, immunohistochemical tests were commonly used for CUP in clinical practice. However, it is unclear whether site-specific therapy based on predicted primary sites by pathological examination contributes survival benefit for unfavourable CUP subsets. PATIENTS AND METHODS: In this study, 122 patients with unfavourable subsets of CUP were retrospectively reviewed. Ninety patients assigned to cohort A after July 2012 had received chemotherapy according to predicted primary sites; 32 patients assigned to cohort B before June 2012 had received platinum-based empiric chemotherapy. RESULTS: In cohort A, 56 patients (62.2%) with predicted primary sites by pathological examination received site-specific therapy; 34 patients (37.8%) with unpredictable primary sites received platinum-based empiric chemotherapy, the same as cohort B. The median overall survival was 20.3 months in patients with predictable primary sites in cohort A and 10.7 months in those of cohort B, with a significant difference between these cohorts (P = 0.03, adjusted hazard ratio = 0.57, 95% confidence interval 0.34-0.94). CONCLUSION: Site-specific therapy based on predicted primary sites by pathological examination could improve prognosis in patients with an unfavourable subset of CUP.

Clinical implications of p53 autoantibodies in the sera of patients with non-small-cell lung cancer.

BACKGROUND: The presence of autoantibodies to p53 protein has been associated with the presence of p53 (also known as TP53) gene mutations in primary tumors and with poor prognosis. This study was undertaken to determine the clinical significance of p53 autoantibodies in patients with non-small-cell lung cancer (NSCLC). METHODS: We studied 188 consecutive patients with NSCLC who underwent pulmonary resection and for whom preoperative serum was available. The presence of p53 autoantibodies, detected by use of two amino-terminal and two carboxy-terminal peptides (20-30 mers) as antigens and an enzyme-linked immunosorbent assay, was related to various clinicopathologic parameters and to overexpression of p53 protein in the primary tumor. For 22 patients who had p53 autoantibodies before surgery, we also examined sera taken during postoperative follow-up. Reported P values are two-sided. RESULTS: Autoantibodies to p53 protein were detected in 38 patients. Patients with squamous cell carcinoma, those with more advanced disease (stage III-IV), and those with tumors that overexpressed p53 had a significantly higher incidence of p53 autoantibodies (P = .05,.0079, and .02, respectively). In all but one of the patients with postoperative serum samples, the antibody titer declined after surgery; however, there was no relationship between clinical course and this change in antibody titer. In addition, there was no relationship between the presence of p53 autoantibodies and overall survival in 171 patients who underwent potentially curative resection (P = .28); however, 13 patients with autoantibodies to amino-terminal peptides had a worse overall survival (P = .02). CONCLUSIONS: In NSCLC, the incidence of p53 autoantibodies is associated with histologic type, stage, and p53 overexpression--but not with patient survival. Our data do not support the clinical utility of p53 autoantibodies as diagnostic or prognostic markers in patients with NSCLC.

Somatic in vivo alterations of the JV18-1 gene at 18q21 in human lung cancers.

The chromosome region 18q21 is frequently deleted in lung cancers. Recent identification of JV18-1 at this locus led us to examine whether or not it might also be altered in lung cancers, as is the case for the closely related DPC4 tumor suppressor gene. A missense somatic mutation and a 9-bp in-frame deletion were detected in the highly conserved region of JV18-1 among 57 lung cancer specimens taken directly from patients. The total alterations in JV18-1 and DPC4, however, are not sufficient to account for all 18q21 deletions in lung cancers. These findings suggest that although JV18-1 and DPC4 may play roles in a limited fraction of lung cancers, another tumor suppressor gene may also exist in this chromosome region.

Establishment of human peripheral lung epithelial cell lines (HPL1) retaining differentiated characteristics and responsiveness to epidermal growth factor, hepatocyte growth factor, and transforming growth factor beta1.

Novel human epithelial cell lines retaining characteristic features of normal peripheral airway cells were established by transfecting the SV40 large T antigen gene into primary in vitro outgrowths from normal peripheral lung specimens. These lines, designated as HPL1A to HPL1E, showed the polygonal shapes typical of epithelial cells and expressed cytokeratin in abundance. Ultrastructural examination revealed the presence of microvilli, multivesicular bodies, and multilamellar body-like structures that are characteristic of type II pneumocytes, but expression of CC1O transcripts, a highly specific marker for Clara cells, was also observed. Response to transforming growth factor beta, epidermal growth factor (EGF), and hepatocyte growth factor, all of which are thought to be important growth-regulatory molecules for cellular proliferation and developmental processes of peripheral lung, was apparent. In the HPL1A case, markedly altered cell morphology and cytoskeletal organization, potent inhibition of cell growth, and increased expression of an extracellular matrix protein were noted with transforming growth factor beta. Interestingly, both EGF and hepatocyte growth factor stimulated anchorage-dependent growth, whereas only EGF could sustain anchorage-independent proliferation. The HPL1 lines are, to our knowledge, the first series of stable epithelial lines of human peripheral lung to be described. They should be valuable for investigating various aspects of growth regulation and oncogenic processes, including the mechanisms of acquisition of anchorage independence and the interrelationships of genetic changes identified previously in lung cancers. In addition, the HPL1 lines may also prove useful for development of in vitro models for other human lung disorders as well as to elucidate the mechanisms of peripheral lung differentiation.

Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas.

Cyclooxygenase (COX)-2 expression was immunohistochemically examined in 59 human lung cancers as well as in normal and premalignant lung specimens. In contrast to scattered weak reactivity seen in normal peripheral airway epithelial cells, markedly up-regulated COX-2 expression was detected in about one-third of atypical adenomatous hyperplasias and carcinoma in situ specimens, and a significant increase in COX-2 expression was observed in 70% of invasive adenocarcinoma cases. Interestingly, the proportion of adenocarcinoma cells with marked COX-2 expression was much greater in lymph node metastases than in the corresponding primary tumors. In contrast, small cell carcinomas showed virtually negligible expression, and squamous cell carcinomas showed infrequent and low expression. These findings suggest that an increase in COX-2 expression may be associated with the development of adenocarcinomas and possibly with acquisition of an invasive and metastatic phenotype.

p27KIP1 in human lung cancers: differential changes in small cell and non-small cell carcinomas.

Small cell lung cancers (SCLCs) and non-small cell lung cancers (NSCLCs), two major categories of human lung cancers, have been shown to exhibit considerably different clinicopathological, biological, and molecular genetic characteristics. Inactivation of cyclin-dependent kinase inhibitors is now thought to play an important part in the pathogenesis of this fatal disease. In the present study, we show that in vitro p27KIP1 expression was associated with cell density-dependent growth inhibition in human lung epithelial cells in vitro, whereas in vivo, p27KIP1 expression in lung cells showed an inverse correlation with proliferative activity in the developing and adult normal lungs. Our immunohistochemical examination of 166 lung tumor specimens also revealed a striking difference in p27KIP1 expression between SCLCs and NSCLCs. Of 149 NSCLCs, 107 (72%) showed reduced p27KIP1 expression, with 8 being virtually negative. Furthermore, p27KIP1 expression status was found to be a significant prognostic factor for patient survival in the analysis of the 149 primary, resected NSCLC cases (P = 0.03 by the log-rank test). In contrast, all SCLC specimens thus far examined exhibited significantly increased staining when compared to the corresponding normal lung epithelium. These findings provide additional evidence for the heterogeneity prevalent in human lung cancers and suggest that p27KIP1 might play distinct biological roles in the pathogenesis of the two major histological categories, warranting additional studies to elucidate the functional consequences of such differences.