Facilitating Repeat Intracarotid Injections in Mouse Models by a Novel Injection Site Repair Technique.

Given recent advances in the delivery of novel antitumor therapeutics using endovascular selective intraarterial delivery methods in neuro-oncology, there is an urgent need to develop methods for intracarotid injections in mouse models, including methods to repair the carotid artery in mice after injection to allow for subsequent injections. We developed a method of intracarotid injection in a mouse model to deliver therapeutics into the internal carotid artery (ICA) with two alternative procedures. During injection, the needle is inserted into the common carotid artery (CCA) after tying a suture around the external carotid artery (ECA) and injected therapeutics are delivered into the ICA. Following injection, the common carotid artery (CCA) can be ligated, which limits the number of intracarotid injections to one. The alternative procedure described in this article includes a modification where intracarotid artery injection is followed by injection site repair of the CCA, which restores blood flow within the CCA and avoids the complication of cerebral ischemia seen in some mouse models. We also compared the delivery of bone marrow-derived human mesenchymal stem cells (BM-hMSCs) to intracranial tumors when delivered through intracarotid injection with and without injection site repair following the injection. Delivery of BM-hMSCs does not differ significantly between the methods. Our results demonstrate that injection site repair of the CCA allows for repeat injections through the same artery and does not impair the delivery and distribution of injected material, thus providing a model with greater flexibility that more closely emulates intracarotid injection in humans.

Tumor treating fields suppress tumor cell growth and neurologic decline in models of spinal metastases.

Spinal metastases can result in severe neurologic compromise and decreased overall survival. Despite treatment advances, local disease progression is frequent, highlighting the need for novel therapies. Tumor treating fields (TTFields) impair tumor cell replication and are influenced by properties of surrounding tissue. We hypothesized that bone's dielectric properties will enhance TTFields-mediated suppression of tumor growth in spinal metastasis models. Computational modeling of TTFields intensity was performed following surgical resection of a spinal metastasis and demonstrated enhanced TTFields intensity within the resected vertebral body. Additionally, luciferase-tagged human KRIB osteosarcoma and A549 lung adenocarcinoma cell lines were cultured in demineralized bone grafts and exposed to TTFields. Following TTFields exposure, the bioluminescence imaging (BLI) signal decreased to 10%-80% of baseline, while control cultures displayed a 4.48- to 9.36-fold increase in signal. Lastly, TTFields were applied in an orthotopic murine model of spinal metastasis. After 21 days of treatment, control mice demonstrated a 5-fold increase in BLI signal compared with TTFields-treated mice. TTFields similarly prevented tumor invasion into the spinal canal and development of neurologic symptoms. Our data suggest that TTFields can be leveraged as a local therapy within minimally conductive bone of spinal metastases. This provides the groundwork for future studies investigating TTFields for patients with treatment-refractory spinal metastases.

Development of a rabbit human glioblastoma model for testing of endovascular selective intra-arterial infusion (ESIA) of novel stem cell-based therapeutics.

BACKGROUND: Endovascular selective intra-arterial (ESIA) infusion of cellular oncotherapeutics is a rapidly evolving strategy for treating glioblastoma. Evaluation of ESIA infusion requires a unique animal model. Our goal was to create a rabbit human GBM model to test IA infusions of cellular therapies and to test its usefulness by employing clinical-grade microcatheters and infusion methods to deliver mesenchymal stem cells loaded with an oncolytic adenovirus, Delta-24-RGD (MSC-D24). METHODS: Rabbits were immunosuppressed with mycophenolate mofetil, dexamethasone, and tacrolimus. They underwent stereotactic xenoimplantation of human GBM cell lines (U87, MDA-GSC-17, and MDA-GSC-8-11) into the right frontal lobe. Tumor formation was confirmed on magnetic resonance imaging, histologic, and immunohistochemistry analysis. Selective microcatheter infusion of MSC-D24 was performed via the ipsilateral internal carotid artery to assess model utility and the efficacy and safety of this approach. RESULTS: Twenty-five rabbits were implanted (18 with U87, 2 MDA-GSC-17, and 5 MDA-GSC-8-11). Tumors formed in 68% of rabbits (77.8% for U87, 50.0% for MDA-GSC-17, and 40.0% for MDA-GSC-8-11). On MRI, the tumors were hyperintense on T2-weighted image with variable enhancement (evidence of blood brain barrier breakdown). Histologically, tumors showed phenotypic traits of human GBM including varying levels of vascularity. ESIA infusion into the distal internal carotid artery of 2 ml of MSCs-D24 (107 cells) was safe in the model. Examination of post infusion specimens documented that MSCs-D24 homed to the implanted tumor at 24 hours. CONCLUSIONS: The intracranial immunosuppressed rabbit human GBM model allows testing of ESIA infusion of novel therapeutics (eg, MSC-D24) in a clinically relevant fashion.

Tumor-specific polycistronic miRNA delivered by engineered exosomes for the treatment of glioblastoma.

BACKGROUND: Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for GBM, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs. METHODS: We conducted an unbiased screen of over 600 miRs against 7 glioma stem cell (GSC) lines representing all GBM subtypes to identify a set of pan-subtype-specific anti-GBM miRs and then used available TCGA GBM patient outcomes and miR expression data to hone in on miRs that were most likely to be clinically effective. To enhance delivery and expression of the miRs, we generated a polycistronic plasmid encoding 3 miRs (pPolymiR) and used HEK293T cells as biofactories to package pPolymiR into engineered exosomes (eExos) that incorporate viral proteins (Gag/VSVg) in their structure (eExos+pPolymiR) to enhance function. RESULTS: Our stepwise screen identified miR-124-2, miR-135a-2, and let-7i as the most effective miRs across all GBM subtypes with clinical relevance. Delivery of eExos+pPolymiR resulted in high expression of all 3 miRs in GSCs, and significantly decreased GSC proliferation in vitro. eExos+pPolymiR prolonged survival of GSC-bearing mice in vivo when compared with eExos carrying each of the miRs individually or as a cocktail. CONCLUSION: eExos+pPolymiR, which includes a pan-subtype anti-glioma-specific miR combination encoded in a polycistronic plasmid and a novel exosome delivery platform, represents a new and potentially powerful anti-GBM therapeutic.

Characterization of patient-derived bone marrow human mesenchymal stem cells as oncolytic virus carriers for the treatment of glioblastoma.

OBJECTIVE: Delta-24-RGD is an oncolytic adenovirus that is capable of replicating in and killing human glioma cells. Although intratumoral delivery of Delta-24-RGD can be effective, systemic delivery would improve its clinical application. Bone marrow-derived human mesenchymal stem cells (BM-hMSCs) obtained from healthy donors have been investigated as virus carriers. However, it is unclear whether BM-hMSCs can be derived from glioma patients previously treated with marrow-toxic chemotherapy or whether such BM-hMSCs can deliver oncolytic viruses effectively. Herein, the authors undertook a prospective clinical trial to determine the feasibility of obtaining BM-hMSCs from patients with recurrent malignant glioma who were previously exposed to marrow-toxic chemotherapy. METHODS: The authors enrolled 5 consecutive patients who had been treated with radiation therapy and chemotherapy. BM aspirates were obtained from the iliac crest and were cultured to obtain BM-hMSCs. RESULTS: The patient-derived BM-hMSCs (PD-BM-hMSCs) had a morphology similar to that of healthy donor-derived BM-hMSCs (HD-BM-hMSCs). Flow cytometry revealed that all 5 cell lines expressed canonical MSC surface markers. Importantly, these cultures could be made to differentiate into osteocytes, adipocytes, and chondrocytes. In all cases, the PD-BM-hMSCs homed to intracranial glioma xenografts in mice after intracarotid delivery as effectively as HD-BM-hMSCs. The PD-BM-hMSCs loaded with Delta-24-RGD (PD-BM-MSC-D24) effectively eradicated human gliomas in vitro. In in vivo studies, intravascular administration of PD-BM-MSC-D24 increased the survival of mice harboring U87MG gliomas. CONCLUSIONS: The authors conclude that BM-hMSCs can be acquired from patients previously treated with marrow-toxic chemotherapy and that these PD-BM-hMSCs are effective carriers for oncolytic viruses.

An immune-competent, replication-permissive Syrian Hamster glioma model for evaluating Delta-24-RGD oncolytic adenovirus.

BACKGROUND: Oncolytic adenoviruses are promising new treatments against solid tumors, particularly for glioblastoma (GBM), and preclinical models are required to evaluate the mechanisms of efficacy. However, due to the species selectivity of adenovirus, there is currently no single animal model that supports viral replication, tumor oncolysis, and a virus-mediated immune response. To address this gap, we took advantage of the Syrian hamster to develop the first intracranial glioma model that is both adenovirus replication-permissive and immunocompetent. METHODS: We generated hamster glioma stem-like cells (hamGSCs) by transforming hamster neural stem cells with hTERT, simian virus 40 large T antigen, and h-RasV12. Using a guide-screw system, we generated an intracranial tumor model in the hamster. The efficacy of the oncolytic adenovirus Delta-24-RGD was assessed by survival studies, and tumor-infiltrating lymphocytes (TILs) were evaluated by flow cytometry. RESULTS: In vitro, hamGSCs supported viral replication and were susceptible to Delta-24-RGD mediated cell death. In vivo, hamGSCs consistently developed into highly proliferative tumors resembling high-grade glioma. Flow cytometric analysis of hamster gliomas revealed significantly increased T-cell infiltration in Delta-24-RGD infected tumors, indicative of immune activation. Treating tumor-bearing hamsters with Delta-24-RGD led to significantly increased survival compared to hamsters treated with phosphate buffered saline (PBS). CONCLUSIONS: This adenovirus-permissive, immunocompetent hamster glioma model overcomes the limitations of previous model systems and provides a novel platform to study the interactions between tumor cells, the host immune system, and oncolytic adenoviral therapy; understanding of which will be critical to implementing oncolytic adenovirus in the clinic.

RNAi technology targeting the FGFR3-TACC3 fusion breakpoint: an opportunity for precision medicine.

BACKGROUND: Fusion genes form as a result of abnormal chromosomal rearrangements linking previously separate genes into one transcript. The FGFR3-TACC3 fusion gene (F3-T3) has been shown to drive gliomagenesis in glioblastoma (GBM), a cancer that is notoriously resistant to therapy. However, successful targeting of F3-T3 via small molecular inhibitors has not revealed robust therapeutic responses, and specific targeting of F3-T3 has not been achieved heretofore. Here, we demonstrate that depleting F3-T3 using custom siRNA to the fusion breakpoint junction results in successful inhibition of F3-T3+ GBMs, and that exosomes can successfully deliver these siRNAs. METHODS: We engineered 10 unique siRNAs (iF3T3) that specifically spanned the most common F3-T3 breakpoint with varying degrees of overlap, and assayed depletion by qPCR and immunoblotting. Cell viability assays were performed. Mesenchymal stem cell-derived exosomes (UC-MSC) were electroporated with iF3T3, added to cells, and F3-T3 depletion measured by qPCR. RESULTS: We verified that depleting F3-T3 using shRNA to FGFR3 resulted in decreased cell viability and improved survival in glioma-bearing mice. We then demonstrated that 7/10 iF3T3 depleted F3-T3, and importantly, did not affect levels of wild-type (WT) FGFR3 or TACC3. iF3T3 decreased cell viability in both F3T3+ GBM and bladder cancer cell lines. UC-MSC exosomes successfully delivered iF3T3 in vitro, resulting in F3-T3 depletion. CONCLUSION: Targeting F3-T3 using siRNAs specific to the fusion breakpoint is capable of eradicating F3T3+ cancers without toxicity related to inhibition of WT FGFR3 or TACC3, and UC-MSC exosomes may be a plausible vehicle to deliver iF3T3.

Contemporary trends in the use of primary repair for gastroschisis in surgical infants.

BACKGROUND: Gastroschisis is a newborn anomaly requiring emergent surgical intervention. We review our experience with gastroschisis to examine trends in contemporary surgical management. METHODS: Infants who underwent initial surgical management of gastroschisis from 1996 to 2014 at a pediatric hospital were reviewed. Closure techniques included primary fascial repair using suture or sutureless umbilical closure, and staged repair using sutured or spring-loaded silo (SLS). Data were separated into 3 clinical eras: pre-SLS (1996 to 2004), SLS (2005 to 2008), and umbilical closure (2009 to 2014). RESULTS: In the pre-SLS era, 60% (34/57) of infants with gastroschisis underwent primary repair. With the advent of SLS, there was a decrease in primary repair (15%, 10/68, P < .0001). Following introduction of sutureless umbilical closure, 61% (47/77) of infants have undergone primary repair. On multivariate regression, primary repair was associated with shorter intensive care unit stays (P < .001) and time to initiate enteral nutrition (P < .01). CONCLUSIONS: Following introduction of a less invasive technique for gastroschisis repair, most infants with gastroschisis were able to be repaired primarily. Primary repair should be considered in all babies with gastroschisis and favorable anatomy.

Thyroid surgery in children.

Although surgical conditions of the thyroid gland are uncommon in children, the increased incidence of thyroid cancer, combined with the fact that children's hospitals are increasingly treating older adolescents, means that it is important that all pediatric surgeons have a knowledge of these conditions. Abnormalities of the thyroid can be associated with abnormalities of thyroid function (hyperthyroidism or hypothyroidism) and/or can be associated with symmetrical or asymmetrical enlargement of the gland.

Reversible left recurrent laryngeal nerve palsy in pediatric Graves' disease.

Vocal cord paralysis associated with goiter usually indicates the presence of a malignancy. Pediatric patients retain significant thymic tissue that regresses only later in life. This thymic tissue can develop significant hyperplasia during an acute autoimmune process. We describe a case of a 17-year-old girl who presented with a goiter secondary to severe Graves' disease and a 2-month history of hoarseness, choking on liquid intake, and small-volume vomiting especially after eating. She demonstrated a left vocal cord paralysis probably secondary to a unilateral left recurrent laryngeal nerve palsy. A marked enlargement of the thymus was discovered on thoracic imaging. Treatment was initiated with methimazole, with near complete remission of her vocal cord paralysis within 3 months. Given the immunomodulatory effects of methimazole, a potential mechanism of the left recurrent laryngeal nerve palsy was autoimmune hyperstimulation of the thymus and consequent hyperplasia, resulting in distension of the nerve. Attenuation of the hyperactive immune process with methimazole may have resulted in regression of the mass effect of the thymus and associated reduction of the nerve distension. This case illustrates the unique risk of left recurrent laryngeal nerve palsy in pediatric patients with an acute immune stimulation and hyperplasia of the thymus and the reversibility in the context of mitigation of the immune hyperactivity. Methimazole may be an optimal initial treatment choice in pediatric patients with Graves' disease and left recurrent laryngeal nerve palsy.

Role of bottle feeding in the etiology of hypertrophic pyloric stenosis.

IMPORTANCE Bottle feeding has been implicated in the etiology of hypertrophic pyloric stenosis (HPS). Further data are needed to define the nature of this relationship and the clinical variables that influence it. OBJECTIVE To determine if bottle feeding after birth is associated with the development of HPS in infants. We hypothesized that bottle feeding is associated with an increased risk of HPS and that this risk is modified by other risk factors. DESIGN, SETTING, AND PARTICIPANTS Population-based case-control study of births from January 1, 2003, to December 31, 2009, using Washington State birth certificates linked to hospital discharge data. Cases included all singleton infants born within the study period and subsequently admitted with both a diagnostic code for HPS and a procedure code for pyloromyotomy (n = 714). Controls were randomly chosen among singleton infants who did not develop HPS and were frequency matched to cases by birth year. EXPOSURE Feeding status (breast vs bottle) was coded on the birth certificate as the type of feeding the infant was receiving at birth discharge. MAIN OUTCOME AND MEASURE Diagnosis of HPS. RESULTS Hypertrophic pyloric stenosis incidence decreased over time, from 14 per 10,000 births in 2003 to 9 per 10,000 in 2009. Simultaneously, breastfeeding prevalence increased from 80% in 2003 to 94% in 2009. Compared with controls, cases were more likely to be bottle feeding after birth (19.5% vs 9.1%). After adjustment, bottle feeding was associated with an increased risk of HPS (odds ratio [OR], 2.31; 95% CI, 1.81-2.95). This association did not differ according to sex or maternal smoking status but was significantly modified by maternal age (<20 years OR, 0.98; 95% CI, 0.51-1.88; ≥35 years OR, 6.07; 95% CI, 2.81-13.10) and parity (nulliparous OR, 1.60; 95% CI, 1.07-2.38; multiparous OR, 3.42; 95% CI, 2.23-5.24). CONCLUSIONS AND RELEVANCE Bottle feeding is associated with an increased risk of HPS, and this effect seems to be most important in older and multiparous women. These data suggest that bottle feeding may play a role in HPS etiology, and further investigations may help to elucidate the mechanisms underlying the observed effect modification by age and parity.

Congenital abdominal wall defects and reconstruction in pediatric surgery: gastroschisis and omphalocele.

The embryology, epidemiology, associated anomalies, prenatal course and the neonatal and surgical care of newborns with gastroschisis and omphalocele are reviewed. For gastroschisis temporary intestinal coverage is often done before a more definitive operative closure that may be immediate or delayed. Outcomes in gastroschisis are determined by associated bowel injury. For omphalocele small defects are closed primarily while large defects are treated topically to allow initial skin coverage before a later definitive closure. Outcomes for omphalocele are determined mainly by the presence of associated anomalies.

Time course of C-reactive protein and inflammatory mediators after neonatal surgery.

OBJECTIVE: To characterize the perioperative course of C-reactive protein (CRP) and inflammatory mediators in neonates ≤44 weeks' corrected gestational age. STUDY DESIGN: Prospective study of CRP and inflammatory mediators interleukin (IL)-1ß, IL-6, IL-8, IL-10, and tumor necrosis factor-α in 55 neonates undergoing thoracic or abdominal surgery. RESULTS: In the absence of infection, CRP increased after surgery, peaking on post-operative day 2. The perioperative patterns of CRP differed by diagnosis and inflammatory state. Surgery alone did not cause an increase in CRP because in 13 of 55 infants (24%), CRP remained <1.0 mg/dL at all time points. For thoracic procedures, patent ductus arteriosus ligation showed the least post-operative increase in CRP, and patients undergoing repair of congenital diaphragmatic hernia or tracheoesophageal fistula had a greater response. Abdominal procedures with low CRP response included repair of imperforate anus and pyloric stenosis, while gastroschisis repair and bowel reanastomosis after necrotizing enterocolitis were accompanied by a robust CRP response. IL-6 concentrations peaked on post-operative day 1 and correlated with the post-operative day 2 CRP peak (r=0.398, P=.004). The additional inflammatory mediators measured were not informative. CONCLUSIONS: The range and time course of perioperative CRP differ by diagnosis. Serial measurements may be more informative than CRP magnitude.

Complications as a result of the Heimlich maneuver.

The Heimlich maneuver is a well-described emergency procedure for management of foreign body airway obstructions. Although rare, complications of the Heimlich maneuver do exist. The purpose of this report is to review the known complications of this procedure. All reported complications published in English on Medline and PubMed were reviewed. Additionally, we present a rare case of acute pancreatitis with associated pseudocyst formation after the administration of the Heimlich maneuver on a healthy 3-year-old boy. Although life saving, the Heimlich maneuver may be associated with significant complications; thus, symptomatic patients after this maneuver should be thoroughly evaluated with appropriate laboratory and radiographic studies.

Initial nonoperative management and delayed closure for treatment of giant omphaloceles.

PURPOSE: Traditional treatment of giant omphaloceles with silo closure has been associated with respiratory insufficiency, hemodynamic compromise, dehiscence, and inability to close the abdomen with subsequent death. To minimize such complications, initial nonoperative management with delayed closure of the defect has been used. METHODS: Between January 1981 and December 2002, 111 patients with omphaloceles were treated. Twenty-two patients with giant omphaloceles (19 containing liver) underwent initial nonoperative management consisting of silver sulfadiazine dressing changes. After pulmonary and other comorbidities stabilized, the contents were gradually reduced with a loose elastic bandage, and delayed closure was planned at 6 to 12 months. The medical records of these 22 patients were retrospectively reviewed to determine the efficacy and safety of this technique in the setting of severe associated anomalies. Those 15 patients (n = 15) from the latter 10 years were further reviewed to determine additional end points (length of hospital stay, length of intensive care unit stay, duration of mechanical ventilation, time to feed, time to closure, and type of closure). RESULTS: Of the 15 patients treated during the latter 10 years, mean gestational age and birth weight were 38 +/- 1.4 weeks and 3.1 +/- 0.57 kg, respectively. Median length of stay after birth was 20 days (range, 5-239 days). Median time to full diet was 8 days (range, 4-80 days). Four patients were discharged on oral feedings only, 7 with combination oral/gavage, and 4 with tube feedings. Pulmonary hypoplasia or pulmonary hypertension was present in 11 (50%) of 22 patients. There were 11 patients with major cardiac anomalies, 14 with a patent ductus arteriosus, and 8 with a patent foramen ovale. Three early complications (2 ruptured sacs and 1 bleeding sac) and 1 late complication (gastric necrosis) occurred in the initial nonoperative period. In addition, 4 patients were treated for line sepsis, 1 patient for acute renal insufficiency, and 1 for aspiration pneumonia. Three patients required tracheostomy and were discharged with home ventilators. There were no complications associated with the use of silver sulfadiazine. Of the 22 patients, 16 have undergone delayed repair, 2 did not require repair, 1 is awaiting repair, 2 died before closure, and 1 was lost to follow-up. Delayed closure was achieved at a median age of 14 months (range, 2-28 months) and mean weight of 8.8 +/- 3.3 kg. Four patients required implantation of mesh for definitive closure. Median postoperative length of stay was 4 days (range, 2-21 days). Postoperative complications included prolonged ileus, recurrent ventral hernia, and prolonged intubation. Overall mortality rate was 9.1%. One death occurred after diaphragmatic hernia repair, and 1 death was from overwhelming sepsis in the patient with a late gastric perforation. CONCLUSION: The use of silver sulfadiazine dressing changes for initial nonoperative management of giant omphaloceles is a safe and effective bridge to delayed closure. We recommend this method as initial nonoperative management given the high incidence of associated cardiopulmonary malformations because it may facilitate enteral feeding, minimize respiratory compromise, and reduce morbidity and mortality.

The anomalous splenic vein: a case report and review of the literature.

The spleen arises from a mesenchymal bulge at the 6-mm stage of development. There are a wide variety of splenic anomalies and variations that range from benign to clinically significant, and this article presents a brief review of splenic embryology and a case report of an anomalous splenic vein that precluded the formation of a Nissen fundoplication.

Pyloromyotomy: a comparison of laparoscopic, circumumbilical, and right upper quadrant operative techniques.

BACKGROUND: Ramstedt pyloromyotomy through a right upper quadrant (RUQ) transverse incision has been the traditional treatment for hypertrophic pyloric stenosis. Recently, laparoscopic (LAP) and circumumbilical (UMB) approaches have been introduced as alternative methods to improve cosmesis, but concerns about greater operative times, costs, and complications remain. This study compares the three operative techniques and examines their advantages and complication rates. STUDY DESIGN: We performed a retrospective review of patients undergoing pyloromyotomy at a children's hospital between January 1997 and June 2003. RESULTS: Two hundred ninety patients underwent pyloromyotomy by LAP (n = 51), RUQ (n = 190), or UMB (n = 49). Complication rate, time to ad libitum feeding, incidence of emesis, and postoperative length of stay did not differ considerably among groups. Two LAP patients were converted to RUQ. Mucosal perforation occurred in three patients each in the RUQ and UMB groups, but none in the LAP group. Operative times were considerably less for LAP (25 +/- 9 minutes) than for RUQ (32 +/- 9 minutes) and UMB (42 +/- 12 minutes) (p < 0.05, ANOVA, Bonferroni). Charges related to operations and anesthesia were considerably greater for UMB (operation: US 1,574 dollars +/- US 433 dollars; anesthesia: US 731 dollars +/- US 190 dollars) compared with the other two groups (p < 0.05, ANOVA, Bonferroni), but did not differ between LAP (operation: US 1,299 dollars +/- US 311 dollars; anesthesia: US 586 dollars +/- US 137 dollars) and RUQ (operation: US 1,237 dollars +/- US 411 dollars; anesthesia: US 578 dollars +/- US 167 dollars). Data are presented as mean +/- SD. CONCLUSIONS: Advantages of LAP include a shorter mean operative time without higher complications or costs. UMB is associated with the greatest mean operative time and costs. Laparoscopic pyloromyotomy is a safe and effective approach to the treatment of hypertrophic pyloric stenosis.

Fraternal twins with Morgagni hernias.

Fraternal twins with identical left-sided foramen of Morgagni hernias are described. The occurrence of this rare type of congenital diaphragmatic hernia in twins suggests that genetic factors play a role in the formation of this lesion.