Prophylactic Hyperthermic Intraperitoneal Chemotherapy for Patients at High Risk of Developing Gallbladder Cancer Peritoneal Metastases: Case Report and Rationale for a Prospective Clinical Trial.

Gallbladder cancer is a devastating disease with a 5-year survival of only 18%. The majority of gallbladder cancers are discovered incidentally in patients undergoing cholecystectomy. During non-oncologic laparoscopic cholecystectomy for gallbladder disease, gallbladder perforation occurs in 29% of cases and spillage of gallstones occurs in 9% of cases. Patients with gallbladder cancer frequently develop peritoneal recurrence, particularly after intra-operative bile spillage during cholecystectomy for incidental gallbladder cancer. The high likelihood of spillage and peritoneal seeding during cholecystectomy for incidental gallbladder cancer suggests the need for prophylactic strategies to prevent peritoneal carcinomatosis. Hyperthermic intraperitoneal chemotherapy (HIPEC) has efficacy in gallbladder cancer patients with macroscopic peritoneal disease undergoing cytoreductive surgery and has been associated with a survival advantage in a multi-institutional retrospective case series. However, the utilization of HIPEC with a prophylactic intent against the development of peritoneal disease following resection of gallbladder cancer has not yet been prospectively studied. Here, we review the literature surrounding gallbladder cancer and HIPEC, report an institutional experience utilizing prophylactic HIPEC, and discuss a recently proposed prospective clinical trial evaluating the efficacy of prophylactic HIPEC in the prevention of gallbladder peritoneal metastasis.

Follistatin-induced muscle hypertrophy in aged mice improves neuromuscular junction innervation and function.

Sarcopenia, or age-related loss of muscle mass and strength, is an important contributor to loss of physical function in older adults. The pathogenesis of sarcopenia is likely multifactorial, but recently the role of neurological degeneration, such as motor unit loss, has received increased attention. Here, we investigated the longitudinal effects of muscle hypertrophy (via overexpression of human follistatin, a myostatin antagonist) on neuromuscular integrity in C57BL/6J mice between the ages of 24 and 27 months. Following follistatin overexpression (delivered via self-complementary adeno-associated virus subtype 9 injection), muscle weight and torque production were significantly improved. Follistatin treatment resulted in improvements of neuromuscular junction innervation and transmission but had no impact on age-related losses of motor units. These studies demonstrate that follistatin overexpression-induced muscle hypertrophy not only increased muscle weight and torque production but also countered age-related degeneration at the neuromuscular junction in mice.

Muscle contractility dysfunction precedes loss of motor unit connectivity in SOD1(G93A) mice.

INTRODUCTION: Electrophysiological measurements are used in longitudinal clinical studies to provide insight into the progression of amyotrophic lateral sclerosis (ALS) and the relationship between muscle weakness and motor unit (MU) degeneration. Here, we used a similar longitudinal approach in the Cu/Zn superoxide dismutase (SOD1[G93A]) mouse model of ALS. METHODS: In vivo muscle contractility and MU connectivity assays were assessed longitudinally in SOD1(G93A) and wild type mice from postnatal days 35 to 119. RESULTS: In SOD1(G93A) males, muscle contractility was reduced by day 35 and preceded MU loss. Muscle contractility and motor unit reduction were delayed in SOD1(G93A) females compared with males, but, just as with males, muscle contractility reduction preceded MU loss. DISCUSSION: The longitudinal contractility and connectivity paradigm employed here provides additional insight into the SOD1(G93A) mouse model and suggests that loss of muscle contractility is an early finding that may precede loss of MUs and motor neuron death. Muscle Nerve 59:254-262, 2019.

Muscle strength and size are associated with motor unit connectivity in aged mice.

In older adults, the loss of muscle strength (dynapenia) and the loss of muscle mass (sarcopenia) are important contributors to the loss of physical function. We sought to investigate dynapenia, sarcopenia, and the loss of motor unit function in aging mice. C57BL/6J mice were analyzed with cross-sectional (males: 3 vs. 27 months; males and females: 8 vs. 12 vs. 20 months) and longitudinal studies (males: 10-25 months) using in vivo electrophysiological measures of motor unit connectivity (triceps surae compound muscle action potential and motor unit number estimation), in vivo measures of plantar flexion torque, magnetic resonance imaging of hind limb muscle volume, and grip strength. Compound muscle action potential amplitude, motor unit number estimation, and plantar flexion torque were decreased at 20 months. In contrast, grip strength was reduced at 24 months. Motor unit number estimates correlated with muscle torque and hind limb muscle volume. Our results demonstrate that the loss of motor unit connectivity is an early finding in aging male and female mice and that muscle size and contractility are both associated with motor unit number.