Lori Watumull

Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer

In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.

LAPAROSCOPIC APPLICATION OF RADIO FREQUENCY ENERGY ENABLES IN SITU RENAL TUMOR ABLATION AND PARTIAL NEPHRECTOMY

PURPOSE To our knowledge we present the initial series of renal mass in situ laparoscopic radio frequency ablation. We also discuss the indications for and results of subsequent laparoscopic partial nephrectomy. MATERIALS AND METHODS Laparoscopic radio frequency ablation was performed in 13 patients with a mean age of 59 years (range 18 to 81) and a total of 17 small enhancing renal masses. In 5 patients the tumor was subsequently excised completely, whereas in 7 it was left in situ after treatment. In 1 patient with 5 lesions only the largest lesion was excised, while the other 4 were left in situ. RESULTS Mean tumor size was 1.96 cm. (range 0.9 to 3.6). Tumors that remained in situ tended to be endophytic and located in the mid pole. Pathological analysis revealed renal cell carcinoma in 10 patients, angiomyolipoma in 2 and oncocytoma in the patient with multiple lesions. None of the 8 patients with renal cell carcinoma who had at least 6 weeks of followup (mean 9.8 months, range 1.5 to 22) had any evidence of persistent tumor enhancement on surveillance computerized tomography or any other evidence of disease progression. There was 1 focal positive margin in a patient who underwent radio frequency ablation and excision of renal cell carcinoma but the patient remained disease-free 1 year after treatment. CONCLUSIONS Early experience with laparoscopic radio frequency ablation in situ or combined with partial nephrectomy shows that it appears to be a safe method of managing small enhancing renal masses. Radio frequency assisted laparoscopic partial nephrectomy is reserved for easily accessible exophytic tumors, while strict surveillance is required for lesions remaining in situ after ablation. Additional followup is required to assess long-term effectiveness.

Accuracy and effectiveness of laparoscopic vs open hepatic radiofrequency ablation

BackgroundThe purpose of this study was to compare the accuracy (in terms of ultrasound-guided probe placement) and the effectiveness (in terms of pathologic tumor-free margin) of laparoscopic vs open radiofrequency (RF) ablation.MethodsUsing a previously validated tissue-mimic model, 1-cm simulated hepatic tumors were ablated in 10 pigs randomized to open or laparoscopic techniques. Energy was applied until tissue temperature reached 100°C (warm-up) and thereafter for 8 min. A pathologist blinded to technique examined all specimens immediately after treatment. Analysis was by Fisher’s exact test and the Mann-Whitney U test; p<0.05 was considered significant.ResultsOff-center distance (3.5±1.6 vs 4.2±1.4 mm), size (24.7±3.1 vs 25.6±3.8 mm), symmetry (40% vs 73%), margin positivity (33% vs 9%), and margin distance (1.1±1.2 vs 2.2±1.6 mm) were not significantly different between laparoscopic (n=15) and open (n=11) ablations, respectively. The proportion of round/ovoid lesions (20% vs 64%) was lower (p=0.043), and warm-up time (20.2±14.0 vs 10.7±7.5) was longer (p=0.049) for the laparoscopic than for the open groups, respectively.ConclusionAccurate probe placement can be achieved using laparoscopic and open RF ablation techniques. The physiologic effects of laparoscopy may alter ablation shape and warm-up time. Additional studies are needed to establish effective ways of achieving complete tumor destruction.

The effect of hepatic inflow occlusion on laparoscopic radiofrequency ablation using simulated tumors.

BackgroundThe purpose of this study was to determine the effect of hepatic inflow occlusion (the Pringle maneuver) on laparoscopic radiofrequency (RF) ablation.MethodsUsing a previously validated agarose tissuemimic model, 1-cm simulated hepatic tumors (three per animal) were laparoscopically ablated in five pigs with normal perfusion and then in five pigs with hepatic artery and portal vein occlusion. Energy was applied until tissue temperature reached 100°C (warm-up) and there-after for eight min. Specimens were examined immediately after treatment.ResultsVascular occlusion was successful in all cases per color-flow Doppler ultrasound. Pringle time was 11.4±1.6 min. Warm-up time (2.7±1.4 vs 20.2±14.0 min) was significantly faster in the Pringle group. Ablation diameter (34.8±2.9 vs 24.7±3.1 mm), proportion of round/ovoid lesions (93% vs 20%), ablation symmetry (100% vs 40%), and margin distance (5.1±3.0 vs 1.1±1.2 mm) were significantly better for the Pringle group than the No Pringle group, respectively.ConclusionUsing a Pringle maneuver during laparoscopic RF ablation significantly enhances ablation geometry and results in larger margins.

Sirolimus and Temsirolimus for Epithelioid Angiomyolipoma

A 24-year-old man with familial tuberous sclerosis complex (TSC) presented to University of Texas Southwestern (Dallas, TX) in February 2009 with abdominal pain, vomiting, and generalized weakness. Five months previously, at another institution, he had undergone a right radical nephrectomy of a 24-cm epithelioid angiomyolipoma (EAML) that ruptured during surgery. Pathologic examination of the tumor at our institution showed sheets of epithelioid cells surrounding haphazardly shaped vessels embedded in a hyalinized stroma with focal myxoid change (Fig 1A; H&E, hematoxylin and eosin). The neoplastic cells were large, round or oval, with eccentric round nuclei, prominent nucleoli, and eosinophilic cytoplasm. They resembled ganglion cells and rare mitoses were appreciated (one in ten high-power fields). Immunohistochemical studies showed that the neoplastic cells expressed, as is characteristic of this tumor type,

Development of an in vivo tumor-mimic model for learning radiofrequency ablation

Radiofrequency ablation requires accurate probe placement using ultrasound guidance. The purpose of this study was to develop an in vivo tumor-mimic model for learning open and laparoscopic radiofrequency ablation. Tumor-mimics were created in ex vivo porcine livers by injecting a mixture of 3% agarose, 3% cellulose, 7% glycerol, and 0.05% methylene blue, which formed 1 cm hyperechoic, discrete lesions on ultrasound. Open and laparoscopic (using a box-trainer) ablation techniques were practiced. In vivo experiments were then conducted in 10 pigs. Three tumor-mimics were created in each animal using a laparoscopic approach. Lesions were characterized sonographically, ablated using an open (n = 5) or laparoscopic (n = 5) approach, and examined pathologically. An ablation in normal liver tissue was performed as a control. Tissue impedance was recorded. Target creation took 81 minutes per animal and 96% of injections were successful. Tissue impedance (48.8 ±5.8 vs. 49.6 ±5.4) and ablation size (25.1 ±3.4 vs. 24.3 ±5.1) were not significantly different for controls (n = 8) and tumor-mimics (n = 26), respectively. One animal died of a pulmonary embolism following injection of agarose into a hepatic vein. The agarose-based tissue-mimic creates realistic sonographic targets for learning ultrasound-guided open and laparoscopic radiofrequency ablation in an in vivo model.

Hereditary Lung Cancer Syndrome Targets Never Smokers with Germline EGFR Gene T790M Mutations

Introduction: Hereditary lung cancer syndromes are rare, and T790M germline mutations of the epidermal growth factor receptor (EGFR) gene predispose to the development of lung cancer. The goal of this study was to determine the clinical features and smoking status of lung cancer cases and unaffected family members with this germline mutation and to estimate its incidence and penetrance. Methods: We studied a family with germline T790M mutations over five generations (14 individuals) and combined our observations with data obtained from a literature search (15 individuals). Results: T790M germline mutations occurred in approximately 1% of non–small-cell lung cancer cases and in less than one in 7500 subjects without lung cancer. Both sporadic and germline T790M mutations were predominantly adenocarcinomas, favored female gender, and were occasionally multifocal. Of lung cancer tumors arising in T790M germline mutation carriers, 73% contained a second activating EGFR gene mutation. Inheritance was dominant. The odds ratio that T790M germline carriers who are smokers will develop lung cancer compared with never smoker carriers was 0.31 (p = 6.0E-05). There was an overrepresentation of never smokers with lung cancer with this mutation compared with the general lung cancer population (p = 7.4E-06). Conclusion: Germline T790M mutations result in a unique hereditary lung cancer syndrome that targets never smokers, with a preliminary estimate of 31% risk for lung cancer in never smoker carriers, and this risk may be lower for heavy smokers. The resultant cancers share several features and differences with lung cancers containing sporadic EGFR mutations.

Clinical, Biochemical, and Molecular Characterization of Macronodular Adrenocortical Hyperplasia of the Zona Reticularis: A New Syndrome

CONTEXT Macronodular adrenocortical hyperplasia classically presents with progressive hypercortisolemia and Cushing syndrome. We describe a 29-yr-old man with massive macronodular adrenocortical hyperplasia without hypercortisolemia but rather markedly elevated and nonsuppressible production of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). OBJECTIVE To characterize the clinical and molecular features of this case and to determine whether the tissue biochemically resembles the zona reticularis or fetal adrenal. SETTING University clinic, hospital, and laboratories. DESIGN Static and dynamic blood and urine testing were performed preoperatively. Tissue was studied by light microscopy, immunoblot, RNA microarray, and enzyme assay. PARTICIPANT A 29-yr-old man with incidentally discovered bilateral adrenal enlargement. INTERVENTION Bilateral adrenalectomy. MAIN OUTCOME MEASURES Molecular studies compared with control samples. RESULTS Hypercortisolism and 21-hydroxylase deficiency were excluded. DHEA, DHEAS, and 17-hydroxypregnenolone were markedly elevated and did not suppress with dexamethasone 2 mg/d for 4 d. Homogenates of the adrenals demonstrated high 17-hydroxylase, good 17,20-lyase, and low or absent 21-hydroxylase and 3β-hydroxysteroid dehydrogenase activities. Immunoblots confirmed robust expression of cytochrome P450c17 and AKR1C3 but not P450c21. Microarray analysis demonstrated high CYP11A1 and CYP17A1 expression but low or absent HSD3B1, HSD3B2, and CYP21A2 expression. Expression of mRNA for cytochrome b(5) (CYB5A) and AKR1C3, markers of the zona reticularis, were markedly elevated. CONCLUSION This is the first case of macronodular hyperplasia of the adrenal zona reticularis confirmed with studies of enzyme activity, mRNA expression, and protein identification. We speculate that this condition can be clinically silent in men but might cause severe hyperandrogenemia in women.

Inframanubrial Parathyroid Glands in Patients with Primary Hyperparathyroidism: Alternatives to Sternotomy

Deep inframanubrial parathyroid tumors have traditionally been excised through a median sternotomy. With the advent of minimally invasive surgical access, we chose to examine the treatment options and outcomes of patients with inframanubrial mediastinal parathyroid tumors. Patients with primary hyperparathyroidism seen at a university medical center over a 12-year period were retrospectively reviewed. The utility of localization studies, methods of treatment, complications, and outcomes were examined in patients with a parathyroid tumor located in the mediastinum inferior to the manubrium. Patients with parathyroid adenomas located at the thoracic inlet were excluded. Sixteen patients with inframanubrial mediastinal tumors were treated during the study period. Altogether, 81% of the patients had undergone at least one prior neck exploration for primary hyperparathyroidism. Preoperative calcium and parathyroid hormone levels were 12.4 ± 0.36 mg/dl and 273 ± 70 pg/ml, respectively. Localization studies identified mediastinal parathyroid adenomas in the following locations: anterior mediastinum (n = 8), middle mediastinum (n = 7), posterior mediastinum (n = 1). Mediastinal computed tomography and technetium-sestamibi scans demonstrated the best sensitivity, 92% and 85%, respectively. Seven patients underwent successful excision of the mediastinal adenoma by transcervical mediastinal exploration with the Cooper retractor. The other patients underwent angiographic ablation (n = 4), anterior mediastinotomy (n = 3), video-assisted thoracoscopy (VATS) (n = 1), and VATS plus thoracotomy (n = 1). The mean hospital stay for the study group was 2.9 ± 0.7 days. The complication rate was 25%. All patients were normocalcemic after a mean follow-up of 15 ± 7 months. Most inframanubrial mediastinal parathyroid tumors can be successfully managed without median sternotomy.

Laparoscopic gonadectomy and excision of müllerian remnant in an adult intersex patient

Laparoscopy can assist in the diagnosis and treatment of intersex patients. We report a rare case in which laparoscopic gonadectomy and hysterosalpingectomy were performed in a phenotypically-male intersex patient first diagnosed in adulthood.