Peter F. Nichol

Radioguided parathyroidectomy in patients with secondary and tertiary hyperparathyroidism.

BACKGROUND To date there have been no reports on the feasibility of radioguided parathyroidectomy (RGP) in patients with secondary and tertiary hyperparathyroidism. METHODS Twenty-three consecutive patients with secondary (n=5) or tertiary hyperparathyroidism (n=18) underwent RGP. Patients were injected with 10 mCi of technetium 99-sestamibi before surgery. All parathyroid glands were localized during operation with a neoprobe. RESULTS The mean patient age was 50+/-3 years. The mean preoperative calcium and intact parathyroid hormone levels were 11.0+/-0.3 mg/dL and 400+/-107 pg/mL, respectively. Eighteen patients had 3- or 4-gland hyperplasia, 2 had double adenomas, 2 had forearm graft hyperplasia, 1 had 6-gland disease, and 3 had ectopic glands. All hyperplastic glands had ex vivo counts >20% of background (mean, 63%+/-6%), making frozen section unnecessary. When compared with 66 historical control subjects who underwent surgery without radioguidance for tertiary hyperparathyroidism, patients undergoing RGP had decreased operative times (96+/-8 minutes vs 151+/-15 minutes; P<.001) and lengths of stay (1.3+/-0.1 days vs 3.7+/-0.3 days; P<.001). CONCLUSIONS RGP in patients with secondary and tertiary hyperparathyroidism is feasible, may reduce operative time, and permits omission of frozen section. Thus RGP appears to be a useful adjunct in the treatment of secondary and tertiary hyperparathyroidism.

Long-Term Follow-Up of Patients With Tertiary Hyperparathyroidism Treated by Resection of a Single or Double Adenoma

ObjectiveTo determine whether patients with tertiary hyperparathyroidism due to single- or two-gland disease undergoing limited resection have similar long-term outcomes compared with patients with hyperplasia undergoing subtotal or total parathyroidectomy. Summary Background DataTertiary hyperparathyroidism occurs in less than 2% of patients after renal transplantation. Approximately 30% of these cases are caused by one or two hyperfunctioning glands. Nevertheless, the standard operation for this disease has been subtotal or total parathyroidectomy with autotransplantation. MethodsSeventy-one patients underwent surgery for tertiary hyperparathyroidism. At the time of surgery, 19 patients who had a single or double adenoma underwent limited resection of the enlarged glands only (adenoma group). The remaining 52 patients with three- or four-gland hyperplasia had subtotal or total parathyroidectomy with implantation (hyper group). Long-term cure rates between the two groups were compared. ResultsIn the adenoma group, 7 patients had a single adenoma and 12 underwent resection of a double adenoma. In the hyper group, 49 patients had subtotal and 3 had total parathyroidectomies. After surgery, 70 of 71 patients (99%) were cured of their hypercalcemia. The incidence of postoperative transient hypocalcemia was significantly higher in the hyper group (27% vs. 5%). No patients in either group had permanent hypocalcemia requiring long-term supplementation. With up to 16 years of follow-up, there have been no recurrences in the adenoma group, whereas three patients (6%) in the hyper group have had recurrent or persistent hyperparathyroidism. ConclusionsPatients with tertiary hyperparathyroidism who underwent limited resection of a single or double adenoma only had equivalent long-term cure rates compared with patients undergoing more extensive resections. Therefore, the authors recommend in patients with tertiary hyperparathyroidism and enlargement of only one or two parathyroid glands that the resection be limited to these abnormal glands only.

What is the optimal treatment for children with primary hyperparathyroidism

PURPOSE Little information exists regarding the optimal surgical treatment of pediatric primary hyperparathyroidism. We hypothesized that primary hyperparathyroidism in children, in the absence of a family history, is caused by single-gland disease and is amenable to minimally invasive parathyroidectomy (MIP). METHODS We reviewed the records of individuals younger than 25 years who underwent parathyroidectomy in a prospectively collected database at a single tertiary hospital from 2003 to 2009. RESULTS Twenty-five patients were identified, with a mean (SD) age of 19 (3.7) years. Sixty percent had single-gland disease (n = 15). Familial disease was present in 6 patients. All of the children younger than 18 years without a family history of disease (9/9) were found to have a single-gland disease (P < .001). Seventy-eight percent of patients without a family history were successfully treated without a bilateral exploration. Average length of stay was less than 1 day with no complications or recurrences. CONCLUSIONS Primary hyperparathyroidism in patients younger than 18 years without a family history was uniformly caused by single-gland disease. Minimally invasive parathyroidectomy was successful in these patients and avoided the morbidity of bilateral exploration. We recommend MIP be used in pediatric patients at large referral centers with prior successful institutional experience with the technique.

Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of Teduglutide in Pediatric Short Bowel Syndrome

Objective To determine safety and pharmacodynamics/efficacy of teduglutide in children with intestinal failure associated with short bowel syndrome (SBS‐IF). Study design This 12‐week, open‐label study enrolled patients aged 1‐17 years with SBS‐IF who required parenteral nutrition (PN) and showed minimal or no advance in enteral nutrition (EN) feeds. Patients enrolled sequentially into 3 teduglutide cohorts (0.0125 mg/kg/d [n = 8], 0.025 mg/kg/d [n = 14], 0.05 mg/kg/d [n = 15]) or received standard of care (SOC, n = 5). Descriptive summary statistics were used. Results All patients experienced ≥1 treatment‐emergent adverse event; most were mild or moderate. No serious teduglutide‐related treatment‐emergent adverse events occurred. Between baseline and week 12, prescribed PN volume and calories (kcal/kg/d) changed by a median of −41% and −45%, respectively, with 0.025 mg/kg/d teduglutide and by −25% and −52% with 0.05 mg/kg/d teduglutide. In contrast, PN volume and calories changed by 0% and −6%, respectively, with 0.0125 mg/kg/d teduglutide and by 0% and −1% with SOC. Per patient diary data, EN volume increased by a median of 22%, 32%, and 40% in the 0.0125, 0.025, and 0.05 mg/kg/d cohorts, respectively, and by 11% with SOC. Four patients achieved independence from PN, 3 in the 0.05 mg/kg/d cohort and 1 in the 0.025 mg/kg/d cohort. Study limitations included its short‐term, open‐label design, and small sample size. Conclusions Teduglutide was well tolerated in pediatric patients with SBS‐IF. Teduglutide 0.025 or 0.05 mg/kg/d was associated with trends toward reductions in PN requirements and advancements in EN feeding in children with SBS‐IF. Trial registration ClinicalTrials.gov: NCT01952080; EudraCT: 2013‐004588‐30.

Conditional mutation of fibroblast growth factor receptors 1 and 2 results in an omphalocele in mice associated with disruptions in ventral body wall muscle formation

BACKGROUND/PURPOSE We observed that fibroblast growth factor receptors 1 and 2 (Fgfr1, Fgfr2) are expressed during abdominal wall development in mice and hypothesized that conditional mutation of these genes would result in abdominal wall defects. METHODS Section in situ hybridizations were performed for Fgfr1 and Fgfr2 on wild-type embryos at embryonic day (E) 11.5 and E13.5. Conditional mutation of Fgfr1and Fgfr2 was achieved with a tamoxifen inducible Cre at E8.5. Litters were harvested at E17.5, whole mount photographs were taken, and paraffin sections were generated and stained with hematoxylin and eosin. RESULTS Fgfr1 was expressed in ectoderm, lateral plate mesoderm, and myoblasts, whereas Fgfr2 was expressed almost exclusively in the early dermis and ectoderm of the abdominal wall. Conditional mutation of both Fgfr2 alleles and one Fgfr1 allele resulted in omphalocele in 38.7% of mutants. Histologic examination in mutants demonstrated disruptions in dermal and muscle development. CONCLUSIONS Mutant embryos with omphalocele arising from mutation in Fgfr1 and Fgfr2 exhibit disruptions in the development of the secondary abdominal wall structures. These findings are consistent with a model of ventral abdominal wall development in which organization of the muscles and connective tissue (secondary abdominal wall structures) is influenced by positional information emanating from the primary abdominal wall.

Humans, Mice, and Mechanisms of Intestinal Atresias: A Window into Understanding Early Intestinal Development

IntroductionIntestinal atresias have long been hypothesized to result from either failure of recanalization of the intestinal lumen or in utero vascular accidents. Recent work in animal models is now calling for a reassessment of these widely held paradigms.PurposeIn this review, we will examine the data that led to the original hypotheses and then evaluate more recent work challenging these hypotheses. Furthermore, we will discuss how defining the mechanism of atresia formation in animal models may provide insight into early intestinal development and the mechanism of lengthwise intestinal growth.ConclusionSuch insight will be critical in developing regenerative therapies for patients with intestinal failure.

Clinical considerations in gastroschisis: incremental advances against a congenital anomaly with severe secondary effects.

Gastroschisis is one of the most challenging congenital anomalies that physicians treat in the first 2 months of life. Over the last 40 years, tremendous progress has been made in the management of this defect. Survival has increased significantly during this period as well. However, gastroschisis still presents the clinician with a unique set of challenges as a result of secondary effects on intestinal development. These challenges or clinical considerations are discussed in this review including a history of the management of the defect, prenatal counseling, prenatal intervention, postnatal and surgical management, complications and long‐term outcomes.

A call for a standardized definition of perforated appendicitis.

BACKGROUND Abscess rates have been reported to be as low as 1% and as high as 50% following perforated appendicitis (PA). This range may be because of lack of universal definition for PA. An evidence-based definition (EBD) is crucial for accurate wound classification, risk-stratification, and subsequent process optimization. ACS NSQIP-Pediatric guidelines do not specify a definition of PA. We hypothesize that reported postoperative abscess rates underrepresent true incidence, as they may include low-risk cases in final calculations. METHODS Local institutional records of PA patients were reviewed to calculate the postoperative abscess rate. The ACS NSQIP-Pediatric participant use file (PUF) was used to determine cross-institutional postoperative abscess rates. A PubMed literature review was performed to identify trials reporting PA abscess rates, and definitions and rates were recorded. RESULTS 20.9% of our patients with PA developed a postoperative abscess. The ACS NSQIP-Pediatric abscess rate was significantly lower (7.61%, p<0.001). In the eighteen published studies analyzed, average abscess rate (14.49%) was significantly higher than ACS NSQIP-Pediatric (p<0.001). There was significantly more variation in trials that do not employ an EBD of perforation (Levenes test F-value =6.980, p=0.018). CONCLUSIONS A standard EBD of perforation leads to lower variability in reported postoperative abscess rates following PA. Nonstandard definitions may be significantly altering the aggregate rate of postoperative abscess formation. We advocate for adoption of a standard definition by all institutions participating in ACS NSQIP-Pediatric data submission. LEVEL OF EVIDENCE III.

A more efficient method to generate null mutants using Hprt-Cre with floxed alleles

PURPOSE The generation of nonviable homozygous null mouse embryos from heterozygote null/+ breedings can be highly resource consuming, with only 25% of the embryos in the litter being null mutants. We hypothesized that (1) we could double the number of homozygous null mouse embryos in a litter without reducing litter size using Hypoxanthine-guanine phosphoribosyltransferase-Cre (Hprt)-Cre (which is active in the female germ line at the time of fertilization), and (2) these homozygous null mutants would be identical to mutants generated through traditional null/+ breedings. METHODS To test this hypothesis, we used a conditional allele Fgfr2IIIb(flox). This allele when recombined is identical to the Fgfr2IIIb(null) allele. An F1 generation of Fgfr2IIIb(rec/+); Hprt(Cre/+) females was created by mating Fgfr2IIIb(+/+); Hprt(cre)(/cre) females to a Fgfr2IIIb(flox/flox) male. The F1 females were then mated to a Fgfr2IIIb(flox/flox) male. F2 embryos were genotyped, and the morphology and histology of the lungs, intestine, limbs, and brain were analyzed. RESULTS The Hprt-Cre mating strategy results in 51% of pups being genotypic homozygous null embryos (85/166) vs 23% for the standard null/+ approach (38/167). These embryos did not express the Fgfr2IIIb transcript and were phenotypically identical to null embryos generated through standard null/+ breedings. CONCLUSIONS The Hprt-Cre mating strategy increases the number of homozygous mutant embryos in a litter without decreasing litter size. Embryos generated through this approach are phenotypically identical to those from standard heterozygous breedings. We recommend this approach to investigators using a model system that relies on the generation of homozygous null embryos.

Tapering duodenoplasty and Roux-en-Y duodenojejunostomy in the management of adult megaduodenum

CASE REPORT A 41-year-old man with a history of chronic diarrhea and fatty stools since childhood and an inability to gain weight presented with C6 and T3 vertebral fractures. A bone mineral density scan of the lumbar spine from L2 to L4 was 61% of predicted, which was 4.3 standard deviations below the mean for an individual his age. An extensive endocrine work-up revealed a parathyroid hormone level of 4.1 and a serum calcium level of 7.8 mg/dL with an albumin of 3.5 g/dL. Based on these findings, malabsorption of vitamin D was suspected to be the cause of his bone disease. He underwent an upper gastrointestinal series that revealed a massively dilated duodenum (Fig 1). The remainder of his gastrointestinal evaluation was unremarkable. Based on these finding and our clinical suspicion that his bone disease and malabsorption were a direct result of megaduodenum and bacterial overgrowth, the patient was surgically explored. The duodenum was approxi-