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We report a mediastinal neuroblastoma in an octogenarian with paraneoplastic syndrome of inappropriate antidiuretic hormone secretion (SIADH). Neuroblastomas are very rare tumors in adults, with thoracic or mediastinal locations being especially uncommon. These neoplasms have been occasionally associated with the SIADH. Given the rarity of incidence and paucity of diagnostic and outcomes data, the significance of standard neuroblastoma prognostic characteristics is unclear, and no treatment paradigms exist for these patients. Further studies are needed to inform future clinical guidelines.

Mutations in the retinoblastoma (RB) tumour suppressor pathway are a hallmark of cancer and a prevalent feature of lung adenocarcinoma1–3. Although RB was the first tumour suppressor to be identified, the molecular and cellular basis that underlies selection for persistent RB loss in cancer remains unclear4–6. Methods that reactivate the RB pathway using inhibitors of cyclin-dependent kinases CDK4 and CDK6 are effective in some cancer types and are currently under evaluation for the treatment of lung adenocarcinoma7–9. Whether RB pathway reactivation will have therapeutic effects and whether targeting CDK4 and CDK6 is sufficient to reactivate RB pathway activity in lung cancer remains unknown. Here we model RB loss during lung adenocarcinoma progression and pathway reactivation in established oncogenic KRAS-driven tumours in mice. We show that RB loss enables cancer cells to bypass two distinct barriers during tumour progression. First, RB loss abrogates the requirement for amplification of the MAPK signal during malignant progression. We identify CDK2-dependent phosphorylation of RB as an effector of MAPK signalling and critical mediator of resistance to inhibition of CDK4 and CDK6. Second, RB inactivation deregulates the expression of cell-state-determining factors, facilitates lineage infidelity and accelerates the acquisition of metastatic competency. By contrast, reactivation of RB reprograms advanced tumours towards a less metastatic cell state, but is nevertheless unable to halt cancer cell proliferation and tumour growth due to adaptive rewiring of MAPK pathway signalling, which restores a CDK-dependent suppression of RB. Our study demonstrates the power of reversible gene perturbation approaches to identify molecular mechanisms of tumour progression, causal relationships between genes and the tumour suppressive programs that they control and critical determinants of successful cancer therapy. Loss of RB promotes both malignant progression and the development of metastatic disease; however, whereas reactivation of the RB pathway can revert metastatic tumour cell states to non-metastatic cell states, malignant cell proliferation is supported by MAPK–CDK2-dependent suppression of RB.

Classic biphasic pulmonary blastoma (CBPB) is a rare and aggressive type of non–small cell lung carcinoma (NSCLC) presenting in adults in the fourth to fifth decade. The prognosis is poor and after surgical resection, therapeutic options are often limited. ROS1 is a proto-oncogene receptor tyrosine kinase that has been identified in some types of NSCLC. We report a case of a 36-year-old woman with CBPB, which was subsequently found to have a ROS1 rearrangement. This is the first reported case of a ROS1-rearranged CBPB. This finding has therapeutic implications as these tumors have the potential to be treated with receptor tyrosine kinase inhibitors.

This report details the successful use of bilateral lung transplantation for the management of severe postoperative bleomycin-associated lung injury. This case highlights that the extremely favorable prognosis of advanced testicular germ cell tumors after systemic chemotherapy (>90% cure rate) should not preclude lung transplant consideration in all cases, despite current guidance that considers an advanced malignancy to be a contraindication for lung transplant listing.

Infiltrating inflammatory cells are highly prevalent within the tumor microenvironment and mediate many processes associated with tumor progression; however, the contribution of specific populations remains unclear. For example, the nature and function of tumor-associated neutrophils (TANs) in the cancer microenvironment is largely unknown. The goal of this study was to provide a phenotypic and functional characterization of TANs in surgically resected lung cancer patients. We found that TANs constituted 5%-25% of cells isolated from the digested human lung tumors. Compared with blood neutrophils, TANs displayed an activated phenotype (CD62L(lo)CD54(hi)) with a distinct repertoire of chemokine receptors that included CCR5, CCR7, CXCR3, and CXCR4. TANs produced substantial quantities of the proinflammatory factors MCP-1, IL-8, MIP-1α, and IL-6, as well as the antiinflammatory IL-1R antagonist. Functionally, both TANs and neutrophils isolated from distant nonmalignant lung tissue were able to stimulate T cell proliferation and IFN-γ release. Cross-talk between TANs and activated T cells led to substantial upregulation of CD54, CD86, OX40L, and 4-1BBL costimulatory molecules on the neutrophil surface, which bolstered T cell proliferation in a positive-feedback loop. Together our results demonstrate that in the earliest stages of lung cancer, TANs are not immunosuppressive, but rather stimulate T cell responses.

Metabolic activity in the lung is known to change in response to external insults, inflammation, and cancer. We report measurements of metabolism in the isolated, perfused rat lung of healthy controls and in diseased lungs undergoing acute inflammation using hyperpolarized 1-13C-labeled pyruvate. The overall apparent activity of lactate dehydrogenase is shown to increase significantly (on average by a factor of 3.3) at the 7 day acute stage and to revert substantially to baseline at 21 days, while other markers indicating monocarboxylate uptake and transamination rate are unchanged. Elevated lung lactate signal levels correlate well with phosphodiester levels as determined with 31P spectroscopy and with the presence of neutrophils as determined by histology, consistent with a relationship between intracellular lactate pool labeling and the density and type of inflammatory cells present. We discuss several alternate hypotheses, and conclude that the most probable source of the observed signal increase is direct uptake and metabolism of pyruvate by inflammatory cells and primarily neutrophils. This signal is seen in high contrast to the low baseline activity of the lung. Copyright © 2014 John Wiley & Sons, Ltd.

Epstein-Barr virus (EBV), a gamma herpesvirus, has been associated with a variety of human malignancies such as Burkitt's lymphoma, Hodgkin's lymphoma, NPC, and gastric cancer. A controversy regarding the association of EBV with breast cancers has recently been reported in the literature. These reports have mainly used the DNA detection techniques of polymerase chain reaction and Southern blot hybridization, with the inherent lacunae associated with these techniques for signal localization. Our group has studied EBV association with breast cancer by using in situ hybridization for detecting nonpolyadenylated EBV RNA (EBERs), along with using protein localization technique of immunohistochemistry, studying the EBV nuclear antigen 1 (EBNA1) and the latent membrane proteins (LMP1 and LMP2A). This is the first article analyzing the expression of LMP2A in breast cancer cells. In all of our 43 female breast cancer cases under study, we failed to detect expression of any of the EBV viral gene products tested.

Objective: The monoclonal antibody (mAb) designated as mAb Das-1 was generated against a colonic epithelial protein. It reacts with bronchiolar epithelium and submucosal glands and weakly with alveolar lining cells of fetal lung. Adult alveolar epithelium is, however, nonreactive for mAb Das-1. The present study was designed to evaluate the immunoexpression of Das-1 and to correlate it with the histomorphology of primary lung adenocarcinomas and intestinal metaplasia. Methods: Eighty-four cases of primary lung adenocarcinomas were reviewed and categorized according to histologic grade and subtype. Immunohistochemical staining with mAb Das-1 was performed with normal colon as control. Results: Expression of Das-1 in the submucosal bronchial glands also served as internal control. Strong and diffuse staining was seen in 33 of the 84 cases of adenocarcinomas (39%). Conclusions: Expression of Das-1 was seen in primary lung adenocarcinomas even though adult alveolar epithelium is negative. Staining with mAb Das-1 was seen regardless of the grade or histological subtype of the lung adenocarcinomas. As most primary lung adenocarcinomas are not of bronchial gland origin, expression of Das-1 represents activation of oncofetal antigens.

Tumor necrosis factor alpha (TNF alpha) is a pleiotropic cytokine that is constitutively produced by leukemic cells in B Chronic Lymphocytic Leukemia (B-CLL). It has been shown to have autocrine and paracrine functions in normal B cells and in B lymphoproliferative diseases. This study was conducted to determine the effect of TNF alpha (in vitro) on CD20 expression on cells from patients with B-CLL. Currently, anti-CD20 monoclonal antibody therapy is becoming a second line treatment in the management of B cell disorders like low-grade non-Hodgkin's lymphoma (NHL) and B-CLL. Our results demonstrate amply that very low doses of TNF alpha (0. 0125 ng/ml) can be used to significantly increase CD20 expression on cells from patients of B-CLL as evidenced by increases in both percentage positivity and mean fluorescence intensity. The upregulation is evident as early as 24 hours and is maintained for up to 72 hours. We propose that the upregulation is a direct result of in vitro differentiation stimulated by TNF alpha. The results presented can be exploited in the designing of priming protocols prior to antibody therapy and this is discussed.

Tracheobronchopathia osteochondroplastica is a rare, benign disorder of upper airways characterized by multiple submucosal metaplastic cartilaginous and bony nodules arising from the tracheal cartilage. We report an unusual presentation of tracheobronchopathia osteochondroplastica as a single dominant nodule arising from the anterior tracheal rings in a young adult man who presented with wheezing and symptoms of airway obstruction. The differential diagnosis of cartilaginous and bony endotracheal lesions is discussed.