Real-world clinical outcome and safety of adjuvant therapy in stage III melanoma patients: Data from two Academic Italian Institutions

Adjuvant immunotherapy (IO) and targeted therapy (TT) have improved relapse-free survival (RFS) in patients with stage III melanoma, although about 25% of them relapse within a year. However, real-world data on treatment efficacy and safety as well as management of treatment recurrences are still limited. We retrospectively analyzed 113 patients with stage III melanoma who received at least one cycle of anti-PD-1 (nivolumab or pembrolizumab) or dabrafenib + trametinib as adjuvant therapy. Most of patients included into the analyses harbor BRAV600E mutation (66.4%) and had a stage IIIC melanoma (63.7%). Immunotherapy was administered in 48.7% of patients, whereas targeted therapy in 51.3% At data cut-off, median RFS was not reached with 12- and 24-months RFS of 81% and 64%, respectively. No new adverse events were registered. Thirty patients (26.5%) relapsed, mainly at distant sites. Patient treated with IO recurred mostly during adjuvant treatment (ON-treatment) while patients treated with TT relapsed at the end of treatment (OFF-treatment). At relapse, surgery, radiotherapy and systemic therapy were used alone or in combination. Among patients who started a first-line therapy, an excellent response switching to a different treatment was observed. Real-world outcomes and safety of adjuvant treatment for resected stage III melanoma appear comparable to clinical trials data. Moreover, management of recurrences depends on type of relapse (loco-regional vs distant) and timing (during vs OFF treatment). Furthermore, patients who relapse after adjuvant TT respond well to subsequent anti-PD1 based therapy.     

中医药辅助治疗儿童重症肌无力的研究进展

近年来儿童重症肌无力(myasthenia gravis,MG)发病率居高不下,严重影响儿童身心健康。西医对儿童MG的治疗有效,但存在巨大的副作用。中医在辅助治疗儿童MG方面有着良好的效益,可明显改善西医西药的毒副作用及不良反应。中医认为本病发生的主要原因是“肺热叶焦”,儿童根据其独特的生理病理,当代医家多从脾胃虚损等方面认识儿童MG,在此基础上提出从五脏虚损、络脉虚滞、地域影响等不同方面认识本病,湿邪是儿童MG的重要病理因素,其与本病相互影响,形成恶性循环。治疗上提出“治痿独取阳明”和“各补其荥而通其俞”的治疗原则,在辩证论治的基础上可酌情采用中药、成药、推拿、针刺等多种疗法“杂合以治”,综合调理,提高患儿免疫力,改善症状,疗效确切。     

Melanoma-associated antigen-A3 vaccination in the treatment of non-small-cell lung cancer

ABSTRACT

Introduction: The pathophysiology of diabetic macular edema (DME) is complex, involving vascular endothelial growth factor (VEGF) and other inflammatory mediators. DME is currently treated first-line with intravitreal anti-VEGF treatments, though some cases are refractory to multiple anti-VEGF treatments.

Areas covered: This article examines the evolution of treatment practices for DME, with discussion of the recent studies that guide treatment for refractory cases of DME. A literature search was performed using the following terms: anti-VEGF, DME, aflibercept, bevacizumab, ranibizumab, refractory macular edema, and VEGF.

Expert opinion: Focal extrafoveal DME may be treated first-line with laser. In patients with center-involving DME and only mild vision loss, consider starting treatment with bevacizumab, especially when cost is an issue, whereas aflibercept may be considered more strongly in patients with moderate visual loss or worse. There are no standard protocols that define ‘treatment failure,’ but several studies have reported that switching from bevacizumab to either ranibizumab or aflibercept will result in further reduction of CSFT and improvement in BCVA. Further study with prospective randomized trials is warranted to validate these findings. Switching to intravitreal corticosteroids may be of particular benefit to pseudophakic patients. Anti-VEGF combination with sustained-release corticosteroids also appears promising for refractory DME.     

Application of Quillaja saponaria extracts as oral adjuvants for plant-made vaccines

Extracts from the Quillaja saponaria tree are known to provide immune potentiating responses and, hence, can be useful as adjuvants. Partial purification from the crude (food-grade) extract results in Quil A, which is contained in several veterinary vaccines. Further purification can provide concentrated saponin fractions such as QS-21, which is currently under investigation as a potential adjuvant for use in humans. Purified saponins have proven safe and effective when injected and have significantly enhanced the efficacy of some oral vaccines under clinical investigation. Toxicity of the food-grade extract from Quillaja saponaria has limited its use as a parenteral adjuvant; however, this toxicity seems to be abated when delivered orally. It is commonly used within the food and beverage industries and has no documented toxicity in humans at the present levels of consumption. Use of transgenic plants has been proposed as an alternative system for oral vaccine production and administration, and it is likely that an oral adjuvant will be required in most cases. Food-grade saponins have significant advantages for use with plant-made vaccines and are likely to provide a broad adjuvant effect due to the multiple saponin components. A review of the origin, production, biological activity, toxicity and use in the food industry is provided for Quillaja saponaria extract. Previous evaluation of this adjuvant in preclinical studies with plant made vaccines is discussed and a proposed level of experimental use in humans is provided.     

Taking a Toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents

Toll-like receptor (TLR) agonists are being developed for use as vaccine adjuvants and as stand-alone immunomodulators because of their ability to stimulate innate and adaptive immune responses. Among the most thoroughly studied TLR agonists are the lipid A molecules that target the TLR4 complex. One promising candidate, monophosphoryl lipid A, which is a derivative of lipid A from Salmonella minnesota, has proven to be safe and effective as a vaccine adjuvant in > 120,000 human doses. A new class of synthetic lipid A mimetics, the aminoalkyl glucosaminide 4-phosphates (AGPs), have been engineered specifically to target human TLR4 and are showing promise as vaccine adjuvants and as monotherapeutic agents capable of eliciting nonspecific protection against a wide range of infectious pathogens. In this review, the authors provide an update of the preclinical and clinical experiences with the TLR4 agonists, MPL^® (Corixa Corporation) adjuvant and the AGPs.     

Capecitabine for the treatment of pancreatic cancer

Introduction: Capecitabine is an oral prodrug of 5-fluorouracil (5-FU) which is converted to 5FU by a series of reactions catalyzed by different enzymes, the last of the enzymes being thymidine phosphorylase (TP). TP is found to be elevated in tumor cells in comparison to normal cells, which consequently tumor-localizes the production of 5-FU, thereby limiting its systemic toxicity. Today, capecitabine is extensively used for the treatment of many solid malignancies, with a particular focus in breast and gastrointestinal tumors, but also in pancreatic cancer.

Areas covered: This review summarizes the pharmacology and the clinical evidence relevant to the use of capecitabine in the treatment of pancreas cancer. The authors provide, furthermore, provide their expert perspectives on its use.

Expert opinion: Capecitabine has the advantage over other therapeutics in so much that it has both convenient oral administration and a favorable toxicity profile. Current data has promised the use of capecitabine in all stages of pancreatic cancer. However, predictive markers for outcome and toxicity remain to be validated.