Implementation of dihydropyrimidine dehydrogenase deficiency testing in Europe.

BACKGROUND: The main cause for fluoropyrimidine-related toxicity is deficiency of the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). In 2020, the European Medicines Agency (EMA) recommended two methods for pre-treatment DPD deficiency testing in clinical practice: phenotyping using endogenous uracil concentration or genotyping for DPYD risk variant alleles. This study assessed the DPD testing implementation status in Europe before (2019) and after (2021) the release of the EMA recommendations. METHODS: The survey was conducted from 16 March 2022 to 31 July 2022. An electronic form with seven closed and three open questions was e-mailed to 251 professionals with DPD testing expertise of 34 European countries. A descriptive analysis was conducted. RESULTS: We received 79 responses (31%) from 23 countries. Following publication of the EMA recommendations, 87% and 75% of the countries reported an increase in the amount of genotype and phenotype testing, respectively. Implementation of novel local guidelines was reported by 21 responders (27%). Countries reporting reimbursement of both tests increased in 2021, and only four (18%) countries reported no coverage for any testing type. In 2019, major implementation drivers were 'retrospective assessment of fluoropyrimidine-related toxicity' (39%), and in 2021, testing was driven by 'publication of guidelines' (40%). Although the major hurdles remained the same after EMA recommendations-'lack of reimbursement' (26%; 2019 versus 15%; 2021) and 'lack of recognizing the clinical relevance by medical oncologists' (25%; 2019 versus 8%; 2021)-the percentage of specialists citing these decreased. Following EMA recommendations, 25% of responders reported no hurdles at all in the adoption of the new testing practice in the clinics. CONCLUSIONS: The EMA recommendations have supported the implementation of DPD deficiency testing in Europe. Key factors for successful implementation were test reimbursement and clear clinical guidelines. Further efforts to improve the oncologists' awareness of the clinical relevance of DPD testing in clinical practice are needed.

Carpal boss: effect of wedge excision depth on third carpometacarpal joint stability.

PURPOSE: We hypothesize that carpal-metacarpal (CMC) instability after carpal boss wedge excision is not caused only by damage to the dorsal ligament but mainly depends on the depth of the bony resection. METHODS: To test our hypothesis, this study analyzes the effect of wedge excisions with different depths (0, 15%, 35%, 55% of the third CMC joint) and the effect of different forces (0, 50, 100 N.m) on the stability (measured as the passive flexion) of the third CMC joint using 12 fresh-frozen human cadaver wrists. The passive flexion is defined as the increase in angular motion of the third CMC joint and represents change in stability during flexion of the joint. RESULTS: The results show that the mean passive flexion measured in the wedge excisions of 15% and 35% of the joint did not differ from that of neutral controls. Joints analyzed after a 55% wedge excision showed a significant increase in angular motion (increased passive flexion). This relates to the 50 N.m as well as the 100 N.m loaded test position. CONCLUSIONS: This study shows that a wedge excision of clinically applicable depth of 35% does not create instability during flexion of the third CMC joint when loaded with physiologically relevant forces. Yet an extended and hardly clinically relevant 55% wedge excision results in a change in stability of the joint. To prevent instability when performing a wedge excision for symptomatic carpal boss, care must be taken to avoid excisions that exceed 35% of the third CMC joint.

Vascular anatomy of the hamster retractor muscle with regard to its microvascular transfer.

BACKGROUND: The hamster retractor muscle (RET) is used as an in vivo model in studies of skeletal muscle ischemia-reperfusion injury. The RET is unique in that the muscle can be isolated while preserving the primary vascular supply so that its contractile function can be measured simultaneously with local microvascular responses to experimental interventions. The goal of this study was to understand the anatomical origin of the vascular supply to the RET and determine whether the RET can be used as a free flap after surgical isolation of the thoracodorsal vessels. METHODS: Microdissection was performed to determine the anatomy of the vasculature that supplies and drains the RET. RESULTS: Distinct numbers and patterns of feed arteries (2-4) and collecting veins (1-3) were identified (n = 26 animals). Dye injection (n = 8) of the thoracodorsal artery demonstrated that the RET remains perfused following its isolation on the thoracodorsal pedicle. Heterotopic allograft transplantation of the RET (n = 2) was performed by anastomosing the thoracodorsal vessels to the femoral vessels using the end-to-side technique. CONCLUSIONS: The anatomical relationships indicate that the RET can be used as a free flap model for evaluating the effect of preservation strategies and transplantation on skeletal muscle microcirculation and contractile function.

Improving the preservation of isolated rat skeletal muscles stored for 16 hours at 4 degrees C.

BACKGROUND: Limiting factors for long-term cold preservation of isolated skeletal muscles are increased intracellular calcium levels, the occurrence of hypercontraction, and the overproduction of oxygen free radicals. In the present study, we investigated whether muscle preservation during cold storage could be improved by additives that can protect against such processes or by oxygen supply. METHODS: The soleus (SOL) and a strip of the cutaneus trunci muscle (CT) from the rat were isolated and stored for 16 hr at 4 degrees C in Bretschneider's Histidine Tryptophane Ketoglutarate (HTK) and subsequently acclimatized in Krebs-Henseleit solution for 90 min at room temperature. The protective effects of 2,3-butanedione monoxime (BDM; reduces intracellular calcium release and inhibits fiber contraction) and of the following antioxidants were investigated: N-tert-butyl-alpha-phenylnitrone (PBN), trolox, desferal, and deferione. The antioxidants and BDM were added to both HTK and Krebs-Henseleit solution. Dose-response curves were made for each of the additives (n> or =4 for each dose). To evaluate the effect of oxygen supply, HTK was aerated with 95% O2/5% CO2. Muscle function (P0), energy metabolism (ATP), and cytoarchitecture were analyzed. The measured values were compared with those of fresh unstored muscles (% of control) and with those of muscles stored in HTK without any additive (multivariate analysis of variance, P<0.05). RESULTS: We found a significant protection of the contractile function (P0) of both muscles after the addition of 1 mM of trolox (SOL: 46% of control; CT: 53%) and after the addition of 3 mM or 0.3 mM of deferione to the SOL and CT, respectively (P0 for both muscles: 55%), whereas no protection was found with PBN (0.03-1 mM) and Desferal (0.001-1 mM). The addition of BDM (10 or 30 mM) resulted in the highest increase of P0 (84% and 60% for the SOL and CT, respectively). The combinations BDM-trolox and BDM-deferione did not further improve the preservation of the SOL function, but P0 values (88% and 91% of control, respectively) were not different from those found for control muscles. Oxygenation of HTK was only beneficial for the SOL (P0: 83%). The improved preservation of muscle function was accompanied by a reduction of the twitch threshold current, increased by storage, suggesting a protective effect of the intervention on the preservation of the muscle cell membrane integrity. Biochemical and histological data corresponded well with the functional data. CONCLUSIONS: The results showed that the addition of BDM and antioxidants (trolox and deferione) to the bathing solutions improved the preservation of the function, metabolism, and cytoarchitecture of isolated skeletal muscles after cold storage for 16 hr.