Resound Trial: A phase 2 study of regorafenib in patients with thymoma (type B2-B3) and thymic carcinoma previously treated with chemotherapy.

BACKGROUND: Angiogenesis has an important role in thymic epithelial tumors (TETs). Regorafenib inhibits vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor ß (PDGFR-ß), and fibroblast growth factor receptors (FGFRs). This study explored the activity of regorafenib as monotherapy in patients with advanced or recurrent B2-B3 thymoma (T) and thymic carcinoma (TC) previously treated with platinum-containing chemotherapy. METHODS: A Fleming single-arm, single-stage, phase 2 trial to evaluate the activity of regorafenib (160 mg once a day by mouth for 3 weeks on/1 week off) was planned. The study was designed to reject the null hypothesis of an 8-week progression-free survival (PFS) rate ≤25% with a type I error of 0.10 and a statistical power of 80% at the alternative hypothesis of an 8-week PFS rate of ≥50% (≥8 of 19 evaluable patients progression-free at 2 months). RESULTS: From June 2016 to November 2017, 19 patients were enrolled (11T/8TC). We observed partial response (PR) in 1 patient (1T) (5.3%), stable disease (SD) in 14 patients (9T/5TC) (73.7%), and progressive disease in 2 patients (1T/1TC) (10.5%), with a disease control rate of 78.9%. According to Choi-criteria, 13 patients (68.4%) achieved PR, and 2 patients SD (10.5%). The median PFS was 9.6 months whereas median overall survival was 33.8 months. The 8-week PFS rate was 78.9% (15 of 19 patients). Grade 3-4 treatment-related adverse events were observed in 10 patients (52.6%). CONCLUSIONS: The primary end point of this study was reached. The high rate of PR (Choi-criteria) suggests antitumor activity of regorafenib in TETs. On the basis of survival outcomes, the efficacy of regorafenib should be further evaluated in larger studies.

In vitro radioprotection studies of organoselenium compounds: differences between mono- and diselenides.

Organoselenium compounds belonging to the class of monoselenides, such as selenomethionine (SeM) and methylselenocysteine (MSeCys) and diselenides including selenocystine (SeCys) and selenopropionic acid (SePA), were examined for their comparative radioprotective effects using in vitro models. Effects of these compounds on the inhibition of gamma-radiation induced lipid peroxidation in liposomes, protein carbonylation in bovine serum albumin (BSA) and strand breaks in pBR322 plasmid DNA, assessed, respectively, by the formation of thiobarbituric acid reactive substances, formation of 2,2'-dinitrophenyl hydrazine (DNPH) carbonyl complex and horizontal gel electrophoresis, were used to compare their radioprotective ability. The IC 50 values for SeCys, SePA, SeM and MSeCys for lipid peroxidation were 27 +/- 1, 33 +/- 2, 200 +/- 8 and 163 +/- 4 microM, respectively, and the values for inhibition of protein carbonylation were >200, 300 +/- 6, 464 +/- 8 and 436 +/- 3 microM, respectively. Inhibition of DNA strand break formation was tested at 200 microM for all the compounds and SePA and SeCys exhibited a protective effect on DNA, while SeM and MSeCys did not lead to any protection. The in vitro cytotoxicity studies in normal and tumor cells revealed that MSeCys and SeM were not cytotoxic to lymphocytes and EL4 tumor cells at the concentrations employed. In contrast, SeCys was toxic, with a higher effect on tumor cells than lymphocytes. Our studies suggest that the non-toxic diselenides like SePA should be explored as protective agents against gamma-irradiation induced damage.

[Association between thymic MALT lymphoma and Sjögren's syndrome]. / Association d'un lymphome thymique de type MALT et d'un syndrome de Gougerot-Sjögren.

INTRODUCTION: Thymic mucosa-associated lymphoid tissue (MALT) lymphoma is a rare pathology, often associated with autoimmune diseases. The authors report the case of an Asian woman with Sjögren's syndrome. OBSERVATION: A 48-year-old Chinese woman, without past medical history and a non-smoker, presented an alteration in her overall condition, dyspnoea at exercise, inflammatory polyarthralgia, and a dry eye and mouth syndrome over the last few months. Thoracic tomodensitometry detected an anterior heterogenic cystic mediastinal mass. A mediastinotomy was performed. The diagnosis of the surgical biopsy was thymic MALT lymphoma. The authors also diagnosed Sjögren's syndrome with the presence of four diagnostic criteria. Chemotherapy by rituximab, cyclophosphamide, vincristine, prednisone induced major tumoral regression. The patient declined surgery and will be monitored. CONCLUSION: Thymic MALT lymphoma is a rare pathology. There is a high correlation with autoimmune diseases, like Sjögren's syndrome. Its appearance is that of an anterior mediastinal mass with a cystic component. The treatment is not well codified and is most often based on surgical resection, eventually followed by chemotherapy or radiotherapy. As far as the authors know, this is the second case of thymic MALT lymphoma treated by exclusive chemotherapy.

Povidone-iodine results in rapid killing of thymic epithelial tumour cells through cellular fixation†.

OBJECTIVES: Hyperthermic pleural lavage with povidone-iodine (PVP-I) is utilized to control micrometastatic disease following cytoreductive surgery for thymic epithelial tumours (TETs). Our objective was to investigate whether PVP-I demonstrates direct cytotoxicity against human TET cells. METHODS: Human Met-5A (immortalized mesothelial cell), IU-TAB-1 (thymoma) and Ty-82 (thymic carcinoma) cell lines were treated with serial dilutions of PVP-I (0.01-10%) for 5, 30 and 60 min at 37°C and 42°C. MTT assays and flow cytometry were used to evaluate cell death and apoptosis. Membrane permeability was assayed by intracellular staining of cleaved poly-ADP-ribose polymerase. Cellular fixation was evaluated by membrane disruption of dead cells by dimethylsulphoxide and by comparing cleaved poly-ADP-ribose polymerase staining following PVP-I with known fixatives. RESULTS: MTT assays demonstrated that PVP-I concentrations greater than 0.5% led to rapid cell death in both TET cell lines regardless of temperature. IC50 values following 5 min of exposure to PVP-I were 8.4 mM (0.3%) and 13.3 mM (0.48%) for IU-TAB-1 and Ty-82, respectively and 8.9 mM (0.32%) for MeT-5A. Flow cytometry demonstrated that 5-min exposure of either cell line to 1% PVP-I resulted in profound cell death: 74% and 58% at 5 min and 97% and 95% at 30 min, for IU-TAB-1 and Ty-82 cells, respectively. Resistance of PVP-I-treated cells to dimethylsulphoxide lysis and similar cleaved poly-ADP-ribose polymerase expression following PVP-I and known fixatives revealed cellular fixation as the mechanism of death following PVP-I exposure. CONCLUSIONS: PVP-I results in rapid death of human TET cells and normal mesothelial cells through a cellular fixation mechanism and may, therefore, favourably impact the control of micrometastatic disease following resection of TETs with pleural dissemination.

A phase II study of saracatinib (AZD0530), a Src inhibitor, administered orally daily to patients with advanced thymic malignancies.

OBJECTIVES: Thymic malignancies are rare, and options are limited for metastatic disease. Src plays a role in normal thymic epithelial maturation, and its inhibition with the oral compound saracatinib was postulated to be effective in controlling thymic malignancy. MATERIALS AND METHODS: Patients with unresectable thymic malignancy were treated with saracatinib 175mg by mouth daily in 28 days cycles with radiographic evaluation at cycle 2 day 1 for safety, then cycle 3 day 1 and every 8 weeks thereafter. Response was evaluated by RECIST 1.0. A two-stage optimal design was used, powered to detect a true response rate of 20%. RESULTS: 21 patients were enrolled at two institutions, 12 of them with thymoma, 9 with thymic carcinoma. Thymoma patients received a median of 4.5 cycles and thymic carcinoma patients a median of 1 cycle. There were no responses, so accrual was halted after the first stage per protocol. 9 patients had stable disease beyond the first assessment. Median time to progression was 5.7 months for thymoma patients and 3.6 months for thymic carcinoma patients. Saracatinib was well tolerated. CONCLUSION: Src inhibition by saracatinib did not produce any radiographic responses, though some patients did experience stable disease. Though negative, this study shows the feasibility of completing a trial in this rare disease, and of accruing reasonably significant numbers of thymic carcinoma patients. More clinical trials are required for this population (NCT00718809).

Risk factors for pegylated liposomal doxorubicin-induced palmar-plantar erythrodysesthesia over time: assessment of monocyte count and baseline clinical parameters.

PURPOSE: Pegylated liposomal doxorubicin (PLD) is widely used in relapsing ovarian carcinoma. Its original formulation is metabolized by the monocyte-macrophage system. One of its main toxicities is the palmoplantar erythrodysesthesia (PPE) syndrome. To date, no predictive factors of PPE have been identified. METHODS: Data of patients (pts) treated with PLD between 2005 and 2014 were retrospectively collected. A case-control study was performed, comparing main baseline clinical and biological characteristics of pts experiencing PPE and those who did not, after at least three cycles of PLD. A pilot analysis of blood monocyte subpopulations (classical, intermediate and non-classical) was performed by FACS in selected pts. RESULTS: Among 88 pts treated with PLD, 28 experienced PPE of any grade (31, 95 % CI 21-41). The first occurrence of PPE was at first cycle in only 11 % of pts, peaked at cycle 2 (32 %) and represented 57 % of cases after cycle 3. Baseline characteristics of pts with PPE were compared to 27 control pts who received at least 3 cycles. Older pts represented 61 % of pts with PPE and 15 % of pts without PPE (p = 0.04 by Chi-square test). Monocyte count and inflammatory parameters were not associated with PPE. However, the analysis of monocyte subpopulations revealed a large inter-patient variability. CONCLUSION: Contrary to most acute toxicities, PPE occurred more frequently after several cycles, suggesting a PLD body accumulation through repeated cycles. PPE was more frequent in pts older than 70 years. Monocyte subpopulations may have different roles on PLD metabolism and warrant further studies.

Diaminosulfide based polymer microparticles as cancer vaccine delivery systems.

The aim of the research presented here was to determine the characteristics and immunostimulatory capacity, in vivo, of antigen and adjuvant co-loaded into microparticles made from a novel diaminosulfide polymer, poly(4,4'-trimethylenedipiperdyl sulfide) (PNSN), and to assess their potential as cancer vaccine vectors. PNSN microparticles co-loaded with the antigen, ovalbumin (OVA), and adjuvant, CpG 1826, (PNSN(OVA + CpG)) were fabricated and characterized for size (1.64 µm diameter; PDI=0.62), charge (-23.1 ± 0.3), and loading efficiencies of antigen (7.32 µg/mg particles) and adjuvant (0.95 µg/mg particles). The ability of PNSN(OVA + CpG) to stimulate cellular and humoral immune responses in vivo was compared with other PNSN microparticle formulations as well as with poly(lactic-co-glycolic acid)(PLGA)-based microparticles, co-loaded with OVA and CpG (PLGA(OVA + CpG)), an adenovirus encoding OVA (Ad5-OVA), and OVA delivered with incomplete Freund's adjuvant (IFA(OVA)). In vivo OVA-specific IgG1 responses, after subcutaneous prime/boosts in mice, were similar when PNSN(OVA + CpG) and PLGA(OVA + CpG) were compared and the presence of CpG 1826 within the PNSN microparticles demonstrated significantly improved responses when compared to PNSN microparticles loaded with OVA alone (PNSN(OVA)), plus or minus soluble CpG 1826. Cellular immune responses to all particle-based vaccine formulations ranged from being negligible to modest with PNSN(OVA + CpG) generating the greatest responses, displaying significantly increased levels of OVA-specific CD8+ T lymphocytes compared to controls and IFA(OVA) treated mice. Finally, it was shown that of all vaccination formulations tested PNSN(OVA + CpG) was the most protective against subsequent challenge with an OVA-expressing tumor cell line, E.G7. Thus, microparticles made from poly(diaminosulfide)-based macromolecules possess promising potential as vaccine vectors and, as demonstrated here, may have impact as cancer vaccines in particular.

In vitro and in vivo anti-tumor activities of nanoparticles based on doxorubicin-PLGA conjugates.

Doxorubicin was chemically conjugated to a terminal end group of poly(D,L-lactic-co-glycolic acid) [PLGA] by an ester linkage and the doxorubicin-PLGA conjugate was formulated into nanoparticles. A carboxylic acid end group of PLGA was conjugated to a primary hydroxyl group of doxorubicin. The primary amine group of doxorubicin was protected during the conjugation process and then deprotected. The nanoparticles containing the conjugate exhibited sustained doxorubicin release profiles over a 1-month period, whereas those containing unconjugated free doxorubicin showed a rapid doxorubicin release within 5 days. Doxorubicin release patterns could be controlled by conjugating doxorubicin to PLGA having different molecular weights. The conjugated doxorubicin nanoparticles showed increased uptake within a HepG2 cell line, which was quantitated by a flow cytometry and visualized by confocal microscopy. The nanoparticles exhibited slightly lower IC(50) value against the HepG2 cell line compared to that of free doxorubicin. In vivo anti-tumor activity assay also showed that a single injection of the nanoparticles had comparable activity to that of free doxorubicin administered by daily injection. The conjugation approach of doxorubicin to PLGA was potentially useful for the formulation of nanoparticles that requires targeting for cancer cells as well as sustained release at the site.

A case of myasthenia gravis accompanied by invasive thymoma, alopecia areata and dry mouth.

We report a 43-year-old man suffering from myasthenia gravis with invasive thymoma accompanied with alopecia areata and dry mouth. These complications are extremely rare and the pathogenetic etiology of these complications was thought to depend on a generalized immunological disturbance.