Purpose: The purpose of this study was to investigate the relationship between the level of expression of ATPbinding cassette (ABC) transporter proteins, and response to chemotherapy and prognosis in advanced non-small cell lung cancer (NSCLC).Experimental Design: Expression of ABC transporter proteins, including P-glycoprotein, multidrug resistance protein (MRP) 1, MRP2, MRP3, and breast cancer resistance protein (BCRP), was examined immunohistochemically in 72 formalin-fixed tumor samples from untreated stage IIIB or IV NSCLC patients. All of the patients received platinum-based chemotherapy. Response to chemotherapy, progression-free survival (PFS), and overall survival were compared in relation to expression of each of the ABC transporter proteins and clinicopathological factors.Results: Expression of P-glycoprotein, MRP1, and MRP3 was not significantly associated with response to chemotherapy or survival. MRP2 expression was associated with overall survival (P ‫؍‬ 0.002) but not with response to chemotherapy and PFS. By contrast, the response rate to chemotherapy of patients with BCRP-negative tumors was 44%, as opposed to 24% in patients with BCRP-positive tumors. Response rate was lower in BCRP-positive tumors, although this difference was not statistically significant (P ‫؍‬ 0.08). BCRP-positive patients had also shorter PFS (P ‫؍‬ 0.0003) and overall survival (P ‫؍‬ 0.004) than BCRP-negative patients. Multivariate analysis confirmed BCRP status as an independent variable related to PFS (P ‫؍‬ 0.001).Conclusions: Positive immunostaining for BCRP appears to be a predictor of survival in patients with advanced NSCLC. These findings indicate that BCRP may serve as a molecular target for reducing drug resistance to chemotherapy in advanced NSCLC patients.

A case of apocrine adenocarcinoma of the eyelid that showed unusually aggressive biological behavior is reported. The patient was a 57-year-old man who complained of discomfort and excessive lacrimation of the left eye. A subcutaneous tumor measuring 2.5 cm was found at the medial canthus of the upper eyelid, and a plica-like subconjunctival spread was noted in the lacrimal caruncle. Invasion into the extraocular muscles and metastasis to the cervical lymph nodes and bone were already present at the time of initial presentation. Histopathologically, the tumor showed features of poorly differentiated adenocarcinoma, and polygonal tumor cells had large, hyperchromatic nuclei with prominent nucleoli and abundant eosinophilic cytoplasm. The formation of ductal structures was found occasionally. The differentiation of the tumor cells towards the apocrine gland was corroborated by immunohistochemistry using monoclonal antibodies GCDFP-15 and B72.3. The histogenesis and pathological differential diagnosis are discussed briefly, and the tumor was considered to have originated in the Moll's gland in the eyelid. This case emphasizes that apocrine adenocarcinomas of the ocular region have the potential for aggressive biological behavior, including distant metastasis.

Abstract. The combination of oral tegafur-uracil (UFT) with leucovorin (LV) is used to treat patients with stage II to III colon cancer based on the results of postoperative randomized studies in which UFT/LV treatment showed an equivalent efficacy to intravenous 5-FU plus LV therapy. However, whether the addition of LV to UFT can elevate the antitumor activity of UFT in colorectal tumors with high expression levels of thymidylate synthase (TS), which affects 5-FU efficacy, remains to be clarified. This study investigated the effect of LV on the antitumor activity of UFT and/or 5-FU prodrugs in low folate diet-fed nude mice using human colorectal cancer xenografts with various expression levels of TS. The addition of LV to UFT resulted in a 55-79% inhibition of tumor growth among 11 types of colorectal tumor xenograft, whereas UFT alone showed 23-67% antitumor activity. Although there was an inverse relationship between the antitumor effect of UFT alone and UFT plus LV and tumoral TS activity, UFT plus LV appeared to have a more potent antitumor effect than UFT alone on colorectal tumors such as Co-3 and KM12C/5-FU with high expression levels of TS. This finding was confirmed by the significant positive correlation between the relative inhibition ratio of UFT/LV to UFT alone and TS levels in tumors. To investigate the reason for the higher efficacy of UFT/LV on colorectal cancer xenografts with high TS activity, intratumoral levels of reduced folates and a ternary complex of TS after oral UFT with or without LV were measured using Co-3 xenografts. Elevated levels of reduced folates and an increased ternary complex of TS in LV-treated tumors were noted. Our results indicate that a combined therapy of UFT with LV may contribute to the treatment of colorectal cancer patients with low and high expression levels of tumoral TS by increased formation of the ternary complex of TS leading to potentiated antitumor efficacy of UFT. More recently, the molecular-targeted drug bevacizumab, in combination with oxaliplatin-based and/or CPT-based regimens, has been shown to prolong the survival time of CRC patients. Regarding the use of oral fluoropyrimidines instead of intravenous 5-FU, UFT combined with LV and capecitabine have been shown to have equivalent efficacy to 5-FU/LV for the treatment of CRC patients, as noted in tegafur-uracil (UFT)/LV vs. 5-FU/LV (5), NSABP C-06 (6) and X-ACT (7) trials.UFT is an orally active combination of tegafur (a prodrug of 5-FU) and uracil in a 1:4 molar ratio. FT is mainly metabolized to 5-FU by cytochrome P-450 in the liver, whereas uracil is a biochemical modulator of 5-FU degradation catalyzed by dihydropyrimidine dehydrogenase (DPD) and competes with 5-FU for the enzyme, resulting in significantly high and prolonged plasma 5-FU levels. In tumor cells, 5-FU is metabolized to 5-fluorouridine 5'-monophosphate (FUMP), mainly by uridine monophosphate synthetase, to yield the active form, 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). FdUMP forms a ternary complex with thymidylate synthas...

A 36-year-old woman with a long history of amenorrhea underwent endometrial curettage. An aggregate of short spindle cells containing a finely granular, dark brown pigment with the histochemical characteristics of melanin was detected in the endometrial stroma. This finding is considered analogous to the occurrence of similar cells in the endocervical stroma and is most appropriately designated a "blue nevus" of the endometrium. The occurrence of nonneoplastic, melanin-laden cells in the endometrial stroma is an extremely rare phenomenon, which has been reported only once previously.