Organizing pneumonia following treatment with pembrolizumab for metastatic malignant melanoma - A case report.

Pembrolizumab is a monoclonal antibody against the programmed cell death 1 (PD-1) receptor, and is widely used for the treatment of various malignancies, most commonly malignant melanoma. Here we report the first documented and pathology proven case of Organizing Pneumonia complicating treatment with Pembrolizumab. This was a man who presented with a dense lung consolidation four months following treatment with Pembrolizumab. A thorough microbiological workup was negative and his findings did not improve with broad spectrum anti-microbial treatment. Transbronchial biopsy revealed organizing pneumonia, and treatment with cortico-steroids resulted in complete resolution of clinical and radiological disease. This report highlights the importance of recognizing immune related adverse events, specifically pulmonary inflammation, in patients receiving treatment with novel immune-modulating agents.

Using macrophage activation to augment immunotherapy of established tumours.

BACKGROUND: Successful immunotherapy will require alteration of the tumour microenvironment and/or decreased immune suppression. Tumour-associated macrophages (TAMs) are one major factor affecting tumour microenvironment. We hypothesised that altering TAM phenotype would augment the efficacy of immunotherapy. METHODS: We and others have reported that 5,6-Dimethylxanthenone-4-acetic-acid (DMXAA, Vadimezan) has the ability to change TAM phenotypes, inducing a tumour microenvironment conducive to antitumour immune responses. We therefore combined DMXAA with active immunotherapies, and evaluated anti-tumour efficacy, immune cell phenotypes (flow cytometry), and tumour microenvironment (RT-PCR). RESULTS: In several different murine models of immunotherapy for lung cancer, DMXAA-induced macrophage activation significantly augmented the therapeutic effects of immunotherapy. By increasing influx of neutrophils and anti-tumour (M1) macrophages to the tumour, DMXAA altered myeloid cell phenotypes, thus changing the intratumoural M2/non-M2 TAM immunoinhibitory ratio. It also altered the tumour microenvironment to be more pro-inflammatory. Modulating macrophages during immunotherapy resulted in increased numbers, activity, and antigen-specificity of intratumoural CD8(+) T cells. Macrophage depletion reduced the effect of combining immunotherapy with macrophage activation, supporting the importance of TAMs in the combined effect. CONCLUSION: Modulating intratumoural macrophages dramatically augmented the effect of immunotherapy. Our observations suggest that addition of agents that activate TAMs to immunotherapy should be considered in future trials.

Neoadjuvant in situ gene-mediated cytotoxic immunotherapy improves postoperative outcomes in novel syngeneic esophageal carcinoma models.

Esophageal carcinoma is the most rapidly increasing tumor in the United States and has a dismal 15% 5-year survival. Immunotherapy has been proposed to improve patient outcomes; however, no immunocompetent esophageal carcinoma model exists to date to test this approach. We developed two mouse models of esophageal cancer by inoculating immunocompetent mice with syngeneic esophageal cell lines transformed by cyclin-D1 or mutant HRAS(G12V) and loss of p53. Similar to humans, surgery and adjuvant chemotherapy (cisplatin and 5-fluorouracil) demonstrated limited efficacy. Gene-mediated cyototoxic immunotherapy (adenoviral vector carrying the herpes simplex virus thymidine kinase gene in combination with the prodrug ganciclovir; AdV-tk/GCV) demonstrated high levels of in vitro transduction and efficacy. Using in vivo syngeneic esophageal carcinoma models, combining surgery, chemotherapy and AdV-tk/GCV improved survival (P=0.007) and decreased disease recurrence (P<0.001). Mechanistic studies suggested that AdV-tk/GCV mediated a direct cytotoxic effect and an increased intra-tumoral trafficking of CD8 T cells (8.15% vs 14.89%, P=0.02). These data provide the first preclinical evidence that augmenting standard of care with immunotherapy may improve outcomes in the management of esophageal carcinoma.

Exogenous lipoid pneumonia caused by paraffin in an amateur fire breather.

BACKGROUND: Paraffin has characteristics that make it popular among fire breathers. AIMS: To describe a case of paraffin-induced lipoid pneumonia in a fire breather. METHODS: The patient was evaluated clinically in relation to his occupational history. RESULTS: A 32-year-old man presented with dyspnoea, tachypnoea and non-productive cough of 2 h duration that started immediately following an attempt to blow fire using paraffin as the volatile substance. He was discharged from the emergency ward but returned the next day presenting again with dyspnoea accompanied by mid-sternal pain, fever (38.1 degrees C) and leucocytosis. Chest radiography showed perihilar punctuate infiltrations. A diagnosis of exogenous lipoid pneumonia caused by paraffin was made, and the patient was treated, with full recovery within a week. CONCLUSIONS: Fire breathers must be viewed as a population at risk of paraffin-induced lipoid pneumonia.

Telomerase activity in bleomycin-induced epithelial cell apoptosis and lung fibrosis.

Epithelial cell injury and apoptosis are recognised as early features in idiopathic pulmonary fibrosis and bleomycin-induced fibrosis in mice. Telomerase is a known apoptosis-alleviating factor. The role of telomerase was studied during bleomycin-induced lung epithelial cell (LEC) apoptosis in vitro in a mouse LEC line, and in vivo in LECs isolated from bleomycin-treated mice. The current authors evaluated changes in murine telomerase reverse transcriptase (mTERT) mRNA levels and changes in telomerase activity with the TRAPeze Detection Kit, telomeric length with the TeloTTAGGG Telomere Length Kit, and LEC apoptosis with FACScan and 4,6-diamino-2-phenylindole dihydrochloride stain. There was a significant elevation in mTERT mRNA and a transient 41% increase in telomerase activity 24 h after in vitro bleomycin treatment. At 72 h, telomerase activity had fallen to 26% below levels in untreated cells. Reduction of telomerase activity over time, or by direct inhibition, significantly elevated LEC apoptosis. No change in average telomeric length was noted. In vivo, telomerase activity of LECs from bleomycin-treated mice increased at 7 and 14 days. In conclusion, telomerase activity may play a protective role against robust bleomycin-induced lung epithelial cell apoptosis. Moreover, stabilising telomerase activity may decrease epithelial cell apoptosis and the resulting lung fibrosis.

[Pneumomediastinum following drug abuse].

Pneumomediastinum is termed spontaneous when not associated with trauma or other identifiable pathological process. There are several reports of pneumomediastinum following narcotic drug inhalation or smoking while applying positive pressure. We describe a 37-year-old male drug addict, hospitalized after having being found unconscious with shortness of breath. CT scan demonstrated bilateral pneumonia with pneumomediastinum. After a day of mechanical ventilation he gradually recovered and the mediastinal air disappeared. Pneumomediastinum may occur in addicts but usually has no dangerous clinical consequences. If there is respiratory deterioration another cause should be sought.

Monocytes confer CD14 antigenicity on activated lymphocytes.

In the present study, exposure of human peripheral blood mononuclear cells (PBMC) to phorbol 12-myristate 13-acetate (PMA) was found to elicit the expression of CD14 on lymphocytes. Less than 3% of the lymphocytes present among freshly isolated PBMC were stained with 63D3 anti-CD14 monoclonal antibody (mAb). Within two days of exposure of PBMC to PMA, up to 30% of the lymphocytes reacted with the 63D3 anti-CD14 mAb, though not with the LeuM3 and My4 anti-CD14 mAbs. The appearance of CD14 on lymphocytes was also elicited by exposure of PBMC to phytohemagglutinin (PHA), concanavalin A (Con A), or agarose-bound phytohemagglutinin but not by exposure to lipopolysaccharide, interferon-alpha, or interleukin-2. Purified lymphocyte preparations did not acquire CD14 following stimulation with PMA. Monocytes lost their reactivity with CD14 mAbs (63D3, LeuM3, and My4) within a few hours after exposure to PMA. The level of soluble CD14 was higher in supernatant fluids of cultures of untreated PBMC than of PMA-stimulated PBMC. The addition of PMA to cultures of T cells and monocytes separated by Millipore filters lead to the expression of CD14 on the lymphocytes. The present study indicates that activation of lymphocytes in the presence of monocytes leads to the appearance of CD14 on lymphocytes, and raises the possibility that the expression of CD14 on lymphocytes may result from the transfer of CD14 molecules from monocytes to lymphocytes.

Changes in cytokine production of breast cancer patients treated with interferons.

A clinical randomized study was performed on advanced breast cancer patients who were treated by interferons (IFN) beta and gamma in combination with hormonotherapy (Megace or Tamoxifen). Cytokine levels (IL-1beta, IL-2, IL-6, TNF-alpha, IFN-gamma) and sIL-2R of individual patients before, during (3 months) and after (6 months) therapy were evaluated and correlated to clinical response according to UICC criteria (responder patients-partial or Complete Response versus non-responder patients-Stable/Progression). Decreases in IL-1beta, IL-6 and sIL-2R were associated with clinical response to therapy versus increases in their levels which corresponded to progression of disease. A significant and dramatic increase in IFN-gamma levels was associated with a favourable response to therapy in the IFNs-treated patients, mainly in the group of Tamoxifen. Baseline levels of sIL-2R and of IFN-gamma were prognostic of clinical response and were found to be the most sensitive cytokine parameters for defining the clinical utility of the combination of IFNs and hormonotherapy in breast cancer patients.