Citations

AbstractIntroductionAlthough an infrequent cause of small penile size in adult men, acquired penile shortening represents a particular reconstructive challenge due to preexisting penile anatomic deformities.AimWith numerous techniques being performed, the purpose of our study is to assess available literature on length enhancement procedures used for acquired penile shortening deformities.MethodsA systematic review was performed using the guidelines outlined in the Preferred Reporting Items for Systematic reviews and Meta-analyses. Medline/PubMed, Scopus, and Cochrane Databases were used to identify papers on augmentation Phalloplasty in non-transgender males with acquired penile shortening from 1990 to 2018.Main Outcome MeasureOutcomes, complications, and patient-reported satisfaction were analyzed.Results12 articles, involving 931 patients and 8 primary procedures, met our inclusion criteria. The majority of articles had level of evidence of 4 (83%) and Newcastle Ottawa Scale score of 6 (92%, moderate risk of bias). All studies reported mean penile length gain; however, inconsistent methodology was used when measuring penile dimensions. Mean length gain ranged from 0.6 to 6.4 cm. Overall, the mean complication rate for all techniques ranged from 0% to 50%. Post-operative satisfaction was reported in 10 (83%) studies, 7 of which used a validated scale. Patients were generally satisfied, with reported satisfaction rates ranging from 77% to 100%.Clinical ImplicationsWhile numerous procedures have been described, the significant limitations in the available data preclude identifying a single superior procedure.Strengths & LimitationsThe significant heterogeneity in the reported literature is a limitation of this study and highlights the need for standardized reporting. However, this study is the first to analyze augmentation phalloplasty literature in the setting of acquired penile shortening.ConclusionAugmentation phalloplasty techniques for acquired penile shortening are evolving and are continuously being modified; best-practice guidelines are crucial to achieve safe and satisfactory outcomes in this population.

Abstract Objective This study was aimed to provide a key update to the seminal works of Prof. Albert L. Rhoton Jr., MD, with particular attention to previously unpublished insights from the oral tradition of his fellows, recent technological advances including endoscopy, and high-dynamic range (HDR) photodocumentation, and, local improvements in technique, we have developed to optimize efficient neuroanatomic study. Methods Two formaldehyde-fixed cadaveric heads were injected with colored latex to demonstrate step-by-step specimen preparation for microscopic or endoscopic dissection. One formaldehyde-fixed brain was utilized to demonstrate optimal three-dimensional (3D) photodocumentation techniques. Results Key steps of specimen preparation include vessel cannulation and securing, serial tap water flushing, specimen drainage, vessel injection with optimized and color-augmented latex material, and storage in 70% ethanol. Optimizations for photodocumentation included the incorporation of dry black drop cloth and covering materials, an imaging-oriented approach to specimen positioning and illumination, and single-camera stereoscopic capture techniques, emphasizing the three-exposure-times-per-eye approach to generating images for HDR postprocessing. Recommended tools, materials, and technical nuances were emphasized throughout. Relative advantages and limitations of major 3D projection systems were comparatively assessed, with sensitivity to audience size and purpose specific recommendations. Conclusion We describe the first consolidated step-by-step approach to advanced neuroanatomy, including specimen preparation, dissection, and 3D photodocumentation, supplemented by previously unpublished insights from the Rhoton fellowship experience and lessons learned in our laboratories in the past years such that Prof. Rhoton's model can be realized, reproduced, and expanded upon in surgical neuroanatomy laboratories worldwide.

Background: While a large volume of literature has focused on risk factors for anterior shoulder instability, the rates of recurrence are inconsistent and require additional population-based epidemiologic data. Purpose/Hypothesis: The purpose was to report the effect of patient age on the number of instability events before physician consultation, rate of surgical stabilization, recurrent instability, and progression to osteoarthritis in patients <40 years old with anterior shoulder instability, utilizing an established US geographic population. We hypothesized that younger patients would be more likely to experience multiple episodes of instability before evaluation, undergo surgery, and experience recurrent instability after surgical intervention. Study Design: Descriptive epidemiologic study. Methods: An established geographic database of more than 500,000 patients was used to identify patients <40 years of age with anterior shoulder instability between 1994 and 2016. Medical records were reviewed to obtain patient characteristics, history, imaging, surgical details, and outcomes. Patients were divided into 5 groups based on age (≤15, 16-20, 21-25, 26-30, and 31-40 years) at initial instability. Comparative analysis was performed to identify differences between groups. Results: The study population consisted of 654 patients with a mean follow-up of 11.1 years (range, 2.0-25.2 years). This resulted in 118 patients (18%) ≤15 years of age at initial instability; 250 (38%), 16 to 20 years; 110 (17%), 21 to 25 years; 80 (12%), 26 to 30 years; and 96 (15%), 31 to 40 years. Of patients ≤15 years old at initial instability 47% had 3+ instability events, compared with 12% of patients aged 31 to 40 years ( P < .001). At 10 years of follow-up, patients ≤15 and 16 to 20 years old demonstrated the highest recurrent instability rates of 38.8% and 47.1% after nonoperative management, respectively. Patients 16 to 20 years old demonstrated the highest rates of both surgical intervention (40.4%) and recurrence after surgery (24.8%). Patients 31 to 40 years of age were significantly more likely to develop clinically symptomatic osteoarthritis (15.6%) than all other age groups. Conclusion: In a US epidemiologic population of patients <40 years old, the rate of recurrent anterior shoulder instability was roughly one-third after initial physician consultation. Younger patients, particularly those ≤15 and 16 to 20 years of age, were more likely to have experienced multiple instability events at the time of initial evaluation, require surgery, and experience recurrent instability compared with older patients. For every year of decrease in age at initial instability, the risk of recurrent instability or surgical intervention after physician consultation increased by 4.1% and 2.8%, respectively.

Abstract BACKGROUND: Burkitt Lymphoma (BL) represents approximately 40% of all childhood and adolescent non-Hodgkin lymphoma (Miles/Cairo, BJH 2012). Children with relapsed or progressive BL develop chemoimmunotherapy-resistant disease and can rarely be cured with salvage therapy (Cairo et al, JCO 2012). Bruton's tyrosine kinase (BTK) is a regulator of normal B-cell development and is activated upon B-cell receptor (BCR) stimulation. Chronic active BCR signaling through BTK activation can be inhibited by the selective and covalent BTK inhibitor, ibrutinib (Young/Staudt et al, Nat Rev Drug Dicov 2013). Preclinical studies of ibrutinib in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) suggest that its inhibitory effect on cell proliferation is in the range of 1.0uM to 25.0uM (Herman et al, Blood 2011; Cinar et al, Leuk Res 2013), which is higher than the typical plasma concentration range in patients at the recommended dose of 560mg (<0.6uM) (Advani et al, JCO 2013). Despite these relatively high IC50 values in vitro, ibrutinib has been highly effective in the treatment of patients with refractory CLL and MCL (Byrd et al, NEJM 2013 and Wang et al, NEJM 2013). Ibrutinib was initially approved by the FDA (IMBRUVICA, USPI) for patients with MCL in November 2013 and CLL in February 2014, who have received at least one prior therapy. BL, however, is associated with tonic vs chronic active BCR signaling; while, both CLL and MCL have chronic active BCR signaling. These findings suggest that the antitumor activity of ibrutinib in BL, which is associated with tonic BCR signaling, may be less pronounced than in Activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL), CLL or MCL. OBJECTIVES: We hypothesize that ibrutinib may be a potential adjuvant agent in the treatment of BL. Therefore, we investigated the in vivo anti-tumor activity of ibrutinib in BL xenografted NSG mice. METHODS: Raji Burkitt lymphoma (BL) cells (ATCC) were exposed to ibrutinib (0-10uM, generously provided by Janssen R&D LLC) alone and in combination with dexamethasone (1uM) for 5 days and then MTS cell proliferation assay (Promega) was performed. The IC50 values were determined with CompuSynTM software (Chou and Martin, ComboSyn, 2005) based on data derived from MTS assay. Raji BL cells were stably transfected with a firefly luciferase expression plasmid (ffluc-zeo), kindly provided by Laurence Cooper MD, PhD. NSG mice (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ, 6-8 weeks old) from Jackson laboratory were irradiated (2.5 Gy) and then mice were subcutaneously injected with one million ffluc-zeo tumor cells. Tumor progression and tumor burden were monitored by Bioluminescent Imaging system using the Xenogen IVIS-200 (Caliper Life Sciences). Mice were orally gavaged with either vehicle or ibrutinib (12.5mg/kg) for 10 days (once a day) at post-tumor cells injection. Analysis of survival rates were determined by the Kaplan-Meier method and differences evaluated by log-rank test using the Prism Version 6.0 software. RESULTS: Ibrutinib compared to control induced a significant dose-dependent decrease in cell proliferation in Raji BL cells (5uM, 0.561 ± 0.170, p<0.03, IC50=5.20uM) following 120 hours (5 days) of ibrutinib treatment. Interestingly, we observed a significant decrease in cell proliferation in Raji BL cells (5uM, 0.213 ± 0.078, p<0.002, IC=0.50 ± 0.374uM) following ibrutinib and 1uM dexamethasone combination treatment following 120 hours (5 days) of treatment. We observed a significant decrease of tumor progression by tumor luminescence signal intensity following ibrutinib treated Raji BL xenografted NSG mice at day 20 (12.5mg/kg, p<0.001 and 25mg/kg, p<0.05) and day 25 (12.5mg/kg, p<0.05 and 25mg/kg, p<0.05) compared to control (Figure 1A).Ibrutinib (12.5 mg/kg) treated mice (n=39) significantly prolonged survival compared to vehicle controls (n=28) (p<0.0001) (Figure 1B). CONCLUSIONS: Ibrutinib (12.5mg/kg) significantly decreased tumor progression and significantly increased survival in Raji BL xenografted NSG mice, suggesting that ibrutinib may be a potential adjuvant agent for therapy in the treatment of BL. Future studies will investigate the efficacy of combination therapy with ibrutinib on survival in BL xenografted NOD/SCID mice. Disclosures Galardy: Mission Therapeutics: Research Funding.

Abstract Glioblastoma (GBM) is a common deadly malignant brain cancer of the central nervous system (CNS), with a median survival of 12–15 months. Scientific advancements are lacking in developing effective therapies for both primary GBM, as well as secondary GBMs, that typically originate as malignant transformation of lower-grade isocitrate dehydrogenase (IDH) 1-mutant tumors. The unique metabolomic profile of IDH1-mutant tumors may present opportunities to develop biomarker signatures of therapeutic efficacy. Microdialysis is an extracellular fluid sampling collection technique utilizing a perfused semipermeable catheter to permit diffusion of molecules between brain interstitium and the perfusate. We hypothesized that microdialysis may identify a metabolomics-based biomarker response to therapy in IDH1-mutant tumors. To test this hypothesis, orthotopic xenografts were generated from two patient-derived GBM lines harboring mutations in IDH1. Perfusates were collected from intra-cranial tumors in aythmic nude mice sampled at baseline and 72h post treatment with temozolomide, an oral alkylating agent used to treat IDH1-mutant gliomas, compared with vehicle treatment, and TMZ-treated non-tumor bearing animals. Perfusates were analyzed via unsupervised metabolomic profiling using both gas and liquid chromatography-mass spectrometry (GC/LC-MS). Tumor specific metabolites such as carnitine and pyruvic acid were detected in microdialysate from tumor bearing mice compared to non-tumor bearing mice. Microdialysis is a feasible technology to identify metabolomics-based biomarker in IDH1-mutant PDX. This work is complemented by parallel analysis of non-IDH1-mutant and TMZ resistant xenografts to yield predictive in vivo tissue biomarkers of drug responsiveness translatable to clinical practice.

Abstract BACKGROUND Despite best current therapies, median survival for glioblastoma remains little more than a year. There remains an urgent need for improved treatment strategies. Current therapies, including radiation and temozolomide, are known to induce senescence in tumor cells. Advances in aging research have identified drugs with “senolytic” properties to kill senescent cells. This work tests the hypothesis that induction of senescence pathways following radiation can provide a window of opportunity to eliminate residual glioblastoma cells using drugs that block senescent cell-associated pathways (SCAPs). METHODS Human glioblastoma cells were radiated with 10, 15, or 20 Gy and maintained in culture for 3 to 4 weeks to facilitate maturation of a senescent phenotype. Given existence of multiple SCAPs, we evaluated the IC50 for several senolytic candidates including Dasatinib, Quercetin, Fisetin, AMG-232, Onalespib, A1331852, and Navitoclax in radiated vs non-radiated cells. RESULTS Among these, the Bcl-XL inhibitors A1331852 and Navitoclax both selectively killed multiple lines of radiated, senescent tumor cells at lower concentrations as compared to unirradiated, non-senescent tumor cells. Across multiple GBM cell line, the average IC50 for senescent cells was 12.88 nM (95%CI= 9.068–18.58 nM), as compared to the IC50 of non-senescent cells of 103.2 nM (95%CI= 74.24–143.9 nM; p< 0.005). Such differential sensitivity to Bcl-XL inhibition after radiation was not observed in the non-GBM control cells evaluated to date. CONCLUSION Our findings suggest that blocking the anti-apoptotic pathway Bcl-XL in GBM cells rendered at least transiently senescent following radiation may provide an avenue to selectively ablate residual glioblastoma cells following radiation. Our data provide proof of principle that senolytic therapy may represent a previously untapped window of opportunity to increase extent of tumor ablation following completion of standard cytotoxic therapies.

AbstractAblation is now recommended by international guidelines for the definitive treatment of hepatocellular carcinoma (HCC). Extensive clinical studies have demonstrated outcomes comparable to surgical resection with shorter hospital stays, decreased costs, and improved quality of life. Successful ablation requires complete treatment of both tumor and margin while preserving critical adjacent structures. HCC exhibits highly variable presentations in both anatomic involvement and biology which have significant implications on choice of ablative therapy. There are now abundant ablation modalities and adjunctive techniques which can be used to individualize ablation and maximize curative results. This article provides a patient-centered summary of approaches to HCC ablation in the context of patient performance, hepatic reserve, tumor phenotype and biology, intra- and extrahepatic anatomy, and ablation technology.

Abstract Introduction Neurosurgical anatomy is traditionally taught via anatomic and operative atlases; however, these resources present the skull base using views that emphasize three-dimensional (3D) relationships rather than operative perspectives, and are frequently written above a typical resident's understanding. Our objective is to describe, step-by-step, a retrosigmoid approach dissection, in a way that is educationally valuable for trainees at numerous levels. Methods Six sides of three formalin-fixed latex-injected specimens were dissected under microscopic magnification. A retrosigmoid was performed by each of three neurosurgery residents, under supervision by the senior authors (C.L.W.D. and M.J.L.) and a graduated skull base fellow, neurosurgeon, and neuroanatomist (M.P.C.). Dissections were supplemented with representative case applications. Results The retrosigmoid craniotomy (aka lateral suboccipital approach) affords excellent access to cranial nerve (CN) IV to XII, with corresponding applicability to numerous posterior fossa operations. Key steps include positioning and skin incision, scalp and muscle flaps, burr hole and parasigmoid trough, craniotomy flap elevation, initial durotomy and deep cistern access, completion durotomy, and final exposure. Conclusion The retrosigmoid craniotomy is a workhorse skull base exposure, particularly for lesions located predominantly in the cerebellopontine angle. Operatively oriented neuroanatomy dissections provide trainees with a critical foundation for learning this fundamental skull base technique. We outline a comprehensive approach for neurosurgery residents to develop their familiarity with the retrosigmoid craniotomy in the cadaver laboratory in a way that simultaneously informs rapid learning in the operating room, and an understanding of its potential for wide clinical application to skull base diseases.

OBJECTIVEGanglioglioma is a low-grade central nervous system neoplasm with a pediatric predominance, accounting for 10% of all brain tumors in children. Gangliogliomas of the cervicomedullary junction (GGCMJs) and brainstem (GGBSs) present a host of management challenges, including a significant risk of surgical morbidity. At present, understanding of the prognostic factors—including BRAF V600E status—is incomplete. Here, the authors report a single-institution GGCMJ and GGBS experience and review the pertinent literature.METHODSA prospectively maintained neurosurgical database at a large tertiary care academic referral center was retrospectively queried for cases of GGCMJ pathologically confirmed in the period from 1995 to 2015; appropriate cases were defined by diagnosis codes and keywords. Secondary supplemental chart review was conducted to confirm or capture relevant data. The primary study outcome was treatment failure as defined by evidence of radiographic recurrence or progression and/or clinical or functional decline. A review of the literature was conducted as well.RESULTSFive neurosurgically managed GGBS patients were identified, and the neoplasms in 4 were classified as GGCMJ. All 5 patients were younger than 18 years old (median 15 years, range 4–16 years) and 3 (60%) were female. One patient underwent gross-total resection, 2 underwent aggressive subtotal resection (STR), and 2 underwent stereotactic biopsy only. All patients who had undergone STR or biopsy required repeat resection for tumor control or progression. Progressive disease was treated with radiotherapy in 2 patients, chemotherapy in 2, and chemoradiotherapy alone in 1. Immunostaining for BRAF V600E was positive in 3 patients (60%). All 5 patients experienced at least one major complication, including wound infection, foot drop, hemiparesis, quadriparesis, cranial neuropathy, C2–3 subluxation, syringomyelia, hydrocephalus, aspiration, and coma. Overall mortality was 20%, with 1 death observed over 11 years of follow-up.CONCLUSIONSGGBS and GGCMJ are rare, benign posterior fossa tumors that carry significant perioperative morbidity. Contemporary management strategies are heterogeneous and include combinations of resection, radiotherapy, and chemotherapy. The BRAF V600E mutation is frequently observed in GGBS and GGCMJ and appears to have both prognostic and therapeutic significance with targeted biological agents.