BackgroundThymic epithelial tumors are PD-L1–expressing tumors of thymic epithelial origin characterized by varying degrees of lymphocytic infiltration and a predisposition towards development of paraneoplastic autoimmunity. PD-1–targeting antibodies have been evaluated, largely in patients with thymic carcinoma. We sought to evaluate the efficacy and safety of the anti-PD-L1 antibody, avelumab (MSB0010718C), in patients with relapsed, advanced thymic epithelial tumors and conduct correlative immunological studies.MethodsSeven patients with thymoma and one patient with thymic carcinoma were enrolled in a phase I, dose-escalation trial of avelumab (MSB0010718C), and treated with avelumab at doses of 10 mg/kg to 20 mg/kg every 2 weeks until disease progression or development of intolerable side effects. Tissue and blood immunological analyses were conducted.ResultsTwo of seven (29%) patients with thymoma had a confirmed Response Evaluation Criteria in Solid Tumors–defined partial response, two (29%) had an unconfirmed partial response and three patients (two thymoma; one thymic carcinoma) had stable disease (43%). Three of four responses were observed after a single dose of avelumab. All responders developed immune-related adverse events that resolved with immunosuppressive therapy. Only one of four patients without a clinical response developed immune-related adverse events. Responders had a higher absolute lymphocyte count, lower frequencies of B cells, regulatory T cells, conventional dendritic cells, and natural killer cells prior to therapy.ConclusionThese results demonstrate anti-tumor activity of PD-L1 inhibition in patients with relapsed thymoma accompanied by a high frequency of immune-related adverse events. Pre-treatment immune cell subset populations differ between responders and non-responders.Trial registrationClinicalTrials.gov - NCT01772004. Date of registration – January 21, 2013.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0723-9) contains supplementary material, which is available to authorized users.

BACKGROUND: In the current study, the authors sought to identify the molecular mechanisms underlying the chemoresistance of lung cancer stem or initiation cells (cancer stem cells). METHODS: A549 lung cancer cells before and after selective enrichment of a subpopulation of cancer stem cells were treated with superoxide and traditional chemotherapeutics to determine their sensitivity or resistance to these cytotoxic agents. Apoptotic activity was measured using a variety of fluorescence‐based and biochemical techniques. Specific pathways involved in the chemoresistance of cancer stem cell‐enriched lung cancer cells were analyzed with Western blotting and pharmacologic targeting therapy in a xenograft model. RESULTS: Lung cancer stem cells exhibited significantly decreased apoptotic response to treatment with superoxide, cisplatin, gemcitabine, or a combination of cisplatin and gemcitabine compared with control A549 cells. Apoptotic resistance was mediated through the inactivation of caspase‐9 and caspase‐3. Increased activation of p38MAPK, MAPKAPK2, and Hsp27 was observed in lung cancer stem cells compared with control A549 cells both before and after exposure to superoxide and chemotoxic agents. In a mouse model of lung cancer, chemotherapy‐induced cells increased in the antiapoptosis pathway, and quercetin, an inhibitor of Hsp27, combined with traditional chemotherapy was effective in blocking the pathway and in the treatment of lung tumors in vivo. CONCLUSIONS: The authors' data demonstrate that lung cancer stem cells have elevated levels of activated Hsp27 upon treatment with superoxide and traditional chemotherapy. When combined with chemotoxic agents, blockage of Hsp27 decreased the survival of lung cancer stem cells, which otherwise were resistant to traditional chemotherapy. Cancer 2011. © 2010 American Cancer Society.

We sought to determine the possible neural conduction blockade of tramadol and whether there is evidence of localized neural toxicity with spinal somatosensory evoked potential (SSEP) measurements. Male Wistar rats were used. SSEP, elicited by supramaximally stimulating the hind paw and recorded from the thoracolumbar and the first and second lumbar interspinous ligaments, was monitored. SSEPs were obtained before drug application as the pretreatment baseline and measured every 15 min after treatment for 2 h and at 60-min intervals thereafter until SSEP returned to baseline or for another 4 h. Two small strips of Gelfoam (0.6 x 1.0 cm(2)) soaked with the drug were placed under and over the left sciatic nerve for a 30-min period. Gelfoam was prepared with tramadol hydrochloride (Tramal; the US trade name is Ultram) 5, 2.5, and 1.25 mg, diluted if needed with saline to a total volume of 100 microL (5%, 2.5%, and 1.25%, respectively). The control data were obtained from the right side limb with normal saline by following the same method. Spinal SSEPs were measured after 48 h to detect the late neural damage. The results showed that direct tramadol application on sciatic nerves dose-dependently reduced both the amplitude and conduction velocity of SSEPs when compared with the pretreatment baseline. All SSEPs returned to pretreatment baseline, and no significant changes of SSEP between bilateral limbs were noted at the 48-h measurements. No evidence of irreversible conduction blockade indicative of local neural toxicity was seen. Pretreatment with naloxone 1 mg/kg failed to block the changes of SSEP produced by 2.5% tramadol 100 microL. We conclude that tramadol exerts a local anesthetic-type effect on peripheral nerves.