Formulation Development for Transdermal Delivery of Raloxifene, a Chemoprophylactic Agent against Breast Cancer.

Raloxifene (RLX) is a second-generation selective estrogen receptor modulator approved for the prevention of invasive breast cancer in women. Oral therapy of RLX requires daily intake and is associated with side effects that may lead to low adherence. We developed a weekly transdermal delivery system (TDS) for the sustained delivery of RLX to enhance the therapeutic effectiveness, increase adherence, and reduce side effects. We evaluated the weekly transdermal administration of RLX using passive permeation, chemical enhancers, physical enhancement techniques, and matrix- and reservoir-type systems, including polymeric gels. In vitro permeation studies were conducted using vertical Franz diffusion cells across dermatomed human skin or human epidermis. Oleic acid was selected as a chemical enhancer based on yielding the highest drug delivery amongst the various enhancers screened and was incorporated in the formulation of TDSs and polymeric gels. Based on in vitro results, both Eudragit- and colloidal silicon dioxide-based transdermal gels of RLX exceeded the target flux of 24 µg/cm2/day for 7 days. An infinite dose of these gels delivered 326.23 ± 107.58 µg/ cm2 and 498.81 ± 14.26 µg/ cm2 of RLX in 7 days, respectively, successfully exceeding the required target flux. These in vitro results confirm the potential of reservoir-based polymeric gels as a TDS for the weekly administration of RLX.

Case report of co-existing keratotic balanitis and squamous cell carcinoma in a 42-year-old male.

Although a number of premalignant and malignant lesions affect the genitalia of men, such as condyloma acuminata, erythroplasia of queyrat, squamous cell carcinoma, hyperkeratotic balanitis is rare and a patient showing both hyperkeratotic and well-differentaited squamous cell carcinoma is rarer. We report the case of a 42-year-old male, who had a hyperkeratotic plaque like lesions over the glans, with accompanied atrophic areas.

Satisfaction and genital perception after orchiectomy for prostate cancer: does the technique matter? A randomized trial.

OBJECTIVES: Bilateral extracapsular or total orchiectomy (BEO) for prostate cancer is presumed to have psychological consequences after the surgery due to perception of an empty scrotum. Bilateral subcapsular orchiectomy (BSO) was designed to preserve perception of palpable testes. We compared the patients' satisfaction and genital perception following BEO and BSO. MATERIALS AND METHODS: Prostate cancer patients eligible for androgen deprivation therapy who opted for orchiectomy were enrolled in prospective randomized study. Patients with bleeding disorder or uncorrected coagulopathy, poor performance score, and psychiatric problems were excluded. Outlook to life and own health in-general, overall satisfaction to the procedure and genital perception was evaluated using modified Fugl-Meyer questionnaire (FMQ) which was administered before and after 3 months of the surgery. Patients were randomized to BEO and BSO groups at the time of surgery using block randomization. Primary outcome was to compare the genital perception of testicular loss and patients' satisfaction to BSO and BEO. Secondary outcomes included testosterone and PSA control, operative time, and complications. RESULTS: Total 35 patients were enrolled in each group which was comparable. There was no difference in PSA control at 3 months. Mean operative time and blood loss were significantly lesser in BEO group. FMQ score at 3 months did not show significant difference. Majority of the patients in both groups were satisfied with procedure and the aesthetic value of scrotum after surgery. However, 84% in BSO group did not feel that testes were removed on self-examination, as compared to 28% in BEO group. Majority patients in both groups did not report physical or psychological discomfort from change in scrotal content. CONCLUSIONS: Results showed that patients' satisfaction and genital perception following BSO and BEO were similar. Feeling of remaining intrascrotal contents after BSO did not had added psychological advantage in terms of perception of genitalia.

Development of a Transdermal Delivery System for Tenofovir Alafenamide, a Prodrug of Tenofovir with Potent Antiviral Activity Against HIV and HBV.

Tenofovir alafenamide (TAF) is an effective nucleotide reverse transcriptase inhibitor that is used in the treatment of HIV-1 and HBV. Currently, it is being investigated for HIV prophylaxis. Oral TAF regimens require daily intake, which hampers adherence and increases the possibility of viral resistance. Long-acting formulations would significantly reduce this problem. Therefore, the aim of this study was to develop a transdermal patch containing TAF and investigate its performance in vitro through human epidermis. Two types of TAF patches were manufactured. Transparent patches were prepared using acrylate adhesive (DURO-TAK 87-2516), and suspension patches were prepared using silicone (BIO-PSA 7-4301) and polyisobutylene (DURO-TAK 87-6908) adhesives. In vitro permeation studies were performed while using vertical Franz diffusion cells for seven days. An optimized silicone-based patch was characterized for its adhesive properties and tested for skin irritation. The acrylate-based patches, comprising 2% w/w TAF and a combination of chemical enhancers, showed a maximum flux of 0.60 ± 0.09 µg/cm²/h. However, the silicone-based patch comprising of 15% w/w TAF showed the highest permeation (7.24 ± 0.47 µg/cm²/h). This study demonstrates the feasibility of developing silicone-based transdermal patches that can deliver a therapeutically relevant dose of TAF for the control of HIV and HBV infections.

Positive ureteric margins at radical cystectomy: Can it be predicted at initial transurethral resection of bladder tumour?

OBJECTIVE: To identify primary tumour-related factors at transurethral resection of bladder tumour (TURBT) that may predict positive distal ureteric margins (PUM) at the time of radical cystectomy (RC). PATIENTS AND METHODS: A retrospective, cohort study was conducted using our institution's data from June 2007 to June 2016. Patients who underwent TURBT followed by RC for non-metastatic urothelial carcinoma (UC) of the bladder were identified. In all, 211 patients underwent RC for UC during the study period. The patients were divided into two groups: Group-I (n = 17) with PUM and Group-II (n = 194) with negative ureteric margins. Univariate and multivariate analyses were performed to determine the predictors of PUM. RESULTS: On univariate analysis, multifocality, tumours involving the ureteric orifice, trigonal tumours, presence of carcinoma in situ (CIS), and lymphovascular invasion at TURBT, were significantly more common in Group-I. On multivariate analysis, tumour involvement in the ureteric orifice(s) and presence of associated CIS significantly predicted PUM. CONCLUSIONS: Primary tumour-related factors on initial TURBT that predicted PUM (at RC) were involvement of the ureteric orifice(s) and presence of associated CIS. These results may help to select patients who can be selectively offered intraoperative frozen section analysis.

Contemporary use of ultrasonic versus standard electrosurgical dissection in laparoscopic nephrectomy: Safety, efficacy and cost.

OBJECTIVE: To assess the safety, efficacy and cost-effectiveness of ultrasonic dissection (USD) compared with standard monopolar electrosurgery (ES) in laparoscopic nephrectomy (LN). PATIENTS AND METHODS: Retrospective analysis of patients' records who underwent elective LN was performed. Patients were divided in to two groups: USD and ES groups depending on the energy source used during LN. The preoperative (demographics, indication for surgery), intraoperative (conversion to open surgery, operative time, estimated blood loss [EBL], complications), and postoperative (morbidity/mortality, volume of drainage, hospital stay, cost) data were collected and analysed. RESULTS: Between February 2004 and February 2008, 136 patients were included. The indications for nephrectomy were: inflammatory (51 patients), non-inflammatory (64), and tumours (21). The two groups were similar for preoperative data. The conversion rate to open surgery (12.5%) and mean operative time did not differ significantly between the groups. However, intraoperative mean EBL was significantly less with USD, at 140.8 mL vs 182.6 mL for ES. There were no differences in postoperative parameters and morbidity. USD was significantly more expensive than ES (59 000 vs 26 000 Indian Rupees). CONCLUSIONS: ES is a safe and feasible tool like USD in LN when used with caution. USD facilitates completion of difficult cases and reduces intraoperative blood loss. However, the majority of LNs can be completed safely with ES. ES is sturdy and cheap; therefore, selective use of USD appears to be the most cost-effective policy in the developing world.

Transitional cell carcinoma of the renal pelvis with venous tumor thrombus.

Renal cell carcinoma (RCC) is the most common malignancy that results in venous tumor thrombosis. Transitional cell carcinoma of the renal pelvis with renal or vena cava thrombus is extremely rare. Fewer than 40 cases have been reported. We report a similar case of a patient who underwent radical nephrectomy with a preoperative diagnosis of RCC.

MET network in PubMed: a text-mined network visualization and curation system.

Metastasis is the dissemination of a cancer/tumor from one organ to another, and it is the most dangerous stage during cancer progression, causing more than 90% of cancer deaths. Improving the understanding of the complicated cellular mechanisms underlying metastasis requires investigations of the signaling pathways. To this end, we developed a METastasis (MET) network visualization and curation tool to assist metastasis researchers retrieve network information of interest while browsing through the large volume of studies in PubMed. MET can recognize relations among genes, cancers, tissues and organs of metastasis mentioned in the literature through text-mining techniques, and then produce a visualization of all mined relations in a metastasis network. To facilitate the curation process, MET is developed as a browser extension that allows curators to review and edit concepts and relations related to metastasis directly in PubMed. PubMed users can also view the metastatic networks integrated from the large collection of research papers directly through MET. For the BioCreative 2015 interactive track (IAT), a curation task was proposed to curate metastatic networks among PubMed abstracts. Six curators participated in the proposed task and a post-IAT task, curating 963 unique metastatic relations from 174 PubMed abstracts using MET.Database URL: http://btm.tmu.edu.tw/metastasisway.

Pharmacogenetics of UGT1A4, UGT2B7 and UGT2B15 and Their Influence on Tamoxifen Disposition in Asian Breast Cancer Patients.

Tamoxifen (TAM) is an established endocrine treatment for all stages of oestrogen receptor (ER)-positive breast cancer. Its complex metabolism leads to the formation of multiple active and inactive metabolites. One of the main detoxification and elimination pathways of tamoxifen and its active metabolites, 4-hydroxytamoxifen (4-OHT) and endoxifen, is via glucuronidation catalysed by uridine 5'-diphospho-glucuronosyltransferases (UGTs). However, few studies have comprehensively examined the impact of variations in the genes encoding the major hepatic UGTs on the disposition of tamoxifen and its metabolites. In the present study, we systematically sequenced exons, exon/intron boundaries, and flanking regions of UGT1A4, UGT2B7 and UGT2B15 in 240 healthy subjects of different Asian ethnicities (Chinese, Malays and Indians) to identify haplotype tagging single nucleotide polymorphisms. Subsequently, 202 Asian breast cancer patients receiving tamoxifen were genotyped for 50 selected variants in the three UGT genes to comprehensively investigate their associations with steady-state plasma levels of tamoxifen, its active metabolites and their conjugated counterparts. The UGT1A4 haplotype (containing variant 142T>G, L48 V defining the *3 allele) was strongly associated with higher plasma levels of TAM-N-glucuronide, with a twofold higher metabolic ratio of TAM-N-glucuronide/TAM observed in carriers of this haplotype upon covariate adjustment (P < 0.0001). Variants in UGT2B7 were not associated with altered O-glucuronidation of both 4-OHT and endoxifen, while UGT2B15 haplotypes had a modest effect on (E)-endoxifen plasma levels after adjustment for CYP2D6 genotypes. Our findings highlight the influence of UGT1A4 haplotypes on tamoxifen disposition in Asian breast cancer patients, while genetic variants in UGT2B7 and UGT2B15 appear to be of minor importance.

Naphthoflavones as Antiproliferative Agents: Design, Synthesis and Biological Evaluation.

The present study involves the design and synthesis of naphthoflavones as antiproliferative agents. The strategy presents naphthoflavones as hybrids of naphthyl based chalcones and flavones. A panel of human cancer cell lines were employed for the cytotoxicity studies. DK-13 exhibited significant cytoxicity against MiaPaCa-2 cell lines with IC50 value of 1.93 µM and 5.63 µM against MCF-7 cell lines. The compound DK-13 was found to induce apoptosis evidenced through phase contrast microscopy, DAPI staining, and mitochondrial membrane potential loss. The cell phase distribution studies indicated an increase from 11.26 % (control sample) to 55.19 % (sample treated with 20 µM compound DK-13) in the apoptotic population.

Association of CYP2C19*2 and associated haplotypes with lower norendoxifen concentrations in tamoxifen-treated Asian breast cancer patients.

AIM: The aim was to examine the influence of CYP2C19 variants and associated haplotypes on the disposition of tamoxifen and its metabolites, particularly norendoxifen (NorEND), in Asian patients with breast cancer. METHODS: Sixty-six CYP2C19 polymorphisms were identified in healthy Asians (n = 240), of which 14 were found to be tightly linked with CYP2C19*2, CYP2C19*3 and CYP2C19*17. These 17 SNPs were further genotyped in Asian breast cancer patients receiving tamoxifen (n = 201). Steady-state concentrations of tamoxifen and its metabolites were quantified using liquid chromatography­mass spectrometry. Non-parametric tests and regression methods were implemented to evaluate genotypic­phenotypic associations and haplotypic effects of the SNPs. RESULTS: CYP2C19 functional polymorphisms and their linked SNPs were not significantly associated with plasma concentrations of tamoxifen and its main metabolites N-desmethyltamoxifen, (Z)-4-hydroxytamoxifen and (Z)-Endoxifen. However, CYP2C19*2 and its seven linked SNPs were significantly associated with lower NorEND concentrations, MRNorEND/NDDM and MRNorEND/(Z)-END. Specifically, patients carrying the CYP2C19*2 variant allele A had significantly lower NorEND concentrations [median (range), GG vs. GA vs. AA: 1.51 (0.38­3.28) vs. 1.28 (0.30­3.36) vs. 1.15 ng ml−1 (0.26­2.45, P = 0.010)] as well as significantly lower MRNorEND/(Z)-END [GG vs. GA vs. AA: 9.40 (3.27­28.35) vs. 8.15 (2.67­18.9) vs. 6.06 (4.47­14.6), P < 0.0001] and MRNorEND/NDDM [GG vs. GA vs. AA: 2.75 (0.62­6.26) vs. 2.43 (0.96­4.18) vs. 1.75 (1.10­2.49), P < 0.00001]. CYP2C19 H2 haplotype, which included CYP2C19*2, was also significantly associated with lower NorEND concentrations (P = 0.0020), MRNorEND/NDDM (P < 0.0001) and MRNorEND/(Z)-END (P < 0.0001), indicating significantly lower formation rates of NorEND. CONCLUSION: These data highlight the potential relevance of CYP2C19 pharmacogenetics in influencing NorEND concentrations in tamoxifen-treated patients, which may influence treatment outcomes.

Primary Retroperitoneal Inter-aorto-Caval Paraganglioma of the Organ of Zuckerkandl.

Tumour that arise from chromaffin cells at extra-adrenal locations are termed paragangliomas which are rare tumour. The organ of Zuckerkandl located along aortic bifurcation is the most common site of their occurrence. Herein, we report a case of 20-year-old male with large abdomino-pelvic paraganglioma of the organ of zuckerkandl with multiple pedicles to abdominal aorta. On exploratory laparotomy it revealed a large retroperitoneal mass with variable consistency with surfaces covered with tortuous vessels. This mass was adhered to the retroperitoneum with multiple arterial pedicles to abdominal aorta. Histopathologic evaluation revealed features of extra-adrenal paraganglioma with characteristic Zellballen appearance. Postoperative course was uneventful.

Laparoscopic ureterolysis and omental wrapping in patients with retroperitoneal fibrosis and obstructive uropathy: a single-center experience.

OBJECTIVES: To analyze the outcomes with mid- to long-term follow-up of laparoscopic ureterolysis (LU) and omental wrapping in retroperitoneal fibrosis (RPF) with obstructive uropathy. PATIENTS AND METHODS: Records of 9 patients with RPF who had obstructive uropathy at presentation and had undergone LU and omental wrapping at our center during January 2004 to June 2012 were collected and analyzed. RESULTS: Six females and three males underwent LU for RPF. Underlying causes of RPF could not be found in 8 (89%) cases. Two patients underwent bilateral LU. Mean operative time and estimated blood loss were 213 minutes (range, 180-280 minutes) and 119 mL (range, 70-200 mL), respectively. No case required conversion to open surgery. The only significant intraoperative complication (1/9 [11%]) was ureteral injury, which was easily repaired intraoperatively. The postoperative complication rate was 44% (4/9). Most complications (75% [3/4]) were minor and did not need specific treatment. The mean follow-up period was 46 months (range, 4-72 months). The success rate at last follow-up was 89%. CONCLUSIONS: Treatment of RPF is still controversial. Any future prospective randomized comparative trials seem unlikely in view of the low incidence of RPF. LU and omental wrapping in the setting of obstructive uropathy are safe and an effective alternative with a high success rate at mid- to long-term follow-up.

Pharmacogenetic effects of regulatory nuclear receptors (PXR, CAR, RXRα and HNF4α) on docetaxel disposition in Chinese nasopharyngeal cancer patients.

PURPOSE: This exploratory study was aimed at elucidating the pharmacogenetics of regulatory nuclear receptors (PXR, CAR, RXRα and HNF4α) and their implications on docetaxel pharmacokinetics and pharmacodynamics in local Chinese nasopharyngeal cancer patients. METHODS: A total of 59 single nucleotide polymorphisms (SNPs), including tag-SNPs and functionally relevant SNPs of the genes encoding these regulatory nuclear receptors (PXR/NR1I2, CAR/NR1I3, RXRα/NR2B1 and HNF4α/NR2A1), were profiled in the patients enrolled in our study by direct sequencing (N = 50). The generalized linear model was employed to estimate the haplotypic effects on the pharmacokinetics and pharmacodynamics of the patients. RESULTS: The pharmacokinetic profiles of docetaxel in these patients were characterized by marked interindividual variability, with approximately four- to sixfold variations observed in Cmax, AUC0-∞ and CL. Individual SNP association tests revealed that polymorphisms in NR2B1 and NR2A1 were significantly correlated with altered docetaxel pharmacokinetics. Subsequent haplotype association analysis identified the NR2B1 LD block 2 AG haplotype [*+4458G>A(rs3132291) and *+4988A>G(rs4842198)] to be significantly associated with altered pharmacokinetics, in which patients carrying two copies of the AG haplotype had approximately a 20 % decreased Cmax and AUC0-∞ and a 21 % increased CL compared to those who carried only one copy or no copies of the haplotype. A number of SNPs in NR1I2, NR1I3, NR2B1 and NR2A1 were also associated with a significant decrease in blood counts from baseline. No haplotype was found to exert any effects on the pharmacodynamics parameters. CONCLUSIONS: The present exploratory study identified several SNPs in the genes encoding regulatory nuclear receptors which may account for the interpatient variability in docetaxel pharmacokinetics and pharmacodynamics. These findings highlight the important role of regulatory nuclear receptors on the disposition of docetaxel.

Ureteral metastasis as the presenting manifestation of pancreatic carcinoma.

We recently cared for a patient with adenocarcinoma of the pancreas who presented with ureteral metastasis followed by hydroureteronephrosis long before the appearance of any symptoms related to the primary lesion. The entity is extremely rare; only seven similar cases are on record in the scientific literature. No recent review exists on this topic. This encouraged us to present our case along with the previous cases of adenocarcinoma of the pancreas with ureteral metastasis that have been reported.

Crystal structures of ASK1-inhibtor complexes provide a platform for structure-based drug design.

ASK1, a member of the MAPK Kinase Kinase family of proteins has been shown to play a key role in cancer, neurodegeneration and cardiovascular diseases and is emerging as a possible drug target. Here we describe a 'replacement-soaking' method that has enabled the high-throughput X-ray structure determination of ASK1/ligand complexes. Comparison of the X-ray structures of five ASK1/ligand complexes from 3 different chemotypes illustrates that the ASK1 ATP binding site is able to accommodate a range of chemical diversity and different binding modes. The replacement-soaking system is also able to tolerate some protein flexibility. This crystal system provides a robust platform for ASK1/ligand structure determination and future structure based drug design.

8q24 and 17q prostate cancer susceptibility loci in a multiethnic Asian cohort.

OBJECTIVES: Recently, several genome-wide association studies have demonstrated a cumulative association of 5 polymorphic variants in chromosomes 8q24 and 17q with prostate cancer (CaP) risk in Caucasians, particularly those harboring aggressive clinicopathologic characteristics. The purpose of this study was to evaluate the influence of these variants on CaP susceptibility in Singaporean Asian men. MATERIALS AND METHODS: We performed a case-control study in 289 Chinese CaP patients and 412 healthy subjects (144 Chinese, 134 Malays, and 134 Indians), and examined the association of the 5 single nucleotide polymorphisms (SNPs) with CaP. RESULTS: In the healthy subjects, rs16901979 A-allele frequency was highest amongst Chinese (0.32) compared with Malays (0.13; P < 0.0001) or Indians (0.09; P < 0.0001); rs6983267 G-allele was highest in Indians (0.51) compared with Chinese (0.42; P = 0.041) or Malays (0.43; P = 0.077); whereas rs1859962 G-allele frequency was highest amongst Indians (0.56) compared with Chinese (0.40; P = 0.0002) or Malays (0.38; P < 0.0001). Individuals with the rs4430796 TT genotype were at increased CaP risk in the Chinese via a recessive model (odds ratios (OR) = 1.56, 95% CI = 1.04-2.33). Significant associations were observed for rs4430796 TT with Gleason scores of ≥ 7 (OR = 1.76, 95% CI = 1.14-2.73) and prostate-specific antigen (PSA) levels of ≥ 10 ng/ml at diagnosis (OR = 1.63, 95% CI = 1.01-2.63), as well as for rs6983267 GG with stage 3-4 CaPs (OR = 1.91, 95% CI = 1.01-3.61). A cumulative gene interaction influence on disease risk, which approximately doubled for individuals with at least 2 susceptibility genotypes, was also identified (OR = 2.18, 95% CI = 1.10-4.32). CONCLUSIONS: This exploratory analysis suggests that the 5 genetic variants previously described may contribute to prostate cancer risk in Singaporean men.

A case of extensive genitourinary tuberculosis: combined augmentation ileo-cystoplasty, ureteric ileal replacement and buccal mucosal graft urethroplasty.

Genitourinary tuberculosis (GUTB) is the second most common form of extrapulmonary TB after lymph nodes. Advanced GUTB leading to strictures of ureters and urethra, and bladder contracture frequently need surgical management. These are usually treated by ileal replacement of ureter, substitution urethroplasty using buccal mucosal graft (BMG) and augmentation ileo-cystoplasty, respectively. These procedures have been well demonstrated individually but all these three procedures have never been combined as single procedure in the same patient. We report a case of advanced GUTB with ureteric and urethral strictures, and bladder contracture which was treated by the ileal replacement of ureter, augmentation ileo-cystoplasty combined with BMG substitution urethroplasty in a single sitting.

SLC22A1-ABCB1 haplotype profiles predict imatinib pharmacokinetics in Asian patients with chronic myeloid leukemia.

OBJECTIVE: This study aimed to explore the influence of SLC22A1, PXR, ABCG2, ABCB1 and CYP3A5 3 genetic polymorphisms on imatinib mesylate (IM) pharmacokinetics in Asian patients with chronic myeloid leukemia (CML). PATIENTS AND METHODS: Healthy subjects belonging to three Asian populations (Chinese, Malay, Indian; n = 70 each) and CML patients (n = 38) were enrolled in a prospective pharmacogenetics study. Imatinib trough (C(0h)) and clearance (CL) were determined in the patients at steady state. Haplowalk method was applied to infer the haplotypes and generalized linear model (GLM) to estimate haplotypic effects on IM pharmacokinetics. Association of haplotype copy numbers with IM pharmacokinetics was defined by Mann-Whitney U test. RESULTS: Global haplotype score statistics revealed a SLC22A1 sub-haplotypic region encompassing three polymorphisms (rs3798168, rs628031 and IVS7+850C>T), to be significantly associated with IM clearance (p = 0.013). Haplotype-specific GLM estimated that the haplotypes AGT and CGC were both associated with 22% decrease in clearance compared to CAC [CL (10(-2) L/hr/mg): CAC vs AGT: 4.03 vs 3.16, p = 0.017; CAC vs CGC: 4.03 vs 3.15, p = 0.017]. Patients harboring 2 copies of AGT or CGC haplotypes had 33.4% lower clearance and 50% higher C(0h) than patients carrying 0 or 1 copy [CL (10(-2) L/hr/mg): 2.19 vs 3.29, p = 0.026; C(0h) (10(-6) 1/ml): 4.76 vs 3.17, p = 0.013, respectively]. Further subgroup analysis revealed SLC22A1 and ABCB1 haplotypic combinations to be significantly associated with clearance and C(0h) (p = 0.002 and 0.009, respectively). CONCLUSION: This exploratory study suggests that SLC22A1-ABCB1 haplotypes may influence IM pharmacokinetics in Asian CML patients.