Sarah C. Oltmann

Non-nuclear estrogen receptor α signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice

Steroid hormone receptors function classically in the nucleus as transcription factors. However, recent data indicate that there are also non-nuclear subpopulations of steroid hormone receptors, including estrogen receptors (ERs), that mediate membrane-initiated signaling of unclear basis and significance. Here we have shown that an estrogen-dendrimer conjugate (EDC) that is excluded from the nucleus stimulates endothelial cell proliferation and migration via ERalpha, direct ERalpha-Galphai interaction, and endothelial NOS (eNOS) activation. Analysis of mice carrying an estrogen response element luciferase reporter, ER-regulated genes in the mouse uterus, and eNOS enzyme activation further indicated that EDC specifically targets non-nuclear processes in vivo. In mice, estradiol and EDC equally stimulated carotid artery reendothelialization in an ERalpha- and G protein-dependent manner, and both agents attenuated the development of neointimal hyperplasia following endothelial injury. In contrast, endometrial carcinoma cell growth in vitro and uterine enlargement and MCF-7 cell breast cancer xenograft growth in vivo were stimulated by estradiol but not EDC. Thus, EDC is a non-nuclear selective ER modulator (SERM) in vivo, and in mice, non-nuclear ER signaling promotes cardiovascular protection. These processes potentially could be harnessed to provide vascular benefit without increasing the risk of uterine or breast cancer.

Cannot exclude torsion—a 15-year review

BACKGROUND Ovarian torsion remains a challenging diagnosis, often leading to delayed operative intervention and resultant ovarian loss. METHODS Charts of patients with ovarian operative cases were retrospectively reviewed at a free-standing childrens hospital over 15 years. Torsion was based on intraoperative findings. RESULTS Of 328 operative ovarian cases, 97 (29.6%) demonstrated torsion. Mean patient age was 9.2 years (2 days to 17 years, +/-0.54 SEM), with 52% occurring between 9 and 14 years. Of the patients, 97% presented in pain. Presence of a pelvic mass 5 cm or larger on imaging had 83% sensitivity for torsion: an ultrasound reading was only 51% sensitive. Elevated white blood cell count was the only preoperative characteristic associated with prompt operative intervention. Utilization of laparoscopy increased during the latter half of the study (18%-42%, P < .0434). There was a positive trend, although insignificant, in the use of laparoscopy and ovarian salvage. Pathology was overwhelmingly benign (infarction [46%], cysts [33%], and benign neoplasms [19%]). CONCLUSION Torsion was responsible for one third of all operative ovarian cases. Sonography is not reliable in diagnosis or exclusion of ovarian torsion. Thus, a strategy of earlier and liberal use of Diagnostic Laparoscopy (DL), particularly with a pelvic mass of approximately 5 cm, may improve ovarian salvage. Because pathology is predominantly benign, the edematous detorsed ovary is safe to salvage.

Pediatric ovarian malignancy presenting as ovarian torsion: incidence and relevance.

PURPOSE With ovarian torsion, concern for underlying malignancy in the enlarged ovary has previously driven surgeons to resection. Detorsion alone has been recommended to allow for resolution of edema of the ovary with follow-up ultrasound surveillance to evaluate for a persistent mass, yet is not routine practice. However, the incidence of malignancies presenting as ovarian torsion is not documented. Does the risk of an underlying malignancy justify salpingoophorectomy and decreased fertility? METHOD After institutional review board exemption (IRB#-022008-095), a 15(1/2)-year retrospective review was conducted to identify cases of operative ovarian torsion in our medical center. Tumors with neoplastic pathology (malignant and benign) were analyzed and compared with all reported cases in the literature. RESULTS A total of 114 patients (mean +/- SEM age, 10 years, 2 days to 19 years +/- 0.53) with operatively proven ovarian torsion were identified. Four malignancies (3.5%) and 26 benign neoplasms (23%) were present in this age group. Malignancies consisted of serous borderline tumors (2), juvenile granulosa cell tumor (1), and dysgerminoma (1). All were stage I: the former were stage IA and cured with resection alone, and 1 was a stage IB dysgerminoma, which required chemotherapy. The literature yielded a total of 593 cases of operative ovarian torsion with 9 (1.5%) malignancies and 193 (33%) benign neoplasms. The malignancies were juvenile granulosa cell tumor (n = 4), dysgerminoma (n = 2), serous borderline tumors (n = 2), and 1 undifferentiated adenocarcinoma. CONCLUSION By combining our series with 13 in the literature, a 1.8% malignancy rate occurred in 707 patients with ovarian torsion, markedly less than the reported malignancy rate of 10% in children with ovarian masses. Thus, neither a pathologic nor malignant lead point should be assumed in cases of torsion. In our series, which represents the largest series of torsion in the pediatric literature, all malignancies presented as stage I. These data further support the implementation of operative detorsion and close postoperative ovarian surveillance, with reoperation for persistent masses. Further study is needed to determine if delaying resection by weeks in those cases of persistent masses would result in tumor progression and thus change prognosis.

Can we preoperatively risk stratify ovarian masses for malignancy

PURPOSE Given a 10% malignancy rate in pediatric ovarian masses, what preoperative factors are helpful in distinguishing those at higher risk to risk stratify accordingly? METHODS After institutional review board approval (IRB#022008-095), a 15(1/2)-year retrospective review of operative ovarian cases was performed. RESULTS A total of 424 patients were identified, with a mean age 12.5 years (range, 1 day to 19 years), without an age disparity between benign (12.54 years, 89%) and malignant (11.8 years, 11%) cases. The 1- to 8-year age group had the highest percentage of malignancies (22%; odds ratio [OR], 3.02; 95% confidence interval [CI], 1.33-6.86). A chief complaint of mass or precocious puberty versus one of pain had an OR for malignancy of 4.84 and 5.67, respectively (95% CI, 2.48-9.45 and 1.60-20.30). Imaging of benign neoplasms had a mean size of 8 cm (range, 0.9-36 cm) compared with malignancies at 17.3 cm (6.2-50 cm, P < .001). An ovarian mass size of 8 cm or longer on preoperative imaging had an OR of 19.0 for malignancy (95% CI, 4.42-81.69). Ultrasound or computed tomographic findings of a solid mass, although infrequent, were most commonly associated with malignancy (33%-60%), compared with reads of heterogeneous (15%-21%) or cystic (4%-5%) lesions. The malignancies (n = 46) included germ cell (50%, n = 23), stromal (28%, n = 13), epithelial (17%, n = 8), and other (4%, n = 2). Tumor markers obtained in 71% of malignancies were elevated in only 54%, whereas 6.5% of those sent in benign cases were similarly elevated. Elevated beta-human chorionic gonadotropin (beta-HCG), alpha fetoprotein (alphaFP), and cancer antigen 125 (CA-125) were significantly associated with malignancy (P < .02) and an elevated carcinoembryonic antigen (CEA) was not (P = .1880). CONCLUSION This reported series of pediatric ovarian masses demonstrates that preoperative indicators that best predict an ovarian malignancy are a complaint of a mass or precocious puberty, a mass exceeding 8 cm or a mass with solid imaging characteristics. Those patients aged 1 to 8 years have the greatest incidence of malignancy. Tumor markers, positive or negative, were not conclusive in all cases but useful for postoperative surveillance.

Single-incision laparoscopic surgery: feasibility for pediatric appendectomies

INTRODUCTION Single-incision laparoscopic surgery (SILS) is a novel area of minimally invasive surgery using a single incision. The end result is a lone incision at the umbilicus for a perceived scarless abdomen. We report our early experience using the SILS technique for appendectomies in the pediatric population. METHODS A retrospective chart review was performed on our first patients to undergo SILS appendectomy (SILS-A) or laparoscopic appendectomy (LAP-A) during the same period at a freestanding childrens hospital. RESULTS Thirty-nine patients were reviewed. Nineteen patients underwent SILS-A (8.7 +/- 0.76 [SEM] years old), and 20 patients underwent LAP-A (10.5 +/- 0.87 years old, 2-17). Ages were 19 months to 14 years in the SILS-A group, with 21% (4 patients) not older than 6 years. Median weight for SILS-A was 32 kg (14.5-80.3). Twelve patients had acute nonperforated appendicitis (62%). Mean duration of operation was 58 +/- 5.6 (30-135) minutes vs 43 +/- 3.6 (30-85) minutes for standard LAP-A. Two patients were converted to a transumbilical appendectomy, one for inability to maintain a pneumoperitoneum and one for extensive adhesions. Postoperative complications consisted of one wound seroma. No wound infections, hernias, readmissions, or difference in length of stay were noted. CONCLUSION The SILS approach for acute appendicitis is feasible in the pediatric population even in patients as young as 19 months. Operating room times are somewhat longer than with LAP-A, but should decrease with improved instrumentation and experience. Larger studies and further technical refinements are needed before its widespread implementation.

Ovarian torsion: diagnosis of inclusion mandates earlier intervention

PURPOSE The treatment of ovarian torsion (OT) is often delayed because of diagnostic uncertainty and dependence on radiologic confirmation. In contrast, when testicular torsion (TT) is suspected, diagnosis and management are expedited despite lack of certainty, and operative exploration is not delayed by radiologic investigations. We compared the management of torsion in both sexes to define a better clinical pathway for suspected OT. METHODS A 2.5-year review of the Pediatric Health Information System database was performed to determine the incidence of TT and OT at large childrens hospitals. A 10-year retrospective review of children (0-19 years) diagnosed with TT or OT at a single academic center was performed to identify differences in diagnosis and management and determine the impact on gonadal salvage rates. RESULTS The incidence of TT was comparable with OT in the Pediatric Health Information System database (0.03% vs 0.02%). A total of 158 patients with TT and 90 patients with OT were managed at our center with a median age of 12 years in both groups. Boys presented earlier after the onset of pain (36 vs 72 hours, P < .0001) and were imaged more quickly (0.77 vs 1.86 hours, P < .0001). Time to operating room (OR) was also shorter for TT (2.3 vs 6.3 hours, P < .0001). The salvage rate for TT was 30.3% vs 14.4% for OT (P < .01). CONCLUSIONS Girls with suspected OT waited 2.5 times as long for diagnostic imaging and 2.7 times as long to be taken to the operating room. In addition, the gonadal salvage rate was significantly worse for girls compared with boys with TT. More urgent intervention for OT, with liberal use of diagnostic laparoscopy and without reliance on a definitive diagnosis by imaging, should be considered in girls with lower abdominal pain.

Pediatric ovarian malignancies: how efficacious are current staging practices?

PURPOSE Conventional staging is not routinely practiced because of a lack of preoperative indicators for pediatric ovarian malignancy. Childrens Oncology Group (COG) developed guidelines for germ cell tumors to revise staging to correlate with primary pediatric ovarian pathology. Are COG guidelines being used, and are they applicable to all pediatric ovarian malignancies? METHODS A 15(1/2)-year retrospective review of operative ovarian masses from a single academic center was performed. RESULTS There were 424 patients identified, with 46 malignancies (11%). Most were stage I (73%). Complete COG staging was performed in 24%. Each staging component performed was as follows: oophorectomy (91%), examination with or without biopsy of omentum (72%), peritoneum (67%), retroperitoneum (63%), contralateral ovary (56%), and washings (46%). Advanced stages had visible findings at exploration to guide biopsies. Of site-directed biopsies, 40.5% were positive, whereas all random biopsies (n = 38) were negative. Two recurrences and all mortalities (n = 4) had complete initial COG operative staging. Mean duration of follow-up was 3.62 +/- 0.365 years. CONCLUSION The COG staging is not consistently followed. All cases of advanced disease were visibly obvious and confirmed with site-directed biopsies. Random samplings were all negative and did not impact stage. Negative outcomes reflected inherent tumor biology not deviation from COG staging. The COG guidelines appear to be sufficient for all pediatric ovarian malignancies.

Significance of elevated parathyroid hormone after parathyroidectomy for primary hyperparathyroidism.

OBJECTIVE To provide a clinical update on persistent parathyroid hormone (PTH) elevation after surgical resection for primary hyperparathyroidism (PHPT) and to suggest a schedule for follow-up monitoring and strategies for future study. METHODS We reviewed the literature targeting studies with detailed analysis of biochemical parameters before and after parathyroidectomy for PHPT. We focused on potential etiologies and currently available outcome data. RESULTS PTH elevation with eucalcemia after parathyroidectomy for PHPT occurs in 12% to 43% of patients. Underlying etiology is probably multifactorial, and possible causes include bone hunger, vitamin D deficiency, inadequate calcium intake or absorption, reduced peripheral sensitivity to PTH, underlying chronic kidney disease, and/or a renal leak of calcium. No consensus exists on how to follow-up and treat these patients. CONCLUSIONS Although most patients with PTH elevation after parathyroidectomy will have normalization of PTH levels with time and/or calcium and vitamin D supplementation, this finding may be an early indicator of autonomous parathyroid secretion in a small number of patients. Patients with persistent PTH elevation should be monitored over time for recurrence of PHPT and other possible complications. A standardized follow-up protocol is needed to better study and elucidate the clinical significance of elevated PTH after parathyroidectomy.

Postoperative surveillance of small appendiceal carcinoid tumors

BACKGROUND The necessity and frequency of postoperative surveillance for appendiceal carcinoid tumors ≤1 cm are undetermined. METHODS A retrospective review was conducted of all patients with appendiceal carcinoid tumors ≤1 cm managed at an academic, tertiary referral center. Clinicopathologic characteristics, treatment, surveillance, recurrence, and survival were assessed and analyzed. RESULTS Over a 16-year period, 31 patients met the inclusion criteria. Appendicitis (n = 17) and pelvic mass (n = 5) were the most common presentations. Median tumor diameter was 5 mm (range, 1-10 mm). Two patients had mesoappendiceal involvement. No patients had regional lymph node involvement or distant metastasis. Postoperatively, 14 patients (45%) received follow-up recommendations, including ≥1 of the following: imaging (n = 9), medical oncology referral (n = 7), colonoscopy (n = 5), and laboratory studies (n = 5). There were no recurrences or disease-specific deaths during a median follow-up period of 5 years (range, 0-15 years). CONCLUSIONS Appendiceal carcinoids ≤1 cm are unlikely to recur. Therefore, postoperative surveillance may be unnecessary.

Primary hyperparathyroidism across the ages: presentation and outcomes

BACKGROUND Primary hyperparathyroidism (PHPT) is a disease process traditionally thought to present during middle age, but can occur at any age. The purpose of this study was to compare PHPT patient characteristics based on patient age at the time of surgical referral. METHODS A retrospective review of a prospectively managed database of adult patients undergoing parathyroid surgery for PHPT was conducted. Patients with a negative family history, no previous parathyroid surgery, and ≥6-mo follow-up were included. Patients were grouped by age for comparison. RESULTS From 2001-2012, 1372 patients met inclusion criteria. Age groups were as follows: ≤50 y, 51-60 y, 61-70 y, and >70 y. Female predominance increased with age (P>0.01). Baseline serum parathyroid hormone levels were higher at the extremes of age (P<0.001). Young patients had the highest serum calcium (P<0.01), urinary calcium (P<0.001), and T-score (P<0.001) measures, and greater incidence of vitamin D deficiency (P=0.03). The use of local anesthesia increased with age, whereas use of outpatient parathyroidectomy decreased with age (both P<0.01). Rates of disease persistence (2.3%-2.9%, P=0.95) and recurrence (2.1%-3.3%, P=0.75) were low, and did not differ. CONCLUSIONS Patients at the extremes of age are referred with more elevated laboratory indices whereas those in the traditional age range have milder biochemical indices. This may result from differential surgical referral. Individuals with laboratory evidence of abnormal calcium and parathyroid hormone regulation should be evaluated for parathyroidectomy regardless of age because all ages can be successfully treated.