Harold N. Lovvorn

Congenital hyperinsulinism and the surgeon: Lessons learned over 35 years

BACKGROUND/PURPOSE Congenital hyperinsulinism induces severe and unremitting hypoglycemia in newborns and infants. If poorly controlled, seizures and irreversible brain damage may result. Subtotal (<95%) or near-total (95% to 98%) pancreatectomy have been performed for glycemic control in babies who do not respond to aggressive medical therapy. Because hypoglycemia often persists after subtotal resection, 95% pancreatectomy has emerged as the procedure of choice. To define the effect of more or less extensive pancreatectomy on the management and outcome of refractory congenital hyperinsulinism, the authors examined our single institutional experience. METHODS The records of children treated between 1963 and 1998 for congenital hyperinsulinism, and who required pancreatectomy, were reviewed. Outcome parameters included glycemic response to surgery, need for reresection, surgical morbidity, surgical and long-term mortality, and development of diabetes mellitus (DM). A complete response was defined as discharge to home on no glycemic medications, no continuous feedings, and without DM. Histological reports were reviewed and categorized as either diffuse or focal disease. RESULTS Of 101 children treated for congenital hyperinsulinism during this period, 53 (50%) required pancreatectomy for glucose control. Mean follow-up for the study population was 9.8 +/- 1.1 years. Overall, 23 children (43%) showed a complete response, occurring in 50% of patients having > or = 95% pancreatectomy (n = 34), but in only 19% having less than 95% resection (n = 16). The remaining three babies had local excision of a solitary focal lesion, and each showed a complete response. Histopathology showed diffuse islet abnormalities in 42 specimens (79%) and solitary focal lesions in 11 (21%). A complete response was observed for 82% of focal but only 33% of diffuse lesions. Eight patients (15%) required reresection for persistent hypoglycemia, seven having diffuse lesions and one focal. Surgical morbidity occurred in 13 cases (26%), and the 30-day surgical mortality rate was 6%, each death (n = 3) occurring before 1975. DM developed in seven children (14%), each having diffuse lesions, and was independent of resection type. CONCLUSION Because euglycemia is more readily restored, and because the risks for surgical complications and DM do not appear increased, the authors recommend 95% pancreatectomy as the initial procedure of choice for newborns and infants with congenital hyperinsulinism.

Early experience with needleoscopic inguinal herniorrhaphy in children

BACKGROUND/PURPOSE To validate its safety and efficacy, the authors evaluated their early experience with needleoscopic inguinal herniorrhaphy in children. METHODS Twelve consecutive children, older than 6 months, with unilateral (n = 8) or bilateral (n = 4) inguinal hernias underwent a needleoscopic herniorrhaphy. A 1.7-mm needle laparoscope was introduced through the umbilicus, and a grasper placed laterally was used for traction. A curved stainless steel awl introduced percutaneously anterolateral to the internal ring was used to pass a ligature circumferentially to complete an extraperitoneal high ligation of the sac (without handling the vas deferens and spermatic vessels in males). Four of 12 patients underwent their repair combined with other procedures. Children who underwent herniorrhaphy only were allowed immediate return to unrestricted activity. Data recorded with IRB approval included operating time, postoperative discomfort, recurrence, and complications. RESULTS For herniorrhaphy only the mean operating time was 23 minutes (unilateral, n = 5) or 46 minutes (bilateral, n = 3). All were able to return to immediate unrestricted activity. None required any analgesics other than acetaminophen. There were no recurrences or complications. CONCLUSIONS Needleoscopic inguinal herniorrhaphy in children is safe and effective. This technique potentially offers less risk of injury to cord structures with a superior cosmetic result.

Hyaluronan receptor expression increases in fetal excisional skin wounds and correlates with fibroplasia

BACKGROUND/PURPOSE The midgestation fetus heals incisional skin wounds scarlessly, whereas large excisional wounds scar. High concentrations of hyaluronan (HA) are associated with scarless fetal as opposed to scar-forming adult wound repair. Because expression of the HA receptors, CD44 and RHAMM (Receptor for HA-Mediated Motility), has been associated with adult wound fibroplasia, the authors postulated that fetal excisional wounds would show increased expression of CD44 and RHAMM as compared with incisional wounds. METHODS Two models of fetal wound healing were examined. Fetal skin from human abortuses was heterotransplanted subcutaneously into severe combined immunodeficient (SCID) mice. Fourteen days after grafting, incisional or 2-mm excisional wounds were created (n = 6 per time-point). In addition, incisional and excisional (6 to 10 mm) wounds (n = 5 per time-point) were created on the backs of 70- to 75-day fetal lambs (term, 145 days). Tissue from both models was harvested at sequential time-points after injury. Wounds were studied histologically for fibroplasia and assayed for their HA content. CD44 and RHAMM expression were analyzed by immunohistochemistry and immunoblotting. RESULTS As expected, in both models, incisional wounds healed scarlessly, whereas excisional wounds showed fibroplasia. Incisional wounds of fetal lambs maintained a significantly higher HA content than excisional wounds 3 days after injury. Between 1 and 7 days in either human or sheep fetal wounds, immunostaining for CD44 and RHAMM markedly increased along the margins of excisional wounds as compared with incisional wounds and unwounded skin. Immunoblot analysis confirmed this increased HA receptor expression in both models. CONCLUSIONS HA receptor expression increased in both human and sheep fetal excisional wounds and correlated with fibroplasia and a reduced HA content. The authors speculate that strategies to limit the expression or function of HA receptors during postnatal wound repair may modify the development of scar.

Early life establishment of site-specific microbial communities in the gut

Fecal sampling is widely utilized to define small intestinal tissue-level microbial communities in healthy and diseased newborns. However, this approach may lead to inaccurate assessments of disease or therapeutics in newborns because of the assumption that the taxa in the fecal microbiota are representative of the taxa present throughout the gastrointestinal tract. To assess the stratification of microbes in the newborn gut and to evaluate the probable shortcoming of fecal sampling in place of tissue sampling, we simultaneously compared intestinal mucosa and fecal microbial communities in 15 neonates undergoing intestinal resections. We report three key results. First, when the site of fecal and mucosal samples are further apart, their microbial communities are more distinct, as indicated by low mean Sørensen similarity indices for each patients fecal and tissue microbiota. Second, two distinct niches (intestinal mucosa and fecal microbiota) are evident by principal component analyses, demonstrating the critical role of sample source in defining microbial composition. Finally, in contrast to adult studies, intestinal bacterial diversity was higher in tissue than in fecal samples. This study represents an unprecedented map of the infant microbiota from intestinal mucosa and establishes discernable biogeography throughout the neonatal gastrointestinal tract. Our results question the reliance on fecal microbiota as a proxy for the developing intestinal microbiota. Additionally, the robust intestinal tissue-level bacterial diversity we detected at these early ages may contribute to the maturation of mucosal immunity.

Wilms tumor survival in Kenya

PURPOSE Survival from Wilms Tumor (WT) exceeds 90% at 5 years in developed nations, whereas at last report, 2-year event-free survival (EFS) in Kenya reached only 35%. To clarify factors linked to these poor outcomes in Kenya, we established a comprehensive web-based WT registry, comprised of patients from the four primary hospitals treating childhood cancers. MATERIALS AND METHODS WT patients diagnosed between January 2008 and January 2012 were identified. Files were abstracted for demographic characteristics, treatment regimens, and enrollment in the Kenyan National Hospital Insurance Fund (NHIF). Children under 15 years of age having both a primary kidney tumor on imaging and concordant histology consistent with WT were included. RESULTS Two-year event-free survival (EFS) was 52.7% for all patients (n=133), although loss to follow up (LTFU) was 50%. For the 33 patients who completed all scheduled standard therapy, 2-year EFS was 94%. Patients enrolled in NHIF tended to complete more standard therapy and had a lower hazard of death (Cox 0.192, p < 0.001). CONCLUSION Survival of Kenyan WT patients has increased slightly since last report. Notably, WT patients completing all phases of standard therapy experienced 2-year survival approaching the benchmarks of developed nations. Efforts in Kenya should be made to enhance compliance with WT treatment through NHIF enrollment.

Assessing gonadal function after childhood ovarian surgery.

PURPOSE We aimed to assess the late effects of ovarian salvage or oophorectomy on gonadal function and fertility as measured by menstrual regularity. METHODS We performed a 10-year retrospective review of females aged 20 years or younger who required surgery to treat an ovarian disorder. A mail survey was distributed to these patients to evaluate the effects of ovarian surgery on menarche, menstrual regularity, and pregnancy. RESULTS A total of 180 females had surgery to treat an ovarian disorder. Eighty-six of these underwent unilateral oophorectomy (48%), whereas 94 (52%) had an ovary sparing procedure. Eighty-one patients (45%) returned completed surveys. Of the respondents, 44 had oophorectomy, and 37 had ovarian salvage. Ages of menarche were similar between surgical groups. Symptoms of menstrual irregularity differed most significantly according to painful menses (oophorectomy, 27.3%; salvage, 59.5%; P < .04). Interestingly, continuation of regular menses after surgery was higher in the oophorectomy group (oophorectomy, 70%; salvage, 15%; P = .013). CONCLUSIONS Unilateral oophorectomy does not appear to impair late gonadal function when compared with ovarian salvage. Surprisingly, oophorectomy appears to maintain more normal ovarian activity as estimated by menstrual regularity. Oophorectomy may be performed without apparent adverse effect on gonadal activity.

Race Disparities in Wilms Tumor Incidence and Biology

BACKGROUND Wilms tumor (WT) is thought to arise in children of Black African ancestry with greater frequency than in Whites. To clarify the biological basis for race disparities in WT, we first verified that Black children residing in Tennessee have an increased incidence of WT, and second, established molecular profiles in WT that are specific to race. MATERIALS AND METHODS To assess race disparities in WT epidemiology, the Tennessee Cancer Registry (TCR) was queried for all in-state patients less than 20 y of age and registered between 1999 and 2008. To explore race disparities in WT biology, six Black and four White WT specimens acquired in Tennessee were analyzed using imaging mass spectrometry (IMS). RESULTS TCR data show that Black children are over-represented among WT patients (29%) relative to all other childhood cancers (18.5%; P = 0.01). WT ranked the fifth most common cancer diagnosis among Blacks, but ninth among Whites. The diagnosis of WT occurred 79% more frequently among Blacks (n = 28) than Whites (n = 69; P = 0.01), and proportionally more Blacks tended to present with distant disease. Although overall survival from WT was not statistically different between Blacks (92.9%) and Whites (94.0%), Black males showed the lowest survival (85%; P = 0.21). IMS analysis identified peptide spectra from both WT blastema and stroma that independently classify specimens according to race with greater than 80% accuracy. CONCLUSIONS In Tennessee, Black children appear more susceptible than Whites to develop WT. Race-specific molecular profiles can be determined that may help to clarify pathways of Wilms tumorigenesis and the biological basis for race disparities in WT incidence and biology.

Extra corporeal membrane oxygenation and plasmapheresis for pulmonary hemorrhage in microscopic polyangiitis

Early initiation of extracorporeal membrane oxygenation to treat acute hypoxemic respiratory failure secondary to massive pulmonary hemorrhage in microscopic polyangiitis in children can be life-saving while awaiting control of the autoimmune disease process by plasmapheresis and immunosuppression.

Aberrant activation, nuclear localization, and phosphorylation of yes‐associated protein‐1 in the embryonic kidney and Wilms tumor

The Yes‐associated‐protein‐1 (YAP1) is a novel, direct regulator of stem cell genes both in development and cancer. FAT4 is an upstream regulator that induces YAP1 cytosolic sequestering by phosphorylation (p‐Ser 127) and therefore inhibits YAP1‐dependent cellular proliferation. We hypothesized that loss of FAT4 signaling would result in expansion of the nephron progenitor population in kidney development and that YAP1 subcellular localization would be dysregulated in Wilms tumor (WT), an embryonal malignancy that retains gene expression profiles and histologic features reminiscent of the embryonic kidney.

Effect of a Clinical Practice Guideline for Pediatric Complicated Appendicitis.

IMPORTANCE Complicated appendicitis is a common condition in children that causes substantial morbidity. Significant variation in practice exists within and between centers. We observed highly variable practices within our hospital and hypothesized that a clinical practice guideline (CPG) would standardize care and be associated with improved patient outcomes. OBJECTIVE To determine whether a CPG for complicated appendicitis could be associated with improved clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS A comprehensive CPG was developed for all children with complicated appendicitis at Monroe Carell Jr Childrens Hospital at Vanderbilt, a freestanding childrens hospital in Nashville, Tennessee, and was implemented in July 2013. All patients with complicated appendicitis who were treated with early appendectomy during the study period were included in the study. Patients were divided into 2 cohorts, based on whether they were treated before or after CPG implementation. Clinical characteristics and outcomes were recorded for 30 months prior to and 16 months following CPG implementation. EXPOSURE Clinical practice guideline developed for all children with complicated appendicitis at Monroe Carell Jr Childrens Hospital at Vanderbilt. MAIN OUTCOMES AND MEASURES The primary outcome measure was the occurrence of any adverse event such as readmission or surgical site infection. In addition, resource use, practice variation, and CPG adherence were assessed. RESULTS Of the 313 patients included in the study, 183 were boys (58.5%) and 234 were white (74.8%). Complete CPG adherence occurred in 78.7% of cases (n = 96). The pre-CPG group included 191 patients with a mean (SD) age of 8.8 (4.0) years, and the post-CPG group included 122 patients with a mean (SD) age of 8.7 (4.1) years. Compared with the pre-CPG group, patients in the post-CPG group were less likely to receive a peripherally inserted central catheter (2.5%, n = 3 vs 30.4%, n = 58; P < .001) or require a postoperative computed tomographic scan (13.1%, n = 16 vs 29.3%, n = 56; P = .001), and length of hospital stay was significantly reduced (4.6 days post-CPG vs 5.1 days pre-CPG, P < .05). Patients in the post-CPG group were less likely to have a surgical site infection (relative risk [RR], 0.41; 95% CI, 0.27-0.74) or require a second operation (RR, 0.35; 95% CI, 0.12-1.00). In the pre-CPG group, 30.9% of patients (n = 59) experienced any adverse event, while 22.1% of post-CPG patients (n = 27) experienced any adverse event (RR, 0.72; 95% CI, 0.48-1.06). CONCLUSIONS AND RELEVANCE Significant practice variation exists among surgeons in the management of pediatric complicated appendicitis. In our institution, a CPG that standardized practice patterns was associated with reduced resource use and improved patient outcomes. Most surgeons had very high compliance with the CPG.