Efficacy of a preprostatectomy multi-modal penile rehabilitation regimen on recovery of postoperative erectile function.

To evaluate the efficacy of a novel, multi-modal, preoperative approach to postprostatectomy penile rehabilitation (PR), we performed a retrospective review of patients who underwent nerve-sparing robotic-assisted laparoscopic prostatectomy (NS-RALP). All patients were evaluated at a comprehensive, academic sexual medicine clinic between 2016 and 2017. The "prehabilitation" PR group (n = 106) consisted of men who were seen in the pre-op period and began tadalafil and L-citrulline 2 weeks prior to surgery. Vacuum erectile device (VED) therapy was started at 1-month post-op. These interventions were continued throughout the 12-month follow-up period. Individuals refractory to these therapies could start treatment with intracavernosal injections. The postprostatectomy PR group (n = 25) consisted of men who were not seen in the pre-op period and started the above therapies immediately following their first visit. A higher percentage of men in the prehabilitation group reported return of erectile function within 12 months (56% vs. 24%, P = 0.007). The prehabilitation group also showed better compliance with PR (PDE5i [96% vs. 64%, P < 0.001], L-citrulline [93% vs. 49%, P < 0.001], and VED [55% vs. 20%, P < 0.001]). Seventy-eight percent of men who attended 4-5 follow-up visits reported return of erectile function. Our results suggest that men undergoing a preoperative protocol show superior recovery of erectile function following NS-RALP. Further studies with prospective designs are warranted.

Sixty years in the making: collagenase Clostridium histolyticum, from benchtop to FDA approval and beyond.

PURPOSE: The introduction of collagenase Clostridium histolyticum (CCH) as the first and only FDA-approved non-surgical treatment for Peyronie's disease (PD) has been an important step in its management. Our aim is to provide an overview of the historical origins of CCH and its development through FDA approval and beyond for the treatment of PD. METHODS: A PubMed search using the terms Peyronie OR Peyronie's AND collagenase and limited to clinical research studies resulted in 24 articles that were examined for the current review. RESULTS: PD is a connective tissue disorder of the penile tunica albuginea involving fibrotic penile plaques that cause abnormal curvature and, in many cases, erectile pain. Although the exact mechanism and underlying pathophysiology are not well characterized, the known lability of these plaques to exogenous bacterial collagenase combined with a lack of effective medical therapies led to the development of CCH as an evidence-based treatment of PD. The initial discovery of collagenase was followed by in vitro studies on PD plaque tissue and following the phase 3 IMPRESS trial culminated in FDA approval of CCH in 2013. Future directions in CCH therapy include improved patient selection, use in acute phase PD, adjuvant and combination therapies, and novel delivery mechanisms. CONCLUSION: CCH provides an effective non-surgical treatment option for men with PD. We have traced the development of CCH in the treatment of PD from the earliest in vitro investigations to comprehensive multi-study meta-analyses confirming its highly rated efficacy when compared to other historical non-surgical remedies.

A modified technique for intralesional injection of collagenase Clostridium histolyticum for Peyronie's disease results in reduced procedural morbidity using a standardized hematoma classification rubric.

PURPOSE: Early clinical trials of injectable collagenase Clostridium histolyticum (CCh) for Peyronie's disease (PD) demonstrated safety and efficacy. Since then, modified injection protocols have been proposed. Adverse events-such as bruising, swelling, hematoma, and corporal rupture-exceed 50% in many studies, but lack of standardization of hematoma severity limits conclusions about the relative safety of protocols. We propose a modification of the standard injection technique that aims to decrease the rates of adverse events. We further describe a hematoma classification rubric that may standardize safety assessment. METHODS: A modified injection procedure, termed the "fan" technique, was employed in the treatment of PD. All men receiving CCh from January 2016 through January 2019 at a single institution were included in an institutional review board (IRB) approved database. Treatment outcomes and adverse events were retrospectively assessed. A three-tiered hematoma classification rubric was devised to standardize reporting of hematoma, which was defined as concurrent bruising and swelling at the site of injection without loss of erection. RESULTS: Using the fan technique, 152 patients received 1323 injections. Eight hematomas (5.3% of all patients, 0.6% of all injections) were observed. The number of grade I, grade II, and grade III hematomas were 3, 2, and 3, respectively. Bruising or swelling not meeting the definition of hematoma was seen in 54.6% and 27.0% of patients, respectively. There were zero corporal ruptures. CONCLUSION: A modified injection technique results in reduced procedural morbidity. A hematoma classification system provides clarity and standardization to the assessment of safety in PD treatment. Further clinical studies with control arms are required to verify these findings.

Vaginal Dehiscence and Evisceration After Robotic-assisted Radical Cystectomy: A Case Series and Review of the Literature.

OBJECTIVE: To describe a rare complication in 5 women who had vaginal prolapse, dehiscence, and/or evisceration after having undergone robotic-assisted radical cystectomy with creation of ileal conduit urinary diversion. Radical cystectomy is the standard of care in the extirpative treatment for muscle invasive urothelial carcinoma. Anterior exenteration in the female patient requires removal of the anterior vaginal wall, urethra, uterus, and adnexa which results in significant changes to the pelvic floor. METHODS: Retrospective identification of all women having undergone robotic-assisted radical cystectomy for urothelial carcinoma who ultimately represented with vaginal prolapse, dehiscence, and/or evisceration between January 2012 and April 2019. We identified patient characteristics detailing their presentation. A review of the available literature highlighted the lack of available information in this uncommon cohort. RESULTS: Five women with vaginal dehiscence and/or evisceration who had previously undergone robotic-assisted radical cystectomy, anterior vaginectomy with urethrectomy, pelvic lymph node dissection, and creation of ileal conduit by 4 surgeons were identified. Mean interval time to initial presentation of prolapse or dehiscence was 44.4 weeks (range 11-120). In the 2 patients that eviscerated prior to repair, this occurred at 5 and 25 weeks after initial outpatient consultation. All reconstructive efforts were approached transvaginally. Two patients underwent 2 or more repairs. Management options included expectant management, pessary, and immediate vs delayed transvaginal surgical repair. CONCLUSION: Our case series describes the unique and potentially devastating complication of vaginal dehiscence and bowel evisceration in women with history of robotic-assisted radical cystectomy.

Comparison of Times to Ureteral Efflux after Administration of Sodium Fluorescein and Phenazopyridine.

PURPOSE: There is currently a national shortage of indigo carmine. In efforts to identify the most efficient aid for visualizing ureteral efflux intraoperatively we investigated the time to excretion of phenazopyridine vs a newly identified alternative, sodium fluorescein. MATERIALS AND METHODS: We analyzed prospectively collected data on a cohort of women who underwent pelvic reconstructive surgery in 2015. Per provider preference patterns a number of patients were administered 200 mg phenazopyridine orally with a sip of water 1 hour prior to the start of operative time. Other patients were given 0.5 ml 10% sodium fluorescein intravenously in the operating room. In all cases time was measured between the administration of the agent and the visualization of color changes consistent with agent efflux in an indwelling catheter, which was placed at the start of the operation. Differences in excretion times between the groups were compared with the Wilcoxon rank sum test. RESULTS: Seven women received phenazopyridine and 5 received sodium fluorescein. Mean excretion time was significantly longer in the phenazopyridine group compared to the sodium fluorescein group (81.9 vs 5.1 minutes, p = 0.0057). Median excretion time for phenazopyridine was 70 minutes (range 59 to 127) and for sodium fluorescein it was 5 minutes (range 3 to 9). CONCLUSIONS: Sodium fluorescein is excreted significantly faster in the operating room compared to phenazopyridine. Depending on the cost of these agents at an institution, in addition to the desire to decrease operative time, this may impact practice patterns and agent selection.

Keyhole Transsylvian Resection of Infiltrative Insular Gliomas: Technique and Anatomic Results.

AIM: Insular gliomas have traditionally been approached through variations of large frontotemporal craniotomies exposing much of the Sylvian fissure. Due to the importance of many structures exposed by such an approach, a less-invasive approach to these lesions is a viable alternative for resection. We present the technique and results of our keyhole transsylvian approach to remove infiltrating insular tumors. MATERIAL AND METHODS: A small linear incision and keyhole craniotomy is planned under image guidance to open a transsylvian window. Using a combination of the microscope and endoscope, we remove the insula circumferentially outward. We present our results of 20 patients with gliomas confined to the insula evaluated with volumetric imaging analysis. RESULTS: There were 12 right-sided and 8 left-sided tumors. The median skin-to-skin operative time was 215 minutes. 15/20 patients were discharged from the hospital on or before post-operative day 3, with 5 of those going home the day after surgery. Greater than 90% of the tumor was removed in 18 of 20 cases, with an additional case achieving 89.5% resection. In no case was the residual tumor volume greater than 3 cc. Permanent weakness occurred in 2 patients (10%). Despite a significant number of left-sided tumors, temporary dysphasia occurred in only 1 patient (12.5%), which resolved by first follow up. CONCLUSION: Localized insular gliomas can be effectively removed through a minimally invasive approach without increasing the risk of neurological morbidity. This minimizes manipulation of uninvolved, potentially eloquent cortices, and minimizes damage to the overlying soft tissue.

Supratentorial hemangioblastoma: clinical features, prognosis, and predictive value of location for von Hippel-Lindau disease.

Supratentorial hemangioblastoma is a rare form of hemangioblastoma; little information is available regarding prognosis, treatment, and clinical characteristics, because the available literature is primarily composed of case reports and small case series. Therefore, we performed a systematic review of the literature to analyze clinical characteristics, disease progression, and surgical outcomes with respect to survival for supratentorial hemangioblastomas. The rate of progression-free survival (PFS) was determined using Kaplan-Meier analysis. Differences in categorical factors, including location of tumor and diagnosis of von Hippel-Lindau (VHL) disease, were analyzed using the Pearson χ(2) test. A total of 106 articles met the search criteria, which combined for a total of 132 patients. Of the patients with supratentorial tumors, 60% had VHL disease, and 31 (84%) of 37 patients with tumors in the sellar/suprasellar region had associated VHL (χ(2), P < .001). Five-year PFS for gross-total resection and subtotal resection were 100% and 53%, respectively (Log rank, P < .01). On the basis of our analysis of the literature on published cases of supratentorial hemangioblastoma, gross-total resection appears to be superior to other treatment modalities in extending PFS. Von Hippel-Lindau disease is positively correlated with supratentorial hemangioblastoma when compared with non-supratentorial CNS hemangioblastomas, particularly when present in the sellar/suprasellar region.

Signaling pathways in cranial chondrosarcoma: potential molecular targets for directed chemotherapy.

Cranial chondrosarcoma is an indolent tumor of the skull base, which is difficult to treat due to its inaccessible location. The current mainstay of treatment is surgical resection followed by adjuvant radiation therapy. To date, chemotherapy has been largely ineffective for chondrosarcoma due to a lack of targeted therapies. This review highlights numerous active signaling pathways that have been described in human chondrosarcoma. A limited number of functional experiments suggest that integrin activation at the cell surface results in upregulation of matrix metalloproteinases and extracellular matrix degradation, leading to increased tumor cell migration. This pathway appears to be dependent on phosphoinositide-3 kinase and MEK-extracellular signal-regulated kinase (ERK) signaling. Additionally, chondrosarcoma cell proliferation and degradation is dependent on peroxisome proliferator-activated receptor-gamma (PPAR-γ) activity, with a loss of PPAR-γ expression and associated apoptosis in high-grade tumors. The data suggest that targeting these pathways may improve control of cranial chondrosarcoma and decrease the need for hazardous recurrent operations.

Embolization of skull base meningiomas and feeding vessels arising from the internal carotid circulation.

BACKGROUND: Practice patterns regarding the preoperative embolization of skull base tumors vary widely among institutions and are driven by surgeon preference and concerns about safety. OBJECTIVE: We present a recent experience at our institution with a specific focus on procedural decision-making, embolization of vessels arising from the internal carotid circulation, and complication rates. METHODS: During a 7.5-year period, 262 meningiomas were referred for embolization. of which 119 (45%) originated from the skull base. Tumors were categorized by location, feeding artery origin, and arteries embolized. Complication rates were reviewed. RESULTS: Sixty-four of 119 patients with skull base tumors (54%) underwent embolization of at least 1 feeding artery. Feeding arteries arose from the external carotid artery (ECA) circulation in 26 (22%), the internal carotid artery (ICA) circulation in 30 (25%), a combination of ECA/ICA/Vert in 54 (45%), and had only pial supply in 10 (8%). In total, 15 of 85 (18%) ICA feeding vessels were embolized. This included 9 of 28 vessels from the meningohypopheseal trunk, 3 of 4 vessels from the anterior temporal artery, 1 of 35 vessels from the ophthalmic artery, 1 of 8 vessels directly from the ICA, and 1 of 5 vessels from the inferolateral trunk. Complete devascularization occurred in 6 of 64 patients; subtotal devascularization was seen in 58 of 64. The overall angiographic complication rate for all meningiomas embolized in the study period was 2.5% (5/199). None of the complications occurred in the skull base group. CONCLUSION: Preoperative embolization of skull base meningiomas and ICA feeding vessels can be done with low complication rates when intraprocedural decision-making favors complication avoidance over complete devascularization.

The next step: innovative molecular targeted therapies for treatment of intracranial chordoma patients.

BACKGROUND: Chordomas are rare, locally aggressive malignancies that often exhibit an insidious natural history and are difficult to eradicate. Surgery and radiotherapy are the treatment mainstays of chordoma, but the chance of local recurrence remains high. Patients who relapse or cannot undergo a complete en bloc resection generally have a poor prognosis. New agents for postoperative adjuvant treatment of chordomas are needed. OBJECTIVE: To highlight potential clinical trials that could evolve from new insights into the molecular biology of chordoma. METHODS: We performed a review of recent studies published in the literature that have begun to characterize the molecular features of chordoma, and with this knowledge, several targets for potential clinical therapies have been determined. RESULTS: Several receptor tyrosine kinases and their downstream signaling cascades show dysregulation in chordoma and represent attractive targets for future therapeutic interventions. The pathways shown to be of particular importance in chordoma involve the platelet-derived growth factor receptor, epidermal growth factor receptor, hepatocyte growth factor receptor, and common downstream cascade of phosphoinositide 3-kinases, Akt, and mammalian target of rapamycin. CONCLUSION: Recent findings characterizing the molecular biology of chordoma have illuminated multiple possible targets for future clinical trials. The availability of inhibitors against these aberrant pathways makes clinical trials with chordoma both feasible and immediately realizable. Additionally, we emphasize the rationale for combination therapy when implementing molecular therapy in chordoma and other cancers.

Complication avoidance in minimally invasive neurosurgery.

Although minimally invasive neurosurgery (MIN) holds the potential for reducing the approach-related impact on normal brain, bone, and soft tissues, which must be manipulated in more conventional transcranial microneurosurgery, the techniques necessary to perform minimally invasive, yet maximally effective neurosurgery place significant demands on the surgeon because in many ways the more limited exposure creates a number of unique ways these operations can go wrong. Safe and effective MIN requires the conscious institution of specific alterations to the surgeon's usual operative case flow, which are designed to make specific well-known mistakes impossible or at least very unlikely. Thus, it is important for the aspiring MIN surgeons to learn from the mistakes of their predecessors and to institute patterns of behavior that prevent a repetition of these mistakes. This article provides practical information regarding known pitfalls in intraventricular and transcranial neuroendoscopic surgeries and practical methods to reduce the incidence of these complications to the lowest rate possible.

Implications for immunotherapy of tumor-mediated T-cell apoptosis associated with loss of the tumor suppressor PTEN in glioblastoma.

The ability of glioma cells to escape the immune system remains a significant barrier to successful immunotherapy. Here we demonstrate that loss of the PTEN tumor suppressor gene, with associated activation of the PI3K/Akt/mTOR pathway, leads to a human glioma phenotype that induces autologous T-cell apoptosis upon contact. The PTEN status of pathologically confirmed glioblastoma specimens was defined, and primary cultures established after surgical resection of tumor from 26 patients. Autologous T-cells were isolated from these patients, and after T-cell activation was induced, these cells were co-cultured with matched autologous glioma cells, either alone, or after treatment with one of three inhibitors of the PI3K/Akt/mTOR pathway. When co-cultured with autologous T-cells, PTEN wild-type tumor cells induced apoptosis in a minimal number of activated T-cells (6-12% of T-cells), whereas tumors with PTEN loss induced much more profound levels of T-cell apoptosis (42-56% of T-cells). Prior treatment of PTEN-deficient tumor cells with specific inhibitors of the PI3K/Akt/mTOR pathway diminished T-cell apoptosis to levels seen after co-culture with wild-type PTEN tumor cells, suggesting that PTEN loss confers this immunoresistant phenotype through the PI3K/Akt/mTOR pathway. These results suggest that PTEN-deficient glioblastoma patients are suboptimal candidates for immunotherapy. In addition, our results raise the possibility of combining T-cell based immunotherapy protocols with clinical inhibitors of the PI3K/Akt/mTOR pathway.

Cancer and the complement cascade.

Despite significant research on the role of inflammation and immunosurveillance in the immunologic microenvironment of tumors, little attention has been given to the oncogenic capabilities of the complement cascade. The recent finding that complement may contribute to tumor growth suggests an insidious relationship between complement and cancer, especially in light of evidence that complement facilitates cellular proliferation and regeneration. We address the hypothesis that complement proteins promote carcinogenesis and suggest mechanisms by which complement can drive the fundamental features of cancer. Evidence shows that this diverse family of innate immune proteins facilitates dysregulation of mitogenic signaling pathways, sustained cellular proliferation, angiogenesis, insensitivity to apoptosis, invasion and migration, and escape from immunosurveillance. Given that the traditionally held functions for the complement system include innate immunity and cancer defense, our review suggests a new way of thinking about the role of complement proteins in neoplasia.

Complement and the central nervous system: emerging roles in development, protection and regeneration.

As expanding research reveals the novel ability of complement proteins to promote proliferation and regeneration of tissues throughout the body, the concept of the complement cascade as an innate immune effector has changed rapidly. In particular, its interactions with the central nervous system have provided a wealth of information regarding the ability of complement proteins to mediate neurogenesis, synaptogenesis, cell migration, neuroprotection, proliferation and regeneration. At numerous phases of the neuronal and glial cell cycle, complement proteins exert direct or indirect influence over their behavior and fate. Neuronal stem cells differentiate and migrate in response to complement, and it prevents injury and death in adult cells in response to toxic agents. Furthermore, complement proteins promote survival via anti-apoptotic actions, and can facilitate clearance and regeneration of injured tissues in various models of CNS disease. In summary, we highlight the protean abilities of complement proteins in the central nervous system, underscoring an exciting avenue of research that has yielded greater understanding of complement's role in central nervous system health and disease.

Predictors of mortality following treatment of intracranial hemangiopericytoma.

OBJECT: Intracranial hemangiopericytoma (HPC) is a rare and malignant extraaxial tumor with a high proclivity toward recurrence and metastasis. Given this lesion's rarity, little information exists on prognostic factors influencing mortality rates following treatment with surgery or radiation or both. A systematic review of the published literature was performed to ascertain predictors of death following treatment for intracranial HPC. METHODS: The authors identified 563 patients with intracranial HPC in the published literature, 277 of whom had information on the duration of follow-up. Statistical analysis of survival was performed using Kaplan-Meier and Cox regression analysis. RESULTS: Hemangiopericytoma was diagnosed in 246 males and 204 females, ranging in age from 1 month to 80 years. Among patients treated for HPC, overall median survival was 13 years, with 1-, 5-, 10-, and 20-year survival rates of 95%, 82%, 60%, and 23%, respectively. Gross-total resection alone (105 patients) was associated with superior survival rates overall, with a median survival of 13 years, whereas subtotal resection alone (23 patients) resulted in a median survival of 9.75 years. Subtotal resection plus adjuvant radiotherapy led to a median survival of 6 years. Gross-total resection was associated with a superior survival benefit to patients regardless of the addition or absence of radiation, and patients receiving > 50 Gy of radiation had worse survival outcomes (median survival 4 vs 18.6 years, p < 0.01, log-rank test). Patients with tumors of the posterior fossa had a median survival of 10.75 versus 15.6 years for those with non-posterior fossa tumors (p < 0.05, log-rank test). CONCLUSIONS: Treatment with gross-total resection provides the greatest survival advantage and should be pursued aggressively as an initial therapy. The addition of postoperative adjuvant radiation does not seem to confer a survival benefit.