November 2022

This RCT comparing synthetic versus biologic mesh in patients undergoing elective single-stage repair of clean-contaminated and contaminated ventral hernias demonstrated significantly lower hernia recurrence risk with use of synthetic mesh. 

Summary:
This study was a multicenter, single-blinded randomized clinical trial of 253 patients comparing retromuscular biologic vs. synthetic mesh (medium-weight polypropylene) in elective clean-contaminated and contaminated ventral hernia repairs. The study was performed between 2012-2017 with a follow-up period of two years. The primary outcome was hernia recurrence at two years, and secondary outcomes included 30-day hospital costs and adverse events (including ileus, bowel obstruction, VTE, cardiac event, renal failure, respiratory failure, transfusion requirement, infections including sepsis/UTI/pneumonia, and death), and overall risk of surgical site infection (SSI) requiring a procedural intervention (defined as opening of the wound, wound debridement, suture excision, percutaneous drainage, or partial/complete mesh removal).  

There were no differences between the two patient cohorts (biologic n=127, synthetic n=126) with regards to baseline comorbidities. The only operative detail that differed between the two groups was related to mesh dimensions, as at the start of the trial the biologic mesh utilized was not available in sizes as large as the synthetic mesh. As such, while there was no difference between groups regarding hernia size, patients in the synthetic group had a higher mesh to defect ratio (3.0 vs. 2.5, p=0.001). The hernia recurrence rate was 20.5% in the biologic arm, compared to 5.6% in the synthetic arm, resulting in an absolute risk reduction of 14.9% with the use of synthetic mesh (p=0.001). On multivariate cox regression analysis, use of synthetic mesh significantly reduced the risk of hernia recurrence (Hazard Ratio [HR] 0.31, p=0.009). Additionally, between the two groups there was no difference in rates of SSI, with comparable risks at different time points throughout the study (30 days, 6 months, 1 year, and 2 years). Most patients who required procedural intervention had their wound opened (13.4% biologic vs. 12% synthetic, p=0.87) with only one patient (biologic arm) undergoing mesh excision. Notably, patients in the biologic arm had a higher risk of 30-day adverse events (66% vs. 51.6%, p=0.026). Lastly, patients who received biologic mesh had a higher median hospital cost ($44,936 vs. $17,289, p<0.001) likely due to the difference in cost between the different types of mesh, with a median price for biologic mesh of $21,539 compared to $105 for synthetic mesh (p<0.001). 

The results of this study are notable, with patients receiving synthetic mesh having lower rates of hernia recurrence, 30-day adverse events, and hospital costs, with a comparable rate of SSI compared to patients with biologic mesh. However, the study has some noteworthy limitations. The exclusion criteria were quite strict, which likely led to the overall small number of patients over a 5-year period. Exclusion criteria included obesity, immunosuppression, malnutrition, ascites, ESRD, liver disease, smoking, and receipt of an MIS repair. These patients were thus ideal surgical candidates for hernia repair. Additionally, only patients undergoing elective repair were included. While these inclusion/exclusion criteria remove many potential confounding variables, they somewhat decrease the relevance. Many patients undergoing clean-contaminated or contaminated hernia repairs at our institution are doing so in an emergent setting, so the results from this study are not extrapolatable to that cohort of patients. Additionally, the mesh in this trial was placed in the retromuscular position. Previous studies have shown that retromuscular mesh placement has the lowest rates of SSI. Thus, the results of this study may not hold for mesh placed in alternative positions (i.e., underlay or onlay). Lastly, only one type of synthetic mesh was used (a medium weight polypropylene mesh), which may not be available at all settings. While these results have important implications for patients receiving elective, open hernia repairs, there is still much to learn in the emergent setting where patients have comorbidities, and retromuscular mesh placement may not be achievable.

Onset of detrimental, irreversible pathology occurs prenatally in patients with lysosomal storage disorders and other congenital diseases, making a strong argument for earlier intervention to mitigate disease severity. This report describes safe and effective in utero enzyme replacement therapy in a patient with Pompe’s disease who remains symptom-free after fetal treatment. 

Summary:
Lysosomal storage diseases such as mucopolysaccharidosis type VII (Pompe’s Disease) are congenital disorders of metabolism, with developmental abnormalities manifesting before birth. Pompe’s disease presents prenatally with hypertropic cardiomyopathy, skeletal dysplasias, and can lead to fetal demise. If the child survives to birth, they additionally suffer from pulmonary dysfunction and neurocognitive impairment. Untreated, the life expectancy of infant-onset Pompe’s disease is 2 years. The mainstays of treatment are enzyme replacement therapy, which is limited by the development of antibodies to the exogenous enzyme, or hematopoietic stem cell transplantation (HSCT) to provide a permanent source of replacement enzyme, limited by peri-transplant morbidity and graft failure. Both treatment options do little to address the progressive neurologic impairment due to the inability of the enzyme to cross the blood-brain barrier and the low engraftment of microglial cells. Additionally, organ damage incurred prenatally is irreversible regardless of postnatal treatment. 

The group at UCSF previously presented successful in utero enzyme replacement as well as in utero HSCT in a mouse model of MPS VII with increased survival, improvement in neurological deficits, absence of anti-enzyme antibodies and with high levels of microglial engraftment [Nguyen, Sci Trans Med 2020]. On the basis of these results, they obtained approval for phase I clinical trial of in utero enzyme replacement therapy (IUERT) and here report the first patient treated. 

The patient was diagnosed prenatally via chorionic villus sampling in a family with at least three previous pregnancies affected by infantile-onset Pompe’s disease of which all affected children had died. From 24-34 weeks gestation, the fetus was transfused every 2 weeks with exogenous enzyme under ultrasound guidance via the umbilical vein. Enzyme replacement continued after birth, consistent with standard-of-care treatment. At the time of the report, the patient has survived to 13 months of age with: normal creatine kinase levels (marker of muscle damage); age-appropriate gross and fine motor development, muscle tone, and power; normal echocardiograms without evidence of ventricular hypertrophy seen at birth in untreated patients. Anti-enzyme antibodies were detected in utero with peak levels at 34 weeks gestation. However, postnatally titers remained below clinically significant levels, though patient continued to receive regular rituximab and IVIG infusions for immune tolerance and passive immunity, respectively. Importantly, there were no maternal side effects.

Especially with the advances in prenatal screening and diagnosis, there is a strong rationale for pushing the therapeutic window earlier in conditions in which pathologic processes start in utero. Demonstrating safe and effective prenatal treatment of a congenital disorder with marked improvement in postnatal outcomes represents a potential paradigm shift in how we approach these conditions. There are of course significant additional considerations, including ethical implications and approaches to appropriate patient selection. It is important to accurately predict a severe phenotype for potential candidates before offering a novel, potentially harmful therapy that places unnecessary risk on the mother. While this treatment appears to be safe, the techniques for delivery are not widely performed and therefore will not be available to all patients. Ultimately, studies such as this one forge the way for other in utero therapies such as in utero gene editing to address congenital disorders [Bose, Nat Comm 2021].

Citations:
Nguyen QH, Witt RG, Wang B, Eikani C, et al. Tolerance induction and microglial engraftment after fetal therapy without conditioning in mice with Mucopolysaccharidosis type VII. Sci Trans Med. 2020. 

Bose SK, White BM, Kashyap MV, et al. In utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease. Nat Comm. 2021.

This 2-cohort RCT comparing endovascular therapy versus surgical revascularization for chronic limb-threatening ischemia among patients with and without appropriate saphenous vein for surgery found that surgical therapy was associated with decreased major adverse limb events and death if the patient had adequate vein conduit.

Summary:
Chronic limb threatening ischemia (CLTI) affects approximately 11% of the 200 million patients with peripheral artery disease (PAD) worldwide. This disease presents with rest pain or ischemic ulceration in the lower extremities, and without revascularization the amputation rate is 25% within one year. In the early 2000s, the BASIL trial investigated bypass versus angioplasty in patients with CLTI and found no significant difference in amputation free survival between these two methods. Over the past twenty years, endovascular therapy has improved beyond angioplasty given new technologies like drug coated balloons, improved stents and atherectomy devices. To address these improvements, the BEST-CLI (Best Endovascular versus Best Surgical Therapy in Critical Limb Ischemia) study was designed to investigate both approaches to CLTI.

BEST-CLI is an international randomized trial that enrolled 1830 patients who presented with CLTI and infrainguinal PAD. Patients were divided into two cohorts before randomization: patients with adequate segment of greater saphenous vein (GSV) for a bypass, and patients who needed an alternative bypass conduit. The primary outcome was a composite of major adverse limb events (MALE; amputation or reintervention) and death from any cause over a two-year follow up period.

In patients with suitable GSV for bypass, 709 were randomized to receive surgical bypass; 302 (42.6%) of these patients experienced MALE or death from any cause. The other 711 patients with suitable GSV were randomized to endovascular therapy; 408 of these patients (57.4%) had either MALE or death in follow up (HR, 0.68; 95% CI 0.59-0.79; P<0.001). Major reinterventions occurred in 9.2% of patients in the surgical group 23.5% of patients in the endovascular group (HR, 0.35; 95% CI 0.27-0.47); major amputation occurred 10.4% of patients in the surgical group and 14.9% of patients in the endovascular group (HR, 0.73; 95% CI 0.54-0.98). In patients without suitable GSV for bypass, 83 of 194 (42.8%) surgically-treated patients experienced MALE or death, compared to 95 of 199 (47.7%) of endovascular therapy treated patients (HR, 0.79; 95% CI 0.58 -1.06; P = 0.12).  In both cohorts the hospital length of stay was longer for the surgical group compared to the endovascular group; there was no difference in major adverse cardiovascular events (myocardial infarction or stroke) or death.

This study found that in patients with adequate GSV for bypass, a surgery-first revascularization strategy was associated with a 32% lower risk of a composite of major adverse limb events or death when compared to the endovascular strategy in patients presenting with CLTI. This appears to be driven by fewer major reinterventions in the surgical group. This suggests that despite the improvements in endovascular technology, the durability and long-term patency of a GSV bypass continues to provide a superior initial strategy for revascularization in patients with CLTI.