Intratumoral delivery of tavokinogene telseplasmid yields systemic immune responses in metastatic melanoma patients.

BACKGROUND: Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT01502293). PATIENTS AND METHODS: Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre- and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). RESULTS: The objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance. CONCLUSIONS: Intratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/distal lesions, adaptive immune resistance limited the response.

Grafts for Peyronie's disease: a comprehensive review.

The difficulty implicit in combining all the characteristics that an ideal patch to treat Peyronie's disease with a lengthening procedure should have, together with the challenges of comparing results from different series, means that the ideal patch has yet to be determined. Our objective with this review was to determine whether any given patch type is preferable to the others based on the evaluation of the results of published studies. A systematic search of the literature was conducted from PubMed until December 2016. Articles reporting basic research, animal research, reviews or meta-analyses and studies in children were eliminated. Series with patients undergoing some kind of other surgical intervention were only included if results were reported separately. Case reports and series of five patients were excluded. Five variables were selected to evaluate the results: number of patients, follow-up period, straightening rate, shortening rate and post-operative ED rate. For this purpose, 69 papers were included for review, and the outcomes of the use of autologous dermis, tunica vaginalis, dura mater, fascia, saphenous vein, tunica albuginea, buccal mucosa, porcine intestinal submucosa, pericardium, TachoSil® and synthetic materials were presented and analysed separately. The different series published are extremely variable and heterogeneous in terms of the number of patients included, patient selection, follow-up periods, and in the measurement and interpretation of the outcomes analysed. Given these facts, it is not possible to draw any definitive conclusion, homogeneous, prospective studies using validated tools are required to determine which the ideal graft is.

The Influence of Post-Build Microstructure on the Electrochemical Behavior of Additively Manufactured 17-4 PH Stainless Steel.

The additive manufacturing (AM) build process produces a segregated microstructure with significant variations in composition and phases that are uncommon in traditional wrought materials. As such, the relationship between the post-build microstructure and the corrosion resistance is not well understood. Stainless steel alloy 17-4PH is an industrially-relevant alloy for applications requiring high-strength and good corrosion resistance. A series of potentiodynamic scans conducted in a deaerated 0.5 mol/L NaCl solution evaluated the influence of these microstructural differences on the pitting behavior of SS17-4. The pitting potentials were found to be higher in the samples of additively-processed material than in samples of the alloy in wrought form. This indicates that the additively-processed material is more resistant to localized corrosion and pitting in this environment than the wrought alloy. The results also suggest that after homogenization, the additively-produced SS17-4 could be more resistant to pitting than wrought SS17-4 in an actual service environment.

Surgical outcomes from limiting the use of nonabsorbable suture in tunica albuginea plication for Peyronie's disease.

Tunica albuginea plication (TAP) surgery for Peyronie's disease (PD) is classically described using nonabsorbable suture. Many patients are aware of nodularity at the suture sites (50-88%), and some find them painful (10-33%). We explore whether limiting permanent sutures provides a durable correction of curve and report the incidence of bothersome nodules. Beginning in 2007, we modified our TAP procedure to limit the use of permanent sutures. We reviewed all patients who underwent TAP procedures from 2007 to 2014 at our institution. Patients were contacted to complete a previously published survey regarding postoperative satisfaction. In total, 142 PD patients underwent the TAP procedure and 81/142 (57%) completed the postoperative survey. Mean office follow-up and survey follow-up were 17.3 and 56.3 months, respectively. Of the surveyed patients, 6.2% complained of a bothersome residual curve, 19.8% experienced nodularity and 4.9% reported bothersome nodules. Men with dorsal curves experienced less painful nodularity than those with ventral (P=0.047) or lateral curves (P=0.017). In total, 4/142 (2.8%) of men underwent repeat intervention. At long-term follow-up, limiting permanent sutures during TAP procedures for PD is durable with respect to curvature correction and has encouragingly low levels of nodularity and bother at suture sites.

Designing a Uniaxial Tension/Compression Test for Springback Analysis in High-Strength Steel Sheets.

We describe an innovative design for an in-plane measurement technique that subjects thin sheet metal specimens to bidirectional loading. The goal of this measurement is to provide the critical performance data necessary to validate complex predictions of the work hardening behavior during reversed uniaxial deformation. In this approach, all of the principal forces applied to the specimen are continually measured in real-time throughout the test. This includes the lateral forces that are required to prevent out of plane displacements in the specimen that promote buckling. This additional information will, in turn, improve the accuracy of the compensation for the friction generated between the anti-bucking guides and the specimen during compression. The results from an initial series of experiments not only demonstrate that our approach is feasible, but that it generates data with the accuracy necessary to quantify the directionally-dependent changes in the yield behavior that occur when the strain path is reversed (i.e., the Bauschinger Effect).

Topical treatment for acute phase Peyronie's disease utilizing a new gel, H-100: a randomized, prospective, placebo-controlled pilot study.

Safety and efficacy of topically applied gel H-100 composed of Nicardipine, superoxide dismutase and emu oil for treatment of acute phase Peyronie's disease (PD) was evaluated. Twenty-two patients (PD <12 months duration) were studied in a prospective, randomized, double-blind, placebo-controlled study. Eleven patients received H-100 and 11 patients received placebo for 3 months. All 22 patients then received H-100 for the final 3 months. Flaccid-stretched penile length, degree of penile curvature, pain level and side effects were assessed monthly. H-100 showed significant improvement in all PD parameters at 6 months: mean stretched penile length increase (22.6%, P=0.0002), mean curvature reduction (40.8%, P=0.0014), and mean pain level reduction (85.7%, P=0.004). Placebo group showed no significant improvement except for mean stretched penile length increase (6.8%, P=0.009). Crossover patients from placebo to H-100 showed significant improvement in all parameters: mean stretched penile length increase (17.5%, P=0.000007), mean curvature reduction (37.1%, P=0.006), and mean pain level reduction (40%, P=0.17). Treatment was well tolerated. A self-limited rash was the only side effect in three patients. Statistically significant improvements in flaccid-stretched penile length, curvature and pain suggest that H-100 is a safe and possibly effective non-invasive, topically applied treatment for acute phase Peyronie's Disease.

Peyronie's disease: urologist's knowledge base and practice patterns.

Peyronie's disease (PD) is a poorly understood clinical entity. We performed an in-depth analysis of the knowledge base and current practice patterns of urologists in the United States. A 46-question instrument was created by two experienced PD practitioners and emailed to current American Urology Association members nationally. Questions were either multiple-choice or used a visual analogue scale. Responses regarding treatment options were answered by ranking a list of utilized therapies by preference. Data were aggregated and mean values for each category compiled. Responses were received from 639 urologists (67% in private practice). Almost all (98%) reported seeing PD patients with regularity. Twenty-six percent believed PD prevalence is ≤1%, a small fraction (5%) reporting prevalence as ≥10%. Only 3% referred patients to a subspecialist in PD. Twenty-six percent believed PD is a condition that does not warrant any treatment. The preferred initial management was with oral agents (81%). Of those who used intralesional injections as first line, verapamil was most commonly selected (67%). Seventy-nine percent perform surgery for PD with 86% reporting the optimal timing at ≥12 months after onset of symptoms. Seventy percent perform penile plication, most commonly the Nesbit technique (54%), 61% perform implant surgery and 37% reported performing plaque incision/excision and grafting. Although PD is now a more recognized condition, there are still large variances in knowledge and management strategies. Prospective clinical studies are needed to elucidate standardized management guidelines and a more cohesive strategy to manage this common disease.

Review of non-surgical treatment options for Peyronie's disease.

Non-surgical treatment of Peyronie's disease (PD) has come a long way since it was first described in 1743. A myriad of treatment options are currently available, including oral, intralesional and external energy therapies. The purpose of this article is to review the contemporary literature on non-surgical therapies for PD, and where possible, focus on randomized, placebo-controlled trials, as well as review the latest guidelines for the management of PD from the International Committee on Sexual Medicine, which conveyed its findings in July 2009. At this time, it appears that a combination of oral agents and/or intralesional injection with traction therapy may provide a synergy between the chemical effects of the drugs and the mechanical effects of traction. Until a reliable treatment emerges, it does appear that some of the non-surgical treatments discussed can be used to stabilize the scarring process and may result in some reduction of deformity with improved sexual function.

Carbonic anhydrase IX (CA-IX) and high-risk human papillomavirus (H-HPV) as diagnostic biomarkers of cervical dysplasia/neoplasia in Japanese women with a cytologic diagnosis of atypical glandular cells (AGC): a Gynecologic Oncology Group (GOG) Study.

BACKGROUND: High-risk human papillomavirus (H-HPV) infection is linked to cervical neoplasia but its role in detecting cervical glandular lesions (GLs) is unclear. Carbonic anhydrase IX (CA-IX) is a hypoxic biomarker that is highly expressed in neoplastic cervical GLs. The diagnostic utility of these biomarkers was evaluated by the Gynecologic Oncology Group in Japanese women with a cytological diagnosis of atypical glandular cells. METHODS: Immunostaining was used to detect CA-IX in a conventional Pap smear. Immunoreactivity of CA-IX was interpreted by a panel of pathologists blinded to the histological diagnosis. Polymerase chain reaction was used to detect H-HPV in a liquid-based cytology specimen. RESULTS: Significant cervical lesions (SCLs), defined as cervical intraepithelial neoplasia (CIN2, CIN3), adenocarcinoma in situ or invasive carcinoma, were observed in 37/88 (42%) of women. CA-IX testing alone (n=88) had a sensitivity of 89, 100 or 73% for SCLs, GLs or significant squamous lesions (SLs), respectively, with a false negative rate (FNR) of 14%. Testing for H-HPV (n=84) had a sensitivity of 65, 53 or 80% for SCLs, GLs or SLs, respectively, with a FNR of 22%. The combination of CA-IX and H-HPV testing had a sensitivity of 97, 100 or 93% for SCLs, GLs or SLs, respectively, with a FNR of 5%. Among eight H-HPV-negative GLs, six (75%) had a diagnosis of lobular endocervical glandular hyperplasia (LEGH). CONCLUSION: The combination of CA-IX and HPV testing improved the diagnostic accuracy. The low rate of H-HPV positivity in the GLs was associated with coexisting LEGH independent of H-HPV.

Randomized, double-blind, placebo-controlled study of postoperative nightly sildenafil citrate for the prevention of erectile dysfunction after bilateral nerve-sparing radical prostatectomy.

Four weeks after bilateral nerve-sparing radical retropubic prostatectomy, men with normal erectile function before surgery were randomized to double-blind sildenafil (50 or 100 mg) or placebo nightly for 36 weeks, followed by an 8-week drug-free period before assessment of erectile function. Enrollment was prematurely ceased and only 76 men completed because, assuming a placebo response rate similar to the published literature (for example, 34% in meta-analysis), the 25% response at blinded interim review suggested a lack of treatment effect. On the contrary, spontaneous erectile function (a combined score of >or=8 for questions 3 and 4 of the International Index of Erectile Function and a positive response to 'Were erections good enough for satisfactory sexual activity?') occurred in only 4% of the placebo group (n=1 of 25) versus 27% (n=14 of 51, P=0.0156, Fisher's exact test) of the sildenafil group. Nightly sildenafil administration for 36 weeks after surgery markedly increased the return of normal spontaneous erections.

Establishing a standardized evaluation of the man with Peyronie's disease.

The goal of this article is to encourage development of a standardized approach to the evaluation of the man with Peyronie's disease. An additional aim is to identify those subjective and objective measures of change occurring as a result of treatment which would allow uniform reporting of treatment outcome. Systematic review of current clinical parameters used in assessing the man with Peyronie's disease including demographic data, physical findings, objective measures of penile deformity and erectile function as well as questionnaires employed to gain more reliable subjective data. As there is no accepted standard approach or previously published analysis of existing approaches, a survey of 68 recently published articles is included to query current outcome reporting on Peyronie's disease therapy. Results were as follows. An algorithm is suggested as an initial format for evaluation and outcome analysis. The pros and cons of subjective and objective measures of penile deformity is presented and a standardized questionnaire and penile duplex ultrasound report form is included for current use. The literature survey revealed the broad unscientific approach to outcome reporting making assessment of treatment quite difficult. In conclusion, it is clear that it is time to establish a standardized and globally acceptable evaluation and outcome reporting algorithm. There is interest to develop and validate a specific Peyronie's disease index questionnaire. In the meantime, this article presents specific recommendations to obtaining meaningful objective measures and methods to report them.

Review of current nonsurgical management of Peyronie's disease.

The current nonsurgical treatment options for men with Peyronie's disease is reviewed. The treatments currently employed and published in the English literature are discussed. A wide variety of nonsurgical treatment options are available to the practicing physician, including oral and topical medications, intralesional injection therapy, as well as employing external energy sources to drive medicine into the tunica albuginea by iontophoresis or direct stimulation of plaque change by shock wave therapy. Nonsurgical treatment of Peyronie's disease clearly has a place in the armamentarium of the practicing urologist. Oral therapy appears to have little therapeutic benefit. Injection and topical approaches deserve further attention. Yet, no single treatment stands out as the most effective remedy for all men with Peyronie's disease. Further controlled, large-scale studies are necessary to establish the benefits of these nonsurgical approaches. In the meantime, combination therapy appears to make sense in the nonsurgical treatment of men with Peyronie's disease.

Nuclear receptor agonists stimulate release of arachidonic acid from rat liver cells.

Release of arachidonic acid (AA) from rat liver cells is stimulated after a 6 h incubation with compounds that are members of the nuclear receptor superfamily, including vitamin D(3), clofibrate, 22(R) OH cholesterol, farnesol, progesterone, testosterone, 17beta-estradiol, hydrocortisone, 3,3'5 triiodothyronine, juvenile hormone III, WY14643, L -thyroxine, the tyrosine analog of thiazolidinediones, GW7845, tamoxifen, hydroxytamoxifen, 17alpha-estradiol and D -thyroxine. Squaline, lanosterol, cholesterol and the 17beta-estradiol antagonist, ICI-182,780, do not stimulate. ICI-182,780 inhibits the release stimulated by 17beta-estradiol, vitamin D(3), 22(R) OH cholesterol, celecoxib or indomethacin. Actinomycin D abolishes the release stimulated by 15-deoxy-delta(12,14) PGJ(2), but is less effective at inhibiting the release stimulated by all of the agonists listed above as well as the release stimulated by 9-cis retinoic acid, all trans -retinoic acid, the thiazidinedione, ciglitazone and the non-steroidal anti-inflammatory drugs, indomethacin and celecoxib. Based on the effects of the 17beta-estradiol antagonist, ICI-182,780, the release of AA appears to be a membrane effect and may not be mediated by the classical estrogen receptors. From the results obtained with actinomycin D, some stimulations may require transcription.

Treatment of erectile dysfunction in patients with Peyronie's disease using sildenafil citrate.

Erectile dysfunction (ED) has frequently been associated with Peyronie's Disease (PD) and may further compromise coitus. This is a retrospective analysis of ED in patients with PD since the release of sildenafil citrate (SC) focusing specifically on our patients' responses to SC. One-hundred seventy six patients with PD were evaluated between April 1998 and May 2001. All patients received a complete medical and sexual history, physical exam, penile duplex ultrasound (PDU, with 30-90 mg of papaverine) to assess penile vascular integrity, plaque dimensions, and erect penile deformity. Based on these findings, appropriate treatment options were offered for their PD and their ED including SC, which was offered to 73 men. Patient response to SC was specifically assessed during patient office interview and via a mailed EDITS (Erectile Dysfunction Inventory of Treatment Satisfaction) questionnaire. Seventy (39.8%) and 104 (59.1%) patients complained of decreased erectile capacity (ie rigidity) occurring before and after the onset of PD, respectively. Only two patients reported no change of erectile capacity. In all, 103 (58.5%) patients complained of significant reduction in sexual function due to diminished rigidity and sought treatment for their ED. Of the ED treatment options available, 73 (70.9%) patients were given a prescription for SC. Forty-eight (75.0%) patients returned the EDITS questionnaire while four of 73 (5.5%) patients did not fill their prescription and five of 73 (6.8%) did not engage in sexual activity following an initial trial of SC due to side effects (flushing, headaches). Based upon the EDITS response, 34 of 48 (70.8%) patients reported that they were either very satisfied or somewhat satisfied, five of 48 (10.4%) patients were neither satisfied nor dissatisfied, and nine of 48 (18.8%) patients were somewhat dissatisfied or very dissatisfied with the effectiveness of SC in enhancing their erectile response. No patient reported worsening of PD deformity or an increase in penile pain. The 30 patients who were not prescribed SC chose the following options to enhance rigidity: eight (7.8%) underwent prosthesis placement, four (3.9%) opted for vacuum constriction device (VCD), four (3.9%) chose intracorporal injections, and 14 (13.6%) used no adjunctive therapy. Erectile dysfunction is a problem associated with PD and all typical treatment options are acceptable. However, to our knowledge, there is no published study reviewing the efficacy of SC in patients with ED associated with PD. There appears to be no contraindication to using SC as being the least invasive and most convenient treatment option for ED with PD. Although the potential risk of coital trauma to the erect penis with PD is present, there is no evidence from this study that erections and coitus enhanced specifically by SC resulted in worsening deformity or progression of the PD. EDITS questionnaire results reveal that SC is an agent that allowed successful coitus in 70.8% of males with PD.

Intralesional verapamil for the treatment of Peyronie's disease: a review.

Multiple treatment options have been used for Peyronie's disease (PD) including intralesional injection of the calcium antagonist verapamil. The use of verapamil is based on its capacity to alter fibroblast function at several levels, including cell proliferation, extracellular matrix protein synthesis and secretion, as well as collagen degradation. Consequently, calcium antagonists may have the capacity to slow, prevent, or even reverse plaque formation and the progression of PD. The multicenter international experience with intralesional verapamil injection suggests that the majority of men with PD that receive treatment demonstrate durable reduction in pain, decrease in curvature, and improved sexual function. We review the scientific rationale, published literature, clinical experience, and technique of intralesional injection of verapamil.

Septo-optic dysplasia with olfactory tract and bulb hypoplasia.

Optic nerve hypoplasia can be associated with other central nervous system malformations. When associated with absence of the septum pellucidum or thinning of the corpus callosum, it is termed septo-optic dysplasia. Considered to be a first trimester event, the embryologic timing and etiology of this syndrome still is not clearly defined. This report represents the first documented case of septo-optic dysplasia with associated hypoplasia of the olfactory tract. Optic nerve hypoplasia is attributed to an abnormal developmental process during gestation. Generally accepted to be due to a first trimester insult, the timing of this abnormality has been debated given its association with other central nervous system abnormalities. These central nervous system abnormalities often include cerebral hemispheric and hypothalmic-pituitary axis abnormalities. Specifically, the presence of optic nerve hypoplasia with absence of the septum pellucidum and thinning of the corpus callosum has been termed septo-optic dysplasia or de Morsier's syndrome. Septo-optic dysplasia in association with olfactory tract and bulb hypoplasia has not been reported previously.

Ocular motility complications after endoscopic sinus surgery with powered cutting instruments.

OBJECTIVE: The purpose of this study was to describe 2 unique cases of ocular motility dysfunction after powered endoscopic sinus surgery and identify potential risk factors for extraocular muscle injury. STUDY DESIGN: Interventional case series. RESULTS: Patient 1 developed a restrictive global ophthalmoplegia after inadvertent entry into the medial orbit during powered endoscopic sinus surgery. Patient 2 had complete loss of adduction of the left eye as a result of transection of the medial rectus muscle by a powered cutting instrument. CONCLUSIONS: Despite advances in endoscopic sinus surgery technique and instrumentation, serious ophthalmic complications may still occur. Inadvertent entry into the medial orbital wall can result in ocular motility complications. Furthermore, it is possible that attraction of orbital contents into the tip of a powered cutting instrument may occur without significant entry into the orbital cavity. SIGNIFICANCE: It is important for endoscopic sinus surgeons to be aware of the intimate anatomical relationship between the orbit and sinuses, as well as the potential risks of the current instruments used in endoscopic sinus surgery.

Effect of hemodilution on tissue perfusion and blood coagulation during radical hysterectomy.

OBJECTIVE: The goal of this study was to evaluate the safety of hemodilution on global and splanchnic perfusion and blood coagulation during radical hysterectomy. METHODS: A pulmonary artery catheter and a gastric tonometry catheter were placed in 16 patients with cervical carcinoma. Global perfusion indices, splanchnic perfusion index, and coagulation tests were obtained. Blood was removed to achieve a hemoglobin measurement of 8-9 9 g/dL. Three more measurements were repeated after hemodilution, at the end of surgery, and after the retransfusion of blood. Analysis of variance was used to determine statistical significance. RESULTS: Sixteen patients with cervical carcinoma had 1.0 +/- 0.3 L (mean +/- SD) of blood removed and had a blood loss of 0.8 +/- 0.7 L. Hemodiluted preoperative hemoglobin was 8.7 +/- 1 g/dL. All of the global perfusion indices, except for arterial pH and oxygen consumption, decreased after hemodilution and recovered with the retransfusion of blood (P < or = 0.004). Splanchnic perfusion and coagulation tests were unchanged (P > or = 0.1). Major complication was pulmonary edema in one patient. CONCLUSION: Hemodilution during radical hysterectomy, in this select group of patients, does not appear to compromise tissue perfusion or coagulation.