1.
Surufatinib in Chinese Patients with Locally Advanced or Metastatic Differentiated Thyroid Cancer and Medullary Thyroid Cancer: A Multicenter, Open-Label, Phase II Trial.
Chen, J, Ji, Q, Bai, C, Zheng, X, Zhang, Y, Shi, F, Li, X, Tang, P, Xu, Z, Huang, R, et al
Thyroid : official journal of the American Thyroid Association. 2020;(9):1245-1253
Abstract
Background: Thyroid cancer is the most common endocrine tumor with an increasing incidence. Limited treatment options are available for patients with advanced or recurrent metastatic disease, resulting in a poor prognosis. Surufatinib targets multiple kinases (vascular endothelial growth factor receptors, fibroblast growth factor receptor-1, and colony-stimulating factor-1 receptor) involved in tumor angiogenesis and tumor immune evasion. Surufatinib has demonstrated promising antitumor activity in various advanced solid tumors. This study aimed to determine the objective response rate (ORR) of surufatinib in patients with locally advanced or distant metastatic differentiated thyroid cancer (DTC) or medullary thyroid cancer (MTC). Methods: This Phase II open-label study by Simon's two-stage design was conducted at 10 sites across China. Patients with radioiodine (RAI)-refractory DTC with locally advanced disease or distant metastasis (DTC1 group); patients who received limited initial surgery and then developed locally advanced unresectable recurrences and were not considered candidates for RAI therapy due to residual normal thyroid tissue (DTC2 group); or patients with MTC with locally advanced disease or distant metastasis (MTC group) were enrolled. A total of 59 patients were enrolled (26 in DTC1, 6 in DTC2, and 27 in MTC) and received 300 mg surufatinib daily in 28-day cycles. The primary endpoint was ORR as determined by the investigators. Results: Overall ORR was 23.2% [95% confidence interval, CI 12.98-36.42]: 21.7% in the DTC1 cohort, 33.3% in the DTC2 cohort, and 22.2% in the MTC cohort. Forty-nine patients achieved disease control (87.5% [CI 75.93-94.82]): 87.0% in the DTC1 cohort, 83.3% in the DTC2 cohort, and 88.9% in the MTC cohort. Median time to response was 59.0 days, and 59.0, 85.5, and 59.0 days in the DTC1, DTC2, and MTC cohorts. Overall median progression-free survival was 11.1 months [CI 5.98-16.69]; 11.1 months in DTC1 and MTC cohorts, while the DTC2 cohort had not reached the median at the data cutoff. The most common treatment-emergent adverse events grade ≥3 were hypertension (20.3%), proteinuria (11.9%), and then elevated blood pressure, hypertriglyceridemia, and pulmonary inflammation (5.1% each). Conclusions: Surufatinib demonstrated promising efficacy with a tolerable and manageable safety profile for patients with locally advanced or metastatic MTC, RAI-refractory DTC, or locally advanced unresectable recurrences unable to receive RAI.
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Influence of the tryptophan-indole-IFNγ axis on human genital Chlamydia trachomatis infection: role of vaginal co-infections.
Aiyar, A, Quayle, AJ, Buckner, LR, Sherchand, SP, Chang, TL, Zea, AH, Martin, DH, Belland, RJ
Frontiers in cellular and infection microbiology. 2014;:72
Abstract
The natural history of genital Chlamydia trachomatis infections can vary widely; infections can spontaneously resolve but can also last from months to years, potentially progressing to cause significant pathology. The host and bacterial factors underlying this wide variation are not completely understood, but emphasize the bacterium's capacity to evade/adapt to the genital immune response, and/or exploit local environmental conditions to survive this immune response. IFNγ is considered to be a primary host protective cytokine against endocervical C. trachomatis infections. IFNγ acts by inducing the host enzyme indoleamine 2,3-dioxgenase, which catabolizes tryptophan, thereby depriving the bacterium of this essential amino acid. In vitro studies have revealed that tryptophan deprivation causes Chlamydia to enter a viable but non-infectious growth pattern that is termed a persistent growth form, characterized by a unique morphology and gene expression pattern. Provision of tryptophan can reactivate the bacterium to the normal developmental cycle. There is a significant difference in the capacity of ocular and genital C. trachomatis serovars to counter tryptophan deprivation. The latter uniquely encode a functional tryptophan synthase to synthesize tryptophan via indole salvage, should indole be available in the infection microenvironment. In vitro studies have confirmed the capacity of indole to mitigate the effects of IFNγ; it has been suggested that a perturbed vaginal microbiome may provide a source of indole in vivo. Consistent with this hypothesis, the microbiome associated with bacterial vaginosis includes species that encode a tryptophanase to produce indole. In this review, we discuss the natural history of genital chlamydial infections, morphological and molecular changes imposed by IFNγ on Chlamydia, and finally, the microenvironmental conditions associated with vaginal co-infections that can ameliorate the effects of IFNγ on C. trachomatis.
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Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination.
Mulder, SF, Jacobs, JF, Olde Nordkamp, MA, Galama, JM, Desar, IM, Torensma, R, Teerenstra, S, Mulders, PF, Vissers, KC, Punt, CJ, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2011;(13):4541-9
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Abstract
PURPOSE The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune response to seasonal flu vaccination in cancer patients treated with sunitinib or sorafenib. PATIENTS AND METHODS Sunitinib- or sorafenib-treated cancer patients were vaccinated against seasonal influenza with an inactivated vaccine. Healthy controls and patients with metastatic renal cell cancer (mRCC) without systemic treatment (nontreated mRCC controls) were included for comparison. Antibody responses were measured at baseline, day 8, and day 22 by a standard hemagglutination inhibition assay and cellular T-cell responses at baseline and day 8 by proliferation assay and secretion of cytokines. RESULTS Forty subjects were enrolled: 16 patients treated with sunitinib, 6 patients with sorafenib, 7 nontreated mRCC controls, and 11 healthy controls. All patients treated with sunitinib and sorafenib developed seroprotection rates comparable with controls. Functional T-cell reactivity was observed in all groups, except for patients treated with sorafenib who showed a decreased proliferation rate and IFN-γ/IL-2 production and increased IL-10 compared with healthy controls. CONCLUSION We conclude that influenza vaccination should be recommended to cancer patients treated with sunitinib or sorafenib.