The effect of pregnancy on renal angiomyolipoma; a world of knowledge to gain, specifically in women with TSC.

BACKGROUND: Women are counseled preconceptionally about the potential risks of rAML progression and chance of complications during and due to pregnancy. However, a systematic search investigating the evidence on which this advice is based does not exist. The aim of this systematic review is to determine the effect of pregnancy on renal angiomyolipoma (rAML) size and risk of haemorrhage in patients with tuberous sclerosis complex (TSC). METHODS: We searched PubMed, EMBASE, Medline and ClinicalTrials.gov using terms for "renal angiomyolipoma" and "pregnancy". English-language articles published between January 1st 2000, and December 31st 2020 of which full-text was available were included. The initial search resulted in 176 articles. After the screening process we included 45 case reports and 1 retrospective study. For the retrospective study we assessed the risk of bias using the Newcastle-Ottawa Scale. We included articles about renal AML and pregnancy with and without an established diagnosis of TSC. From these articles we recorded the rAML sizes and rAML complications. RESULTS: Seven case reports, from a total of 45 case reports, provided follow-up data on renal AML size (these were all cases of renal AML without a known diagnosis of TSC). Of these cases, renal AML size decreased in one patient, was stable in one patient, increased in three patients and fluctuated in two others. Renal AML size of women who suffered a haemorrhage were significantly larger (12.1 ± 4.6 cm) than rAMLs of women who did not suffer a haemorrhage (8.3 ± 3.2 cm). Data from the retrospective study showed no difference in renal complications between the women with and without a history of pregnancy. Haemorrhage occurred in 30% of the women with a history of pregnancy (n = 20) and in 11% in the patients without a history of pregnancy (n = 2), however this retrospective study had methodological limitations. CONCLUSION: The effect of pregnancy on renal AML size and complications in patients with TSC is unclear. More research is needed to determine the risk of pregnancy on TSC-associated kidney disease in TSC patient.

In vivo stabilization of a less toxic asparaginase variant leads to a durable antitumor response in acute leukemia.

Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase. Acute lymphoblastic leukemia (ALL) cells do not express asparagine synthetase or express it only minimally, which makes them completely dependent on extracellular asparagine for their growth and survival. This dependency makes ALL cells vulnerable to treatment with L-asparaginase, an enzyme that hydrolyzes asparagine. To date, all clinically approved L-asparaginases have significant L-glutaminase co-activity, associated with non-immune related toxic side effects observed during therapy. Therefore, reduction of L-glutaminase co-activity with concomitant maintenance of its anticancer L-asparaginase effect may effectively improve the tolerability of this unique drug. Previously, we designed a new alternative variant of Erwinia chrysanthemi (ErA; Erwinaze) with decreased L-glutaminase co-activity, while maintaining its L-asparaginase activity, by the introduction of three key mutations around the active site (ErA-TM). However, Erwinaze and our ErA-TM variant have very short half-lives in vivo. Here, we show that the fusion of ErA-TM with an albumin binding domain (ABD)-tag significantly increases its in vivo persistence. In addition, we evaluated the in vivo therapeutic efficacy of ABD-ErA-TM in a B-ALL xenograft model of SUP-B15. Our results show a comparable long-lasting durable antileukemic effect between the standard-of-care pegylated-asparaginase and ABD-ErA-TM L-asparaginase, but with fewer co-glutaminase-related acute side effects. Since the toxic side effects of current L-asparaginases often result in treatment discontinuation in ALL patients, this novel ErA-TM variant with ultra-low L-glutaminase co-activity and long in vivo persistence may have great clinical potential.

The long-term effect of mTOR inhibition on lipid and glucose metabolism in tuberous sclerosis complex: data from the Dutch TSC registry.

BACKGROUND: MTOR inhibition is an effective treatment for many manifestations of tuberous sclerosis complex. Because mTOR inhibition is a disease modifying therapy, lifelong use will most likely be necessary. This study addresses the long-term effects of mTOR inhibitors on lipid and glucose metabolism and aims to provide better insight in the incidence and time course of these metabolic adverse effects in treated TSC patients. METHODS: All patients who gave informed consent for the nationwide TSC Registry and were ever treated with mTOR inhibitors (sirolimus and/or everolimus) were included. Lipid profiles, HbA1c and medication were analysed in all patients before and during mTOR inhibitor treatment. RESULTS: We included 141 patients, the median age was 36 years, median use of mTOR inhibitors 5.1 years (aimed serum levels 3.0-5.0 µg/l). Total cholesterol, LDL- and HDL-cholesterol levels at baseline were similar to healthy reference data. After start of mTOR inhibition therapy, total cholesterol, LDL-cholesterol and triglycerides increased significantly and were higher compared to healthy reference population. Mean total cholesterol levels increased by 1.0 mmol/L after 3-6 months of mTOR inhibition therapy but did not increase further during follow-up. In this study, 2.5% (3/118) of patients developed diabetes (defined as an HbA1c ≥ 48 mmol/mol) during a median follow-up of 5 years. CONCLUSIONS: Hypercholesterolemia is a frequent side effect of mTOR inhibition in TSC patients, and predominantly occurs within the first year of treatment. Although hyperglycemia is a frequent side effect in other indications for mTOR inhibition, incidence of diabetes mellitus in TSC patients was only 2.5%. This may reflect the difference of mTOR inhibition in patients with normal mTOR complex pathway function versus patients with overactive mTOR complex signaling due to a genetic defect (TSC patients).

Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy.

L-Asparaginase (L-ASNase) is an enzyme that hydrolyses the amino acid asparagine into aspartic acid and ammonia. Systemic administration of bacterial L-ASNase is successfully used to lower the bioavailability of this non-essential amino acid and to eradicate rapidly proliferating cancer cells with a high demand for exogenous asparagine. Currently, it is a cornerstone drug in the treatment of the most common pediatric cancer, acute lymphoblastic leukemia (ALL). Since these lymphoblasts lack the expression of asparagine synthetase (ASNS), these cells depend on the uptake of extracellular asparagine for survival. Interestingly, recent reports have illustrated that L-ASNase may also have clinical potential for the treatment of other aggressive subtypes of hematological or solid cancers. However, immunogenic and other severe adverse side effects limit optimal clinical use and often lead to treatment discontinuation. The design of optimized and novel L-ASNase formulations provides opportunities to overcome these limitations. In addition, identification of multiple L-ASNase resistance mechanisms, including ASNS promoter reactivation and desensitization, has fueled research into promising novel drug combinations to overcome chemoresistance. In this review, we discuss recent insights into L-ASNase adverse effects, resistance both in hematological and solid tumors, and how novel L-ASNase variants and drug combinations can expand its clinical applicability.

[En masse testing is not sensible and economical care]. / Massaal testen is geen zinnige en zuinige zorg.

The current policy is to test en masse for access on the basis that we then have a safe system to prevent the possible spread of an epidemic virus. The question is whether this reasoning is correct. To answer this, we have developed two scenarios. One with a low prevalence, as applied in the Fieldlab experiments and the other with a fictitious high prevalence of 10%. Both examples show that there is both collateral damage in the number of people who are wrongly denied access and in the number of people who are wrongly admitted, which means that it does not provide the security we hope for. The cost of EUR 60 million per month is as much as we spend per year on the national breast cancer screening programme. This expensive testing policy does not offer 100% safety and is not fair. It is not an effective policy, either at an individual or a population level.