Phase II Trial of Sipuleucel-T and Stereotactic Ablative Body Radiation for Patients with Metastatic Castrate-Resistant Prostate Cancer.

(1) We hypothesized that adding concurrent stereotactic ablative radiotherapy (SAbR) would increase the time to progression in patients with metastatic castrate-resistant prostate cancer (mCRPCA) treated with sipuleucel-T. (2) Patients with a history of prostate cancer (PC), radiographic evidence of metastatic disease, and rising prostate-specific antigen (PSA) > 0.2 ng/dL on castrate testosterone levels were enrolled in this single-arm phase II clinical trial and treated with sipuleucel-T and SAbR. The primary endpoint was time to progression (TTP). Cellular and humoral responses were measured using ELISpot and Luminex multiplex assays, respectively. (3) Twenty patients with mCRPC were enrolled and treated with SAbR to 1−3 sites. Treatment was well tolerated with 51, 8, and 4 treatment-related grade 1, 2, and 3 toxicities, respectively, and no grade 4 or 5 adverse events. At a median follow-up of 15.5 months, the median TTP was 11.2 weeks (95% CI; 6.8−14.0 weeks). Median OS was 76.8 weeks (95% CI; 41.6−130.8 weeks). This regimen induced both humoral and cellular immune responses. Baseline M-MDSC levels were elevated in mCRPC patients compared to healthy donors (p = 0.004) and a decline in M-MDSC was associated with biochemical response (p = 0.044). Responders had lower baseline uric acid levels (p = 0.05). No clear correlation with radiographic response was observed. (4) While the regimen was safe, the PC-antigen-specific immune response induced by SAbR did not yield a synergistic clinical benefit for patients treated with sipuleucel-T compared to the historically reported outcomes.

Impact of Implementing Contrast-Enhanced Ultrasound for Antegrade Nephrostogram After Percutaneous Nephrolithotomy.

OBJECTIVES: To report results from a quality improvement (QI) project evaluating diagnostic performance, hospital resource use, and patient response data for postoperative contrast-enhanced ultrasound (CEUS) antegrade nephrostogram after percutaneous nephrolithotomy. METHODS: For this Health Insurance Portability and Accountability Act-compliant, Institutional Review Board-approved study, QI data were deidentified and analyzed. On the first postoperative day after percutaneous nephrolithotomy, patients underwent both CEUS and fluoroscopic antegrade nephrostogram. For CEUS, 1.0 mL of Lumason (sulfur hexafluoride lipid type A microspheres; Bracco Diagnostics, Inc, Monroe Township, NJ) was injected via an indwelling nephrostomy tube, with ureteral patency confirmed by identifying intravesical ultrasound (US) contrast. Diagnostic performance for ureteral patency and contrast extravasation was calculated (with fluoroscopy as the reference standard). The examination time, room time, physician time, hospital costs, and patient response data were compared. The mean, standard deviation, 95% confidence interval, differences in mean, and 95% confidence interval of differences were calculated. RESULTS: Eighty-one examinations were performed in 73 patients during the QI period. The sensitivity and specificity of CEUS for ureteral patency were 96% and 57%, respectively. There was no significant difference in time metrics between modalities, and the cost analysis showed lower direct and indirect costs for CEUS. Patient responses revealed lower levels of comfort for CEUS relative to fluoroscopy, without significant differences in reported pain or effort levels. CONCLUSIONS: Contrast-enhanced US showed very high sensitivity for ureteral patency; the relatively low specificity may have resulted from false-negative results in fluoroscopy. The hospital costs and resource use of CEUS compared favorably to fluoroscopy. Contrast-enhanced US also offers inherent advantages, including portability and lack of ionizing radiation.

Unintended Consequences of Systemic and Ablative Oncologic Therapy in the Abdomen and Pelvis.

Human cancers are genetically complex and diverse. Although advances in oncologic therapy aim to define and target unique steps in carcinogenesis, oncologists often rely on less discriminate anticancer therapies that have consequences for normal tissues. Even many of the so-called targeted therapies currently employed can adversely affect normal cells, leading to complications that necessitate dose reductions or cessation of specific therapies. This article explores the unintended consequences of currently employed systemic and ablative anticancer therapies that might manifest at imaging examinations of the abdomen and pelvis, including cytotoxic, molecular targeted, and immunologic agents; ablation; and hematopoietic stem cell transplant. Each of these treatments can have both major and minor unintended effects in the targeted organ(s), in local or adjacent structures, or at distant sites. Timely detection and reporting of adverse consequences of anticancer therapies by the astute imager can result in critical treatment modifications and/or lifesaving interventions; therefore, knowledge of these unintended effects is paramount for radiologists interpreting the results of imaging examinations in cancer patients. ©RSNA, 2018.

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.

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.

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 3ß-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.

Effect of the Bethesda system for reporting thyroid cytopathology on thyroidectomy rates and malignancy risk in cytologically indeterminate lesions.

BACKGROUND: Cytologically indeterminate thyroid nodules represent a diagnostic and therapeutic challenge. In 2007, the National Cancer Institute recommended The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) as a means of improving the accuracy of thyroid cytopathology. Our objective was to determine the effect of TBSRTC on thyroidectomy rates and malignancy risk in cytologically indeterminate lesions. METHODS: We compared thyroidectomy rates and malignancy risk in patients with indeterminate thyroid cytopathology across 2 time periods, spanning January 2000 and November 2009; pre-TBSRTC (January 2000 to September 2003) and post-TBSRTC (June 2008 to November 2009). Statistical comparisons were performed using the Fisher's exact test and chi-square analysis (P = .05 significant). RESULTS: We performed 938 fine-needle aspirations in the first period, 765 in the second. We identified 78 (8.3%) cytologically indeterminate lesions in the pre-TBSRTC group and 91 (11.9%) lesions in the post-TBSRTC group. We found no difference in thyroidectomy rates between the groups (37/78 [47%] pre-Bethesda versus 32/91 [35%] post-Bethesda; P = .12). However, the malignancy rate was significantly lower in the post-TBSRTC group (13/37 [35%] pre-Bethesda versus 4/32 [13%] post-Bethesda; P = .02). CONCLUSION: Application of TBSRTC is associated with lower malignancy risk in indeterminate thyroid nodules, despite similar thyroidectomy rates. These findings imply that standardization of cytologic classification improves diagnostic accuracy.

Primary hyperaldosteronism: effect of adrenal vein sampling on surgical outcome.

HYPOTHESIS: Adrenal vein sampling is superior to computed tomography for subtype differentiation of primary hyperaldosteronism. DESIGN: Retrospective review. SETTING: University medical center. PATIENTS: Forty-eight patients (32 men and 16 women) with biochemically confirmed primary hyperaldosteronism. MAIN OUTCOME MEASURES: We compared demographic factors, results of biochemical and imaging studies (computed tomography and adrenal vein sampling), therapy, and patient outcomes. RESULTS: Mean +/- SEM adrenal nodule size was 1.54 +/- 0.2 cm. Adrenal vein sampling was performed in 41 (85%) of 48 patients, and it was successful in 39 (95%) of those 41 patients. Concordance between computed tomography and adrenal vein sampling was observed in 22 (54%) of the 41 patients. Thirty-two patients underwent successful laparoscopic adrenalectomy. There was 1 complication and no deaths. All 32 patients were cured of hypokalemia. CONCLUSION: Adrenal vein sampling is superior to image-based techniques for subtype differentiation of primary hyperaldosteronism.

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.

Fine needle aspiration cytology of collecting duct carcinoma of the kidney: report of a case with distinctive features and differential diagnosis.

BACKGROUND: The relative rarity of collecting duct carcinoma (CDC) of the kidney in conjunction with a lack of distinctive cytologic features is a diagnostic challenge for any cytopathologist when dealing with such a tumor on fine needle aspiration cytology. In previous cytologic reports, CDC is not well characterized, and the features overlapped with those of high grade renal cell carcinoma (RCC). Because of the differences in behavior and treatment from conventional RCC, it is important to attempt to diagnose this tumor correctly. CASE: The cytologic findings of CDC in a 56-year-old woman were distinctive and not emphasized previously. Ductal/tubular differentiation, prominent desmoplastic stromal component, neutrophilic infiltration and the presence of numerous tubules ranging from benign to dysplastic and frankly malignant were notable features of this tumor. The expression of high-molecular-weight cytokeratin and Ulex europaeus agglutinin helped to confirm the diagnosis. CONCLUSION: The present case highlights several characteristic cytologic features that were useful in suggesting the diagnosis of CDC on fine needle aspiration cytology. Immunohistochemical stains, such as high-molecular-weight cytokeratin and lectin, helped to confirm the diagnosis.

The radiographic evolution of radio frequency ablated renal tumors.

PURPOSE: Radio frequency ablation (RFA) of renal tumors is a relatively new technology. Few groups are familiar with the posttreatment appearance of these lesions and how they differ from cryoablated renal masses. We describe the evolution of the appearance of these lesions on followup contrast enhanced (CE) computerized tomography (CT). METHODS AND MATERIALS: A total of 64 consecutive renal tumors treated with RFA from April 2000 to September 2003 for which posttreatment CE-CT was done were included in this study. CE-CT was reviewed at 6 weeks, 3 months, 6 months and every 6 months thereafter to determine the characteristic features and evolution of these lesions. RESULTS: Renal tumors were treated with CT guided percutaneous (34), laparoscopic (28) or open (2) RFA. At a median followup of 13.7 months (range 6 weeks to 29 months) 62 RFA lesions demonstrated an absence of contrast enhancement on CE-CT. Treated endophytic tumors developed a low density, nonenhancing, wedge-shaped defect with fat infiltration seen between the ablated tissue and normal parenchyma. Treated exophytic tumors retained a configuration similar to that of the original with a lack of contrast enhancement and minimal shrinkage. Percutaneous treated lesions developed a peritumor scar or halo that demarcated ablated and nonablated tissue (perirenal fat). Persistent tumor was marked by contrast enhancement within the ablation borders of the original mass in 1 case, whereas tumor recurred after initial successful ablation with an enhancing nodule in 1. CONCLUSIONS: The radiographic features and evolution of radio frequency ablated renal tumors are unique. Successfully treated tumors demonstrated no contrast enhancement, minimal shrinkage and occasional retraction from normal parenchyma by fat infiltration.

Sensitivity of chest fluoroscopy compared with chest CT and chest radiography for diagnosing hydropneumothorax in association with percutaneous nephrostolithotomy.

OBJECTIVES: Hydropneumothorax (HPTX) is recognized as a potential complication of percutaneous nephrostolithotomy (PCNL), particularly with supracostal access. Postoperative chest radiography (CXR) is routinely used to evaluate the chest after PCNL. We prospectively compared the sensitivity of intraoperative chest fluoroscopy with immediate postoperative portable CXR and postoperative day 1 chest computed tomography (CT) for the detection of pleural fluid. METHODS: A total of 89 consecutive patients (mean age 47.9 +/- 13.3 years; 100 renal units) undergoing PCNL were prospectively evaluated with intraoperative fluoroscopy at the conclusion of the procedure and then with anteroposterior CXR in the postanesthesia care unit and postoperative day 1 noncontrast, thin-cut CT of the kidneys and lung bases. CT imaging of the lung bases comprised the reference standard for detecting pleural fluid. RESULTS: A total of 104 percutaneous renal accesses in 100 renal units, 60 above and 44 below the 12th rib, were used. In 16 cases (16%), a second-stage procedure was performed to clear residual stone fragments detected on post-PCNL CT. HPTX was detected in 1, 8, and 38 cases by initial fluoroscopy, immediate postoperative CXR, and CT scan, respectively. Intervention was necessary in 7 patients. In 2 patients with fluoroscopic evidence of pleural fluid (1 at the initial PCNL and 1 during second-look flexible nephroscopy), intraoperative pleural drainage was performed percutaneously. In the other 5 patients, intervention was determined by the size of the HPTX on chest CT scan (n = 1) or the presence of symptoms (n = 4). In no case was intervention performed on the basis of the immediate postoperative CXR findings when intraoperative chest fluoroscopy was negative. CONCLUSIONS: Intraoperative chest fluoroscopy during PCNL is sufficient to detect clinically significant HPTXs, and, therefore, routine postoperative CXRs are not necessary. However, a high index of suspicion based on clinical symptoms postoperatively should prompt chest imaging.

Directed parathyroidectomy: feasibility and performance in 100 consecutive patients with primary hyperparathyroidism.

HYPOTHESIS: Directed parathyroidectomy (DP) can be successfully completed in most patients with primary hyperparathyroidism. DESIGN AND SETTING: Retrospective review at a tertiary referral center. PATIENTS: One hundred consecutive patients with untreated, sporadic primary hyperparathyroidism operated on by a single surgeon from April 1, 1999, through December 31, 2001. INTERVENTIONS: Following preoperative imaging with sestamibi scintigraphy and ultrasonography, patients underwent parathyroidectomy with intraoperative parathyroid hormone monitoring using a focused approach through a limited neck incision (DP) or bilateral neck exploration (BNE) through a standard collar incision. MAIN OUTCOME MEASURES: Extent of exploration, operative time, length of stay, morbidity, and cure. RESULTS: Directed parathyroidectomy was completed in 70 patients and BNE in 30. Bilateral neck exploration was performed as the initial procedure in 13 patients and following intraoperative conversion from attempted DP in 17. Indications for predetermined BNE were failed preoperative localization (n = 8) and concomitant thyroid disease that required operative treatment (n = 5). The need for predetermined BNE decreased as preoperative localization improved. Intraoperative factors that necessitated conversion to BNE included persistently elevated intraoperative parathyroid hormone levels that accurately predicted multiglandular disease (n = 6), incorrect localization (n = 5), and inadequate exposure (n = 6). Operative time and length of stay were less for DP compared with BNE patients (66 vs 165 minutes and 0.5 vs 1.6 days, respectively). One patient had a temporary vocal cord paresis. All patients were eucalcemic in follow-up (4 months to 3 years). CONCLUSIONS: With accurate preoperative localization and intraoperative parathyroid hormone monitoring, DP can be successfully completed in most patients with sporadic primary hyperparathyroidism. Patients benefit from DP, which reduces operative time and length of stay and facilitates rapid convalescence.

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.