Feasibility of cytological diagnosis of sarcoidosis with endobronchial US-guided transbronchial aspiration.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high diagnostic value in sarcoidosis if the obtained histological specimen is indicative of a non-caseating epithelioid-cell granuloma. However, EBUS-TBNA in sacoidosis sometimes affords solely cytological specimens. OBJECTIVE: To investigate the relevance of EBUS-TBNA cytology specimens in diagnosing sarcoidosis. DESIGN: The study population comprised 72 patients with sarcoidosis and 116 patients who had thoracic malignancies and intrathoracic lymphadenopathy but were eventually proven to be metastasis-free (controls). The EBUS-TBNA samples obtained for these subjects were blindly evaluated for the presence of epithelioid cell clusters by 2 independent cytoscreeners and a pathologist. RESULTS: Interobserver variability in the specimen grading was minimal. The sensitivity and specificity were 65.3% and 94.0%, respectively. The sensitivity was high, at 87.5%, for the combined cytological and histological examinations. Of 7 controls whose cytological specimens showed epithelioid cell clusters, 3 were also deemed positive for sarcoidosis on histological examination, which indicated that they had sarcoid reaction to cancer. CONCLUSIONS: Cytological evaluation of the EBUS-TBNA specimens had higher sensitivity than histological evaluation alone for intrathoracic lymphadenopathy due to sarcoidosis. It should be recognized, however, that up to 6% of patients with thoracic malignancy may have sarcoid reaction in non-metastatic lymph nodes.

Time trend in treatment-related deaths of patients with advanced non-small-cell lung cancer enrolled into phase III trials of systemic treatment.

PURPOSE: Despite recent improvements in supportive care, treatment-related death (TRD) remains a serious problem for lung cancer patients undergoing systemic chemotherapy. However, few studies have formally assessed possible changes in the TRD rate over the past two decades. PATIENTS AND METHODS: We searched phase III trials to address the role of systemic treatment of advanced non-small-cell lung cancer (NSCLC). Time trend was assessed using linear regression analysis. RESULTS: The overall incidence of TRD was calculated from 119 trials including 263 chemotherapy arms (46 477 patients), with information about the causes of deaths available for 197 arms (75%, 30 147 patients). Cisplatin-based regimens were the most frequently investigated. The crude TRD rate in the overall cohort of 119 trials was 1.26% and has been notably consistent over the investigated time (P = 0.762). The most common cause of death was febrile neutropenia, with no significant change in its incidence over the years (P = 0.139). In contrast, deaths due to renal toxicity decreased significantly (P = 0.042), whereas deaths due to pulmonary disorder increased significantly (P = 0.007). Among the pharmacological agents investigated, docetaxel (Taxotere) and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were associated with relatively high rates of deaths from pulmonary disorders, but EGFR-TKIs were not associated with death from any other cause. CONCLUSIONS: Despite of potential confounders in our results, the overall TRD rate has remained low, but not negligible, in phase III trials for advanced NSCLC, over the past two decades. Notably, the incidence and pattern of TRD stratified by cause have changed considerably.

Association between incremental gains in the objective response rate and survival improvement in phase III trials of first-line chemotherapy for extensive disease small-cell lung cancer.

BACKGROUND: The duration of, resources required for and cost of clinical trials could be reduced if a surrogate end point was to be used in place of survival. We assessed the extent to which the objective response rate (ORR) is predictive of mortality, how much difference in the ORR is needed to predict an obvious survival difference and what factors could affect the association between the two parameters during the first-line treatment of extensive disease (ED)-small-cell lung cancer (SCLC). METHODS: We used the ORRs and median survival times (MSTs) from 48 phase III trials of first-line chemotherapy involving 8779 randomised patients with ED-SCLC in a linear regression analysis. The MST difference was calculated as the difference in MST between the investigational and reference arms; the ORR difference was similarly defined. RESULTS: ORR difference between the treatment arms was modestly associated with the MST difference in the overall trials (R(2) = 0.3314). In contrast, the relationship was stronger among only trials in which prophylactic cranial irradiation was given to those having an objective response to the initial chemotherapy (R(2) = 0.6279). In this trial setting, large differences in ORR were needed to predict a survival advantage (1.2-day survival advantage per 2% increase in ORR). CONCLUSIONS: In the first-line treatment of ED-SCLC, a favourable relationship was detected between the two parameters in the selected trial setting. Large ORR differences were needed to predict a survival benefit, clearly suggesting the need for new chemotherapeutic agents.

Second primary cancer in survivors following concurrent chemoradiation for locally advanced non-small-cell lung cancer.

Long-term cancer survivors risk development of second primary cancers (SPC). Vigilant follow-up may be required. We report outcomes of 92 patients who underwent chemoradiation for unresectable stage III non-small-cell lung cancer, with a median follow-up of 8.9 years. The incidence of SPC was 2.4 per 100 patient-years (95% confidence interval: 1.0-4.9).

Functional anatomy of the lateral collateral ligament complex of the elbow: morphology and strain.

The anatomy of the lateral ulnar collateral ligament (LUCL) of the elbow was investigated in 26 fresh frozen cadavers. Two types of insertion of the LUCL were originally described but we found another type which is characterized by a broad single expansion along with a thin membranous fibre. Strain on the LUCL was measured in situ during extension and flexion with the forearm in supination, pronation and neutral. Strain in the proximal fibres started to occur at around 32 degrees flexion and peaked at between 50 degrees and 60 degrees flexion. Strains measured in the distal fibres were smaller in magnitude. Forearm rotation had little effect on strain during extension to flexion. Based on these results, we conclude that the LUCL functions in unison with the annular ligament.

Phase I/II study of docetaxel and cisplatin with concurrent thoracic radiation therapy for locally advanced non-small-cell lung cancer.

Recent studies have suggested the superiority of concomitant over sequential administration of chemotherapy and radiotherapy. Docetaxel and cisplatin have demonstrated efficacy in advanced non-small-cell lung cancer (NSCLC). This study evaluated the safety, toxicity, and antitumour activity of docetaxel/cisplatin with concurrent thoracic radiotherapy for patients with locally advanced NSCLC. Patients with locally advanced NSCLC (stage IIIA or IIIB), good performance status, age or=3 toxicities of 71, 60, 24, and 19%, respectively. Toxicity was significant, but manageable according to the dose and schedule modifications. Dose intensities of docetaxel and cisplatin were 86 and 87%, respectively. Radiotherapy was completed without a delay in 67% of 42 patients. The overall response rate was 79% (95% confidence interval (CI), 66-91%). The median survival time was 23.4+ months with an overall survival rate of 76% at 1 year and 54% at 2 years. In conclusion, chemotherapy with cisplatin plus docetaxel given on days 1, 8, 29, and 36 and concurrent thoracic radiotherapy is efficacious and tolerated in patients with locally advanced NSCLC and should be evaluated in a phase III study.

Fractionated administration of irinotecan and cisplatin for treatment of non-small-cell lung cancer: a phase II study of Okayama Lung Cancer Study Group.

A phase II study of fractionated administration of irinotecan (CPT-11) and cisplatin (CDDP) in patients with non-small-cell lung cancer (NSCLC) was conducted. Between January 1996 and January 1998, 44 previously untreated patients with stage IIIB or IV NSCLC were enrolled. CDDP at a dose of 60 mg x m(-2) was given first and followed by CPT-11 at a dose of 50 mg x m(-2). Both drugs were given by 1-hour infusion on days 1 and 8, and repeated every 4 weeks up to 4 cycles. 42 patients were evaluated for response and 44 for survival and toxicity. 20 patients (48%: 95% confidence interval 32-63%) achieved an objective response. The median duration of responses was 8 months, and the median survival time and the 1-year survival rate were 12.5 months and 56.8%, respectively. Major toxicities were neutropenia and diarrhoea. Grade 3 or 4 neutropenia occurred in 70.5% of the patients and one patient died of sepsis. Grade 3 or 4 diarrhoea was experienced in 25.0%, but manageable by conventional therapy. In conclusion, fractionated administration of CPT-11 and CDDP was highly effective for advanced NSCLC with manageable toxicities.

Bronchiolitis obliterans organizing pneumonia syndrome in breast-conserving therapy for early breast cancer: radiation-induced lung toxicity.

PURPOSE: Breast-conserving surgery and postoperative radiotherapy have played important roles in the treatment of early breast cancer. Bronchiolitis obliterans organizing pneumonia (BOOP) syndrome has recently been reported to be one of the complications of adjuvant radiotherapy. The purpose of this study was to determine the incidence of and risk factors for BOOP syndrome in breast cancer patients. METHODS AND MATERIALS: Between January 1996 and December 1998, 157 patients with breast cancer underwent radiotherapy after breast-conserving surgery. The criteria used for the diagnosis of BOOP syndrome were as follows: 1) radiation therapy to the breast within 12 months, 2) general and/or respiratory symptoms lasting for at least 2 weeks, 3) radiographic lung infiltrates outside the radiation port, and 4) no evidence of a specific cause. RESULTS: BOOP syndrome developed in 4 (2.5%) patients, who had fever and nonproductive cough, with patchy infiltrative shadows on chest roentgenograms which emerged between 5 and 6 months after radiotherapy. The symptoms and pulmonary infiltrates were rapidly improved by treatment with prednisone (40 mg/day), which was tapered over 2- to 5-month periods. However, BOOP syndrome relapsed in all cases during the tapering period or after withdrawal of prednisone. The eosinophil and neutrophil counts were increased and the ratios of CD4+ to CD8+ lymphocytes were elevated in bronchoalveolar lavage fluid in all four cases. There were no differences in proportions of patients by age, irradiated breast site, use of tamoxifen and/or chemotherapy, or radiation dose between those with and without BOOP syndrome. CONCLUSIONS: BOOP syndrome is considered an intractable form of lung toxicity after radiotherapy to the breast. An immunologic reaction mediated by eosinophils, neutrophils, and lymphocytes may be responsible for the development of this syndrome. Methods of prevention of BOOP syndrome should be established.

Two cases of atypical carcinoid of the thymus.

We describe two cases of atypical carcinoid of the thymus. One was an 82-year-old woman with complaints of nonproductive cough and back pain, and the other a 64-year-old woman with no symptoms. Computed tomography scans of the chest in both cases revealed a large mass in the anterior mediastinum. Multiple metastases to bone and liver were also noted in the former case. Histological examination of their tumors revealed that the tumor cells were arranged in a nested, trabecular, or pseudorosette pattern, with increased numbers of mitoses, nuclear pleomorphism, and presence of necrosis. In addition, immunohistochemically, the cells stained for neuron-specific enolase, synaptophysin and chromogranin A. Combination chemotherapy consisting of carboplatin and etoposide was performed as initial chemotherapy in the former case and as adjuvant therapy in the latter. The former patient achieved a short-term partial response. It is important to differentiate atypical carcinoid from other thymic tumors, since such tumors including thymoma have a much better prognosis than does atypical carcinoid.

Combination of nedaplatin and vindesine for treatment of relapsed or refractory non-small-cell lung cancer.

PURPOSE: A phase II study of nedaplatin and vindesine was conducted to evaluate their efficacy and safety for treatment of relapsed or refractory non-small-cell lung cancer (NSCLC). METHODS: Between August 1996 and September 1998, 48 patients who had previously received chemotherapy, thoracic radiotherapy, and/or surgery were enrolled in the study. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 to 2 and an age between 20 and 79 years. Treatment consisted of nedaplatin (80 mg/m2, day 1) and vindesine (3 mg/m2, days 1 and 8) every 3 to 4 weeks. RESULTS: Of 48 patients, 7 (14.6%) exhibited an objective response. Four (50%) of eight chemotherapy-naive patients had a partial response. However, of the 40 patients who had received prior chemotherapy, a partial response was observed in only 3 (7.5%). At a median follow-up time of 85.1 weeks, the median survival time was 43.6 weeks (95% confidence interval 34.4-52.7) for patients who had received chemotherapy, with a survival rate of 40% at 1 year. Grade 3 or 4 neutropenia occurred in 43 of 48 patients (90%), and neutropenic fever was observed in 3 of the 43 patients, one of whom died of sepsis. Pharmacokinetic and pharmacodynamic analyses of platinum were performed in 43 patients during the first cycle of chemotherapy. Percent reduction in absolute neutrophil count was correlated not only with the area under the plasma ultrafilterable platinum concentration versus time curve (r = 0.41, P = 0.007) but also with the duration of ultrafilterable platinum concentration above 1 microg/ml (r = 0.41, P = 0.007). Patients with progressive disease exhibited a shorter duration of ultrafilterable platinum concentration over 1 microg/ml (P = 0.046) than those with other responses. CONCLUSION: A combination of nedaplatin and vindesine was unsatisfactory as second-line chemotherapy for NSCLC, although the combination was well tolerated. The duration of ultrafilterable platinum concentration above 1 microg/ml was an important pharmacokinetic parameter for predicting both chemotherapy-induced neutropenia and treatment outcome.

Evaluation of the relationship between serum carcinoembryonic antigen level and treatment outcome in surgically resected clinical-stage I patients with non-small-cell lung cancer.

The relationship between preoperative serum carcinoembryonic antigen (CEA) level and treatment outcome for 39 clinical-stage I patients with surgically resected non-small-cell lung cancer (NSCLC) was retrospectively studied. Serum CEA levels were measured with an enzyme-linked immunosorbent assay kit, with the upper limit of normal defined as 6.7 ng/mL based on the 95% specificity level for benign lung disease in our hospital. Patients with serum CEA > or = 6.7 ng/mL (n = 9) were more likely to have advanced disease at surgery than those with serum CEA < 6.7 ng/mL (n = 30) (77.8% vs 16.7%, p = 0.0049). This increase in disease stage at surgery was mainly due to mediastinal lymph node metastasis. The sensitivity and specificity of serum CEA in the detection of pathological N2 disease were 62.5% and 87.1%, respectively. Survival for the high CEA group was significantly worse than that for the low CEA group (median survival time, 40.2 vs 75.8 months, p = 0.0125). Relapse-free survival for the high CEA group was also poorer than that of the low CEA group (p = 0.0032). In a multivariate analysis, serum CEA level was the most dominant factor affecting relapse-free survival (hazard ratio = 6.68, p = 0.0053). These findings suggest that preoperative serum CEA level is useful not only in detection of mediastinal lymph node metastasis, but also in prediction of survival for clinical-stage I patients with NSCLC.

[Combination chemotherapy consisting of ifosfamide and vindesine for non-small cell lung cancer in the elderly].

To evaluate the nature and scope of treatment for non-small cell lung cancer (NSCLC) in the elderly, we retrospectively analyzed the cases of 166 patients (aged 75 years or more) who had been treated at our hospital between 1986 and 1997. In addition, we assessed the effectiveness and feasibility of combination chemotherapy consisting of ifosfamide and vindesine for 21 elderly patients. As their initial treatment, 20 patients (12%) received surgery; 65 (39%), curative chest radiotherapy; 30 (18%), chemotherapy; and 51 (31%), best supportive care. With combination chemotherapy consisting of ifosfamide (1.6 g/m2 on hospital days 1 through 3) and vindesine (2.5 mg/m2 on days 1 and 8), the response rate was 48% and the median survival time was 13.9 months (95% confidence interval: 5.6-22.2). Grade 3 or 4 leukopenia and neutropenia developed in 76% and 86% of the patients, respectively. However, other toxicities were generally mild, and no treatment-related deaths were observed. The combination of ifosfamide with vindesine may be effective for selected elderly NSCLC patients, and warrants further clinical study.

Prognostic factors in advanced non-small cell lung cancer: elevated serum levels of neuron specific enolase indicate poor prognosis.

BACKGROUND: Non-small cell lung cancer (NSCLC) is resistant to chemotherapy and prognosis of advanced NSCLC patients is considered to be dependent on various prognostic factors. METHODS: We analyzed prognostic factors in patients with advanced NSCLC who had been enrolled in clinical trials conducted by the Okayama Lung Cancer Study Group between 1978 and 1992 using two kinds of multivariate analysis, Cox's multivariate analysis and recursive partitioning and amalgamation (RPA) analysis. RESULTS: The first analysis was performed on 261 patients using 28 variables. Performance status (PS), clinical stage, liver metastasis or serum albumin level was an independent prognostic factor by Cox's analysis. In the second analysis performed on 128 patients having data on neuron specific enolase (NSE), NSE was the most important prognostic factor. Using the RPA method, three subgroups with significantly different survival potentials were defined. Among them, patients with normal serum NSE levels and good PS were found to obtain a markedly favorable prognosis [median survival time (MST) 22.1 months, 3-year survival rate 42.9%], whereas the survival of patients with elevated serum NSE levels and bone metastasis was extremely short (MST 4.7 months, 3-year survival rate 0%). CONCLUSIONS: These results indicate that analysis of prognostic factors including serum levels of NSE is useful for predicting the survival of patients with advanced NSCLC.

Psychological impact of informed consent in hospitalized cancer patients. A sequential study of anxiety and depression using the hospital anxiety and depression scale.

Patients with cancer receive an explanation of their disease and the recommended treatment when they are asked to give informed consent (IC). In the course of this process patients suffer severe distress, including anxiety and depression, but physicians tend to underestimate it. The goal of this study was to reveal the magnitude of such stress and any changes to this during the IC process by means of the Hospital Anxiety and Depression (HAD) scale, a self-assessment scale. Of 171 in-patients newly diagnosed with lung cancer, 119 were assessable for serial HAD scale scores on admission, immediately after the IC process, and at 1 and again at 2 weeks after the IC. Both anxiety and depression scores increased significantly immediately after IC. Female patients had significantly higher anxiety and depression scores than males at 1 week after the IC. The patients with poor performance status demonstrated high anxiety scores on admission and immediately after the IC, and substantial depression persisted longer in these patients. The prevalence of high scores of more than 11 (judged as adjustment disorder or more severe state) immediately after the IC was 50% for anxiety and 31% for depression. The prevalence decreased significantly within 1 or 2 weeks, but 41% and 14% of the patients still showed high anxiety and depression scores, respectively. Physicians should be aware of these facts and pay special attention to their patients' psychological distress in routine clinical practice.

Clinical investigation of atypical adenomatous hyperplasia of the lung.

The clinicopathologic characteristics of atypical adenomatous hyperplasia (AAH) remain unclear. A total of 137 patients underwent resection for adenocarcinoma of the lung at our institution. Examination of resected lung tissue showed that in addition to adenocarcinoma AAH was present in 26 cases and was not present in 111 cases. All nonsmokers with AAH (n = 13) had earlier-stage disease (stage IA, IB, IIA, and IIB) and no history of respiratory disease. Among patients with stage IA disease, the relapse-free and overall survival curves for those with AAH (n = 14) tended to be better than for those without AAH (n = 40), but the difference was not statistically significant (P = 0.056 and 0.087, respectively). Concurrent presence of AAH may be a favorable prognostic indicator in patients with stage IA adenocarcinoma.

Clinical investigation of bronchioloalveolar carcinoma: a retrospective analysis of 53 patients in a single institution.

BACKGROUND: Bronchioloalveolar carcinoma (BAC) has been reported to have unique clinicopathological features. PATIENTS AND METHODS: This retrospective study was performed using data base including 871 patients treated for primary lung cancer between 1981 and 1995. RESULTS: The patients with BAC included a larger proportion of female (P = 0.029) and smoked less (P = 0.002) than those with non-BAC. There was no difference in survival between surgically resected patients with BAC and those with non-BAC. Clinical Stage IV patients with BAC had a better response to chemotherapy than did those with non-BAC. Survival in the former group was better than that in the latter on univariate analysis, but the significance of this difference was not confirmed multivariate analysis. CONCLUSION: The patients with BAC included a larger proportion of females and smoked less than those with non-BAC. Treatment results for BAC was comparable to those for non-BAC.

In vitro evaluation of antimicrotubule agents in human small-cell lung cancer cell lines.

BACKGROUND: The improvement of treatment outcome of small-cell lung cancer (SCLC), and search for new effective drugs and to overcome drug-resistance are essential. MATERIALS AND METHODS: We evaluated the cytotoxicity of antimicrotubule agents to seven human SCLC cell lines consisting of one cell line (SBC-3) established from a previously untreated patient as a representative of drug-sensitive cell line, three cell lines (SBC-2, SBC-4, and -7) derived from treated patients as representatives of intrinsic drug-resistance cell lines, and three drug-resistant sublines (SBC-3/ADM, SBC-3/ETP, and SBC-3/CDDP) selected by continuous exposure of the SBC-3 cell line to increasing concentrations of doxorubicin, etoposide, or cisplatin as representatives of acquired drug-resistant cell lines. RESULTS: IC50 values for SBC-2, -3, -4, and -7 cells of antimicrotubule agents were markedly lower than those of doxorubicin, etoposide, and cisplatin. Both SBC-3/ADM and SBC-3/ETP subline were highly resistant to paclitaxel, docetaxel, vinorelbine, vincristine, vindesine, and vinblastine. However, an SBC-3/ADM subline was not fully cross-resistant to rhizoxin, and an SBC-3/ETP subline was as sensitive to rhizoxin as an SBC-3 cell line. A cisplatin-resistant subline, SBC-3/CDDP, showed no cross-resistance to the antimicrotubule agents. CONCLUSION: These results suggest that antimicrotubule agents are useful for SCLC, and rhizoxin may be particularly effective in the salvage treatment of refractory or relapsed patients.

Measurement and evaluation of serum anti-p53 antibody levels in patients with lung cancer at its initial presentation: a prospective study.

Anti-p53 antibodies in sera are known to be products of the host immune response to mutated p53 protein, and are present in some patients with various types of cancer. In this study, we measured serum anti-p53 antibody levels in 52 patients with lung cancer and 63 normal volunteers to determine the relationship between anti-p53 antibody level and clinical features of lung cancer patients. Anti-p53 antibody level was measured by an enzyme-linked immunosorbent assay and expressed as an anti-p53 antibody index, defined as the ratio of absorption of serum sample to that of p53-positive serum. The median anti-p53 antibody index was 6.6 for lung cancer patients, and higher than that in normal volunteers (1.7) (P = 0.0000). For lung cancer patients, significant differences in index levels were found by histology (4.3, n = 25, adenocarcinoma vs 8.7, n = 18, squamous cell carcinoma vs 64.8, n = 2, large-cell carcinoma vs 9.8, n = 7, small-cell carcinoma; P = 0.0109). High anti-p53 antibody index levels were observed for both large-cell carcinoma and small-cell carcinoma. When the cut-off level was set at 7.2, determined using the twice 95% specificity level for normal volunteers, the sensitivities of anti-p53 antibodies were 46.1% for all lung cancers, 28.0% for adenocarcinoma, 55.6% for squamous cell carcinoma, 100% for large-cell carcinoma and 71.4% for small-cell carcinoma. However, there were no significant differences in index level by gender, age, smoking index, presence of previous or concomitant cancer or disease stage. Multivariate analysis using a logistic regression model demonstrated that histological type of tumour was a dominant factor associated with elevation of anti-p53 antibody index level (P = 0.0184). These findings suggest that serum anti-p53 antibody index level might be independent of tumour burden and the presence of previous or concomitant cancer in our series of lung cancer patients, but is clearly strongly correlated with tumour histological type.

Two cases of intrapulmonary lymph node presenting as a peripheral nodular shadow: diagnostic differentiation from lung cancer.

We present two cases of intrapulmonary lymph node. The patients were a 44-year-old woman and a 71-year-old man each with a small peripheral nodule in the lung. On computed tomography (CT) scans, both nodules were spiculated. Since histological diagnosis could not be obtained by bronchoscopic examination or CT-guided needle biopsy, they underwent video-assisted thoracoscopic surgery. Histological examination of the resected material revealed that both nodules were composed of lymph node. Intrapulmonary lymph node has until recently been assigned no clinical significance; however, differential diagnosis of this lesion from lung cancers and other metastatic tumors is now clinically important.