A Comparison of Perioperative Management of Anomalous Aortic Origin of a Coronary Artery Between an Adult and Pediatric Cardiac Center.

BACKGROUND: Anomalous aortic origin of a coronary artery (AAOCA) presents in varying age-groups. Assuming management algorithms differ between pediatric and adult institutions, we compared the perioperative management of patients with AAOCA at two such centers. METHODS: A retrospective review was conducted at a pediatric and an adult institution of patients 14 years or older who underwent surgical repair of AAOCA between January 2000 and May 2014. RESULTS: Twenty patients from the pediatric center (median age: 16.5 years, range: 14-18 years) and nine patients from the adult center (median age: 40 years, range: 37-52 years) were included. An anomalous aortic origin of a right coronary artery was the most frequent pathology at each institution. Chest pain was the most common presenting symptom at both institutions. Preoperative echocardiography was performed in 95% patients at the pediatric center and in 100% of patients at the adult center. Cardiac catheterization was utilized more frequently at the adult center, and cardiac magnetic resonance imaging more commonly employed at the pediatric center. Isolated coronary unroofing was performed in 19 of 20 cases at the pediatric center and in only 2 (22%) cases at the adult institution, both by congenitally trained cardiac surgeons. More concomitant cardiac procedures were performed at the adult center with associated longer operative times and hospital stays. CONCLUSION: Management strategies for AAOCA vary depending on both patient-specific factors and expertise of the managing team. Further studies are needed to optimally standardize diagnostic and treatment pathways regardless of location venue.

Delayed Diagnosis of Vesicouterine Fistula After Treatment for Mixed Urinary Incontinence: Menstrual Cup Management and Diagnosis.

INTRODUCTION: A vesicouterine fistula is a rare form of urogenital fistula, yet there is increasing prevalence in the United States because of the rising rate of cesarean deliveries. Vesicouterine fistulas have various presentations including menouria, hematuria, or urinary incontinence. CASE PRESENTATION: A 39-year-old multiparous woman presented with urine leakage after her third cesarean delivery. She had been treated for mixed urinary incontinence with overactive bladder medications and a midurethral sling with continued complaints of urine leakage. The patient noticed her symptoms of urine leakage improved during menses when she used a menstrual cup. After confirmation of vesicouterine fistula, the patient underwent robotic-assisted surgery and her symptoms of insensible urine leakage resolved. CONCLUSIONS: When evaluating women with urinary incontinence and a history of cesarean deliveries, use of menstrual cup may aid in the diagnosis of vesicouterine fistula. Robotic-assisted laparoscopic repair with tissue interposition flap is an efficacious minimally invasive method for treatment of vesicouterine fistula.

Postmastectomy radiation therapy and immediate autologous breast reconstruction: integrating perspectives from surgical oncology, radiation oncology, and plastic and reconstructive surgery.

BACKGROUND AND OBJECTIVES: The effect of postmastectomy radiation therapy (PMRT) on immediately reconstructed abdominal wall-based tissue remains imprecisely defined. We evaluated evidence from all fields involved in care of the breast cancer patient in order to advance a unified recommendation regarding this therapeutic sequence. METHODS: We performed a MEDLINE and manual reference search to identify studies of PMRT with immediate autologous breast reconstruction. Inclusion criteria required studies to describe patients, flaps, and complication rates. Analyses were based on a random effects model. Surgical and radiation oncology literature was reviewed. RESULTS: Eleven retrospective studies of 337 patients with an average follow-up of 18-60 months (out of 268 patients) were selected for inclusion. Overall rates of fat necrosis, revisional surgery, volume loss, and fibrosis/contracture ranged from 16.9% to 35.4%. One out of 260 patients experienced total flap loss. There was an increased probability of fat necrosis in the irradiated breast (OR = 3.13, 95% CI = 1.42-6.89, P = 0.005) among three studies with non-irradiated controls. Five studies evaluated aesthetics with variable outcomes. CONCLUSIONS: There is mixed evidence for the utility of PMRT with immediate autologous abdominal wall breast reconstruction. Further investigation requires prospective studies with collaboration among surgical oncologists, radiation oncologists, and plastic surgeons.

Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment.

Hedgehog (Hh) signaling is implicated in bone development and cellular transformation. Here we show that inhibition of Hh pathway activity inhibits tumor growth through effects on the microenvironment. Pharmacologic inhibition of the Hh effector Smoothened (Smo) increased trabecular bone in vivo and inhibited osteoclastogenesis in vitro. In addition, enhanced Hh signaling due to heterozygosity of the Hh inhibitory receptor Patched (Ptch1(+/-)) increased bone resorption, suggesting direct regulation of osteoclast (OC) activity by the Hh pathway. Ptch1(+/-) mice had increased bone metastatic and subcutaneous tumor growth, suggesting that increased Hh activation in host cells promoted tumor growth. Subcutaneous growth of Hh-resistant tumor cells was inhibited by LDE225, a novel orally bioavailable SMO antagonist, consistent with effects on tumor microenvironment. Knockdown of the Hh ligand Sonic Hh (SHH) in these cells decreased subcutaneous tumor growth and decreased stromal cell production of interleukin-6, indicating that tumor-derived Hh ligands stimulated tumor growth in a paracrine fashion. Together our findings show that inhibition of the Hh pathway can reduce tumor burden, regardless of tumor Hh responsiveness, through effects on tumor cells, OCs, and stromal cells within the tumor microenvironment. Hh may be a promising therapeutic target for solid cancers and bone metastases.

Persistent expression of activated Notch inhibits corticotrope and melanotrope differentiation and results in dysfunction of the HPA axis.

The hypothalamic-pituitary-adrenal (HPA) axis is an important regulator of energy balance, immune function and the body's response to stress. Signaling networks governing the initial specification of corticotropes, a major component of this axis, are not fully understood. Loss of function studies indicate that Notch signaling may be necessary to repress premature differentiation of corticotropes and to promote proliferation of pituitary progenitors. To elucidate whether Notch signaling must be suppressed in order for corticotrope differentiation to proceed and whether Notch signaling is sufficient to promote corticotrope proliferation, we examined the effects of persistent Notch expression in Pomc lineage cells. We show that constitutive activation of the Notch cascade inhibits the differentiation of both corticotropes and melanotropes and results in the suppression of transcription factors required for Pomc expression. Furthermore, persistent Notch signaling traps cells in the intermediate lobe of the pituitary in a progenitor state, but has no effect on pituitary proliferation. Undifferentiated cells are eliminated in the first two postnatal weeks in these mice, resulting in a modest increase in CRH expression in the paraventricular nucleus, hypoplastic adrenal glands and decreased stress-induced corticosterone levels. Taken together, these findings show that Notch signaling is sufficient to prevent corticotrope and melanotrope differentiation, resulting in dysregulation of the HPA axis.

Numb deletion in POMC-expressing cells impairs pituitary intermediate lobe cell adhesion, progenitor cell localization, and neuro-intermediate lobe boundary formation.

The pituitary gland contains six distinct hormone-secreting cell types that are essential for basic physiological processes including fertility and responding to stress. Formation of hormone-secreting cells during development relies on Notch signaling to prevent progenitors from prematurely differentiating. The nature of the signal curtailing Notch signaling in the pituitary is unknown, but a good candidate is the endocytic adaptor protein NUMB. NUMB targets Notch for proteolytic degradation, but it also has a broad range of actions, including stabilizing adherens junctions through interactions with cadherins and influencing cell proliferation by stabilizing expression of the tumor suppressor protein p53. Here, we show that NUMB and its closely related homolog, NUMBLIKE, are expressed in undifferentiated cells during development and later in gonadotropes in the anterior lobe and melanotropes of the intermediate lobe. All four isoforms of NUMB, are detectable in the pituitary, with the shorter forms becoming more prominent after adolescence. Conditionally deleting Numb and Numblike in the intermediate lobe melanotropes with Pomc Cre mice dramatically alters the morphology of cells in the intermediate lobe, coincident with impaired localization of adherens junctions proteins including E-CADHERIN, N-CADHERIN, ß-CATENIN, and α-CATENIN. Strikingly, the border between posterior and intermediate lobes is also disrupted. These mice also have disorganized progenitor cells, marked by SOX2, but proliferation is unaffected. Unexpectedly, Notch activity appears normal in conditional knockout mice. Thus, Numb is critical for maintaining cell-cell interactions in the pituitary intermediate lobe that are essential for proper cell placement.

Cellular mechanism of decreased bone in Brtl mouse model of OI: imbalance of decreased osteoblast function and increased osteoclasts and their precursors.

The Brtl mouse, a knock-in model for moderately severe osteogenesis imperfecta (OI), has a G349C substitution in half of type I collagen alpha1(I) chains. We studied the cellular contribution to Brtl bone properties. Brtl cortical and trabecular bone are reduced before and after puberty, with BV/TV decreased 40-45%. Brtl ObS/BS is comparable to wildtype, and Brtl and wildtype marrow generate equivalent number of colony-forming units (CFUs) at both ages. However, OcS/BS is increased in Brtl at both ages (36-45%), as are TRACP(+) cell numbers (57-47%). After puberty, Brtl ObS/BS decreases comparably to wildtype mice, but osteoblast matrix production (MAR) decreases to one half of wildtype values. In contrast, Brtl OcS falls only moderately (approximately 16%), and Brtl TRACP staining remains significantly elevated compared with wildtype. Consequently, Brtl BFR decreases from normal at 2 mo to one half of wildtype values at 6 mo. Immunohistochemistry and real-time RT-PCR show increased RANK, RANKL, and osteoprotegerin (OPG) levels in Brtl, although a normal RANKL/OPG ratio is maintained. TRACP(+) precursors are markedly elevated in Brtl marrow cultures and form more osteoclasts, suggesting that osteoclast increases arise from more RANK-expressing precursors. We conclude that osteoblasts and osteoclasts are unsynchronized in Brtl bone. This cellular imbalance results in declining BFR as Brtl ages, consistent with reduced femoral geometry. The disparity in cellular number and function results from poorly functioning osteoblasts in addition to increased RANK-expressing precursors that respond to normal RANKL/OPG ratios to generate more bone-resorbing osteoclasts. Interruption of the stimulus that increases osteoclast precursors may lead to novel OI therapies.