Elective Laparoscopic Cholecystectomy as an Entrustable Professional Activity (EPA) for General Surgical Trainees in Australia.

INTRODUCTION: To evaluate the operation time and surgical outcomes of elective laparoscopic cholecystectomy performed by surgical trainees at different levels of training at Eastern health and hence, to establish the efficacy and safety of elective laparoscopic cholecystectomy as an Entrustable Professional Activity for surgical trainees in general surgery. OBJECTIVE: Elective laparoscopic cholecystectomies performed at our institution between January 2018 and January 2019 were included. Analyses were divided among three groups - consultants (C), fellows (F) and registrars (R). Standard technique with critical view of safety was used. RESULTS: A total of 592 patients was included, with a mean age of 54 ± 63 years old. The average operation time was 84 ± 51 minutes. Surgical education and training (SET) 2 trainees took significantly longer when compared to their SET3 and above counterparts as a primary operator (SET2: 131 ± 32 min, Reference; SET3: 78 ± 21 min, p = 0.003; SET4: 80 ± 33 min, p = 0.004; SET5: 77 ± 28 min, p = 0.003; F: 93 ± 77 min, p = 0.036; C: 85 ± 59 min; p = 0.007). Consultant primary operators took an average of 15 minutes longer to complete the operation when assisted by a SET trainee compared to the non-SET registrars (p = 0.03). The overall complication rate was 3.2% and was not significantly different among all three groups (p = 0.17). No death was recorded during the study period. The readmission and return to theatre rates were 7.8% and 0.8% respectively and were not significantly different among the groups (p-values = 0.61 and 0.69). All conversion to open were performed by the consultant primary operator. CONCLUSIONS: Elective laparoscopic cholecystectomy can be safely performed by surgical trainees at all SET levels when under appropriate supervision, although junior surgical trainees that is SET 2 took longer to complete the procedure. This operation seems to have a steep, but relatively short, learning curve and it may be broken down into various components. These components, with the addition of time, may be suitable as an Entrustable Professional Activity tool for assessing the competency of early SET trainees.

Chemotherapeutic agents induce mitochondrial superoxide production and toxicity but do not alter respiration in skeletal muscle in vitro.

Chemotherapeutic agents (CAs) can independently promote skeletal muscle dysfunction, fatigue and wasting with mitochondrial toxicity implicated as a possible mechanism. Thus, we aimed to characterise the effects of various CAs on mitochondrial function, viability and oxidant production in C2C12 myoblasts and myotubes. All CAs significantly reduced the viable mitochondrial pool but did not affect mitochondrial functional parameters. Doxorubicin and oxaliplatin increased oxidant production in myotubes while all CAs, except for irinotecan, increased oxidant production in myoblasts and reduced myotube diameter. Our data demonstrate CAs mito-toxic effects, highlighting the potential for mitochondria-protective therapeutics to address chemotherapy-induced skeletal muscle damage.

BGP-15 Protects against Oxaliplatin-Induced Skeletal Myopathy and Mitochondrial Reactive Oxygen Species Production in Mice.

Chemotherapy is a leading intervention against cancer. Albeit highly effective, chemotherapy has a multitude of deleterious side-effects including skeletal muscle wasting and fatigue, which considerably reduces patient quality of life and survivability. As such, a defense against chemotherapy-induced skeletal muscle dysfunction is required. Here we investigate the effects of oxaliplatin (OXA) treatment in mice on the skeletal muscle and mitochondria, and the capacity for the Poly ADP-ribose polymerase (PARP) inhibitor, BGP-15, to ameliorate any pathological side-effects induced by OXA. To do so, we investigated the effects of 2 weeks of OXA (3 mg/kg) treatment with and without BGP-15 (15 mg/kg). OXA induced a 15% (p < 0.05) reduction in lean tissue mass without significant changes in food consumption or energy expenditure. OXA treatment also altered the muscle architecture, increasing collagen deposition, neutral lipid and Ca2+ accumulation; all of which were ameliorated with BGP-15 adjunct therapy. Here, we are the first to show that OXA penetrates the mitochondria, and, as a possible consequence of this, increases mtROS production. These data correspond with reduced diameter of isolated FDB fibers and shift in the fiber size distribution frequency of TA to the left. There was a tendency for reduction in intramuscular protein content, albeit apparently not via Murf1 (atrophy)- or p62 (autophagy)- dependent pathways. BGP-15 adjunct therapy protected against increased ROS production and improved mitochondrial viability 4-fold and preserved fiber diameter and number. Our study highlights BGP-15 as a potential adjunct therapy to address chemotherapy-induced skeletal muscle and mitochondrial pathology.

Mitochondria: Inadvertent targets in chemotherapy-induced skeletal muscle toxicity and wasting?

Chemotherapy has been associated with increased mitochondrial reactive oxygen species production, mitochondrial dysfunction and skeletal muscle atrophy leading to severe patient clinical complications including skeletal muscle fatigue, insulin resistance and wasting. The exact mechanisms behind this skeletal muscle toxicity are largely unknown, and as such co-therapies to attenuate chemotherapy-induced side effects are lacking. Here, we review the current literature describing the clinical manifestations and molecular origins of chemotherapy-induced myopathy with a focus on the mitochondria as the target organelle via which chemotherapeutic agents establish toxicity. We explore the likely mechanisms through which myopathy is induced, using the anthracycline doxorubicin, and the platinum-based alkylating agent oxaliplatin, as examples. Finally, we recommend directions for future research and outline the potential significance of these proposed directions.