Oral chronic graft‐versus‐host disease in Australia: clinical features and challenges in management

Data from the Australasian Bone Marrow Transplant Recipient Registry show a steady increase in the number of allogeneic haemopoietic stem cell transplantations (HSCT) performed annually in Australia and New Zealand. In 2012, 629 allogeneic HSCT were performed. Allogeneic HSCT is associated with numerous potential complications, including chronic graft‐versus‐host disease (cGVHD). The oral cavity is one of the most frequent sites affected by cGvHD, often leading to significant disability and reduced quality of life. Management strategies are often complex, of variable efficacy and influenced by the availability of various therapeutic agents, access to compounding pharmacies and associated costs. This paper summarises the current status of allogeneic HSCT in Australia and New Zealand with a focus on oral cGvHD and the associated challenges in its management.     

Twice‐weekly ixazomib in combination with lenalidomide‐dexamethasone in patients with newly diagnosed multiple myeloma

Weekly ixazomib with lenalidomide‐dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice‐weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice‐weekly oral ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9–16) for up to sixteen 21‐day cycles, followed by maintenance with twice‐weekly ixazomib alone. No dose‐limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression‐free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug‐related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug‐related AEs. Thirteen patients discontinued due to AEs. Twice‐weekly ixazomib‐Rd offers substantial activity with promising long‐term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib‐Rd in this setting.     

Oral fluoropyrimidine versus intravenous 5‐fluorouracil for the treatment of advanced gastric and colorectal cancer: Meta‐analysis

Background and Aim

5‐Fluorouracil (5‐Fu) is one of the most commonly prescribed antineoplastic agents against gastric and colorectal cancers. Continuous infusion would be the optimal way of its administration, however, may usually cause thrombosis, infection, and prolonged hospital stay. Oral fluoropyrimidines would be an attractive alternative, but their efficiency and toxicities for the treatment of gastric and colorectal cancer are still obscure as compared with infusion 5‐Fu.

Methods

Literature retrieval, trials selection and assessment, data collection, and statistic analysis were performed according to the Cochrane Handbook. The outcome measures were tumor response rate, progression‐free survival, overall survival, and adverse effects.

Results

Twenty‐nine randomized controlled trials, comprising totally 15 154 patients, were included. Meta‐analysis showed similar overall outcome in terms of response rate (1.01; 95% confidence interval [CI], 0.92–1.12), progression‐free survival (hazard ratio 1.00; 95%CI, 0.94–1.06), and overall survival (hazard ratio 0.96; 95%CI, 0.92–1.01) between oral fluoropyrimidine‐based and intravenous 5‐Fu‐based regimens in gastric and colorectal cancer patients. The risk of grade 3/4 neutropenia, thrombocytopenia, and stomatitis was more prominent in intravenous 5‐Fu‐based regimens; while more frequent grade 3/4 hand‐foot syndrome, diarrhea, and anorexia were detected in oral fluoropyrimidine‐based regimens.

Conclusions

Oral‐fluoropyrimidines showed equivalent response and similar survival outcomes, but different toxicity profiles, as compared with intravenous 5‐Fu. Thus, it would be a more convenient and adjustable alternative in treatment of advanced gastric and colorectal cancer.     

Oral anti‐CD3 immunotherapy for HCV‐nonresponders is safe,promotes regulatory T cells and decreases viral load and liver enzyme levels: results of a phase‐2a placebo‐controlled trial

Orally administered anti‐CD3 antibodies are biologically active in the gut through induction of regulatory T cells, exert an immune‐modulatory effect, and alleviate insulin resistance and liver damage in patients with NASH. Aims: To determine the safety of oral anti‐CD3 monoclonal antibody (MAb) immunotherapy in chronic HCV patients with associated immune dysfunction. Methods: Four groups (n = 9) of chronic HCV patients who were nonresponders to interferon plus ribavirin therapy received oral placebo (group A) or anti‐CD3 MAb at one of three dosage levels for 30 days. Patients were followed for safety parameters and serum levels of liver enzymes, virus, cytokines and regulatory T cells. Results: Oral anti‐CD3 immunotherapy was safe and well tolerated; no treatment‐related adverse events were noted. The following improvements were noted relative to pretreatment levels: HCV viral load and AST and ALT levels decreased in the low‐ and high‐dose groups following 30 days of therapy. In two of the treated groups, an increase in regulatory T cells (CD4⁺ CD25⁺) was noted. The positive effects were somewhat more apparent in subjects with initially elevated liver enzyme levels. Conclusions: Oral anti‐CD3 MAb immunotherapy for nonresponder HCV patients was safe and well tolerated. Trends and statistically significant improvements were observed as reductions in viral load and liver enzyme levels, along with an increase in regulatory T‐cell levels. These data support a role for the immune system in the pathogenesis of HCV infection and suggest that this immunotherapy is worthy of evaluation in combination with HCV antiviral drugs.     

Edoxaban Management in Diagnostic and Therapeutic Procedures (EMIT‐AF/VTE)—Trial design

Non‐vitamin K dependent oral anticoagulants (NOAC) are now widely used in patients with nonvalvular atrial fibrillation (NVAF) for stroke prevention and in patients with venous thromboembolism (VTE) for the treatment and secondary prevention of the disease. Among NOAC, edoxaban demonstrated noninferiority to warfarin for stroke prevention in NVAF and for VTE treatment, with superior safety. EMIT‐AF/VTE (Edoxaban Management in Diagnostic and Therapeutic Procedures) (NCT02950168) is a multicenter, prospective, and noninterventional registry study designed to collect detailed information on the periprocedural management of patients with NVAF and VTE receiving edoxaban. The primary objective of EMIT‐AF/VTE is to document the periprocedural management of patients receiving edoxaban and to collect data on safety and other outcomes in these patients. The primary safety outcome is the rate of major bleeding. Other assessments include the evaluation of efficacy outcomes, periprocedural dosing, and timing of edoxaban. The observation period will start 5 days prior to the procedure and end 30 days post‐procedure. EMIT‐AF/VTE will aim to prospectively enroll up to approximately 1400 procedures from Europe. Enrollment commenced in December 2016 and will be completed in July 2018. As of July 2018, before database lock and with several procedure forms still temporarily inserted, a preliminary number of 1204 patients have been enrolled, who underwent a total of 1453 procedures. The prospective EMIT‐AF/VTE registry program will expand the knowledge of periprocedural management of patients with NVAF and VTE receiving edoxaban in clinical practice.     

Analysis of N1‐acetyl‐N2‐formyl‐5‐methoxykynuramine/N1‐acetyl‐5‐methoxy‐kynuramine formation from melatonin in mice

Abstract: The interactions of melatonin, a potent endogenous antioxidant, with reactive oxygen species generate several products that include N¹‐acetyl‐N²‐formyl‐5‐methoxykynuramine (AFMK) and N¹‐acetyl‐5‐methoxy‐kynuramine (AMK). The physiological or pathological significance of AFMK/AMK formation during the process of melatonin metabolism in mammals has not been clarified. Using a metabolomic approach in the current study, the AFMK/AMK pathway was thoroughly investigated both in mice and humans. Unexpectedly, AFMK and AMK were not identified in the urine of humans nor in the urine, feces or tissues (including liver, brain, and eyes) in mice under the current experimental conditions. Metabolomic analysis did identify novel metabolites of AMK, i.e. hydroxy‐AMK and glucuronide‐conjugated hydroxy‐AMK. These two newly identified metabolites were, however, not found in the urine of humans. In addition, oxidative stress induced by acetaminophen in the mouse model did not boost AFMK/AMK formation. These data suggest that AFMK/AMK formation is not a significant pathway of melatonin disposition in mice, even under conditions of oxidative stress.     

Efficacy of short‐term oral cobalamin therapy for the treatment of cobalamin deficiencies related to food‐cobalamin malabsorption: A study of 30 patients

Background: It has been suggested that oral cobalamin (vitamin B₁₂) therapy may be an effective therapy for treating cobalamin deficiencies related to food‐cobalamin malabsorption. However, the duration of this treatment was not determined. Patients and method: In an open‐label, nonplacebo study, we studied 30 patients with established cobalamin deficiency related to food‐cobalamin malabsorption, who received between 250 and 1000 μg of oral crystalline cyanocobalamin per day for at least 1 month. Endpoints: Blood counts, serum cobalamin and homocysteine levels were determined at baseline and during the first month of treatment. Results: During the first month of treatment, 87% of the patients normalized their serum cobalamin levels; 100% increased their serum cobalamin levels (mean increase, +167 pg/dl; P < 0.001 compared with baseline); 100% had evidence of medullary regeneration; 100% corrected their initial macrocytosis; and 54% corrected their anemia. All patients had increased hemoglobin levels (mean increase, +0.6 g/dl) and reticulocyte counts (mean increase, +35 × 10⁶/l) and decreased erythrocyte cell volume (mean decrease, 3 fl; all P < 0.05). Conclusion: Our findings suggest that crystalline cyanocobalamin, 250–1000 μg /day, given orally for 1 month, may be an effective treatment for cobalamin deficiencies not related to pernicious anemia.     

Oral delivery of mouse [d‐Leu‐4]‐OB3, a synthetic peptide amide with leptin‐like activity,in male C57BL/6J wild‐type and ob/ob mice: effects on energy balance,glycaemic control and serum osteocalcin levels

Background: We have recently shown that intranasal administration of mouse [d ‐Leu‐4]‐OB3 reconstituted in Intravail^® to male Swiss Webster mice resulted in significantly higher bioavailability than commonly used injections methods of delivery. The absorption profile associated with intranasal delivery of mouse [d ‐Leu‐4]‐OB3 showed an early peak representing absorption across the nasal mucosa, and a later peak suggesting a gastrointestinal site of uptake. Aim and Methods: In the present study, we examined the effects of orally administered (by gavage) mouse [d ‐Leu‐4]‐OB3 on energy balance, glycaemic control and serum osteocalcin levels in male C57BL/6J wild‐type and ob/ob mice allowed food and water ad libitum or calorie restricted by 40% of normal intake. Results: In wild‐type mice fed ad libitum, oral delivery of mouse [d ‐Leu‐4]‐OB3 reduced body weight gain, food intake and serum glucose, by 4.4, 6.8 and 28.2% respectively. Serum osteocalcin levels and water intake were essentially the same in control and treated wild‐type mice. In ob/ob mice fed ad libitum, mouse [d ‐Leu‐4]‐OB3 reduced body weight gain, food intake, water intake and serum glucose by 11.6, 16.5, 22.4 and 24.4% respectively. Serum osteocalcin in ob/ob mice treated with mouse [d ‐Leu‐4]‐OB3 was elevated by 62% over controls. Calorie restriction alone caused significant weight loss in both wild‐type (9.0%) and ob/ob (4.8%) mice, and mouse [d ‐Leu‐4]‐OB3 did not further enhance this weight loss. As expected, serum glucose levels in wild‐type and ob/ob mice were significantly reduced by calorie restriction alone. Mouse [d ‐Leu‐4]‐OB3 further reduced serum glucose in wild‐type mice and normalized levels in ob/ob mice. Calorie restriction alone reduced serum osteocalcin levels by 44.2% in wild‐type mice and by 19.1% in ob/ob mice. Mouse [d ‐Leu‐4]‐OB3 prevented this decrease in groups of mice. Conclusions: The results of this study suggest that oral delivery of mouse [d ‐Leu‐4]‐OB3 in Intravail^® is possible and may have potential not only as an alternative therapy in the treatment of human obesity and some of its associated metabolic dysfunctions, but also may help to prevent and/or reverse at least some of the bone loss which accompanies osteoporosis, anorexia nervosa and other wasting diseases.     

Patient self‐management of oral anticoagulation

Patient self‐management of oral anticoagulation is now widely practised in Germany and the USA. There are three different home‐testing monitors available in the UK which are all reliable in terms of accuracy and reproducibility of results. Selected patients can be trained to perform their own International Normalized Ratio (INR) testing and dosing, with outcomes as good if not better than those from specialized anticoagulant clinics. Consensus on the frequency of testing and what quality control should be deployed is lacking. The cost‐effectiveness in the UK is unproven.     

Association between duration of oral contraceptive use and risk of hypertension: A meta‐analysis

A meta‐analysis was conducted to evaluate the association between duration of oral contraceptive use and risk of hypertension. Relevant studies published in English or Chinese were identified by a search of PubMed, Web of Science, Wanfang Database, and China National Knowledge Infrastructure to January 2017. Seventeen articles containing 24 studies with 270,284 participants were included in this meta‐analysis. The pooled relative risk of hypertension for the highest vs lowest category of oral contraceptive duration was 1.47 (95% confidence interval, 1.25–1.73), and excluding three studies with a relative risk >3.0 yielded a pooled relative risk of 1.26 (95% confidence interval, 1.11–1.44). A linear dose‐response relationship was found (P_nonlinearity=0.69) and the risk of hypertension increased by 13% (relative risk, 1.13; 95% confidence interval, 1.03–1.25) for every 5‐year increment in oral contraceptive use. The duration of oral contraceptive use was positively associated with the risk of hypertension in this meta‐analysis.     

Evaluation of a Japanese “Prevention of Long‐term Care” project for the improvement in oral function in the high‐risk elderly

Aim: The purpose of this study was to analyze the improvement in oral function and environment in high‐risk elderly persons participating in a program to improve oral function organized by their local government. Methods: Participants comprised 36 high‐risk elderly and the mean age was 77.11 ± 7.24 years. The program involved training sessions carried out five or six times every 2–3 weeks for 3 months. Oral function and environment was evaluated before and after the program. The research period extended from 2008 to 2010. Results: The effects of intervention were clearly observed in oral diadochokinesis score in the high‐risk elderly. Persons with a lower repetitive saliva swallowing test (RSST) and oral diadochokinesis score before intervention showed a tendency toward even greater improvement. No significant changes were observed in saliva secretion or total amounts of Streptococcus mutans, Lactobacilli, Candida or total microorganisms. Conclusions: The effects of intervention were clearly recognized in regards to oral diadochokinesis. Improvement in RSST and oral diadochokinesis scores was marked in those persons showing a lower number of articulations before intervention. Geriatr Gerontol Int 2013; 13: 451–457.