Total Surface Area Influences Stone Free Outcomes in Shock Wave Lithotripsy for Distal Ureteral Calculi.

Introduction: Current American Urological Association guidelines recommend ureteroscopy (URS) as primary management of distal ureteral stones and shock wave lithotripsy (SWL) as a secondary option. Utilization of SWL in the management of nephrolithiasis in North America has decreased. We hypothesized that SWL continues to be an effective option in the management of distal ureteral calculi and studied data from our center in patients who received SWL for distal ureteral stones. Methods: A retrospective review was performed of 104 patients treated initially with SWL for distal ureteral calculi between 2011 and 2018 at this institution. The success rate of SWL was assessed through radiologic imaging and if subsequent procedures were required to render patients stone free. Results: Operative note and chart review identified 104 patients who presented with distal ureteral stones and were treated with SWL as the initial form of management. Average patient age was 52.2 ± 15.3 years, average BMI was 27.4 ± 5.7, and average total axial stone surface area was 25.96 ± 14.32 mm2. Of these patients, 78.8% (n = 82) were stone free following one SWL and required no subsequent procedures. Of these patients, 87.5% (n = 91) were stone free following a second SWL, and 87.5% (n = 91) were stone free following a secondary URS. After the initial SWL, residual stones were identified in 21.2% of patients (n = 22). Four patients, 3.8%, required a salvage URS following a failed second SWL to achieve stone-free status. Conclusion: One SWL procedure offers a stone-free rate (SFR) of 78.8% and after two SWLs an 87.5% SFR. Only 12.5% of patients undergoing SWL at our center required URS to achieve a stone-free status. SWL is an effective modality in the treatment of distal ureteral stones.

Conversion from Cystine to Noncystine Stones: Incidence and Associated Factors.

PURPOSE: Patients with cystinuria are often treated with medical alkalization and shock wave lithotripsy, although each treatment is hypothesized to increase the risk of calcium phosphate stones. We performed a multicenter retrospective review to evaluate whether stones of another composition develop in patients with cystinuria and with what frequency. MATERIALS AND METHODS: We retrospectively reviewed the records of a multi-institutional cohort of patients with cystinuria. We assessed medications, stone analyses, 24-hour urinalyses and types of procedures. We compared patients who formed only cystine stones vs those with noncystine stones. RESULTS: We identified 125 patients from a total of 5 institutions who were followed a mean of 5.2 years (range 0 to 26). Stones with noncystine components were submitted by 37 patients (29.6%). Potassium citrate medication was not associated with a noncystine composition (p = 0.1877). Regarding surgical management 18 patients (13%) underwent at least 1 shock wave lithotripsy session (range 0 to 9) and 79 (63%) underwent percutaneous nephrolithotomy at least once (range 0 to 10). When stratified based on pure cystine vs converted stones, the average total number of shock wave lithotripsy and percutaneous nephrolithotomy procedures was higher in the group with cystine and subsequent noncystine stone compositions (0.94 vs 0.10, p <0.0001, and 1.7 vs 1.5, p = 0.0053, respectively). On logistic regression male gender (OR 3.1, p = 0.0280) and the number of shock wave lithotripsy sessions (OR 3.0, p = 0.0170) were associated with an increased likelihood of the development of stones with a noncystine composition. CONCLUSIONS: Stones with noncystine components develop in more than 25% of patients with cystinuria, underscoring the importance of continued stone analysis. In this study prior shock wave lithotripsy was associated with conversion to a noncystine stone composition while urinary alkalization therapy was not associated.

Angiopoietin-like 4 promotes angiogenesis in the tendon and is increased in cyclically loaded tendon fibroblasts.

KEY POINTS: Angiopoietin-like 4 (ANGPTL4) modulates tendon neovascularization. Cyclic loading stimulates the activity of transforming growth factor-ß and hypoxia-inducible factor 1α and thereby increases the expression and release of ANGPTL4 from human tendon cells. Targeting ANGPTL4 and its regulatory pathways is a potential avenue for regulating tendon vascularization to improve tendon healing or adaptation. ABSTRACT: The mechanisms that regulate angiogenic activity in injured or mechanically loaded tendons are poorly understood. The present study examined the potential role of angiopoietin-like 4 (ANGPTL4) in the angiogenic response of tendons subjected to repetitive mechanical loading or injury. Cyclic stretching of human tendon fibroblasts stimulated the expression and release of ANGPTL4 protein via transforming growth factor-ß (TGF-ß) and hypoxia-inducible factor 1α (HIF-1α) signalling, and the released ANGPTL4 was pro-angiogenic. Angiogenic activity was increased following ANGPTL4 injection into mouse patellar tendons, whereas the patellar tendons of ANGPTL4 knockout mice displayed reduced angiogenesis following injury. In human rotator cuff tendons, the expression of ANGPTL4 was correlated with the density of tendon endothelial cells. To our knowledge, this is the first study characterizing a role of ANGPTL4 in the tendon. ANGPTL4 may assist in the regulation of vascularity in the injured or mechanically loaded tendon. TGF-ß and HIF-1α comprise two signalling pathways that modulate the expression of ANGPTL4 by mechanically stimulated tendon fibroblasts and, in the future, these could be manipulated to influence tendon healing or adaptation.

Loss of tumor suppressors KAI1 and p27 identifies a unique subgroup of primary melanoma patients with poor prognosis.

Primary melanoma, a highly aggressive malignancy, exhibits heterogeneity in biologic behaviors, clinical characteristics, metastasis potential and mortality. The present study sought to identify the molecular signatures that define a subgroup of primary melanomas with high risks of metastasis and mortality. First, we identified the markers that best differentiated metastatic melanomas from primary melanomas by examining the expression of seven previously reported biomarkers (BRAF, Dicer, Fbw7, KAI1, MMP2, p27 and Tip60) in a training cohort consisting of 145 primary melanomas and 105 metastatic melanomas. KAI1 and p27, both tumor suppressors, emerged as best candidates. Loss of both tumor suppressors occurred in the majority (74.29%) of metastatic melanomas. Further, a subset (metastatic like, or "ML", 33.10%) of primary melanomas also lost these two tumor suppressors. Kaplan-Meier analysis indicated that ML subgroup of primary melanoma patients had much worse 5 year survival compared with other primary melanoma patients (P = 0.002). The result was confirmed in an independent validation cohort with 92 primary melanomas (P = 0.030) and in the combined cohort with 237 melanoma patients (P = 3.00E-4). Additionally, compared to KAI1 and p27 as an individual prognostic marker, the combined signature is more closely associated with melanoma patient survival (P = 0.025, 0.264 and 0.009, respectively). In conclusion, loss of both KAI1 and p27 defines a subgroup of primary melanoma patients with poor prognosis. This molecular signature may help in metastatic melanoma diagnosis and may provide information useful in identifying high-risk primary melanoma patients for more intensive clinical surveillance in the future.

Stage-specific prognostic biomarkers in melanoma.

The melanoma staging system proposed by the American Joint Committee on Cancer (AJCC) (which classifies melanoma patients into four clinical stages) is currently the most widely used tool for melanoma prognostication, and clinical management decision making by clinicians. However, multiple studies have shown that melanomas within specific AJCC Stages can exhibit varying progression and clinical outcomes. Thus, additional information, such as that provided by biomarkers is needed to assist in identifying the patients at risk of disease progression. Having previously found six independent prognostic biomarkers in melanoma, including BRAF, MMP2, p27, Dicer, Fbw7 and Tip60, our group has gone on to investigate if these markers are useful in risk stratification of melanoma patients in individual AJCC stages. First, we performed Kaplan-Meier survival and Cox proportional multivariate analyses comparing prognostication power of these markers in 254 melanoma patients for whom the expression levels were known, identifying the best performing markers as candidates for stage-specific melanoma markers. We then verified the results by incorporating an additional independent cohort (87 patients) and in a combined cohort (341 patients). Our data indicate that BRAF and MMP2 are optimal prognostic biomarkers for AJCC Stages I and II, respectively (P = 0.010, 0.000, Log-rank test); whereas p27 emerged as a good marker for AJCC Stages III/IV (0.018, 0.046, respectively, log-rank test). Thus, our study has identified stage-specific biomarkers in melanoma, a finding which may assist clinicians in designing improved personalized therapeutic modalities.

eIF4E is an adverse prognostic marker of melanoma patient survival by increasing melanoma cell invasion.

Human cutaneous melanoma is a devastating skin cancer because of its invasive nature and high metastatic potential. We used tissue microarray to study the role of human eukaryotic translation initiation factor 4E (eIF4E) in melanoma progression in 448 melanocytic lesions and found that high eIF4E expression was significantly increased in primary melanomas compared with dysplastic nevi (P<0.001), and further increased in metastatic melanomas (P<0.001). High eIF4E expression was associated with melanoma thickness (P=0.046), and poor overall and disease-specific 5-year survival of all, and primary melanoma patients, especially those with tumors ≥1 mm thick. Multivariate Cox regression analysis revealed that eIF4E is an independent prognostic marker. eIF4E knockdown (KD) in melanoma cells resulted in a significant increase in apoptosis (sub-G1 populations) and decrease in cell proliferation, and also resulted in downregulation of mesenchymal markers and upregulation of E-cadherin. In addition, eIF4E KD led to a decrease in melanoma cell invasion, matrix metalloproteinase-2 expression and activity, c-myc and BCL2 expression, and an increase in cleaved PARP and cleaved caspase-3 expression and chemosensitivity. Taken together, our data suggest that the eIF4E may promote melanoma cell invasion and metastasis, and may also serve as a promising prognostic marker and a potential therapeutic target for melanoma.

A combination of p300 and Braf expression in the diagnosis and prognosis of melanoma.

BACKGROUND: To date only a handful of drugs are available for the treatment of melanoma. Among them vemurafenib, a BrafV600E specific inhibitor, showed promising results in terms of response rate and increase in median survival time. However, its effectiveness is limited by development of resistance and the search for additional drugs for melanoma treatment is ongoing. The present study was performed to analyze the correlation between Braf expression and the expression of p300, a known down stream target of the mitogen activated protein kinase (MAPK) pathway, which was recently shown by us to be a prognostic marker for melanoma progression and patient survival. METHODS: The expression of Braf and p300 expression were correlated and analyzed by Chi-square test. A total of 327 melanoma patient cases (193 primary melanoma and 134 metastatic melanoma) were used for the study. Classification & regression tree (CRT), Kaplan-Meier, and multivariate Cox regression analysis were used to elucidate the significance of the combination of Braf and p300 expression in the diagnosis and prognosis of melanoma. RESULTS: Our results demonstrate that Braf expression is inversely correlated with nuclear p300 and positively correlated with cytoplasmic p300 expression. Braf and cytoplasmic p300 were found to be associated with melanoma progression, tumor size and ulceration status. CRT analysis revealed that a combination of Braf and p300 expression (nuclear and cytoplasmic), could be used to distinguish between nevi and melanoma, and primary from metastatic melanoma lesions. The combination of Braf and nuclear p300 was significantly associated with patient survival and nuclear p300 was found to be an independent predictor of patient survival. CONCLUSION: Our results indicate a cross-talk between Braf and p300 in melanoma and demonstrate the importance Braf and p300 expression in the diagnosis and prognosis of melanoma.

DLC1 expression is reduced in human cutaneous melanoma and correlates with patient survival.

Deleted in Liver Cancer-1 (DLC1) is a Rho-GTPase-activating protein known to be downregulated and function as a tumor suppressor in numerous solid and hematological cancers. Its expression status in melanoma is currently unknown however, prompting us to examine this. Using immunohistochemistry and tissue microarrays containing a large set of melanocytic lesions (n=539), we examined the expression profile of DLC1 in melanoma progression, as well as the association between DLC1 and patient survival. We detected both cytoplasmic and nuclear DLC1 expression, and found that whereas cytoplasmic DLC1 was significantly downregulated in metastatic melanoma compared with nevi and primary melanoma, nuclear DLC1 expression was significantly down in primary melanoma compared with nevi, and then further down in metastatic melanoma. Loss of cytoplasmic DLC1 was significantly associated with poorer overall and disease-specific 5-year survival rates of all melanoma (P<0.001 and P=0.001, respectively) and metastatic melanoma patients (P=0.020 and 0.008, respectively), and similar results were seen for nuclear DLC1 (P<0.001 for both overall and disease-specific survival for all melanoma patients, and P=0.004 for metastatic melanoma patients). Next, we examined the correlation between cytoplasmic and nuclear DLC1 and found that concomitant loss of both forms was associated with the worst outcome for metastatic melanoma patients (P=0.013 and P=0.008 for overall and disease-specific 5-year survival, respectively). Finally, multivariate Cox regression analysis determined that strong cytoplasmic and nuclear DLC1 expression was a favorable independent prognostic factor for all melanoma (HR, 0.61; 95% CI, 0.42-0.88; P=0.008) and metastatic melanoma patients (HR, 0.42; 95% CI, 0.23-0.77; P=0.005). Although more research still needs to be done on the topic, these preliminary results support the hypothesis that DLC1 is a tumor suppressor in melanoma.

Pleiotropic function of SRY-related HMG box transcription factor 4 in regulation of tumorigenesis.

In addition to their critical roles in embryonic development, cell fate decision, and differentiation, members of Sox (Sry-related high-mobility group box) family of transcription factors including Sox4 have been implicated in various cancers. Multiple studies have revealed an increased expression along with specific oncogenic function of Sox4 in tumors, while others observed a reduced expression of Sox4 in different types of malignancies and suppression of tumor initiation or progression by this protein. More interestingly, the prognostic value of Sox4 is debated due to obvious differences between various reports as well as inconsistencies within specific studies. This review summarizes our current understanding of Sox4 expression pattern and its transcription-dependent, as well as transcription-independent, functions in tumor initiation or progression and its correlation with patient survival. We also discuss the existing discrepancies between different reports and their possible explanations.

The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis.

BACKGROUND: Mutation of BRAF is a predominant event in cancers with poor prognosis such as melanoma and colorectal cancer. BRAF mutation leads to a constitutive activation of mitogen activated protein kinase pathway which is essential for cell proliferation and tumor progression. Despite tremendous efforts made to target BRAF for cancer treatment, the correlation between BRAF mutation and patient survival is still a matter of controversy. METHODS/PRINCIPAL FINDINGS: Clinical studies on the correlation between BRAF mutation and patient survival were retrieved from MEDLINE and EMBASE databases between June 2002 and December 2011. One hundred twenty relevant full text studies were categorized based on study design and cancer type. Publication bias was evaluated for each category and pooled hazard ratio (HR) with 95% confidence interval (CI) was calculated using random or fixed effect meta-analysis based on the percentage of heterogeneity. Twenty six studies on colorectal cancer (11,773 patients) and four studies on melanoma (674 patients) were included in our final meta-analysis. The average prevalence of BRAF mutation was 9.6% in colorectal cancer, and 47.8% in melanoma reports. We found that BRAF mutation increases the risk of mortality in colorectal cancer patients for more than two times; HR = 2.25 (95% CI, 1.82-2.83). In addition, we revealed that BRAF mutation also increases the risk of mortality in melanoma patients by 1.7 times (95% CI, 1.37-2.12). CONCLUSIONS: We revealed that BRAF mutation is an absolute risk factor for patient survival in colorectal cancer and melanoma.

Effects of opium addiction on bleeding after coronary artery bypass graft surgery: report from Iran.

PURPOSE: Opium abuse is a major type of drug abuse in Iran. This study was designed to find the possible relation between opium addiction and excessive bleeding after coronary artery bypass graft (CABG) surgery. METHODS: In a historical cohort study during a 1.5-year period, consecutive patients scheduled for elective CABG surgery were assigned to two group on the basis of having or not having the criteria for inhalational opium addiction. Before and after operations, the complete blood count, bleeding time, prothrombin time, partial thromboplastin time, and platelet count were checked for all patients. The volumes of infused red blood cells during and after the operation were recorded. After operations, the volumes of bleeding through the patients' chest tubes were recorded. The recorded data were analyzed using SPSS software version 11.5. Independent t, chi-square and repeated measure tests were used; and P < 0.05 was considered statistically significant. RESULTS: In total, 84 nonaddicted patients were assigned in group 1, and 110 patients who fulfilled the addiction criteria were assigned in group 2. Total bleeding from the three chest tubes was significantly different between the two groups (P = 0.001). The mean hemoglobin level, prothrombin time, partial thromboplastin time, and platelet counts before and after the operations were similar in the two groups. Opium-addicted patients received more packed red blood cells during and after the operations. CONCLUSION: Inhalational opium addiction might lead to more hemorrhage after CABG surgery. It is recommended that cardiac surgeons consider these patients at high risk for major complications after surgery.

Impact of psoriasis on quality of life in Iran.

BACKGROUND: The Psoriasis Disability Index (PDI) questionnaire is a widely used instrument to measure psychological morbidity in plaque-type psoriasis patients. AIMS: This study aimed to validate the Persian version of the PDI and to evaluate the impact of psoriasis on quality of life (QOL). METHODS: The English language version of the PDI was translated into Persian (Iranian official language) and was used in this study. The questionnaire was administered to a consecutive sample of 125 chronic plaque-type psoriasis patients and statistical analysis was performed to evaluate the impact of psoriasis on QOL. The other health-related QOL assessment tool included the Persian version of the Dermatology Life Quality Index (DLQI). RESULTS: Overall, 125 patients who had received the PDI and DLQI completed all the questions. Reliability analysis showed a satisfactory result (Cronbach's a coefficient=0.92 and 0.79 for PDI and DLQI, respectively). There was a strong statistical correlation between mean PDI and DLQI scores, with mean Psoriasis Area and Severity Index (PASI) (P=0.005 and 0.02). Also, a significant correlation coefficient existed between DLQI and PDI (r=0.94). The higher the PASI index, the higher the PDI and DLQI scores, which indicated greater impact on QOL. In the patients with lesions on visible exposed skin areas, the correlation was statistically significant (P=0.002 and 0.01). CONCLUSION: The Persian PDI is an acceptable, reliable and valid measure of psychological distress, with more suitable content validity than DLQI for assessment of impact of psoriasis on QOL among psoriasis patients. Data provided may improve the physicians' awareness of the importance of the patients' QOL.

Topical immunotherapy with diphenylcyclopropenone in vitiligo: a preliminary experience.

BACKGROUND: Despite recent significant therapeutic advances, vitiligo remains a clinical conundrum. Topical immunotherapy has been extensively tested in the treatment of various dermatologic disorders, especially those believed to have an immunologic basis. AIM: To evaluate the role of topical diphenylcyclopropenone (DPCP) in the treatment of vitiligo. METHODS: Nineteen patients with limited vitiligo lesions were enrolled in this study. After sensitization with 2% lotion of DPCP in acetone, progressively higher concentrations beginning at 0.001% up to 2% were applied weekly for 6 months to the depigmented skin lesions. RESULTS: Thirteen of the 19 patients were evaluated at the end of 6 months. Four patients with focal vitiligo, one patient with vitiligo vulgaris, and three patients with segmental vitiligo showed marked (grade 3) repigmentation. CONCLUSION: Marginal and central repigmentation with hyperpigmented borders was seen in the majority of lesions. Further controlled trials should be undertaken to evaluate the use of topical DPCP in vitiligo.

Topical captopril as a novel agent against hypertrophic scar formation in new zealand white rabbit skin.

Collagen constitutes the majority of extracellular matrix in tissues such as bone, cartilage, and especially the skin. Over production and/or decreased degradation of collagen fibers could lead to an abnormal wound healing response resulting in hypertrophic scarring or keloid formation. Recently, angiotensin II has been shown to be present in several cutaneous cells and that it stimulates fibroblast proliferation, collagen synthesis, and suppresses matrix metalloproteinase activity. The following study examines the effect of topical captopril, an inhibitor of angiotensin II production, against hypertrophic scar formation in New Zealand white rabbits.Two dermal wounds were made over the ventral surface of the ears of each rabbit (n = 6). In each animal, separate wounds were treated once per day with either topical 5% captopril or the vehicle alone (70% ethanol and 30% propylene glycol) for 7 consecutive days. Wounds were harvested at postoperative day 28, and the scar elevation index (SEI) as well as collagen organization was evaluated. SEI was reduced from 3.06 in the vehicle-treated group to 1.94 in the captopril treated wounds (P < 0.05). However, an increase in collagen organization was achieved by captopril, while an 8.50% decrease in collagen organization scale was derived by captopril compared to the vehicle. Results of this study show, for the first time, the efficacy of topical captopril as a new agent for the prevention of hypertrophic scar formation in an animal model. Thus, captopril might represent the first angiotensin converting enzyme inhibitor with a novel pharmacologic application in dermatology.

Retinoic acid synergistically enhances the melanocytotoxic and depigmenting effects of monobenzylether of hydroquinone in black guinea pig skin.

Monobenzylether of hydroquinone (MBEH) has long been utilized for the depigmentation therapy of patients with extensive vitiligo. In this approach, the normally pigmented areas surrounding vitiligo lesions are depigmented to achieve a uniform skin tone. One of the important disadvantages of MBEH therapy, however, is the resistance of a considerable number of vitiligo patients against the depigmenting effect of this agent. We have previously proposed that the glutathione-dependent cytoprotection of melanocytes can be impaired through the inhibition of the enzyme glutathione S-transferase by retinoic acid (RA). The combination of RA with melanocytotoxic agents could thus lead to increased susceptibility of melanocytes to such compounds. In this study we have shown, for the first time, that the melanocytotoxic and depigmenting effects of MBEH are synergistically enhanced when it is combined with RA. The treatment of black guinea pig skin with RA (0.025%) alone induced no significant changes in the number of epidermal melanocytes and no skin depigmentation. On the other hand, MBEH (10%) produced mild to moderate skin depigmentation and reduced the average number of melanocytes from 76 (+/-5)/field (magnification: x 40) in control sites, to 42 (+/-6)/field in the depigmented skin. The RA (0.025%)-MBEH (10%) combination, however, produced a complete degree of depigmentation in the majority of treated sites after 10 days of application and reduced the average number of melanocytes to only 6 (+/-6)/field. RA-MBEH combination serves as a very potent skin depigmenting formula and now awaits future assessments of its potential use for the treatment of extensive vitiligo.