Plication procedures-excisional and incisional corporoplasty and imbrication for Peyronie's disease.

Plication procedures for the correction of Peyronie's disease (PD) curvature are management options for PD patients. There are basically three types of procedures: excisional corporoplasty, incisional corporoplasty, and plication-only. This review is a compilation of English literature, peer-reviewed, published articles addressing these types of operations for Peyronie's curvature correction, not congenital curvature. According to the urology literature, this surgical type was initially used for correction of curvature associated with hypospadias repair or congenital penile curvature. The procedures also, for the most part, historically became an alternative for plaque excision and graft repair, because of the difficulty with such repairs and the often-resultant erectile dysfunction (ED). A brief section traces some of the origins of these various repairs, followed by a brief section on the selection criteria for these types of surgery for the patient with PD penile curvature. We also review the significant articles in which the three types were presented with modifications. Finally, several articles that compare the various surgical repairs are summarized in the order that they appear in the literature. These types of surgery have become a mainstay for the surgical correction of penile curvature due to PD.

Continent Catheterizable Vesicostomy: An Alternative Surgical Modality for Pediatric Patients With Large Bladder Capacity.

OBJECTIVE: To present a modified technique and early outcomes of a continent catheterizable vesicostomy in pediatric patients with either flaccid neurogenic bladder or intractable voiding dysfunction and large capacity bladder. METHODS: Six patients underwent the procedure from October 2014 to December 2015. A 4-cm Pfannenstiel incision was made, avoiding intraperitoneal dissection. After adequate mobilization, a 2-cm vertical flap at the dome of the bladder was identified and tubularized over a 12Fr catheter with 4-0 vicryl suture. The tubularized flap was then intussuscepted into the bladder with four 4-0 polydioxanone sutures, creating a continent mechanism. The catheterizable channel was then tunneled to the umbilicus, the channel ostomy matured, and the cystotomy closed in two layers. RESULTS: The median patient age was 8 (interquartile range [IQR] 12) years. All patients had urinary dysfunction requiring drainage from etiologies that included Eagle-Barrett syndrome (n = 2), Noonan syndrome (n = 1), Lennox-Gastaut syndrome (n = 1), and Spina bifida (n = 2). Median hospital length of stay was 8 (IQR 3) days. One patient had a superficial wound infection treated with antibiotics, and 1 patient required balloon dilation of the catheterizable channel at 3 months postoperatively, secondary to difficulty self-catheterizing. Five patients were successfully self-catheterizing at last follow-up. Median follow-up was 6 (IQR 5) months and there were no intra- or perioperative complications. CONCLUSION: Continent catheterizable vesicostomy is a novel technique for urinary drainage in patients with large bladder capacity that spares use of the appendix or ileum. Early results are encouraging, providing a catheterizable channel through the umbilicus without urinary leakage between catheterization.

Robotic ultrasound probe for tumor identification in robotic partial nephrectomy: Initial series and outcomes.

OBJECTIVES: Accurate tumor identification during partial nephrectomy is essential for successful tumor control. Intraoperative laparoscopic ultrasonography is useful for tumor localization, but the ultrasound probe is controlled by the assistant rather than the surgeon. We evaluated our initial experience using a robotic ultrasound probe that is controlled by the console surgeon. METHODS: Partial nephrectomy was carried out in 22 consecutive patients between November 2010 and March 2011. A robotic ultrasound probe under console surgeon control was used in all the cases. All patients had at least 1 year follow up. RESULTS: Mean patient age was 59 years and mean tumor size was 2.7 cm. There were six hilar tumors (27%) and 21 (95%) endophytic tumors. Mean R.E.N.A.L. nephrometry score was 6.9 (range 6-9). Mean operative time was 205.7 min and mean warm ischemia time was 17.9 min (range 6-28 min). All patients had negative tumor margins and were free of disease recurrence at a mean follow up of 13 months. CONCLUSION: The use of a robotic ultrasound probe during partial nephrectomy allows the surgeon to optimize tumor identification with maximal autonomy, and to benefit from the precision and articulation of the robotic instrument during this key step of the partial nephrectomy procedure.

Isosteric analogs of lenalidomide and pomalidomide: synthesis and biological activity.

A series of analogs of the immunomodulary drugs lenalidomide (1) and pomalidomide (2), in which the amino group is replaced with various isosteres, was prepared and assayed for immunomodulatory activity and activity against cancer cell lines. The 4-methyl and 4-chloro analogs 4 and 15, respectively, displayed potent inhibition of tumor necrosis factor-α (TNF-α) in LPS-stimulated hPBMC, potent stimulation of IL-2 in a human T cell co-stimulation assay, and anti-proliferative activity against the Namalwa lymphoma cell line. Both of these analogs displayed oral bioavailability in rat.

Health behaviours of community-treated patients with psychosis.

OBJECTIVE: To assess physical health self-reports and health utilization behaviours of community dwelling persons with persistent psychosis. METHOD: A cross-sectional survey was conducted of 106 patients with persistent psychosis. Using self-reported measures, the prevalence of smoking, alcohol consumption and exercise, and body mass index were determined. Health utilization behaviour, especially with respect to general practice, was assessed. Data was compared with that derived from the general population and longitudinally with a historical cohort. RESULTS: Compared with the general population, those with psychosis were more likely to be smokers, overweight or obese, and less likely to be non/ex-smokers. Compared with previous studies, smoking and obesity persisted as major modifiable risk factors. Over 7 years, some risks such as smoking increased, whereas moderating factors such as light exercise, improved. Three-quarters of patients would visit their GP if they had a physical illness but a third reported not having visited their GP or other doctor in the previous 12 months. CONCLUSIONS: Patients with persistent psychosis have increased rates of cardiometabolic risk yet seek medical attention infrequently. These findings have not improved despite an increased awareness of the enhanced risk of developing metabolic disease in this group.

1,1-Diarylalkenes as anticancer agents: dual inhibitors of tubulin polymerization and phosphodiesterase 4.

A series of 1,1-diarylalkene derivatives were prepared to optimize the properties of CC-5079 (1), a dual inhibitor of tubulin polymerization and phosphodiesterase 4 (PDE4). By using the 3-ethoxy-4-methoxyphenyl PDE4 pharmacophore as one of the aromatic rings, a significant improvement in PDE4 inhibition was achieved. Compound 28 was identified as a dual inhibitor with potent PDE4 (IC(50)=54 nM) and antitubulin activity (HCT-116 IC(50)=34 nM and tubulin polymerization IC(50) ∼1 µM). While the nitrile group at the alkene terminus was generally required for potent antiproliferative activity, its replacement was tolerated if there was a hydroxyl or amino group on one of the aryl rings. Conveniently, this group could also serve as a handle for amino acid derivatization to improve the compounds' solubility. The glycinamide analog 45 showed significant efficacy in the HCT-116 xenograft model, with 64% inhibition of tumor growth upon dosing at 20 mg/kg qd.

Robotic partial nephrectomy using robotic bulldog clamps.

BACKGROUND AND OBJECTIVES: The need for a skilled assistant to perform hilar clamping during robotic partial nephrectomy is a potential limitation of the technique. We describe our experience using robotic bulldog clamps applied by the console surgeon for hilar clamping. METHODS: A total of 60 consecutive patients underwent robotic partial nephrectomy, 30 using laparoscopic bulldog clamps applied by the assistant and 30 using robotic bulldog clamps applied with the robotic Prograsp instrument. Perioperative outcomes were compared between groups. RESULTS: All 30 patients underwent successful hilar clamping during robotic partial nephrectomy using robotic bulldog clamps with no intraoperative complications and without the need for readjustment/reclamping. Robotic bulldog clamps provided adequate ischemia even for tumors >4 cm, hilar, endophytic, multiple tumors, and multiple renal arteries. Both groups had similar baseline characteristics. Perioperative outcomes with robotic bulldog clamps were at least comparable to the laparoscopic bulldog group, with a trend to lower console time, warm ischemia time, and estimated blood loss. CONCLUSIONS: Use of robotically applied bulldog clamps is a safe and feasible method of hilar occlusion during robotic partial nephrectomy; they perform at least as well as laparoscopic bulldog clamps while allowing the console surgeon greater autonomy and precision for hilar clamping.

Hypophosphataemic osteomalacia in patients on adefovir dipivoxil.

Fanconi syndrome results from generalised renal tubular toxicity and, owing to phosphate wasting can cause hypophosphataemic osteomalacia. Large clinical trials advocated the safety of adefovir dipivoxil at a daily dose of 10 mg, the standard dose given to patients with hepatitis B. We diagnosed Fanconi syndrome in conjunction with severe osteomalacia in 2 hepatitis B-positive patients on standard-dose adefovir therapy. The first patient was a 40-year-old male with a 5 month history of bone pain involving his knees, ankles, and ribs. He had been receiving adefovir dipivoxil for 27 months before the development of hypophosphataemia, urinary phosphate wasting, and aminoaciduria. These abnormalities resolved within weeks of discontinuation of adefovir dipivoxil and supplementation with elemental phosphate, calcium carbonate, and cholecalciferol. The second patient was a 53-year-old female with a 6 month history of lethargy, cachexia, and generalized bone pain. She had been receiving adefovir for 64 months before the development of these symptoms. She had hypophosphataemia, hypocalcaemia, metabolic acidosis, and severe vitamin D deficiency, but initially no urinary phosphate wasting. Four months of high-dose cholecalciferol supplementation unmasked her Fanconi syndrome including significant urinary phosphate wasting. The patient improved within weeks of discontinuation of adefovir and supplementation with elemental phosphate, calcium carbonate, and calcitriol. Despite large clinical trials advocating the safety of adefovir dipivoxil at 10-mg daily, long-term use of this agent may be nephrotoxic and in rare cases, cause Fanconi syndrome and severe hypophosphataemic osteomalacia. Clinicians prescribing this drug should be aware of this potential complication.

Early renal failure detection by cystatin C in Type 2 diabetes mellitus: varying patterns of renal analyte expression.

AIM: The early stages of renal failure are poorly diagnosed by current routine tests. We studied cystatin C and routine renal analyte patterns in Type 2 diabetes mellitus. METHODS: Type 2 diabetes mellitus patients (n = 48) were tested for serum cystatin C, urine albumin, haemoglobin A1c, serum creatinine, serum urea, urine creatinine, glucose, triglycerides and low density lipoproteins (LDL). Glomerular filtration rate (GFR) estimates were made using Cockroft-Gault and Modification of Diet in Renal Disease formulae. RESULTS: The cystatin C (95%CI) reference range was 0.78-0.86 mg/L. While serum cystatin C showed general correlation with routine renal tests, a plateau was observed in analytes measured against cystatin C. Cystatin C improved sensitivity led to detection of renal abnormality in 19% of patients not diagnosed by routine tests. CONCLUSIONS: Cystatin C is a more sensitive marker of renal disease in Type 2 diabetes mellitus where estimated GFR is unreported at >60 mL/min and where antihypertensive medications render microalbuminuria detection unreliable. Its incorporation into a panel of renal function tests is highly recommended.

Discovery of (S)-N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl] acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-alpha inhibitor.

In this communication, we report the discovery of 1S (apremilast), a novel potent and orally active phosphodiesterase 4 (PDE4) and tumor necrosis factor-alpha inhibitor. The optimization of previously reported 3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-(3,4-dimethoxyphenyl)propionic acid PDE4 inhibitors led to this series of sulfone analogues. Evaluation of the structure-activity relationship of substitutions on the phthalimide group led to the discovery of an acetylamino analogue 1S, which is currently in clinical trials.

The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells.

Lenalidomide (Revlimid; CC-5013) and pomalidomide (CC-4047) are IMiDs proprietary drugs having immunomodulatory properties that have both shown activity in cancer clinical trials; lenalidomide is approved in the United States for a subset of MDS patients and for treatment of patients with multiple myeloma when used in combination with dexamethasone. These drugs exhibit a range of interesting clinical properties, including anti-angiogenic, anti-proliferative, and pro-erythropoietic activities although exact cellular target(s) remain unclear. Also, anti-inflammatory effects on LPS-stimulated monocytes (TNF-alpha is decreased) and costimulatory effects on anti-CD3 stimulated T cells, (enhanced T cell proliferation and proinflammatory cytokine production) are observed. These drugs also cause augmentation of NK-cell cytotoxic activity against tumour-cell targets. Having shown that pomalidomide confers T cell-dependent adjuvant-like protection in a preclinical whole tumour-cell vaccine-model, we now show that lenalidomide and pomalidomide strongly inhibit T-regulatory cell proliferation and suppressor-function. Both drugs inhibit IL-2-mediated generation of FOXP3 positive CTLA-4 positive CD25high CD4+ T regulatory cells from PBMCs by upto 50%. Furthermore, suppressor function of pre-treated T regulatory cells against autologous responder-cells is abolished or markedly inhibited without drug related cytotoxicity. Also, Balb/C mice exhibit 25% reduction of lymph-node T regulatory cells after pomalidomide treatment. Inhibition of T regulatory cell function was not due to changes in TGF-beta or IL-10 production but was associated with decreased T regulatory cell FOXP3 expression. In conclusion, our data provide one explanation for adjuvant properties of lenalidomide and pomalidomide and suggest that they may help overcome an important barrier to tumour-specific immunity in cancer patients.

The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions.

Lenalidomide (Revlimid) is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk Myelodysplastic Syndromes (MDS) associated with a del 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, and in combination with dexamethasone for the treatment of multiple myeloma patients who have received at least one prior therapy. Previous reports suggest that lenalidomide is anti-angiogenic and this property appears to be related to efficacy in patients with MDS. We have investigated the effect of lenalidomide on the formation of microvessels in a novel in vitro angiogenesis assay utilizing human umbilical arterial rings and in a capillary-like cord formation assay using cultured primary endothelial cells. We found that lenalidomide consistently inhibits both sprout formation by arterial rings and cord formation by endothelial cells in a dose-dependent manner. We also found an inhibitory effect of lenalidomide on the associations between cadherin 5, beta-catenin and CD31, adherens junction proteins whose interaction is critical for endothelial cell cord formation. Furthermore, lenalidomide inhibited VEGF-induced PI3K-Akt pathway signaling, which is known to regulate adherens junction formation. We also found a strong inhibitory effect of lenalidomide on hypoxia-induced endothelial cell formation of cords and HIF-1 alpha expression, the main mediator of hypoxia-mediated effects and a key driver of angiogenesis and metastasis. Anti-metastatic activity of lenalidomide in vivo was confirmed in the B16-F10 mouse melanoma model by a >40% reduction in melanoma lung colony counts versus untreated mice. Our results suggest that inhibitory effects on microvessel formation, in particular adherens junction formation and inhibition of hypoxia-induced processes support a potential anti-angiogenic and anti-metastatic mechanism for this clinically active drug.

lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells.

PURPOSE: Lenalidomide has significant activity in myelodysplastic syndromes, multiple myeloma, and non-Hodgkin's lymphoma (NHL). In previous studies, natural killer (NK) cell expansion by lenalidomide was shown to enhance the cytotoxic effect of rituximab. This study assessed the ability of lenalidomide to enhance antibody-dependent cellular cytotoxicity (ADCC) in rituximab-treated NHL cell lines and primary tumor cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) in vitro. EXPERIMENTAL DESIGN: An in vitro ADCC system was used to assess the ability of lenalidomide to enhance human NK cell and monocyte function in response to rituximab. RESULTS: Lenalidomide directly enhanced IFN-gamma production via Fc-gamma receptor-mediated signaling in response to IgG. It was also a potent enhancer of NK cell-mediated and monocyte-mediated tumor cell ADCC for a variety of rituximab-treated NHL cell lines in vitro, an effect that was dependent on the presence of antibody and either interleukin-2 or interleukin-12. Lenalidomide also enhanced the ability of NK cells to kill primary tumor cells derived from three patients with B-CLL who have been treated previously with fludarabine plus cyclophosphamide. Enhanced NK cell ADCC was associated with enhanced granzyme B and Fas ligand expression and could be inhibited by a granzyme B inhibitor and partially inhibited by antibody to FasL. Enhanced NK cell Fc-gamma receptor signaling is associated with enhanced phosphorylated extracellular signal-related kinase levels leading to enhanced effector function. CONCLUSIONS: These findings suggest that lenalidomide has the potential to enhance the rituximab-induced killing of NHL cell lines and primary B-cell chronic lymphocytic leukemia cells via a NK cell-mediated and monocyte-mediated ADCC mechanism in vitro, providing a strong rationale for the combination of lenalidomide with IgG1 antibodies to target tumor-specific antigens in patients with cancer.

Surgical approach to the patient with bimaxillary protrusion.

The patient who has bimaxillary protrusion often is treated using a combination of orthodontics and orthognathic surgery, and the general approach is dental extraction with retraction of the incisors. In certain cases, maxillary excess may be corrected solely with LeFort I osteotomy and setback and without dental extraction or anterior segmental osteotomies. This article discusses (1) treatment evaluation and planning and (2) the specific surgical techniques, primarily anterior segmental osteotomies and the technical details for setback of the LeFort I osteotomized segment (more than 5 mm), as they relate to the surgical approach of the patient who has bimaxillary protrusion.

Giant functioning parathyroid cyst presenting as a retrosternal goitre.

Parathyroid cysts are rare and even more rarely cause a neck mass resembling a goitre. Such large parathyroid cysts may involve the mediastinum, growing to a sufficient size to produce symptoms related to obstruction, and if functioning, primary hyperparathyroidism. Parathyroid cysts should be considered in the list of differential diagnoses of anterior neck masses to allow for appropriate preoperative investigation to avoid unnecessary confusion at the time of operation. We report a case where a functioning parathyroid cyst presented as a retrosternal goitre to emphasize the potential pitfalls associated with their diagnosis and management.

Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells.

Clinical studies involving patients with myelodysplastic syndromes or multiple myeloma have shown the efficacy of lenalidomide by reducing and often eliminating malignant cells while restoring the bone marrow function. To better understand these clinical observations, we investigated and compared the effects of lenalidomide and a structurally related analogue, CC-4047, on the proliferation of two different human hematopoietic cell models: the Namalwa cancer cell line and normal CD34+ progenitor cells. Both compounds had antiproliferative effects on Namalwa cells and pro-proliferative effects on CD34+ cells, whereas p21WAF-1 expression was up-regulated in both cell types. In Namalwa cells, the up-regulation of p21WAF-1 correlated well with the inhibition of cyclin-dependent kinase (CDK) 2, CDK4, and CDK6 activity leading to pRb hypophosphorylation and cell cycle arrest, whereas in CD34+ progenitor cells the increase of p21WAF-1 did not inhibit proliferation. Similarly, antiproliferation results were observed in two B lymphoma cell lines (LP-1 and U266) but interestingly not in normal B cells where a protection of apoptosis was found. Finally, CC-4047 and lenalidomide had synergistic effects with valproic acid [a histone deacetylase (HDAC) inhibitor] by increasing the apoptosis of Namalwa cells and enhancing CD34+ cell expansion. Our results indicate that lenalidomide and CC-4047 have opposite effects in tumor cells versus normal cells and could explain, at least in part, the reduction of malignant cells and the restoration of bone marrow observed in patients undergoing lenalidomide treatment. Moreover, this study provides new insights on the cellular pathways affected by lenalidomide and CC-4047, proposes new potential clinical uses, such as bone marrow regeneration, and suggests that the combination of lenalidomide or CC-4047 with certain HDAC inhibitors may elevate the therapeutic index in the treatment of hematologic malignancies.

The synthetic compound CC-5079 is a potent inhibitor of tubulin polymerization and tumor necrosis factor-alpha production with antitumor activity.

We have found that the synthetic compound CC-5079 potently inhibits cancer cell growth in vitro and in vivo by a novel combination of molecular mechanisms. CC-5079 inhibits proliferation of cancer cell lines from various organs and tissues at nanomolar concentrations. Its IC(50) value ranges from 4.1 to 50 nmol/L. The effect of CC-5079 on cell growth is associated with cell cycle arrest in G(2)-M phase, increased phosphorylation of G(2)-M checkpoint proteins, and apoptosis. CC-5079 prevents polymerization of purified tubulin in a concentration-dependent manner in vitro and depolymerizes microtubules in cultured cancer cells. In competitive binding assays, CC-5079 competes with [(3)H]colchicine for binding to tubulin; however, it does not compete with [(3)H]paclitaxel (Taxol) or [(3)H]vinblastine. Our data indicate that CC-5079 inhibits cancer cell growth with a mechanism of action similar to that of other tubulin inhibitors. However, CC-5079 remains active against multidrug-resistant cancer cells unlike other tubulin-interacting drugs, such as Taxol and colchicine. Interestingly, CC-5079 also inhibits tumor necrosis factor-alpha (TNF-alpha) secretion from lipopolysaccharide-stimulated human peripheral blood mononuclear cells (IC(50), 270 nmol/L). This inhibitory effect on TNF-alpha production is related to its inhibition of phosphodiesterase type 4 enzymatic activity. Moreover, in a mouse xenograft model using HCT-116 human colorectal tumor cells, CC-5079 significantly inhibits tumor growth in vivo. In conclusion, our data indicate that CC-5079 represents a new chemotype with novel mechanisms of action and that it has the potential to be developed for neoplastic and inflammatory disease therapy.

Immunomodulatory drugs (IMiDs) increase the production of IL-2 from stimulated T cells by increasing PKC-theta activation and enhancing the DNA-binding activity of AP-1 but not NF-kappaB, OCT-1, or NF-AT.

Immunomodulatory drugs (IMiDs) are orally available small molecules that potently inhibit tumor necrosis factor-alpha (TNF-alpha) production by lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (HuPBMCs) but enhance secretion of such cytokines as interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) by stimulated T cells. The mechanism of cytokine regulation by IMiDs has not yet been determined. In the present study, we investigated the effects of one of the IMiDs, CC-4047 (Actimid, Celgene, Warren, NJ), on synthesis of IL-2 protein and mRNA and on the activity and expression of transcription factors. Treatment with CC-4047 enhances the secretion of IL-2 protein and the expression of IL-2 mRNA in a dose-dependent and time-dependent manner. In T cells stimulated with phorbol myristate acetate (PMA)/ionomycin, CC-4047 enhanced the DNA-binding activity of activated protein-1 (AP-1) but not NF-kappaB, Octomer-1 (OCT-1), or NFAT by 2-fold and 4-fold after an incubation time of 1 and 3 h, respectively. Luciferase reporter assays in Jurkat cells showed similar effects on transcription factor activity. Using in vitro kinase activity assays, we also showed that CC-4047 enhances the activity of protein kinase C-theta (PKC-theta) in stimulated T cells. The secreted IL-2 from HuPBMCs was shown to activate natural killer (NK) cells to lyse their target cell line K562. Taken together, our results demonstrate that the IMiDs exert their effects at least in part by activating PKC-theta and acting on AP-1 DNA-binding activity in T cells, resulting in augmented IL-2 synthesis and activation of IL- 2-dependent downstream effectors, such as NK cells.