Baseline tumour measurements predict survival in advanced non-small cell lung cancer.

BACKGROUND: The association between tumour measurements and survival has been studied extensively in early-stage and locally advanced non-small cell lung cancer (NSCLC). We analysed these factors in patients with advanced NSCLC. METHODS: Data were derived from the E4599 trial of paclitaxel-carboplatin±bevacizumab. Associations between the Response Evaluation Criteria in Solid Tumors (RECIST) baseline sum longest diameter (BSLD), response rate, progression-free survival (PFS) and overall survival (OS) were evaluated using univariate and multivariable Cox regression models. RESULTS: A total of 759 of the 850 patients (89%) in the E4599 trial had measurable diseases and were included in this analysis. The median BSLD was 7.5 cm. BSLD predicted OS (hazard ratio (HR) 1.41; P<0.001) and had a trend towards association with PFS (HR 1.14; P=0.08). The median OS was 12.6 months for patients with BSLD <7.5 cm compared with 9.5 months for BSLD ≥ 7.5 cm. This association persisted in a multivariable model controlling multiple prognostic factors, including the presence and sites of extrathoracic disease (HR 1.24; P=0.01). There was no association between BSLD and response rate. CONCLUSION: Tumour measurements are associated with survival in the E4599 trial. If validated in other populations, this parameter may provide important prognostic information to patients and clinicians.

Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer.

BACKGROUND: Previous studies have demonstrated the efficacy and safety of bevacizumab in the treatment of non-small-cell lung cancer (NSCLC). METHODS: Summary data from randomised trials comparing first-line bevacizumab plus platinum-based chemotherapy with chemotherapy alone for inoperable locally advanced, recurrent or metastatic NSCLC were meta-analysed. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for adverse events were calculated. The chi-squared tests evaluated interactions between treatment effects, and prognostic factors and patient characteristics. RESULTS: Data of 2194 patients (1313 bevacizumab; 881 controls) from four phase II and III trials: AVF-0757g, JO19907,ECOG 4599 and AVAiL, were analysed. Compared with chemotherapy alone, bevacizumab significantly prolonged OS(HR 0.90; 95% confidence interval [CI] 0.81, 0.99; P=0.03), and PFS (0.72; 95% CI 0.66, 0.79; P<0.001). Bevacizumab showed a significantly greater effect on OS in patients with adenocarcinoma versus other histologies (P=0.03), and patients with body weight loss ≤5% versus >5% (P=0.04). Bevacizumab significantly increased the risk of grade ≥3 proteinuria, hypertension,haemorrhagic events, neutropenia, and febrile neutropenia [corrected]. CONCLUSIONS: Bevacizumab significantly prolonged OS and PFS when added to first-line platinum-based chemotherapy in patients with advanced NSCLC; no unexpected toxicity was evident.

Phase II study of daily oral etoposide plus ifosfamide plus cisplatin for previously treated recurrent small-cell lung cancer: a Hoosier Oncology Group Trial.

PURPOSE: The study was undertaken to determine the activity and toxicity of oral etoposide (VP-16), ifosfamide, and cisplatin combination chemotherapy for previously treated, recurrent small-cell lung cancer (SCLC). PATIENTS AND METHODS: In this phase II trial, 46 patients were enrolled to receive oral VP-16, 37.5 mg/m2/d for 21 days, ifosfamide 1.2 g/m2/d for 4 days, and cisplatin 20 mg/m2/d for 4 days, with courses repeated every 28 days. Response, survival, and toxicity data were then noted. RESULTS: Forty-two of 46 patients were assessable for response, survival, and toxicity. Thirty-six of 42 patients had received prior cisplatin plus VP-16. The first 22 patients received oral VP-16 for 21 days, but the subsequent 20 patients received oral VP-16 for 14 days after an interim analysis showed marked myelosuppression. Twenty-three of 42 patients (55%) had an objective response, with six complete responses (CRs; 14%), and 17 partial responses (PRs; 40%). The median progression-free survival time was 20 weeks (range, 2 to 66) and the overall median survival duration was 29 weeks (range, 1 to 76). Myelosuppression was significant, with six treatment-related deaths, four as a result of sepsis. CONCLUSION: The combination of oral VP-16, ifosfamide, and cisplatin is an active regimen in the treatment of recurrent SCLC. However, hematologic toxicity was severe in this pretreated patient population.

Role of computed tomography in the staging of primary melanoma.

PURPOSE: To evaluate the role of body computed tomography (CT) for the staging of patients with early melanoma. PATIENTS AND METHODS: A total of 151 new patients with American Joint Committee (AJC) clinical stage I, II, and III melanoma who received a CT scan of at least the chest and abdomen are the subject of this study. CT scans considered suspicious for metastases were reviewed again by one of the investigators (A.McB.C.). RESULTS: Of 151 patients, 63 had AJC clinical stage I, 61 stage II, and 23 stage III disease. In addition, one patient each had primary melanoma of the anal canal, esophagus, or vulva. Twenty-nine (19%) of 151 patients had a CT scan that was considered suspicious for metastases. The most common radiologic findings were single hepatic, and single or multiple pulmonary nodules. Of these 29 patients with suspicious scans, 24 subsequently proved to have benign processes by biopsy or follow-up studies, three had second primary tumors (well-differentiated lymphocytic lymphoma, Hodgkin's disease, and renal cell carcinoma), and only two were found to have metastatic melanoma. Of these two patients, one had regional nodal disease (unsuspected on physical examination) and one had distant nodal metastases. CONCLUSION: Body CT is not a useful imaging study in the detection of occult metastases in patients with primary melanoma. Although body CT commonly shows suspicious radiologic abnormalities in patients with early melanoma, these abnormalities most likely represent benign processes or a second primary tumor, rather than metastatic melanoma. The value of body CT in patients who present with nodal metastases needs further study.

Phase I trial of the combination of irinotecan, paclitaxel, and carboplatin in patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose, toxicities, and dose suitable for phase II/III trials of irinotecan (CPT-11) combined with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC were enrolled to this multicenter, phase I study. The initial regimen was paclitaxel 225 mg/m(2)/3 h, followed by carboplatin area under the curve (AUC) 6 over 30 minutes on day 1, and CPT-11 starting at 40 mg/m(2) over 90 minutes, days 1 and 8, every 3 weeks. Dose-limiting toxicity occurred in three of seven patients. The regimen was amended, with doses reduced to paclitaxel 175 mg/m(2)/3 h, carboplatin AUC 5 and CPT-11 at 40 mg/m(2), all on day 1 every 3 weeks. Dose escalation of CPT-11 proceeded to 80 mg/m(2) then 125 mg/m(2) before dose-limiting toxicities were experienced. Subsequent patients received an intermediate CPT-11 dose of 100 mg/m(2). RESULTS: Thirty-three patients were enrolled; 32 patients were assessable for safety, and 31 were assessable for tumor response. The primary first-cycle dose-limiting toxicities were neutropenia and diarrhea. The most common grade 3/4 toxicity observed during all cycles was neutropenia (16 patients [50%], with six [19%] developing neutropenic fever). Objective tumor response was observed in 39% (12/31, 95% confidence interval, 22% to 58%). The median time to tumor progression was 6.8 months, median survival 11.0 months, and 1-year survival probability 0.46. CONCLUSION: CPT-11 100 mg/m(2), paclitaxel 175 mg/m(2), and carboplatin AUC 5 given every 3 weeks can be safely administered in patients with advanced NSCLC. Neutropenia and diarrhea are the dose-limiting toxicities. The combination shows appreciable activity, and survival data are favorable.

Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer.

PURPOSE: The Hoosier Oncology Group has previously reported the results of its phase II trial of the combination of cisplatin plus gemcitabine. In that study of 27 assessable patients with advanced or metastatic non-small-cell lung cancer (NSCLC), the response rate was 33%, with a median survival of 8.4 months. Based on such favorable results, the Hoosier Oncology Group designed this randomized phase III study of gemcitabine plus cisplatin compared with cisplatin alone in chemotherapy-naive patients with advanced NSCLC. PATIENTS AND METHODS: Patients were randomized to receive either cisplatin (100 mg/m(2) intravenously on day 1 of a 28-day cycle) or the combination of cisplatin (100 mg/m(2) intravenously on day 1) plus gemcitabine (1,000 mg/m(2) administered intravenously on days 1, 8, and 15 of a 28-day cycle). RESULTS: From August 1995 to February 1997, 522 assessable chemotherapy-naive patients were randomized. Toxicity was predominantly hematologic and was more pronounced in the combination arm, with grade 4 neutropenia occurring in 35.3% of patients compared with 1.2% of patients on the cisplatin monotherapy arm. The incidence of neutropenic fevers was less than 5% in both arms. Grade 4 thrombocytopenia occurred in 25. 4% of patients on the combination arm compared with 0.8% of patients on the cisplatin monotherapy arm. No serious hemorrhagic events related to thrombocytopenia were reported for either arm. The combination of gemcitabine plus cisplatin demonstrated a significant improvement over single-agent cisplatin with regard to response rate (30.4% compared with 11.1%, respectively; P <.0001), median time to progressive disease (5.6 months compared with 3.7 months, respectively; P =.0013), and overall survival (9.1 months compared with 7.6 months, respectively; P =.004). CONCLUSIONS: For the first-line treatment of NSCLC, the regimen of gemcitabine plus cisplatin is superior to cisplatin alone in terms of response rate, time to disease progression, and overall survival.

Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies.

A Phase I dose escalation trial of i.v. administered recombinant human interleukin 12 (rhIL-12) was performed to determine its toxicity, maximum tolerated dose (MTD), pharmacokinetics, and biological and potential antineoplastic effects. Cohorts of four to six patients with advanced cancer, Karnofsky performance >/=70%, and normal organ function received escalating doses (3-1000 ng/kg/day) of rhIL-12 (Genetics Institute, Inc.) by bolus i.v. injection once as an inpatient and then, after a 2-week rest period, once daily for five days every 3 weeks as an outpatient. Therapy was withheld for grade 3 toxicity (grade 4 hyperbilirubinemia or neutropenia), and dose escalation was halted if three of six patients experienced a dose-limiting toxicity (DLT). After establishment of the MTD, eight more patients were enrolled to further assess the safety, pharmacokinetics, and immunobiology of this dose. Forty patients were enrolled, including 20 with renal cancer, 12 with melanoma, and 5 with colon cancer; 25 patients had received prior systemic therapy. Common toxicities included fever/chills, fatigue, nausea, vomiting, and headache. Fever was first observed at the 3 ng/kg dose level, typically occurred 8-12 h after rhIL-12 administration, and was incompletely suppressed with nonsteroidal anti-inflammatory drugs. Routine laboratory changes included anemia, neutropenia, lymphopenia, hyperglycemia, thrombocytopenia, and hypoalbuminemia. DLTs included oral stomatitis and liver function test abnormalities, predominantly elevated transaminases, which occurred in three of four patients at the 1000 ng/kg dose level. The 500 ng/kg dose level was determined to be the MTD. This dose, administered by this schedule, was associated with asymptomatic hepatic function test abnormalities in three patients and an onstudy death due to Clostridia perfringens septicemia but was otherwise well tolerated by the 14 patients treated in the dose escalation and safety phases. The T1/2 elimination of rhIL-12 was calculated to be 5.3-9.6 h. Biological effects included dose-dependent increases in circulating IFN-gamma, which exhibited attenuation with subsequent cycles. Serum neopterin rose in a reproducible fashion regardless of dose or cycle. Tumor necrosis factor alpha was not detected by ELISA. One of 40 patients developed a low titer antibody to rhIL-12. Lymphopenia was observed at all dose levels, with recovery occurring within several days of completing treatment without rebound lymphocytosis. There was one partial response (renal cell cancer) and one transient complete response (melanoma), both in previously untreated patients. Four additional patients received all proposed treatment without disease progression. rhIL-12 administered according to this schedule is biologically and clinically active at doses tolerable by most patients in an outpatient setting. Nonetheless, additional Phase I studies examining different schedules and the mechanisms of the specific DLTs are indicated before proceeding to Phase II testing.

Current management of small cell lung cancer.

There will be approximately 45,000 new cases of small cell lung cancer (SCLC) this year. Despite the initial sensitivity to chemotherapy, only 10% of all SCLC patients will have significant long-term survival. Studies have yet to show significant survival advantage for maintenance chemotherapy, and it appears that four to six cycles of chemotherapy is as effective as longer durations of chemotherapy. There is as yet no defined role for dose increase in the treatment of SCLC. In extensive disease no one chemotherapy combination has shown a definitive survival advantage, although it appears that single-agent oral etoposide may be inferior to combination intravenous chemotherapy. In limited disease, however, cisplatin plus etoposide alone or in alternation with cyclophosphamide, doxorubicin, and vincristine is superior to other approaches. Also, in limited disease, chemotherapy plus radiotherapy is superior to chemotherapy alone and it appears that early concurrent radiotherapy may be the ideal approach. Myeloid growth factors should not be given concurrently with thoracic radiotherapy. There are several new agents with significant activity in SCLC awaiting further study.

Etoposide plus ifosfamide plus cisplatin in the treatment of small cell lung cancer.

Approximately 25% of all lung cancer cases diagnosed in 1993 were due to small cell lung cancer (SCLC). Approximately one third of all SCLC patients present with limited disease. Efforts to improve treatment results for patients with limited-stage SCLC include two recent meta-analyses of combined-modality treatment involving chemotherapy with thoracic radiotherapy versus chemotherapy alone. Both of these studies showed improvements in survival with the combined-modality approach. In addition, preliminary results of a Hoosier Oncology Group phase II study of cisplatin/ifosfamide/etoposide (VIP) in combination with thoracic radiotherapy in patients with limited disease indicate that VIP has an acceptable toxicity profile and should be studied further. For patients presenting with extensive-stage SCLC, several combination regimens have been shown to be effective in inducing responses of approximately 60%, although none has established superiority. Results of several studies evaluating the standard cyclophosphamide/doxorubicin/vincristine (CAV) regimen versus cisplatin-containing combination regimens have shown no obvious survival advantage of the cisplatin regimens over CAV. On the other hand, results of a Hoosier Oncology Group study of VIP versus cisplatin/etoposide in extensive-disease SCLC showed that overall survival favored (P = .044) the VIP arm (9.1 months v 7.3 months), although these results need to be confirmed in another trial.

The epidemiology of lung cancer.

Lung cancer continues to be the leader in cancer deaths in the United States. The incidence of lung cancer in men has slowly decreased since the late 1980s, but has just now begun to plateau in women at the end of this decade. Despite modest advances in chemotherapy for treating lung cancer, it remains a deadly disease with overall 5-yr survival rates having not increased significantly over the last 25 years, remaining at approximately 14%. Tobacco smoking causes approximately 85-90% of bronchogenic carcinoma. Environmental tobacco exposure or a second-hand smoke also may cause lung cancer in life-long non-smokers. Certain occupational agents such as arsenic, asbestos, chromium, nickel and vinyl chloride increase the relative risk for lung cancer. Smoking has an additive or multiplicative effect with some of these agents. Familial predisposition for lung cancer is an area with advancing research. Developments in molecular biology have led to growing interest in investigation of biological markers, which may increase predisposition to smoking-related carcinogenesis. Hopefully, in the future we will be able to screen for lung cancer by using specific biomarkers. Finally, dietary factors have also been proposed as potential risk modulators, with vitamins A, C and E proposed as having a protective effect. Despite the slow decline of smoking in the United States, lung cancer will likely continue its devastation for years to come.

Irinotecan (CPT-11) in triplet combinations in patients with advanced non small-cell lung cancer: a review and report of a phase I/II trial.

The objectives of this phase I/II trial were to determine the maximum tolerated dose, toxicities, and the dose suitable for phase II/III trials of irinotecan (CPT-11) combined with paclitaxel and carboplatin in patients with advanced non small-cell lung cancer (NSCLC). Seventy-three patients with stage IIIB/IV NSCLC were enrolled in this multicenter, phase I/II study. The initial regimen was paclitaxel 225 mg/m2 over 3 hours, followed by carboplatin at an area under the curve (AUC) of 6 over 30 minutes on day 1 and CPT-11 starting at 40 mg/m2 over 90 minutes on days 1 and 8, every 3 weeks. Dose-limiting toxicity occurred in three of the original seven patients. The regimen was amended with doses reduced to paclitaxel 175 mg/m2 over 3 hours, carboplatin AUC = 5, and CPT-11 at 40 mg/m2, all on day 1 every 3 weeks. Dose escalation of CPT-11 proceeded to 80 mg/m2 and 125 mg/m2 before dose-limiting toxicities were experienced. Subsequent patients received an intermediate CPT-11 dose of 100 mg/m2. Doses suitable for phase II study were determined to be paclitaxel 175 mg/m2 over 3 hours, carboplatin AUC = 5, and CPT-11 100 mg/m2. The pri-mary first-cycle dose-limiting toxicities were neutropenia and diarrhea. The most common grade 3/4 toxicity observed during all cycles was neutropenia. On the phase I portion of the study, objective tumor response was observed in 39% (12 of 31, 95% confidence interval: 22%-58%). The median time to tumor progression was 6.8 months, median survival was 11.0 months, and 1-year survival probability was 0.46. These data were confirmed in the phase II portion with a 30% objective response rate, median time to progression of 5.6 months, median survival of 12.5 months, and a 1-year survival probability of 0.50. In conclusion, CPT-11 100 mg/m2, paclitaxel 175 mg/m2, and carboplatin AUC = 5 given every 3 weeks can be safely administered in patients with advanced NSCLC. Neutropenia and diarrhea are the dose-limiting toxicities. The combination shows appreciable activity, and survival data are favorable, warranting further study of this regimen. A review of other irinotecan-containing triplet combinations is presented.

Correlation between lipid-associated sialic acid and tumor burden in melanoma.

Recent studies have suggested that lipid-associated sialic acid (LSA) may be a useful tumor marker for monitoring patients with melanoma, but the relationship between LSA and tumor burden has not been previously studied. We therefore examined LSA levels in 240 patients of whom 169 had no clinical evidence of disease (NED) and 71 had metastatic disease. There was a statistically significant difference in LSA levels in patients with NED compared with metastatic disease as well as those with high tumor burden compared with low or intermediate tumor burden. There was no difference between the groups with low and intermediate tumor burden. An LSA level of 25 mg/dl provided a positive predictive value of 70% and a negative value of approximately 80%. Our data show that LSA levels correlate with tumor burden in patients with melanoma.

Irinotecan in small-cell lung cancer: the US experience.

There will be approximately 40,000 new cases of small-cell lung cancer this year. Prior to 1990, there were several agents with single-agent response rates of 30% to nearly 90% in the untreated small-cell lung cancer population and approximately 10% to 20% in relapsed patients. During the 1990s, several new chemotherapy agents have displayed activity in small-cell lung cancer (paclitaxel [Taxol], gemcitabine [Gemzar], vinorelbine [Navelbine], topotecan [Hycamtin], and irinotecan [Camptosar, CPT-11]). The majority of studies with irinotecan have been conducted in Japan. The US experience is limited to a single multi-institution trial that was conducted in patients with previously treated small-cell lung cancer. A total of 44 patients were entered in the study. Patients were stratified by response to prior therapy. Responses occurred in 7 of 44 patients for an overall response rate of 14%. The overall median survival was 4.8 months.

Treatment of advanced (stages III and IV) non-small-cell lung cancer.

Lung cancer is the leading cause of cancer deaths, and approximately 85% of patients in whom this neoplasm is diagnosed will die of this disease as a result of micrometastatic disease from tumors that appeared surgically resectable or of surgically unresectable disease that is either locally advanced or metastatic. It will affect approximately 171,000 people in the United States in 1998 and about 75% of these cases will be non-small-cell lung cancer (NSCLC). In only 25% of cases can complete surgical resection and cure be considered. Despite this grim outlook, advances have recently been made that beckon in an era of cautious optimism. In this review, a discussion of the latest developments in the management of locally advanced and metastatic NSCLC will be presented in detail. One of the significant developments has been the modifications to the staging system after the natural history of various stages was better characterized by reviewing the outcome of more than 5000 patients. Advances have also been seen in the diagnostic field. Specifically, positron emission tomography and endoscopic ultrasonography and biopsy are being evaluated to determine their role in diagnosing and staging lung cancer. At the present, however, history and physical examination, serum evaluation, computed tomography, and conventional approaches for obtaining a histologic diagnosis are standard practice. The role of adjuvant therapy, both postoperatively and in the neoadjuvant setting, has been studied. There are no data to support the use of radiotherapy or chemotherapy, with or without radiotherapy, in the postoperative setting. In the neoadjuvant setting, some intriguing results in favor of adjuvant chemotherapy have been observed. As discussed in detail these results provide preliminary data and need to be evaluated on a larger scale. Before the 1990s radiotherapy was the principal treatment modality used in the treatment of patients with locally advanced NSCLC. However, the results of several studies have shown the superiority of chemotherapy and radiotherapy in combination for patients with unresectable stage III NSCLC. Many questions regarding the optimal modes of chemotherapy and radiotherapy and the timing of these two modalities have yet to be answered. Concurrent with these advances has been the development of new chemotherapeutic agents that have been extensively evaluated in phase I and II trials. These agents include gemcitabine, paclitaxel, docetaxel, vinorelbine, and irinotecan. These agents have shown significant activity and acceptable toxicity when used in combination with cisplatin or carboplatin, but the results from the large cooperative trials that are ongoing are eagerly awaited to help define the optimal regimen. Further studies are either planned or ongoing to further define the role of these newer agents in the treatment of metastatic disease, in combination with radiotherapy for unresectable disease, and in the surgical adjuvant setting.

A phase II study of carboplatin plus gemcitabine in advanced non-small-cell lung cancer (NSCLC): a hoosier oncology group study.

The purpose of this study was to evaluate the toxicity and determine the response rate, duration of remission, and survival using gemcitabine plus carboplatin in non-small cell lung cancer (NSCLC). This was a phase II study of gemcitabine and carboplatin in chemotherapy-naive patients with advanced NSCLC and Karnofsky Performance Status of at least 80. Gemcitabine was administered intravenously at 1,000 mg/m2 weekly for 3 weeks followed by 1 week rest. Carboplatin was administered immediately after gemcitabine at an area under the curve (AUC) of 5 given intravenously on day 1 of an every-4-week cycle. Seven patients were entered in the study and five were evaluable for toxicity. The median age of patients was 68 years (range, 52-72). The protocol was prematurely terminated because of severe and unexpected hematologic toxicity. Grade 3-4 thrombocytopenia was observed in four of the first five patients. These toxicities were all observed with the first course of chemotherapy. There were no objective responses seen. Median survival time was 130 days. Carboplatin plus gemcitabine was a logical combination. However, because of the severe thrombocytopenia associated with this regimen, we do not recommend this two-drug combination in the dose and schedule used in this study.

Neuron-specific enolase as a tumor marker in metastatic melanoma.

Neuron-specific enolase (NSE) has been shown by some investigators to be a useful tumor marker for melanoma, but the relationship between NSE and tumor burden has not been extensively studied. We therefore examined NSE levels in 240 patients of whom 169 had no clinical evidence of disease (NED) and 71 had metastatic disease. There was no statistically significant difference in NSE levels in patients with NED compared with metastatic disease as well as those with high tumor burden compared with low or intermediate tumor burden. In addition, the mean absolute values of NSE, despite a slight elevation with tumor burden, were within the normal range (< 20 ng/ml). Our data suggest that NSE levels measured by the method used in our study are of no benefit in melanoma.

Apical dye penetration with four root canal sealers and gutta-percha using longitudinal sectioning.

The purpose of this study was to compare the level of apical dye penetration when different sealers were used with lateral condensation of gutta-percha. Fifty teeth with single root canals were biomechanically prepared using the step-back technique and irrigation with 15% ethylenediaminetetraacetic acid with cetrimide and 1% NaOCl solutions. The teeth were divided into five groups of 10 teeth each. The control group root canals were filled with laterally condensed gutta-percha without sealer and the other four groups were filled with laterally condensed gutta-percha and either Apexit, Sealapex, Tubli-Seal, or AH-26 sealer. After storage in 100% humidity at 37 degrees C for 48 h, the root surfaces were coated with nail varnish (except at the apex), placed in 2% methylene blue dye solution, and centrifuged at 30 x g for 3 min. The roots were sectioned longitudinally to determine the following mean levels of dye penetration: AH-26, 0.48 mm; Apexit, 1.33 mm; Sealapex, 4.59 mm; Tubli-Seal, 5.58 mm; and gutta-percha alone, 7.99 mm. This study demonstrated that a root canal sealer should be used in conjunction with laterally condensed gutta-percha and that AH-26 sealer had significantly less dye penetration than the other three sealers while Apexit had significantly less dye penetration than Sealapex and Tubli-Seal. There was no significant difference between Sealapex and Tubli-Seal.

A comparative study of the apical leakage of four root canal sealers and laterally condensed gutta-percha.

Previous studies have shown that lateral condensation of gutta-percha and sealer can provide an adequate apical seal. The purpose of this study was to compare the level of apical dye penetration when different sealers were used. One-hundred twenty-five teeth with single root canals were biomechanically prepared using the step-back technique and irrigation with EDTAC and 1% NaOCl solutions. The teeth were divided into five groups of 25 teeth each. The control group root canals were filled with laterally condensed gutta-percha and no sealer and the other four groups were filled with laterally condensed gutta-percha and either Apexit, Sealapex, Tubli-Seal, or AH26 sealer. After storage in 100% humidity at 37 degrees C for 48 h, the root surfaces were coated with nail varnish (except at the apex) and placed in 2% methylene blue dye solution and centrifuged at 3 x g for 3 min. The roots were sectioned transversely at 1-mm intervals to determine the following mean levels of dye penetrations: Apexit, 1.67 mm; Sealapex, 2.28 mm; Tubli-Seal, 1.95 mm; AH26, 0.82 mm; and gutta-percha alone, 8.37 mm. This study demonstrated that a root canal sealer should be used in conjunction with laterally condensed gutta-percha and that AH26 sealer provides a significantly better apical seal than the other sealers.

Differential effect of age on survival in advanced NSCLC in women versus men: analysis of recent Eastern Cooperative Oncology Group (ECOG) studies, with and without bevacizumab.

BACKGROUND: The impact of age on prognosis in advanced stage non-small cell lung cancer (NSCLC) may differ by sex. PATIENTS AND METHODS: Eligible patients (N=1590) from E1594, a 4-arm platinum-based chemotherapy trial, and E4599 (carboplatin/paclitaxel ± bevacizumab) chemotherapy arm were divided into male and female cohorts and separated into age groups of <60 or ≥60 years old. Eligible E4599 patients (N=850) were similarly separated by age and sex and by treatment (± bevacizumab). Survival was calculated separately for each cohort. RESULTS: The median survival time (MST) for women ≥60 years old treated with chemotherapy alone on E1594 and E4599 was 11.6 months versus 9.0 months for women <60 (p=0.03). MST was 7.4 and 8.3 months for men ≥60 and <60 years old respectively (NS). In E4599 the age <60 by bevacizumab treatment interaction was statistically significant (p=0.03) for women (younger had greater benefit), with no age effect in men. CONCLUSIONS: In this unplanned, exploratory subgroup analysis of advanced stage NSCLC ECOG trials, women ≥60 years old treated with chemotherapy live longer than men and younger women. In contrast, bevacizumab survival benefit was more pronounced in men of any age and in younger women on E4599.