A phase II study of first-line chemotherapy with weekly carboplatin plus gemcitabine in advanced non-small cell lung cancer.

BACKGROUND: The efficacy and safety of weekly carboplatin (CBDCA) and gemcitabine (GEM) was evaluated as first-line chemotherapy with advanced non-small cell lung cancer (NSCLC). METHODS: 46 chemotherapy-naive patients with measurable NSCLC were enrolled. Patients underwent a combination chemotherapy of GEM 1,000 mg/m2 plus CBDCA at an area under the curve of 2 on days 1 and 8 every 3 weeks. RESULTS: Response rate was 30% (14/46; 95% confidence interval: 17.7-45.8%). The median number of treatment cycles was 3 (range 1-2). Time to progressive disease was 19.4 weeks and the median survival was 46.3 weeks. The 1-year survival rate was 46.9%. The major toxicity was hematotoxicity: grade 3 or 4 neutropenia (58.7%) and thrombocytopenia (45.7%). There were no other severe toxicities. CONCLUSION: Weekly chemotherapy with CBDCA plus GEM is a well-tolerated and promising regimen as first-line treatment of advanced NSCLC.

Clinical implication of the antidiuretic hormone (ADH) receptor antagonist mozavaptan hydrochloride in patients with ectopic ADH syndrome.

Ectopic antidiuretic hormone syndrome is a medical emergency characterized by dilutional hyponatremia. Clinical effectiveness of the vasopressin V2 receptor antagonist mozavaptan was evaluated in 16 patients. In short-term (7-day) treatment with the drug, serum sodium concentration (mean ± standard deviation) significantly (P = 0.002) increased from 122.8 ± 6.7 to 133.3 ± 8.3 mEq/l, and symptoms due to hyponatremia were improved. On the basis of these results, mozavaptan (Physuline(®)) was approved as an orphan drug for the treatment of the syndrome in 2006 in Japan. During the 43 months following its launch, 100 patients have been treated with the drug; overall clinical effects of the drug were found similar to those of this clinical trial. Clinically, mozavaptan may allow hyponatremic patients to be treated by aggressive cancer chemotherapy with platinum-containing drugs. Moreover, the drug may free patients from strict fluid-intake restrictions and thereby improve their quality of life.

Centrally located adenocarcinoma with endobronchial polypoid growth: clinicopathological analysis of five cases.

Lung adenocarcinomas that exhibit endobronchial polypoid growth and arise from the central portion of the respiratory tree are extremely rare and their clinicopathological features are not well understood. We report the clinicopathological characteristics of five cases of centrally located adenocarcinomas. Histologically, in three cases (cases 1, 2, and 3) the tumor had a papillary, acinar, and solid structure. In the other two cases (cases 4 and 5) histological examination revealed a mucin-filled glandular and cystic structure resembling mucoepidermoid carcinoma, although the lesions lacked a squamoid cell component. Immunohistochemical staining revealed that the tumor cells in all five cases were positive for MUC1 and Cytokeratin 7. The tumor cells in cases 4 and 5 were positive for MUC5AC and MUC6, and the expression pattern in these two cases was similar to that of mucoepidermoid carcinoma of the lung. Our findings allowed us to identify two distinct subtypes of centrally located adenocarcinomas with distinct morphological and immunohistochemical characteristics; these should provide new insight into the pathogenesis of central adenocarcinoma of the lung.

Cytological characteristics of pulmonary pleomorphic and giant cell carcinomas.

OBJECTIVE: To establish cytological features of pulmonary pleomorphic carcinoma (PC) or giant cell carcinoma (GC), we evaluated the cytological characteristics of these tumors using a multidisciplinary approach. STUDY DESIGN: Samples from 13 surgically resected and histologically confirmed PC or GC patients were collected from our institutes. Eight cases without prior chemotherapy before surgery were selected, and cytological features were analyzed. RESULTS: The background contained numerous lymphocytes and neutrophils. The tumor cells were arranged in flat loose clusters, but some were in fascicles. The shape of the tumor cell was spindle or pleomorphic, and the sizes of the tumor cells varied by more than 5-fold. The tumor cells had an abundant, thick and well-demarcated cytoplasm. The location of the nucleus was centrifugal, and the nucleus was oval or irregularly shaped. Multinucleated giant cells were frequently observed. The size of the nucleus was more than 5 times that of normal lymphocytes, and its size also varied by more than 5-fold. The nuclear membrane was thin, and nuclear chromatin was coarsely granular, while the nucleolus was single and round. CONCLUSION: PC or GC has characteristic cytological features, however, spindle cells tended to be hardly observed in cytological specimens in some cases.

Fibroblast growth factor receptor 3 mutation in voided urine is a useful diagnostic marker and significant indicator of tumor recurrence in non-muscle invasive bladder cancer.

The fibroblast growth factor receptor (FGFR)-3 gene encodes a receptor tyrosine kinase that is frequently mutated in non-muscle invasive bladder cancer (NMIBC). A sensitive and quantitative assay using peptide nucleic acid-mediated real-time PCR was developed for detecting FGFR3 mutations in the urine samples and evaluated as a molecular marker for detecting intravesical recurrence of NMIBC in patients undergoing transurethral resection of bladder tumor. FGFR3 mutation was examined in tumor tissues and serially taken pre- and postoperative urine sediments in 45 NMIBC patients with a median follow up of 32 months. FGFR3 mutations were detected in 53.3% (24/45) of primary tumor tissues, among which intravesical recurrence developed in 37.5% (9/24) of cases. FGFR3 mutation in the primary tumor was not a significant prognostic indicator for recurrence, while the proportion of FGFR3 mutation (i.e. tumor cellularity was >or=11%) in the preoperative urine sediments was a significant indicator for recurrence in patients with FGFR3 mutations in the primary tumors. FGFR3 mutations were detected in 78% (7/9) of postoperative urine samples from recurrent cases with FGFR3 mutations in the tumor, while no mutations were detected in the urine of 15 non-recurrent cases. Urine cytology was negative in all cases with FGFR3 mutations in the primary tumors, while the sensitivity of cytological examination was as high as 56% (5/9) in cases showing wild-type FGFR3 in the primary tumors. Urine FGFR3 mutation assay and cytological examination may be available in the future as complementary diagnostic modalities in postoperative management of NMIBC.

1-tert-butyl-3-[6-(3,5-dimethoxy-phenyl)-2-(4-diethylamino-butylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea (PD173074), a selective tyrosine kinase inhibitor of fibroblast growth factor receptor-3 (FGFR3), inhibits cell proliferation of bladder cancer carrying the FGFR3 gene mutation along with up-regulation of p27/Kip1 and G1/G0 arrest.

Activating mutation of the fibroblast growth factor receptor-3 (FGFR3) gene is known as a key molecular event in both oncogenesis and cell proliferation of low-grade noninvasive human bladder urothelial carcinoma (UC), which is characterized by frequent intravesical recurrence. In this study, we investigated the antitumor potentiality of 1-tert-butyl-3-[6-(3,5-dimethoxy-phenyl)-2-(4-diethylamino-butylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea (PD173074), a small-molecule FGFR3-selective tyrosine kinase inhibitor (TKI), as a therapeutic modality using eight UC cell lines. In our in vitro cell proliferation assay, PD173074 suppressed cell proliferation remarkably in two cell lines, namely, UM-UC-14 and MGHU3, which expressed mutated FGFR3 protein. In contrast, the other six cell lines expressing wild-type FGFR3 or without FGFR3 expression were resistant to PD173074 treatment. Cell cycle analysis revealed the growth inhibitory effect of PD173074 was associated with arrest at G(1)-S transition in a dose-depending manner. Furthermore, we observed an inverse relationship between Ki-67 and p27/Kip1 expression after PD173074 treatment, suggesting that up-regulation of p27 recruited UC cells harboring activating FGFR3 mutations in G(1) that was analogous with the other receptor TKIs acting on the epidermal growth factor receptors. In the mouse xenograft models using subcutaneously transplanted UM-UC-14 and MGHU3, orally administered PD173074 suppressed tumor growth and induced apoptotic changes comparable with the results of our in vitro assay. These findings elucidated the effectiveness of molecular targeted approach for bladder UC harboring FGFR3 mutations and the potential utility to decrease the intravesical recurrence of nonmuscle invasive bladder UC after transurethral surgical resection.

siRNA-mediated knockdown of the heme synthesis and degradation pathways: modulation of treatment effect of 5-aminolevulinic acid-based photodynamic therapy in urothelial cancer cell lines.

Photodynamic therapy mediated by 5-aminolevulinic acid (ALA-PDT) has been developed as a therapeutic modality for refractory superficial bladder cancers. Here, in experiments using urothelial cancer cell lines, we investigated the effects of siRNA modulating heme-synthetic and degradation pathways for ALA-PDT. Targeted knockdown of ferrochelatase (FECH) suppressed heme synthesis and significantly increased intracellular protoporphyrin IX (PpIX) accumulation, leading to enhanced phototoxicity in four of five cell lines. Heme oxygenase-1 (HO-1) is recognized as important for cytoprotection against oxidative stress such as PDT. Targeted knockdown of HO-1 leads to decreased intracellular PpIX accumulation, resulting in a failure to enhance ALA-PDT effect in four cell lines. Knockdown of HO-1 caused marked growth inhibition in UM-UC-2 overexpressing HO-1, whereas no inhibitory effect was observed in UM-UC-3 lacking HO-1 expression. Moreover, HO-1 protein levels and (GT)n repeat polymorphism of the HO-1 gene promoter region were examined with the implication that the constitutive expressions of HO-1 protein were associated with a shorter (GT)n repeat. Our results suggested that (1) FECH siRNA improved the phototoxicity of ALA-PDT, (2) overexpression of HO-1 was associated with shorter (GT)n repeat of the promoter region, and (3) siRNA-mediated knockdown of HO-1 could suppress the growth of bladder cancer cells overexpressing HO-1.

Cross-sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer.

The prevalence of BRCA1/2 germline mutations in Japanese patients suspected to have hereditary breast/ovarian cancer was examined by a multi-institutional study, aiming at the clinical application of total sequencing analysis and validation of assay sensitivity in Japanese people using a cross-sectional approach based on genetic factors estimated from personal and family histories. One hundred and thirty-five subjects were referred to the genetic counseling clinics and enrolled in the study. Full sequencing analysis of the BRCA1/2 gene showed 28 types of deleterious mutations in 36 subjects (26.7%), including 13 types of BRCA1 mutations in 17 subjects (12.6%) and 15 types of BRCA2 mutations in 19 subjects (14.1%). Subjects were classified into five groups and 22 subgroups according to their personal and family history of breast and/or ovarian cancer, and the prevalence of deleterious mutations was compared with previously reported data in non-Ashkenazi individuals. Statistical analysis using the Mantel-Haenszel test for groups I through IV revealed that the prevalence of Japanese subjects was significantly higher than that of non-Ashkenazi individuals (P = 0.005, odds ratio 1.87, 95% confidence interval 1.22-2.88). Family history of the probands suffering from breast cancer indicated risk factors for the presence of deleterious mutations of BRCA1/2 as follows: (1) families with breast cancer before age 40 within second degree relatives (P = 0.0265, odds ratio 2.833, 95% confidence interval 1.165-7.136) and (2) families with bilateral breast cancer and/or ovarian cancer within second degree relatives (P = 0.0151, odds ratio 2.88, 95% confidence interval 1.25-6.64).

Phase II study of weekly chemotherapy with paclitaxel and gemcitabine as second-line treatment for advanced non-small cell lung cancer after treatment with platinum-based chemotherapy.

PURPOSE: We evaluated the tolerability and activity of the combination of weekly paclitaxel (PTX) and gemcitabine (GEM) in second-line treatment of advanced non-small cell lung cancer (NSCLC) after treatment with platinum-based chemotherapy. PATIENTS AND METHODS: PTX (100 mg/m(2)) and GEM (1,000 mg/m(2)) were administered to patients with previous treated NSCLC on days 1 and 8 every 3 weeks. RESULTS: A total of 40 patients (performance status 0/1/2, 7/27/6 pts) were enrolled. The response rate was 32.5% (95% confidence interval: 18.0-47.0%). The median survival time was 41.7 weeks (95% confidence interval: 28.5-54.7 weeks). The median time to disease progression was 19 weeks. Hematological toxicities (grade 3 or 4) observed included neutropenia in 60%, anemia in 15%, and thrombocytopenia in 12.5% of patients. Non-hematological toxicities were mild, with the exception of grade 3 diarrhea, pneumonitis, and rash in one patient each. There were no deaths due to toxicity. CONCLUSION: The combination of weekly PTX and GEM is a feasible, well-tolerated, and active means of second-line treatment of advanced NSCLC.

Relative and combined performance of mammography and ultrasonography for breast cancer screening in the general population: a pilot study in Tochigi Prefecture, Japan.

BACKGROUND: Breast cancer screening by mammography is thought to be effective in reducing breast cancer mortality while ultrasonography is not accepted as a population screening modality, although the latter has been suggested to be useful in detection of cancer in the dense breast, relatively more typical for a younger woman. METHODS: Mammography with medio-lateral oblique view was offered on trial in 1999-2000 for 3453 female residents in Tochigi prefecture who also underwent clinical breast examination and ultrasonography. The municipalities that provided cancer screening were informed of the final diagnosis for women with positive findings in the screening trial by doctors who performed the diagnostic evaluation. Linkage was also made between the list of participants in the trial and registrations at Tochigi Cancer Registry for breast cancer cases diagnosed during 1999-2001. RESULTS: Thirteen cases with breast cancer were identified during a 2-year follow-up period: 10 were diagnosed subsequent to positive finding in the trial; two were negative in the trial and diagnosed 23 and 24 months after, respectively; and one had a positive finding at the trial but was undiagnosed at first and then diagnosed 18 months after the trial. Among the 11 cases judged as positive in the trial, four were judged only by mammography while three were judged only by ultrasonography. Those mammography alone-detected cases were relatively young, at 36, 40, 47 and 54 years of age, respectively, while the ultrasonography alone-detected cases were aged 50, 55 and 68, respectively. CONCLUSIONS: Combined screening with mammography and ultrasonography may be feasible. A larger study is required to evaluate relative performance of mammography and ultrasonography in detail by characteristics of examinees and their breasts.

Randomized pharmacokinetic and pharmacodynamic study of docetaxel: dosing based on body-surface area compared with individualized dosing based on cytochrome P450 activity estimated using a urinary metabolite of exogenous cortisol.

PURPOSE: Docetaxel is metabolized by cytochrome P450 (CYP3A4) enzyme, and the area under the concentration-time curve (AUC) is correlated with neutropenia. We developed a novel method for estimating the interpatient variability of CYP3A4 activity by the urinary metabolite of exogenous cortisol (6-beta-hydroxycortisol [6-beta-OHF]). This study was designed to assess whether the application of our method to individualized dosing could decrease pharmacokinetic (PK) and pharmacodynamic (PD) variability compared with body-surface area (BSA) -based dosing. PATIENTS AND METHODS: Fifty-nine patients with advanced non-small-cell lung cancer were randomly assigned to either the BSA-based arm or individualized arm. In the BSA-based arm, 60 mg/m(2) of docetaxel was administered. In the individualized arm, individualized doses of docetaxel were calculated from the estimated clearance (estimated clearance = 31.177 + [7.655 x 10(-4) x total 6-beta-OHF] - [4.02 x alpha-1 acid glycoprotein] - [0.172 x AST] - [0.125 x age]) and the target AUC of 2.66 mg/L . h. RESULTS: In the individualized arm, individualized doses of docetaxel ranged from 37.4 to 76.4 mg/m(2) (mean, 58.1 mg/m(2)). The mean AUC and standard deviation (SD) were 2.71 (range, 2.02 to 3.40 mg/L . h) and 0.40 mg/L . h in the BSA-based arm, and 2.64 (range, 2.15 to 3.07 mg/L . h) and 0.22 mg/L . h in the individualized arm, respectively. The SD of the AUC was significantly smaller in the individualized arm than in the BSA-based arm (P < .01). The percentage decrease in absolute neutrophil count (ANC) averaged 87.1% (range, 59.0 to 97.7%; SD, 8.7) in the BSA-based arm, and 87.4% (range, 78.0 to 97.2%; SD, 6.1) in the individualized arm, suggesting that the interpatient variability in percent decrease in ANC was slightly smaller in the individualized arm. CONCLUSION: The individualized dosing method based on the total amount of urinary 6-beta-OHF after cortisol administration can decrease PK variability of docetaxel.

Retrospective analysis of steroid therapy for radiation-induced lung injury in lung cancer patients.

PURPOSE: To disclose characteristics of lung cancer patients developing radiation-induced lung injury treated with or without corticosteroid therapy. METHODS AND MATERIALS: Radiographic changes, symptoms, history of corticosteroid prescription, and clinical course after 50-70 Gy of thoracic radiotherapy were retrospectively evaluated in 385 lung cancer patients. RESULTS: Radiation-induced lung injury was stable without corticosteroid in 307 patients (Group 1), stable with corticosteroid in 64 patients (Group 2), and progressive to death despite corticosteroid in 14 patients (Group 3). Fever and dyspnea were noted in 11%, 50% and 86% (p<0.001), and in 13%, 44% and 57% (p<0.001) patients in Groups 1-3, respectively. Median weeks between the end of radiotherapy and the first radiographic change were 9.9, 6.7 and 2.4 for Groups 1-3, respectively (p<0.001). The initial prednisolone equivalent dose was 30-40 mg daily in 52 (67%) patients. A total of 16 (4.2%) patients died of radiation pneumonitis or steroid complication with a median survival of 45 (range, 8-107) days. CONCLUSION: Development of fever and dyspnea, and short interval between the end of radiotherapy and the first radiographic change were associated with fatal radiation-induced lung injury. Prednisolone 30-40 mg daily was selected for the treatment in many patients.

Immunohistochemical differential diagnosis between large cell neuroendocrine carcinoma and small cell carcinoma by tissue microarray analysis with a large antibody panel.

To elucidate additional phenotypic differences between large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), we performed tissue microarray (TMA) analysis of surgically resected LCNEC and SCLC specimens. Immunostaining with 48 antibodies was scored based on staining intensity and the percentage of cells that stained positively. Four proteins were identified as significantly expressed in LCNEC as compared with SCLC: cytokeratin (CK)7, 113 vs 49 (P < .0301); CK18, 171 vs 60 (P < .0008); E-cadherin, 77 vs 9 (P < .0073); and beta-catenin, 191 vs 120 (P < .0286). Immunostaining of cross-sections containing LCNEC and SCLC components revealed significant expression of CK7, CK18 and beta-catenin in the LCNEC component compared with the SCLC component in 2 of 3 cases. Our results indicate that significant expression of CK7, CK18, E-cadherin, and beta-catenin is more characteristic of LCNEC than of SCLC, and these findings provide further support that these tumor types are separate entities morphologically and immunophenotypically, if not biologically.

Pilot phase II study of weekly chemotherapy with paclitaxel and carboplatin for refractory or relapsed small-cell lung cancer.

PURPOSE: The safety and efficacy of weekly chemotherapy with paclitaxel and carboplatin for the treatment of patients with refractory or relapsed small-cell lung cancer (SCLC) were evaluated. PATIENTS AND METHODS: Paclitaxel (100 mg/m(2)) and carboplatin (with a target area under the concentration versus time curve of 2 mg min/ml using the Calvert formula) were administered to patients with previously- treated SCLC on days 1 and 8 at every 3-4 weeks. RESULTS: A total of 29 patients (pts) [male/female, 26/3 pts; median age 62.7 years (43-74); performance status 0/1/2, 9/10/10 pts] were enrolled between March 2000 and June 2002. The mean number of cycles administered per pt was 3 (1-7). The overall response rate was 69% (95% confidence interval 52-86%), and 83% (15/18) in sensitive pts and 45% (5/11) in refractory pts (P<0.01). The overall median survival time was 29.6 weeks with a 1-year survival rate of 37% [34.1 weeks in sensitive pts and 23.1 weeks in refractory pts (P=0.085), 46.9 weeks in PS 0-1 and 16.3 weeks in PS 2 (P<0.001)]. The median time to progressive disease was 16.4 weeks [21.7 weeks in sensitive pts and 15.3 weeks in refractory pts (P=0.32)]. Hematologic toxicities observed included grade >or=3 neutropenia in 55%, grade >or=3 anemia in 36%, and grade >or=3 thrombocytopenia in 3%. Non-hematologic toxicities were mild except for grade 3 diarrhea in three pts and grade 3 pneumonitis in one pt. CONCLUSION: Weekly chemotherapy with paclitaxel and carboplatin was well- tolerated and gave a high-response rate in pts with refractory or relapsed small-cell lung cancer.

Clinical responses of large cell neuroendocrine carcinoma of the lung to cisplatin-based chemotherapy.

BACKGROUND: The efficacy of chemotherapy in patients with large cell neuroendocrine carcinoma of the lung (LCNEC) remains unclear. METHODS: Patients with LCNEC who received cisplatin-based chemotherapy were identified by reviewing 567 autopsied and 2790 surgically resected lung cancer patients. The clinical characteristics and objective responses to chemotherapy in these patients were analyzed. RESULTS: Overall, 20 cases of LCNEC were identified, including stage IIIA (n=3), stage IIIB (n=6), stage IV (n=6) and postoperative recurrence (n=5) cases. Six patients had received prior chemotherapy, and 14 were chemo-naive patients. The patients had received a combination of cisplatin and etoposide (n=9), cisplatin, vindesine and mitomycin (n=6), cisplatin and vindesine (n=4), or cisplatin alone (n=1). One patient showed complete response and nine showed partial response, yielding an objective response rate of 50%. The response rate did not differ between patients with the initial diagnosis of SCLC and those with the initial diagnosis of NSCLC, however, the response rate in chemo-naive patients (64%) was significantly different from that in previously treated patients (17%). CONCLUSIONS: Our results suggest that the response rate of LCNEC to cisplatin-based chemotherapy was comparable to that of SCLC.

Cytological characteristics of pulmonary large cell neuroendocrine carcinoma.

To establish cytological features of pulmonary large cell neuroendocrine carcinoma (LCNEC), we evaluated the cytological characteristics of LCNEC. Samples from 25 histologically confirmed LCNECs (14 touch imprint (TI) and 11 curettage) were analyzed. The findings were compared with those for seven small cell lung carcinomas. Cytological findings of TIs were as follows: Tumor cells were medium- to large-sized, round or polygonal, and nuclear polymorphism was observed. Some of the tumor cells had clearly identified cytoplasms, but naked nuclei were frequently observed. Nuclei were round, oval, or polygonal, and possessed thin and smooth nuclear membranes. The nuclear chromatin pattern was finely or coarsely granular. One or two nucleoli were observed in the nuclei, but were inconspicuous in some cases. Tumor cells appeared in clusters, and rosette formation was observed, but single cells were frequently observed also. Necrotic background and nuclear streaking were frequently observed. In brush or curettage specimens, the number of cells observed on a glass was small, but the findings were almost the same as those for the TI samples. TI samples have characteristic features, such as a neuroendocrine morphologic pattern, large cell size, abundant cytoplasm, finely or coarsely granular chromatin of the nucleus, and prominent nucleoli, and the diagnosis of LCNEC is possible. In brush or curettage specimen, the LCNEC diagnosis may be possible if a sufficient number of tumor cells are obtained.

Primary lung adenocarcinoma with massive lymphocyte infiltration.

We report 6 cases of adenocarcinoma with massive lymphocyte infiltration. This adenocarcinoma is found in 0.7% of surgically resected primary lung adenocarcinomas. The tumor was located in the peripheral portion in all cases. Lymph node metastasis was detected in 4 cases. The mean follow-up period was 49.8 months; all patients were alive without recurrence despite advanced pathologic stage. Histologically, the tumors revealed an acinar and glandular structure, and the cancer epithelium was destroyed by infiltrating lymphocytes. The lung parenchyma was destroyed by the severe inflammatory cell infiltration without dense fibrosis. Immunohistochemical staining revealed that most infiltrating lymphocytes were positive for CD3 or CD20. None of the tumors were positive for latent membrane protein-1, bcl-2, or Epstein-Barr virus-encoded small RNA-1. This type of adenocarcinoma occurs in old age, and good outcome and distinctive histologic features were observed. We refer to it as primary lung adenocarcinoma with massive lymphocyte infiltration.

Breast cancer resistance protein impacts clinical outcome in platinum-based chemotherapy for advanced non-small cell lung cancer.

PURPOSE: The purpose of this study was to investigate the relationship between the level of expression of ATP-binding 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.

Treatment of small cell lung cancer in the elderly based on a critical literature review of clinical trials.

At diagnosis, 25-40% of patients with small cell lung cancer (SCLC) are 70 years of age or older, and many of them have been undertreated because of fear of excessive toxicity associated with chemotherapy. Papers retrieved by a Medline search using the key words "elderly or older" and "small cell lung cancer" and by a manual search were classified into the three types: (1) case-series studies, (2) subgroup analyses of phase II and phase III trials by age, and (3) prospective clinical trials in the elderly. Treatment regimens, delivery, toxicity, antitumor activity, and patient survival were reviewed in elderly patients with good and poor general condition. The standard chemotherapy regimens for the general population could be applied to elderly patients in good general condition (performance status of 0-1, normal organ function, and no comorbidity), but etoposide and carboplatin regimen with dose modification was frequently used for unselected elderly patients. A combination of full-dose thoracic radiotherapy and chemotherapy was the treatment of choice for limited SCLC in the elderly. Full cycles of chemotherapy were tolerable by 80% of the elderly patients with good general condition, but two cycles may be optimal for unselected elderly patients. Although the evidence levels based on clinical trials available today are low, these results are helpful for clinical practice and future clinical trials for elderly patients with SCLC.

Primary lung carcinoma with signet-ring cell carcinoma components: clinicopathological analysis of 39 cases.

The clinical and histologic profiles of primary lung carcinomas with signet-ring cell carcinoma (SRCC) components were analyzed. The SRCC components were seen in 39 cases (1.5%) of 2640 cases of surgically resected primary lung carcinomas. The patients' mean age was 54.6 years (range, 32-76 years), and the male-to-female ratio was 1.16:1.00. Twenty-six patients (66.7%) were smokers. The SRCC component was seen as part of an adenocarcinoma in 36 cases (acinar, 27 cases; mixed bronchioloalveolar and acinar, 9 cases) and as part of an adenosquamous cell carcinoma in 2 cases; one lesion consisted of only SRCC cells. The morphologic appearance of cancer nests containing SRCC was classified into three patterns: solid, tubuloacinar, and discohesive. Each case was composed of a varying proportion of these three patterns. The carcinomas with SRCC components were divided into two groups, according to those in which the SRCC component occupied <50% of the lesion (L-SRCC; n = 20) and those in which the SRCC component occupied > or = 50% of the lesion (H-SRCC; n = 19). The frequencies of blood vessel invasion, lymph vessel invasion, and lymph node metastasis were significantly higher in the H-SRCC group than in 1634 adenocarcinoma, and adenosquamous cell carcinomas (non-SRCC). The 5-year survival rates of patients non-SRCC, with l-SRCC, or with H-SRCC were 52.7%, 50%, and 28.4%, respectively. The 5-year survival rate of patients with H-SRCC and of patients without SRCC were significantly different. Based on these clinicopathologic characteristics, we classified primary lung carcinomas with SRCC components into the following two groups: 1) SRCC, in which the SRCC component occupies >or = 50% of the lesion, and 2) signet-ring feature, in which the SRCC components occupies <50% of the lesion.