Development of neuro-Behcet's disease in a patient with operable HER2-positive breast cancer during neoadjuvant chemotherapy: A case report.

BACKGROUND: Neuro-Behcet's disease (NBD) is a variant of Behcet's disease (BD). To our knowledge, there have been no previous reports on concurrent NBD in breast cancer patients undergoing chemotherapy. CASE PRESENTATION: Our patient had a history of BD and was asymptomatic. She was diagnosed with human epidermal growth factor receptor 2-positive breast cancer by core needle biopsy and was administered neoadjuvant chemotherapy. After four courses, in addition to the aggravation of the existing adverse events, headache, fever, dysarthria, and muscle weakness in the upper left and lower extremities appeared. On admission, she was diagnosed with acute NBD, and steroid therapy was initiated. After her symptoms improved gradually, she was discharged. Then, she underwent mastectomy and axillary lymph node dissection for breast cancer. Trastuzumab and pertuzumab plus tamoxifen were administered postoperatively. Two years postoperatively, no recurrence of breast cancer and NBD was noted. CONCLUSION: When chemotherapy is administered to breast cancer patients with a history of BD, it is necessary to select chemotherapy with as few adverse events as possible and to continue with treatment while paying attention to the risk of NBD.

A novel MRI-based predictive index can identify patients suitable for preservation of the nipple-areola complex in breast reconstructive surgery.

INTRODUCTION: Accurately predicting nipple-areola complex (NAC) involvement in breast cancer is necessary for identifying patients who may be candidates for a nipple-sparing mastectomy. Although multiple risk factors are indicated in the guidelines, it is difficult to predict NAC involvement (NAC-i) preoperatively even if these factors are evaluated individually. This study aimed to develop a more accurate and practical preoperative NAC-i prediction model using magnetic resonance imaging (MRI). MATERIALS AND METHODS: All tumors in 252 patients were evaluated using postcontrast T1-weighted subtraction on MRI. RESULTS: The receiver operating characteristic curves identified cut-off values for tumor size and tumor-to-nipple distance (TND) as 4 cm and 1.2 cm, respectively. Multivariate analysis demonstrated that TND (p < 0.001), ductal enhancement extending to the nipple (DEEN) (p < 0.001), and nipple enhancement (NE) (p = 0.005) were independent clinical risk factors for pathological NAC-i. A formula was constructed using odds ratios for these three independent preoperative risk factors in multivariate analysis: the MRI-based NAC-i predictive index (mNACPI) = TND × 4 + DEEN × 3 + NE × 1. A total score of ≤4 points was defined as low risk and ≥5 points as high risk. NAC-i rates were 2.4% in the low-risk group and 89.4% in the high-risk group; a significant correlation was observed between the risk group and permanent pathological NAC-i (p < 0.001). Assuming that the NAC was preserved in low-risk patients and resected in high-risk patients, NAC-i was verified using the mNACPI. CONCLUSION: mNACPI may contribute greatly to the improvement of selecting suitable patients for NAC preservation in breast reconstructive surgery while maintaining oncological safety.

Efficacy and Safety of Palbociclib and Fulvestrant in Japanese Patients With ER+/HER2- Advanced/Metastatic Breast Cancer.

BACKGROUND/AIM: Published data have shown that palbociclib-fulvestrant can significantly improve the progression-free survival (PFS) of estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) metastatic breast cancer patients, but not of Japanese patients. We conducted this retrospective study to verify the efficacy and safety of palbociclib-fulvestrant in Japanese patients. PATIENTS AND METHODS: ER+/HER2- metastatic breast cancer patients treated with fulvestrant (n=39) or palbociclib-fulvestrant (n=31) at the Saitama Medical Center from July 2012 to November 2018 were evaluated. RESULTS: Overall response rates (ORRs) were 2.6% (fulvestrant) and 41.9% (palbociclib-fulvestrant) (p<0.001), and clinical benefit rates (CBRs) were 23.1% and 61.3% (p=0.002), respectively. The palbociclib-fulvestrant group had significantly higher CBR and PFS (hazard ratio(HR):0.272, 95% confidence interval(95CI):0.128-0.574 for PFS). Grade 3/4 neutropenia occurred in 80.6% of the palbociclib-fulvestrant group, while febrile neutropenia was not detected. CONCLUSION: Japanese ER+/HER2- metastatic breast cancer patients tolerated palbociclib-fulvestrant, with significantly improved clinical outcomes.

Outcomes and prognostic factors after pulmonary metastasectomy in patients with colorectal cancer with previously resected hepatic metastases.

OBJECTIVES: Outcomes and prognostic factors remain obscure in patients with colorectal cancer after pulmonary metastasectomy who had previously received a curative hepatic metastasectomy. METHODS: We collected data of 757 patients with pulmonary metastasis from colorectal cancer who underwent curative metastasectomy between 2004 and 2008 from 46 Japanese institutions, from which we extracted data on patients who previously received curative hepatic metastasectomy. Disease-free survival, overall survival, and prognostic factors were analyzed. RESULTS: The subjects of this study were 160 patients, of whom 44% had primary rectal tumor, 73% had a single pulmonary metastasis, 11% had a bilateral pulmonary metastasis, and 39% had high (>5 ng/mL) serum carcinoembryonic antigen. Patients' median age was 66 years, and 58% were male. The median follow-up was 64 months. Five-year overall survival and disease-free survival were 65.2% (95% confidence interval, 56.8-72.5) and 33.5% (95% confidence interval, 26.1-41.0), respectively. In multivariable analyses, high prethoracotomy carcinoembryonic antigen level was an independent prognostic factor for overall survival (hazard ratio, 2.01; 95% confidence interval, 1.16-3.47) and disease-free survival (hazard ratio, 2.10; 95% confidence interval, 1.41-3.12). Five-year overall survival and disease-free survival of patients with normal prethoracotomy carcinoembryonic antigen level were 76.4% (95% confidence interval, 66.1-83.9) and 40.7% (95% confidence interval, 30.5-50.5), respectively. CONCLUSIONS: After pulmonary metastasectomy, approximately two thirds of patients with colorectal cancer with a history of curative hepatic metastasectomy survived for 5 years-half of them disease-free. Our results indicate that patients with colorectal cancer with pulmonary metastasis and a history of curative hepatic metastasectomy may benefit from sequential pulmonary metastasectomy, especially if prethoracotomy serum carcinoembryonic antigen levels are within normal range.

Efficacy of adjuvant chemotherapy after resection of pulmonary metastasis from colorectal cancer: a propensity score-matched analysis.

BACKGROUND: Pulmonary metastases from colorectal cancer are resected due to the favourable 5-year overall survival rates of 30-60% reported in many studies. However, the efficacy of subsequent adjuvant chemotherapy remains unclear. PATIENT AND METHODS: We retrospectively collected clinical data of 1237 patients who underwent surgical resection of pulmonary metastasis from colorectal cancer at 46 Japanese institutions between 2004 and 2008. Patients with non-curative resection, pre-operative chemotherapy, extra-thoracic metastasis, complications after surgery, and inadequate data were excluded. Then, a 1:1 propensity score nearest-neighbour matching between patients with and without adjuvant chemotherapy was performed, considering relevant co-variables, and survival of patients between groups was compared. RESULTS: Data of 524 patients (surgery alone, 269 patients; surgery with adjuvant chemotherapy, 255 patients) were used for matching. From each group, 192 patients with similar background characteristics between groups were selected. Adjuvant chemotherapies included fluoropyrimidine alone (71%), an oxaliplatin-containing regimen (23%), or an irinotecan-containing regimen (6%). In the surgery alone and adjuvant chemotherapy groups, 5-year overall survival rates were 68% and 69%, and 5-year disease-free survival rates were 40% and 34%, respectively. There were no significant differences between the two groups in terms of overall survival (hazard ratio [HR]: 1.00, 95% confidence interval [CI]: 0.69-1.45, P = 1.00) and disease-free survival (HR: 1.07, 95% CI: 0.82-1.39, P = 0.62). CONCLUSIONS: Adjuvant chemotherapy after curative resection of lung-limited metastasis from colorectal cancer did not show a survival benefit in the propensity score-matched analysis and should not be recommended without further clinical trials.

Pulmonary Apical Opacities on Thin-Section Computed Tomography: Relationship to Primary Spontaneous Pneumothorax in Young Male Patients and Corresponding Histopathologic Findings.

OBJECTIVE: The purpose of this study was to test the hypothesis that apical opacities on computed tomography (CT) are related to occurrence of primary spontaneous pneumothorax (PSP) in young male patients. METHODS: We compared the frequency of apical opacities on thin-section CT between 70 male patients with PSP (PSP group) and 74 male patients without a history of PSP (non-PSP group). We also evaluated histopathologic findings of 39 specimens from 37 surgical cases in the PSP group. RESULTS: Apical opacities were significantly more frequent in the PSP group than in the non-PSP group (right side, P = 0.01; left side, P = 0.005). Histopathologically, subpleural band-like alveolar collapse was seen in 35 specimens (89.7%), which was always accompanied by fibroelastosis and fibroblastic foci. CONCLUSIONS: Apical opacities on CT were significantly associated with PSP in young male patients. These apical opacities histopathologically correspond to fibrotic pleural thickening with subpleural alveolar collapse.

Surgical Outcome and Prognostic Stratification for Pulmonary Metastasis From Colorectal Cancer.

BACKGROUND: This study investigated recent clinical outcomes and prognostic factors of metastasectomy for pulmonary metastasis (PM) from colorectal cancer. METHODS: Data for 785 patients with PM from colorectal cancer who underwent curative resection, including 376 patients treated with postmetastasectomy adjuvant chemotherapy, between 2004 and 2008, were collected from 46 Japanese hospitals. Disease-free and overall survival was analyzed. Potential prognostic factors were assessed. RESULTS: The 5-year disease-free and overall survival rates (95% confidence interval) of all patients were 37.1% (33.7% to 40.9%) and 68.1% (64.6% to 71.8%), respectively, over a median follow-up of 65 months. On multivariable analysis, no survival benefit for postmetastasectomy adjuvant chemotherapy was observed (hazard ratio, 0.85; 95% confidence interval, 0.65 to 1.12; p = 0.25), and the independent poor prognostic factors for overall survival (hazard ratio, 95% confidence interval) were age 70 years and older (1.50, 1.15 to 1.97), disease-free interval of less than 2 years (1.76, 1.31 to 2.35), extrathoracic metastatic lesion treated curatively before PM resection (1.35, 1.01 to 1.79), abnormal carcinoembryonic antigen level (1.99, 1.53 to 2.58), and three or more PMs (1.72, 1.20 to 2.45). The 5-year overall survival rates (95% confidence interval) of the low-risk (no prognostic factor, n = 87), moderate-risk (1 to 2 factors, n = 539), and high-risk (≥3 factors, n = 159) groups were 89.4% (82.2% to 98.2%), 72.5% (68.3% to 76.8%), and 48.9% (41.7% to 57.3%), respectively. CONCLUSIONS: Metastasectomy of PM from colorectal cancer was associated with a favorable prognosis. Patients could be classified into three risk groups using five prognostic factors. This grouping may be useful for identifying an optimal treatment strategy according to risk in future studies.

Heterogeneity of Tumor Sizes in Multiple Pulmonary Metastases of Colorectal Cancer as a Prognostic Factor.

BACKGROUND: The number of metastatic lesions is closely correlated with prognosis in most cancers. The aim of this study was to clarify the relationship between individual heterogeneity of metastatic tumor sizes and prognosis in patients with multiple pulmonary metastasis of colorectal cancer who received surgical treatment. METHODS: Clinical data for patients who had pulmonary metastasis from colorectal cancer and underwent curative resection at 46 Japanese institutions between January 2004 and December 2008 were collected. Among 898 patients eligible considering these inclusion criteria, 247 patients had multiple metastases and were analyzed. A difference between the maximum and minimum tumor diameters (Dmax-min) on pathologic findings was used to evaluate size heterogeneity. RESULTS: The overall survival rate was 75% at 3 years and 58% at 5 years, with a median follow-up period of 65 months (range, 0 to 112). When Dmax-min of 5 mm was set as a cutoff value, overall survival was significantly different between small (≤5 mm, n = 95) and large (>5 mm, n = 152) tumor groups (5-year survival rates, 66.5% and 53.3%, respectively; log rank test, p = 0.025). Multivariate analysis using a Cox proportional hazards model revealed that disease-free interval from resection of primary lesion, serum carcinoembryonic antigen level, number of pulmonary metastases, and Dmax-min were independent prognostic factors. CONCLUSIONS: The heterogeneity of metastatic tumor sizes may be an indicator for prognosis in patients with multiple pulmonary metastases of colorectal cancer who underwent resection.

Does Repeated Lung Resection Provide Long-Term Survival for Recurrent Pulmonary Metastases of Colorectal Cancer? Results of a Retrospective Japanese Multicenter Study.

BACKGROUND: The purpose of this study was to clarify the long-term survival outcomes after repeated lung resection (RLR) of pulmonary metastases from colorectal cancer (PM-CRC) using data from a Japanese nationwide investigation. METHODS: Among 898 patients who underwent R0 resection of PM-CRC at 46 Japanese institutions between 2004 and 2008, we analyzed the data of 216 patients who experienced recurrence limited to the lung after initial resection of PM-CRC. Overall survival (OS) after RLR was analyzed, and prognostic factors were explored using a multivariate Cox analysis. RESULTS: Of a total 216 patients, 132 (61%) received RLR, and their 5-year OS rate was 75.3%. Twenty-two patients underwent a second RLR, and 2 patients underwent a third RLR; a favorable survival outcome was observed even after a second RLR (5-year OS rate, 55.1%). The prognostic factors associated with worse survival after RLR were concomitant liver metastasis, which had been completely resected or ablated at the initial lung metastasectomy (hazard ratio [HR], 4.84; 95% confidence interval [CI], 1.48-14.8) and location of the primary tumor in the rectum (HR, 3.16; 95% CI, 1.17-9.35). Patients without these 2 poor prognostic factors (n = 58) showed a 5-year OS rate of 82.6% after RLR. CONCLUSIONS: This nationwide database study showed that RLR for resectable lung-limited recurrence after PM-CRC resection could provide favorable survival, especially for patients with colon cancer without liver metastases at the initial PM-CRC resection.

Outcomes of segmentectomy and wedge resection for pulmonary metastases from colorectal cancer.

Objectives: Although wedge resection is the most common surgical procedure for pulmonary metastases from colorectal cancer, there are few reports about segmentectomy for colorectal metastasectomy. Methods: This was a subset analysis of a Japanese nationwide retrospective study of resected pulmonary metastases from colorectal cancer. The study included 553 patients who underwent segmentectomies ( n = 98) or wedge resections ( n = 455) without preoperative chemotherapy between January 2004 and December 2008. Recurrence patterns, recurrence-free survival and overall survival were analysed for each procedure. Results: As for the patients' background factors, only the median size of resected metastases was different between patients with segmentectomies (median 18 mm, range 5-50 mm) and wedge resections (14 mm, 5-51 mm) ( P < 0.001). Prolonged air leak developed more frequently in those undergoing segmentectomy compared with wedge resection (5.1% vs 1.8%) ( P = 0.048). The resection-margin recurrence rate was higher in patients who underwent wedge resection compared with segmentectomy (7.3% vs 2.0%; P = 0.035). The 5-year recurrence-free survival was 48.8% in patients with segmentectomy and 36.0% in patients with wedge resections. The 5-year overall survival was 80.1% in patients with segmentectomy and 68.5% in patients with wedge resection. Multivariable analysis revealed that the surgical procedure, segmentectomy, was a significant favourable factor for recurrence (hazard ratio: 0.63, 95% confidence interval: 0.44-0.87, P = 0.005), but not for overall survival (hazard ratio: 0.65, 95% confidence interval: 0.38-1.05, P = 0.080). Conclusions: Segmentectomy demonstrated a good efficacy with less resection-margin recurrence in patients with resectable pulmonary-limited metastasis from colorectal cancer.

Approaches to Quality Risk Management When Using Single-Use Systems in the Manufacture of Biologics.

Biologics manufacturing technology has made great progress in the last decade. One of the most promising new technologies is the single-use system, which has improved the efficiency of biologics manufacturing processes. To ensure safety of biologics when employing such single-use systems in the manufacturing process, various issues need to be considered including possible extractables/leachables and particles arising from the components used in single-use systems. Japanese pharmaceutical manufacturers, together with single-use suppliers, members of the academia and regulatory authorities have discussed the risks of using single-use systems and established control strategies for the quality assurance of biologics. In this study, we describe approaches for quality risk management when employing single-use systems in the manufacturing of biologics. We consider the potential impact of impurities related to single-use components on drug safety and the potential impact of the single-use system on other critical quality attributes as well as the stable supply of biologics. We also suggest a risk-mitigating strategy combining multiple control methods which includes the selection of appropriate single-use components, their inspections upon receipt and before releasing for use and qualification of single-use systems. Communication between suppliers of single-use systems and the users, as well as change controls in the facilities both of suppliers and users, are also important in risk-mitigating strategies. Implementing these control strategies can mitigate the risks attributed to the use of single-use systems. This study will be useful in promoting the development of biologics as well as in ensuring their safety, quality and stable supply.

Acute exacerbation of interstitial lung disease with lung cancer after surgery: evaluation with 2-[18]-fluoro-2-deoxy-D-glucose positron emission tomography.

PURPOSE: Interstitial lung disease (ILD) has been associated with primary lung cancer and an increased risk of postoperative acute exacerbation (AE). The effectiveness of 2-[18]-fluoro-2-deoxy-D-glucose ((18)F-FDG) positron emission tomography (PET) for staging lung cancer is well established. This study investigates the association of FDG uptake on PET in patients with AE of ILD. METHODS: The subjects of this retrospective study were 1309 patients with lung cancer, who underwent pulmonary resection at Shizuoka Cancer Center between September, 2002 and January, 2011. ILD was diagnosed with chest computed tomography in 95 patients, 81 of whom underwent (18)F-FDG PET before surgery. Six patients suffered from AE after surgery (AE group), while the remaining 75 (non-AE group) did not. We investigated the clinico-pathological findings and the results of FDG uptake on PET using the value of the I/M ratio, which is the ratio of the peak of standardized uptake value (SUV) of the ILD area to the mean SUV of the mediastinum. RESULTS: There was no significant difference in clinico-pathological findings, but a significance difference in the I/M ratio (P = 0.0102). CONCLUSION: The FDG uptake in PET may be a predictive factor for AE of ILD in patients who have undergone lung cancer surgery.

Recurrence of mediastinal node cancer after lobe-specific systematic nodal dissection for non-small-cell lung cancer.

OBJECTIVES: The standard surgical treatment for patients with non-small-cell lung cancer (NSCLC) is lobectomy with systematic nodal dissection (SND). Lobe-specific patterns of nodal metastases have been recognized, and lobe-specific SND (L-SND) has been reported. We performed L-SND depending on patient-related factors, such as age or the presence of diabetes or respiratory dysfunction, or in the context of specific tumour-related factors, such as the presence of a tumour with a wide area of ground-glass opacity. METHODS: Between September 2002 and December 2008, 335 consecutive patients with clinical and intraoperative N0 NSCLC underwent curative lobectomies at Shizuoka Cancer Center Hospital. Among these 335 patients, 206 underwent SND (Group A) and 129 underwent L-SND. Of the 129 patients undergoing L-SND, 98 underwent L-SND due to patient-related factors (Group B) and 31 underwent L-SND due to tumour-related factors (Group C). RESULTS: There were no significant differences in morbidity or blood loss between patients undergoing SND or L-SND, but there was a significant difference in the mean operative times. The 5-year disease-free survival (5-DFS) and 5-year overall survival (5-OS) of patients in Group C were 100%. Although the patients in Group B showed no significant difference in 5-DFS and 5-OS compared with Group A, patients in Group B had significantly more initial recurrence of mediastinal node cancer than did the Group A patients (P = 0.0050). CONCLUSIONS: The recurrence of mediastinal node cancer in patients undergoing L-SND was significantly greater than that in those undergoing SND.

Chest-tube drainage is a sign of acute exacerbation of interstitial lung disease associated with lung cancer.

PURPOSE: Interstitial lung disease (ILD) is associated with primary lung cancer and an increased risk of postoperative acute exacerbation (AE). Although the preoperative factors associated with AE of ILD are well described, there is little information about the postoperative factors. Thus, the present study focuses on the postoperative management of chest-tube drainage associated with AE of ILD. METHODS: We conducted a retrospective chart study of 1,309 patients with lung cancer, who underwent pulmonary resection at Shizuoka Cancer Center between September 2002 and January 2011. ILD was diagnosed by chest computed tomography (CT) findings in 95 patients. After the exclusion of 6 patients with a history of pneumonectomy, the subjects of this study were 8 patients who suffered AE after surgery (AE group) and 81 patients (non-AE group) who did not. We investigated the clinicopathological findings and postoperative management of chest-tube drainage in the two groups. RESULTS: The clinicopathological findings of the two groups did not differ significantly. The chest tubes could not be removed before postoperative day 5 because of pleural effusion in 5 patients (62.5 %) from the AE group and 12 patients (14.8 %) from the non-AE group (P = 0.0040). CONCLUSIONS: The postoperative volume draining from the chest-tube is an important sign of AE of ILD.

A clinicopathological study of peripheral, small-sized high-grade neuroendocrine tumours of the lung: differences between small-cell lung carcinoma and large-cell neuroendocrine carcinoma.

OBJECTIVES: Small-cell lung carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC) are categorized as high-grade neuroendocrine tumours because of their poor prognosis compared with those of other neuroendocrine tumours of the lung. There have been no clinicopathological studies focusing on small-sized high-grade neuroendocrine tumours. We analysed clinicopathological features of peripheral, small-sized high-grade neuroendocrine tumours of the lung retrospectively. METHODS: A total of 28 patients with peripheral, small-sized tumours (maximum diameter of 3.0 cm) of SCLC and LCNEC underwent surgical resection in our hospital and were enrolled in this study. RESULTS: Of 28 tumours, 18 were SCLC and 10 were LCNEC. In terms of serum tumour marker levels, carcinoembryonic antigen was elevated in 50% of both types of tumour, and progastrin-releasing peptide was elevated in 28% of SCLC and 10% of LCNEC. With regard to preoperative diagnosis, only seven SCLC cases were correctly diagnosed as SCLC, but no LCNEC case was correctly diagnosed before surgery. Lymphatic involvement was significantly more frequent in SCLC than in LCNEC (P = 0.013). Although adjuvant chemotherapy was carried out more frequently in the patients with SCLC than LCNEC, the recurrence rate after the standard surgery was significantly higher in the patients with SCLC than LCNEC (P = 0.0037). There was a significant difference between SCLC and LCNEC in terms of overall survival in clinical-stage IA small-sized tumours (P = 0.029). CONCLUSIONS: In peripheral, small-sized high-grade neuroendocrine tumours, there are several clinicopathological differences between SCLC and LCNEC. This study suggested that the prognosis of patients with LCNEC tended to be better than for those with SCLC in small-sized tumours.

MUC1 expression in pulmonary metastatic tumors: a comparison of primary lung cancer.

MUC1 expression has been described as a predictor for tumor progression and worsening of prognosis in various human neoplasms. However, little is known about the role of MUC1 expression in pulmonary metastatic tumors. The aim of this study is to examine the clinicopathological significance of MUC1 expression in pulmonary metastatic tumors (PMT). One hundred forty-seven patients with PMT who underwent (18)F-FDG PET before metastasectomy were included in this study. Tumor sections were stained by immunohistochemistry for MUC1, glucose transporter 1 (Glut1), hypoxia-inducible-1α (HIF-1α) and vascular endothelial growth factor (VEGF). (18)F-FDG uptake and the expression of these biomarkers were correlated in primary lung cancer. MUC1 expression pattern was classified into high-grade polarized expression (HP), low-grade polarized expression (LP), or depolarized expression (DP) group. Of 147 patients, HP, LP and DP group were 9 (6%), 114 (78%) and 24 (16%), respectively. The expression of Glut1, HIF-1αand VEGF, and (18)F-FDG uptake were significantly higher in DP group than HP or LP groups. MUC1 expression with HP and DP pattern was significantly higher in primary lung cancer than in PMT, whereas, MUC1 expression with LP pattern yielded a significantly high positive rate in PMT. LP group was recognized in the majority of patients with pulmonary metastatic adenocarcinoma, especially colon cancer, whereas, HP group was significantly low in pulmonary metastatic adenocarcinoma as compared with primary adenocarcinoma. Polarized MUC1 has a different expression pattern between primary and metastatic tumors with adenocarcinoma, and depolarized MUC1 is closely associated with glucose metabolism and hypoxia.

Thymidylate synthase expression is closely associated with outcome in patients with pulmonary adenocarcinoma.

The aim of this study is to elucidate the prognostic significance of thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD) in completely resected non-small cell lung cancer (NSCLC). One hundred and sixty patients with NSCLC were included in this study. Tumor sections were stained by immunohistochemistry for TS, OPRT, DPD, glucose transporter 1 (Glut1), hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), microvessel density (MVD) determinated by CD34, epidermal growth factor receptor (EGFR), phosph-Akt, phosph-mammalian target of rapamycin (mTOR) and p53. TS, OPRT and DPD were positively expressed in 46, 71 and 54%, respectively. The expression of TS and OPRT was significantly higher in patients with non-adenocarcinoma (non-AC) (n = 53) than adenocarcinoma (AC) (n = 107), and DPD expression was higher in adenocarcinoma as compared with non-adenocarcinoma. A positive TS expression was an independent prognostic factor for predicting a poor outcome in patients with AC, but not in those with non-AC. In AC patients, TS expression was significantly associated with advanced stage, lymph node metastases, vascular invasion, Glut1, HIF-1α, angiogenesis, EGFR signaling pathway and p53. In patients with non-AC, TS expression was not closely correlated with outcome and these biomarkers. A positive TS expression was a powerful prognostic factor to predict a poor outcome in completely resected AC patients.

Depolarized MUC1 expression is closely associated with hypoxic markers and poor outcome in resected non-small cell lung cancer.

MUC1 is transmembrane mucin aberrantly overexpressed in various cancers. However, little is known about how MUC1 expression is associated with hypoxia, glucose metabolism, and epidermal growth factor receptor (EGFR) pathway, which are related to cancer progression. The aim of this study is to evaluate the relationship between MUC1 expression and these molecular markers in lung cancer. Of all 126 patients, high-grade polarized expression (HP), low-grade polarized expression (LP), and depolarized expression (DP) group were 50 (39.7%), 35 (27.8%), and 41 (32.5%), respectively. Depolarized MUC1 expression was significantly associated with poor outcome and was closely correlated with glucose metabolism (Glut1), hypoxia (HIF-1α), angiogenesis (vascular endothelial growth factor and microvessel density), amino acid metabolism (LAT1), and EGFR expression. High-grade polarized MUC1 expression was associated with favorable prognosis and adenocarcinoma. Depolarized MUC1 expression was significantly associated with poor outcome. Glucose metabolism, hypoxia, angiogenesis, amino acid metabolism, and EGFR pathway may play an important role in the development of depolarized MUC1 expression.