125I seeds irradiation inhibits tumor growth and induces apoptosis by Ki-67, P21, survivin, livin and caspase-9 expression in lung carcinoma xenografts.

BACKGROUND: Lung cancer is a fatal disease and a serious health problem worldwide. Patients are usually diagnosed at an advanced stage, and the effectiveness of chemotherapy for such patients is very limited. Iodine 125 seed (125I) irradiation can be used as an important adjuvant treatment for lung carcinoma. The purpose of this study was to examine the role of irradiation by 125I seeds in human lung cancer xenograft model and to determine the underlying mechanisms involved, with a focus on apoptosis. METHODS: 40 mice with A549 lung adenocarcinoma xenografts were randomly divided into 4 groups: control group (n = 10), sham seed (0 mCi) implant group (n = 10), 125I seed (0.6 mCi) implant group (n = 10) and 125I seed (0.8 mCi) implant group (n = 10), respectively. The body weight and tumor volume, were recorded every 4 days until the end of the study. Apoptotic cells were checked by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and activities of caspase-3 and caspase-8 enzyme were tested. Expression of P21, survivin, livin, caspase-9 and proliferating cell nuclear antigen (Ki-67) was detected with immunohistochemical staining. RESULTS: The results of TUNEL staining assays showed that 125I seed irradiation suppresses the growth of lung cancer xenografts in nude mice and induced apoptosis. The activity of caspase-3 and caspase-8 was significantly higher. The expression levels Ki67, survivin and livin were substantially downregulated, while P21 and caspase-9 protein expression were significantly increased following 125I seed irradiation. This study revealed that 125I seed irradiation could significantly change apoptosis-related protein in human lung cancer xenografts. CONCLUSIONS: Overall, our study demonstrates that radiation exposure by 125I seeds could be a new treatment option for lung cancer.

Under-use of radiotherapy in stage III bronchioaveolar lung cancer and socio-economic disparities in cause specific survival: a population study.

BACKGROUND: This study used the receiver operating characteristic curve (ROC) to analyze Surveillance, Epidemiology and End RESULTS (SEER) bronchioaveolar carcinoma data to identify predictive models and potential disparity in outcomes. MATERIALS AND METHODS: Socio-economic, staging and treatment factors were assessed. For the risk modeling, each factor was fitted by a Generalized Linear Model to predict cause specific survival. The area under the ROC was computed. Similar strata were combined to construct the most parsimonious models. A random sampling algorithm was used to estimate modeling errors. Risk of cause specific death was computed for the predictors for comparison. RESULTS: There were 7,309 patients included in this study. The mean follow up time (S.D.) was 24.2 (20) months. Female patients outnumbered male ones 3:2. The mean (S.D.) age was 70.1 (10.6) years. Stage was the most predictive factor of outcome (ROC area of 0.76). After optimization, several strata were fused, with a comparable ROC area of 0.75. There was a 4% additional risk of death associated with lower county family income, African American race, rural residency and lower than 25% county college graduate. Radiotherapy had not been used in 2/3 of patients with stage III disease. CONCLUSIONS: There are socio-economic disparities in cause specific survival. Under-use of radiotherapy may have contributed to poor outcome. Improving education, access and rates of radiotherapy use may improve outcome.

Lymph node ratio may predict the benefit of postoperative radiotherapy in non-small-cell lung cancer.

INTRODUCTION: The use of postoperative radiotherapy (PORT) after resection of non-small-cell lung cancer (NSCLC) is controversial, with some evidence suggesting a benefit in patients with N2 disease. We assessed lymph node ratio (LNR) as a predictor of PORT benefit. METHODS: By using the Surveillance, Epidemiology and End Results database, we analyzed resected, node-positive (N1-N2) NSCLC patients diagnosed between 1998 and 2009. LNR, (number of positive nodes/number of resected nodes) was categorized into four groups: LNR less than 12.5%, 12.5 to 24.9%, 25 to 49.9%, and 50% or more. RESULTS: Of 11,324 node-positive NSCLC patients identified, 6551 (57.9%) had N1 disease. The LNR was prognostic for survival in the entire cohort and within each nodal stage. The median survival in LNR groups 1, 2, 3, and 4 was 43, 40, 30, and 23 months in N1 disease and 40, 32, 27, and 22 months in N2 disease, respectively. PORT was associated with a worse survival on univariate analysis (hazard ratio [HR] =1.09; confidence interval [CI] 1.03-1.15; p = 0.002) but no effect on multivariate analysis (HR = 0.96; CI 0.90-1.02; p = 0.201). When analyzed by nodal stage, the benefit of PORT was limited to N2 disease (HR = 0.9; CI 0.84-0.99; p= 0.026) with no benefit in N1 disease (HR = 1.06; CI 0.97-1.15; p=0.2). After stratifying by LNR, the survival benefit of PORT was limited to those with N2 disease and an LNR of 50% or more. CONCLUSION: A high LNR is associated with a poorer survival in resected, node-positive NSCLC. The survival benefit associated with PORT in this disease seems to be limited to those with an LNR of 50% or more. This warrants further investigation in other cohorts and prospective studies.

Stereotactic body radiation therapy for the treatment of early-stage minimally invasive adenocarcinoma or adenocarcnioma in situ (formerly bronchioloalveolar carcinoma): a patterns of failure analysis.

INTRODUCTION: Ongoing prospective trials exploring stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) often exclude minimally invasive adenocarcinoma or adenocarcnioma in situ, formerly bronchioloalveolar carcinoma (BAC), due to concerns for accurate target delineation on CT. We performed a patterns of failure analysis to compare outcomes between BAC and other NSCLC subtypes. METHODS: One hundred twenty patients with early stage NSCLC were treated with SBRT from 2004-2009. Pathologic confirmation of NSCLC was obtained in 97 patients. Radiotherapy was delivered according to RTOG guidelines. The log-rank test was used to compare outcomes between BAC and other NSCLC. RESULTS: Median follow-up was 29 months. The median SBRT dose was 5400 cGy. Thirteen patients had radiographically diagnosed BAC and five patients had biopsy confirmed BAC, of which two had both. The three-year local control was 100% for biopsy-proven or radiographically diagnosed BAC (n = 18) and 86% for all other NSCLC subtypes (n = 102) (p = 0.13). Likewise, no significant difference was detected between BAC and other NSCLC for 3-year regional failure (12% vs. 20%, p = 0.45), progression-free survival (57.6% vs. 53.5%, p = 0.84) or overall survival (35% vs. 47%, p = 0.66). There was a trend towards lower three-year rates of freedom from distant failure in patients with any diagnosis of BAC compared to those without (26% vs. 38%, p = 0.053). CONCLUSIONS: Compared to other NSCLC subtypes, BAC appears to have similar patterns of failure and survival after treatment with SBRT, however there may be an increased risk of distant metastases with BAC. RTOG guideline-based target delineation provides encouraging local control rates for patients with BAC.

Radiotherapy improves survival in unresected stage I-III bronchoalveolar carcinoma.

PURPOSE: To test the hypothesis that radiotherapy (RT) improves the outcome of patients with unresected, nonmetastatic bronchoalveolar carcinoma (BAC) by performing a population-based analysis within the Surveillance, Epidemiology, and End Results (SEER) registry. METHODS AND MATERIALS: Inclusion criteria were as follows: patients diagnosed with BAC, Stage I-III, between 2001 and 2007. Exclusion criteria included unknown stage, unknown primary treatment modality, Stage IV disease, and those diagnosed at autopsy. Demographic data, treatment details, and overall survival were retrieved from the SEER database. Survival was analyzed using the Kaplan-Meier method and log-rank test. RESULTS: A total of 6933 patients with Stage I-III BAC were included in the analysis. The median age at diagnosis was 70 years (range, 10-101 years). The majority of patients were diagnosed with Stage I (74.4%); 968 patients (14%) did not undergo surgical resection. Unresected patients were more likely to be older (p < 0.0001), male (p = 0.001), black (p < 0.0001), and Stage III (p < 0.0001). Within the cohort of unresected patients, 300 (31%) were treated with RT. The estimated 2-year overall survival for patients with unresected, nonmetastatic BAC was 58%, 44%, and 27% in Stage I, II, and III, respectively. Factors associated with improved survival included female sex, earlier stage at diagnosis, and use of RT. Median survival in those not receiving RT vs. receiving RT was as follows: Stage I, 28 months vs. 33 months (n = 364, p = 0.06); Stage II, 18 months vs. not reached (n = 31, nonsignificant); Stage III, 10 months vs. 17 months (n = 517, p < 0.003). CONCLUSIONS: The use of RT is associated with improved prognosis in unresected Stage I-III BAC. Less than a third of patients who could have potentially benefited from RT received it, suggesting that the medical specialists involved in the care of these patients underappreciate the importance of RT.

[Gefitinib treatment for carcinomatous meningitis in non-small cell lung cancer]. / Géfitinib et méningite carcinomateuse d'un carcinome bronchique non à petites cellules (CBNPC).

BACKGROUND: Carcinomatous meningitis is a major complication in Non Small Cell Lung Cancer (NSCLC). Despite treatment with radiotherapy alone or in combination with intrathecal and systemic chemotherapy, its prognosis remains poor. OBSERVATION: We report a case of a female non-smoker with adenocarcinoma with bronchoalveolar features presenting with carcinomatous meningitis three years after the diagnosis of her primary tumour. Gefitinib treatment was proposed because of the persistence of meningitic symptoms despite cranial irradiation. Clinical response was observed within 3 weeks and lasted for 9 months. CONCLUSION: Gefitinib may be effective in treating carcinomatous meningitis complicating NSCLC and should be considered in this situation given the absence of effective alternatives.

Iatrogenic esophagobronchial fistula arising in irradiated Barrett's esophagus.

A 47-yr-old male underwent a right upper lobectomy for stage IIB bronchoalveolar carcinoma followed by 4600 Gy of irradiation. One year later a fistula formed from an ulcerated region of Barrett's esophagus into the left main bronchus. Bronchotomy repair with onlay patch intercostal muscle flap and esophageal repair with serratus anterior muscle flap plus postoperative esophageal stent placement for stricture resulted in good functional results.

Postoperative radiotherapy in radically resected non-small cell lung cancer.

PURPOSE: To evaluate the value of adjuvant postoperative external-beam radiation (EBR) in patients with radically resected non-small cell lung cancer (NSCLC) pT1-3 pN0-2 compared to patients with resected NSCLC without adjuvant EBR. MATERIALS AND METHODS: In 155 patients (121 male, 34 female; mean age, 59 years) 105 lobectomies, 12 bilobectomies, and 38 pneumonectomies with radical lymph node dissection of the contralateral [corrected] side were performed. Postoperative staging was done according to the TNM system and was as follows: pT1 (n=38), pT2 (n=89), pT3 (n=28); pN0 (n=39), pN1 (n=67) and pN2 (n=49). Histopathologic study revealed 68 squamous cell carcinomas, 53 adenocarcinomas, 21 large cell carcinomas, 6 adenosquamous cell carcinomas, and 7 bronchioloalveolar cell carcinomas. All patients were randomly assigned into two treatment groups: 72 patients with no further treatment (control group), and 83 patients (EBR group) with adjuvant postoperative EBR of the bronchial stump and mediastinum (50 to 56 Gy, 8 or 23 MV photons, 2 Gy/d, 5 d/wk) beginning 4 to 6 weeks after surgery. RESULTS: The overall 5-year survival rate (median observation time, 43 months) of all patients was 24.1% (EBR group, 29.7%; control group, 20.4%; p>0.05, not significant). The relative risk of the EBR group was 0.85 with a two-sided confidence interval of 0.66 to 1.09. The overall 5-year recurrence-free survival was 20.6% (EBR, 27.1%; control group, 15.6%; p=0.07). The relative risk of the EBR group was 0.80 with a confidence interval of 0.63 to 1.01. The rate of local recurrences at the bronchial stump and/or mediastinum was significantly smaller in the EBR group (n=5) than in the control group (n=17) (p<0.01). Multivariate analysis (chi2 test) demonstrated an independent influence of postoperative EBR on the incidence of local recurrences. The incidence of distant metastases was slightly but not significantly higher in patients without EBR (38 patients) compared to those who had EBR (32 patients). CONCLUSION: High-dose postoperative EBR to the mediastinum significantly reduces the risk of local recurrence at the bronchial stump and/or mediastinum. Age, sex, histologic subtype, tumor size, surgical approach, or extent of lymph node involvement had no prognostic value--only postoperative EBR had an independent influence on the risk of local recurrence. The effect of postoperative EBR was on the verge of significance with respect to recurrence-free survival and showed the same tendency in overall survival, however with an attenuated relative risk.

[Bronchiolo-alveolar carcinoma. The computed tomographic picture and histological correlations]. / Carcinoma bronchioloalveolare. Quadri con tomografia computerizzata e correlazioni istologiche.

Twenty-one CT examinations of 18 patients with a known bronchioloalveolar carcinoma in the lung were retrospectively reviewed to describe the CT features of bronchioloalveolar carcinomas. Surgical specimens were available in 13 cases in which CT-histologic correlation was also obtained. In 5 patients the diagnosis was made with cytology and confirmed with radiologic-clinical follow-up. Three patients were reexamined for relapses 6-20 months after the resection of a localized carcinoma. Carcinomas exhibited 3 radiologic patterns: a) solitary pulmonary nodule (11 cases), b) mass or pulmonary consolidation (3 cases) and c) multicentric or diffuse disease (7 cases). Solitary nodular bronchioloalveolar carcinomas were associated with irregular or spiculated margins in 9 of 11 patients. In some cases internal inhomogeneity due to bubble-like radiolucencies was demonstrated. At pathology, bubble-like radiolucencies correlated with air-containing cystic spaces lined by neoplastic epithelium or patent and dilated bronchi. Some nodules exhibited linear and serpentine internal radiolucencies. Pathology demonstrated them to be consistent with patent intratumoral bronchioles (air bronchiologram) and air-containing neoplastic glandular spaces, respectively. In two cases a perinodular ground-glass halo was demonstrated surrounding the nodule (CT halo sign), due to perinodular lepidic tumor growth. Massive or ground-glass opacity involving a pulmonary segment or a lobe was another CT pattern of bronchioloalveolar carcinoma. An air bronchogram was usually demonstrated within the lesion. In the mucinous type of bronchioloalveolar carcinoma, pulmonary consolidations had a low CT value because of the large amount of intratumoral mucus. The diffuse type of tumor presented as multiple pulmonary nodules or multiple pulmonary consolidations, or both. In two cases multiple nodules were associated with carcinomatous lymphangitis. In conclusion, bronchioloalveolar carcinoma should be considered in the differential diagnosis of solitary pulmonary nodules, multiple pulmonary nodules and chronic alveolar opacities. The diagnosis of a bronchioloalveolar carcinoma is of great value since surgery can help nearly 70% of the patients at this stage recover.

Primary placement of osseointegrated implants in microvascular mandibular reconstruction.

The goal of mandibular reconstruction is to rehabilitate the patient by restoring occlusal relationships, lower facial contour, oral continence, and a denture-bearing surface. One of the major advantages of the use of vascularized bone over all other methods of mandibular reconstruction is its ability to achieve dental rehabilitation rapidly. The use of osseointegrated dental implants is a valuable adjunct in oral rehabilitation. It provides the most rigid form of stabilization to withstand the forces of mastication. In situations in which soft tissue reconstruction or the height of the alveolar ridge is not sufficient for a tissue-borne denture, implants offer the most suitable alternative. Mandibular reconstruction with free tissue transfer techniques is ideally suited for the placement of implants. These can be inserted at the time of mandibular reconstruction. Four months after surgery, when the integration process has occurred, the implants are unroofed, loaded, and ready for prosthetic placement. We will present several representative patients who underwent mandibular reconstruction with microvascular free bone transfer who have been successfully rehabilitated by osseointegrated implants. The process of osseointegration, different types of dental implants, and issues regarding radiation and implants are discussed. This is the first report of dental rehabilitation by primary placement of dental implants in patients undergoing microvascular mandibular reconstruction.

[Endoluminal irradiation of tracheobronchial tumors using a high dose rate iridium-192 afterloading device]. / Endoluminale Bestrahlung mit dem HDR-Iridium-192-Afterloadingverfahren bei tracheobronchialen Tumoren.

We report about 50 patients with inoperable bronchus tumors treated since March 1986 in a prospective non randomized study with high dose rate iridium-192 afterloading (AL) irradiation in 140 applications. 26 patients were treated combined with external irradiation. 32 were treated before with laser therapy, one with chemotherapy (small cell carcinoma). The actuarial survival rate (Kaplan-Meier) was 26% after 36 weeks for all patients; 38% for combined endoluminal and external irradiation and 9% for patients treated with AL alone. Death was caused by the local tumor in 85%. In 41% lethal bleeding was seen.

Cytostatic effects of bleomycin and cis-platinum in A549 human lung tumour cells using autofeeder conditions.

Residual colony forming ability (CFA) of cells from a human alveolar carcinoma (A549) was determined after 48 hours of contact with bleomycin (BLM) or cisdichlorodiammineplatinum (II) (DDP) using feeder cells arising from parallel cultures left in contact with sublethal BLM or DDP concentrations. The CFA of untreated cells was 60 to 80% (45% with X-irradiated feeder cells). Growing cultures were more resistant to DDP and more sensitive to BLM than plateau phase cultures. Subclones arising from a first treatment were resistant to a second BLM or X-ray treatment, but more sensitive to a second DDP treatment.

Irradiated lung cancer. An autopsy analysis of spread pattern.

The spread pattern was studied in 48 autopsied cases of irradiated, apparently localized lung cancer. Disease was found in the upper abdomen in 52%, in the brain in 8.7%; in the bones in 20.8%; and confined to the thoracic cavity in 27%. Radical irradiation controlled 38% locally. The pattern of metastasis in these irradiated lung tumors did not seem to differ from that of unirradiated lung cancers reported elsewhere.