Although primary neoplasms of adrenal gland are uncommon, adrenal metastases are frequently encountered in patients with malignancy, and lung is the most common primary tumour site. Among primary tumours of the adrenal gland non-Hodgkin's lymphoma (NHL) is a very rare entity. We describe a case of a 79-year-old man with a previous diagnosis of adenocarcinoma of the lung who presented after 2 years with a unilateral adrenal gland mass. A solitary metastasis from pulmonary carcinoma was suspected and a laparoscopic adrenalectomy was performed. Histological examination revealed a diffuse large B-cell NHL. The patient was treated with CHOP regimen plus rituximab and a total remission was achieved. After an 8-month follow-up the patient was free of disease. This is the first reported case of a rare non-synchronous tumoral combination involving lung and adrenal gland, emphasising at the incidental discovery of the NHL during a procedure performed for a pulmonary adenocarcinoma.

Lung cancer causes more deaths worldwide than any other cancer. In addition to cigarette smoking, dietary factors may contribute to lung carcinogenesis. Epidemiologic studies, including the environment and genetics in lung cancer etiology (EAGLE), have reported increased consumption of red/processed meats to be associated with higher risk of lung cancer. Heme-iron toxicity may link meat intake with cancer. We investigated this hypothesis in meat-related lung carcinogenesis using whole genome expression. We measured genome-wide expression (HG-U133A) in 49 tumor and 42 non-involved fresh frozen lung tissues of 64 adenocarcinoma EAGLE patients. We studied gene expression profiles by high-versus-low meat consumption, with and without adjustment by sex, age, and smoking. Threshold for significance was a false discovery rate (FDR) ≤0.15. We studied whether the identified genes played a role in heme-iron related processes by means of manually curated literature search and gene ontology-based pathway analysis. We found that gene expression of 232 annotated genes in tumor tissue significantly distinguished lung adenocarcinoma cases who consumed above/below the median intake of fresh red meats (FDR = 0.12). Sixty-three (∼28%) of the 232 identified genes (12 expected by chance, P-value < 0.001) were involved in heme binding, absorption, transport, and Wnt signaling pathway (e.g., CYPs, TPO, HPX, HFE, SLCs, and WNTs). We also identified several genes involved in lipid metabolism (e.g., NCR1, TNF, and UCP3) and oxidative stress (e.g., TPO, SGK2, and MTHFR) that may be indirectly related to heme-toxicity. The study's results provide preliminary evidence that heme-iron toxicity might be one underlying mechanism linking fresh red meat intake and lung cancer. © 2013 Wiley Periodicals, Inc.

Numblike (Numbl), a conserved homolog of Drosophila Numb, has been proved to be implicated in early development of the nervous system. A recent study also showed that Numbl played an important role in tumorigenesis and invasion by suppressing NF-κB activation. However, the biological role of Numbl remains unknown in lung cancer up to now. To address the expression of Numbl in the lung cancer cell, four lung cancer cell lines (metastatic cell lines NCI-H292, 95-D, and non-metastatic cell lines A549, HCC827) and non-cancerous human bronchial epithelial cells were used to detect the protein expression of Numbl by western blotting. The results in this study indicated that the expression of Numbl was downregulated in human lung cancer cell lines, especially in metastatic cell lines. To investigate the role of Numbl in lung cancer cell proliferation, apoptosis, and invasion, we generated human lung cancer 95-D cell lines in which Numbl was either overexpressed or depleted. Subsequently, the effects of Numbl on the cell viability, cycle, apoptosis, and invasion properties in 95-D cells were determined with MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] assay, flow cytometry analysis, and Transwell invasion assays. The results indicated that Numbl could decrease cell viability, suppress cell proliferation and invasion, and promote cell apoptosis. In addition, we investigated the effects of Numbl on the expression of the following proteins: TRAF6 (tumor necrosis factor receptor-associated factor 6), p-p65 (phosphor-NF-κB), cyclin D1, caspase-3, and matrix metalloproteinase 9 (MMP9). Results showed that Numbl could decrease the expression of TRAF6, p-p65, cyclin D1, and MMP9 and increase the expression of caspase-3. All these results suggested that Numbl might be involved in the inhibition of growth, proliferation, and invasion of 95-D cells, as well as the potentiation of apoptosis of 95-D cells by abrogating TRAF6-induced activation of NF-κB.

BACKGROUND:

Alveolar soft part sarcoma is a rare but highly malignant tumour and little is known about its radiologic pattern in children.

OBJECTIVE:

To describe the radiologic features of alveolar soft part sarcoma in children and adolescents.

MATERIALS AND METHODS:

We retrospectively analysed the clinical and imaging data of six children age 7-17 years at diagnosis, with histologically or genetically proven alveolar soft part sarcoma.

RESULTS:

The tumours were located deep within muscles of the limbs (n = 4), in chest wall muscle (n = 1) and in the orbit (n = 1). High-flow feeding arteries, large drainage veins and intense enhancement were consistent findings by all imaging modalities. At MRI, all tumours demonstrated high signal intensity on T2-weighted images and high or iso-intense signal on T1-W imaging compared to muscle. In tumours larger than 70 mm in one dimension (n = 3/6), large vessels converging toward the tumour centre led to a highly vascularised central stellar area pattern. Five children demonstrated synchronous (n = 4/5) and metachronous (n = 1/5) lung metastases.

CONCLUSION:

Alveolar soft part sarcoma should be suggested when a highly vascularised, intramuscular mass demonstrating large feeding and drainage vessels converging toward a central stellar area is seen in children, especially if synchronous lung metastases are present.

Pneumonectomy can represent the appropriate surgical treatment option in advanced or centrally localized non-small cell lung cancer (NSCLC). A satisfactory oncologic tumor surgery can be reached in these cases although pneumonectomy is associated with a significantly higher mortality and morbidity than less extensive resection of the lung parenchyma.The aim of this article is a systematic review and the presentation of possible postoperative consequences of pneumonectomy in the early and late phases, which depend not only on the underlying disease but are also primarily affected by the state and function of the remaining contralateral lung parenchyma. Cardiopulmonary complications, especially pneumonia, pulmonary embolism, cardiac arrhythmia or myocardial infarction lead to increased 30-day mortality in the early postoperative period. Moreover, advanced ages over 70 years can be identified as a significant risk factor for poor quality of life after pneumonectomy.

ABSTRACT

BACKGROUND:

Suicide rates among lung cancer patients are higher than the general population. This study aims to identify patient and disease characteristics associated with suicide in lung cancer patients.

METHODS:

We conducted an analysis of subjects with primary lung cancer diagnosed between 1973 - 2008 recorded in the Surveillance, Epidemiology and End Results (SEER) database.

RESULTS:

Of 871,230 persons diagnosed with lung cancer, 1184 suicides were identified. The rate of suicide did not change considerably over time, with 8.83 compared to 7.17 suicides per 10,000 persons-years in 1973-79 and 2000-09, respectively. The standardized mortality ratio (SMR) of the entire cohort was 4.95, with an SMR of 13.4 within 3 months of a cancer diagnosis. Despite most subgroups having a higher SMR than the general population, a wide variation of suicide risk was seen amongst different subgroups, including histologic type (SMR 1.58 vs 7.28 in bronchoalveolar and small cell carcinoma, respectively). The highest SMR's were found in: males; older age; higher grade tumour; metastatic disease, and patients who did not receive or refused treatment. Despite the higher SMR among metastatic patients, over 50% of suicides occurred in those with locoregional, and potentially curable disease.

CONCLUSION(S):

Lung cancer patients have a higher risk of suicide compared with the general US population, especially within 3 months of diagnosis. Despite the higher SMR among poorer prognosis patients, a concerning proportion of suicides occur in potentially curable patients, highlighting the need for effective screening strategies to avoid this preventable cause of death.

Identification of central nervous system (CNS) molecules elucidates normal and pathological brain function. Tumor differentiation factor (TDF) is a recently-found protein secreted by the pituitary into the blood. TDF mRNA was detected in brain; not heart, placenta, lung, liver, skeletal muscle, or pancreas. However, TDF has an unclear function. It is not known whether TDF is expressed only by pituitary or by other brain regions. It is also not known precisely where TDF is expressed in the brain or which cells produce TDF. Database searching revealed that this molecule shares no homology with any known protein. Therefore, we investigated the distribution of TDF in the rat brain using immunohistochemistry (IHC) and immunofluorescence (IF). TDF protein was detected in pituitary and most other brain regions. Double-staining for TDF and glial fibrillary acidic protein (GFAP), an astrocyte marker, showed no co-localization. Double-staining for TDF with NeuN, a neuronal marker, showed co-localization. Not all NeuN positive cells were positive for TDF. Western blotting (WB) using NG108 neuroblastoma and GS9L astrocytoma cell lysate revealed TDF immunoreactivity in cultured neuroblastoma, not astrocytoma. These data suggest that TDF is localized in neurons, not in astrocytes. This is the first report of any cellular localization of TDF. TDF may have specific roles as a pituitary-derived hormone and in the CNS, and appears to be produced by distinct CNS neurons, not astroglia.

INTRODUCTION:

: The International Association for the Study of Lung Cancer (IASLC) recently reclassified adenocarcinomas of the lung on the basis of histologic patterns. However, there is lack of consensus about a grading system for these tumors. We studied a series of invasive lung adenocarcinomas and correlated histologic features with lymph node and distant metastases. A series of invasive lung carcinomas resected over a 5-year period were retrospectively reviewed and classified by the IASLC system. The proportion of each histologic subtype was estimated at 5% increments, and cytologic features were blindly recorded and subsequently correlated with lymph node and distant metastases. The 125 tumors were classified on the basis of the predominant pattern as lepidic predominant (LPA) (n=9), acinar (n=71), solid (n=23), papillary (n=11), and mucinous (n=11). The acinar pattern was heterogenous, in that a cribriform subgroup (n=34) was significantly more likely to demonstrate lymph node metastases compared with a tubular subgroup (n=37) and had a higher mitotic rate, rate of necrosis, vascular invasion, and prominent nucleoli. Mucinous tumors were LPA (n=3), tubular (n=4), and cribriform predominant (n=4). The rate of lymph node metastasis was greatest in the solid type (P=0.02). The rate of distant metastasis was greatest in the mucinous and solid groups (P<0.02). Mitotic activity (≥1/HPF), desmoplasia >20% of the tumor, prominent nucleoli, and vascular invasion, along with a solid growth pattern ≥20%, were independently associated with metastatic potential and considered poor prognostic histologic features. A 3-tiered grading system separated tumors into well differentiated (predominantly LPA, papillary, and tubular patterns), moderately differentiated (predominantly cribriform tumors), and poorly differentiated (≥20% solid growth pattern). Tumors in the well-differentiated group were elevated to moderately differentiated if there were poor prognostic histologic features. Using this system, there was a stepwise increase in the rate of lymph node metastasis (P<0.0001) and distant metastasis (P=0.0004) from well-differentiated, moderately differentiated, to poorly differentiated tumors, the rate being 40, 46, and 39, respectively. Application of the IASLC classification in this series resulted in a predominance of acinar adenocarcinomas. To stratify tumors into clinically relevant grades, grading by pattern (tubular, cribriform, solid), mitotic activity, and nuclear features is useful.

BACKGROUND:

To identify dose-volume parameters predictive for severity of acute esophagitis (CTC > grade 2) in locally-advanced non small-cell lung cancer (LA-NSCLC) patients treated with neoadjuvant concurrent hyperfractionated-accelerated chemoradiotherapy (HA-CRT) a retrospective analysis was performed. 88 patients were treated with HA-CRT followed by radical surgery. Predictive power of absolute oesophageal length, absolute and relative oesophageal volume included in the 95%-isodose, patient- and tumor-related factors for severity of acute esophagitis was assessed.

FINDINGS:

A total of 82 patients (93%) developed radiation-induced acute esophagitis. Grade 1 was documented in 1 (1%), grade 2 in 55 (67%), grade 3 in 23 (28%) and grade 4 in 3 (4%) patients, respectively. Absolute oesophageal volume included in the 95%-isodose (42.8 Gy) achieved 13.5 cm3 (range: 3 -- 29 cm3). Of the tested variables in univariate analysis, absolute oesophageal volume included in the 95%-Isodose was found to be the only significant variable (p = 0.03) predicting severe acute esophagitis (CTC > grade 2). For this volume a gradation scale of the likelihood of severity was built.

CONCLUSION:

Increase of absolute oesophageal volume included in the 95%-isodose correlates with severity of acute esophagitis in LA-NSCLC patients treated with neo-adjuvant concurrent HA-CRT.

BACKGROUND:

It has been shown in many solid tumors that the overexpression of the pro-survival Bcl-2 family members Bcl-2/Bcl-xL and Mcl-1 confers resistance to a variety of chemotherapeutic agents. We designed the BH3 alpha-helix mimetic JY-1-106 to engage the hydrophobic BH3-binding grooves on the surfaces of both Bcl-xL and Mcl-1.

METHODS:

JY-1-106--protein complexes were studied using molecular dynamics (MD) simulations and the SILCS methodology. We have evaluated the in vitro effects of JY-1-106 by using a fluorescence polarization (FP) assay, an XTT assay, apoptosis assays, and immunoprecipitation and western-blot assays. A preclinical human cancer xenograft model was used to test the efficacy of JY-1-106 in vivo.

RESULTS:

MD and SILCS simulations of the JY-1-106--protein complexes indicated the importance of the aliphatic side chains of JY-1-106 to binding and successfully predicted the improved affinity of the ligand for Bcl-xL over Mcl-1. Ligand binding affinities were measured via an FP assay using a fluorescently labeled Bak-BH3 peptide in vitro. Apoptosis induction via JY-1-106 was evidenced by TUNEL assay and PARP cleavage as well as by Bax--Bax dimerization. Release of multi-domain Bak from its inhibitory binding to Bcl-2/Bcl-xL and Mcl-1 using JY-1-106 was detected via immunoprecipitation (IP) western blotting.At the cellular level, we compared the growth proliferation IC50s of JY-1-106 and ABT-737 in multiple cancer cell lines with various Bcl-xL and Mcl-1 expression levels. JY-1-106 effectively induced cell death regardless of the Mcl-1 expression level in ABT-737 resistant solid tumor cells, whilst toxicity toward normal human endothelial cells was limited. Furthermore, synergistic effects were observed in A549 cells using a combination of JY-1-106 and multiple chemotherapeutic agents. We also observed that JY-1-106 was a very effective agent in inducing apoptosis in metabolically stressed tumors. Finally, JY-1-106 was evaluated in a tumor-bearing nude mouse model, and was found to effectively repress tumor growth. Strong TUNEL signals in the tumor cells demonstrated the effectiveness of JY-1-106 in this animal model. No significant side effects were observed in mouse organs after multiple injections.

CONCLUSIONS:

Taken together, these observations demonstrate that JY-1-106 is an effective pan-Bcl-2 inhibitor with very promising clinical potential.