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Background and objectives Cryotherapy for melanocytic lesions is often accompanied by collateral damage to the surrounding skin, resulting in skin necrosis and scarring. Adipocytes, like melanocytes, are neural crest-derived cells. Adipocytes have been shown to be more sensitive to cold exposure than their neighboring cells of ectodermal origin, such as epidermal keratinocytes. Such differential sensitivity to cold exposure has led to the development of novel treatment modalities, like cryolipolysis, to selectively target a cell type while sparing neighboring cells. Study design/materials and methods In this study, we investigated the roles of controlled skin freezing, tissue temperature, and exposure time in inducing selective loss of melanocytes and skin depigmentation in swines. Results The results of our study demonstrated that contact cooling of the skin surface causes selective loss of epidermal melanocytes when the tissue temperature reaches -7.5°C or cooler with an exposure time of 10 minutes or longer, leading to partial skin depigmentation in swine skin. Longer exposures combined with colder temperature exposure led to more complete depigmentation in the treated skin surface. Conclusion Cold-sensitivity of melanocytes can be harnessed to selectively remove melanocytes while sparing surrounding keratinocytes. The results from this study demonstrated that improved clinical treatments specifically targeting melanocytic lesions is possible using skin cooling to achieve tissue temperatures capable of inducing selective loss of melanocytes without skin necrosis or scarring. Additional studies are needed to optimize the treatment conditions to prolong the selective removal of melanocytes. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington&rsquo, s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington&rsquo, s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.

Background: In stage I/II natural killer (NK)/T-cell lymphoma, concurrent chemoradiotherapy (CCRT) had previously been shown to result in superior outcome compared with anthracycline-containing regimens, which have since been considered ineffective. The role of CCRT in comparison with approaches employing nonanthracycline-containing chemotherapy (CT) and sequential radiotherapy (RT) in such patients remains to be defined. Patients and methods: Three hundred and three untreated patients (207 men, 96 women; median age: 51, 18-86 years) with stage I/II NK/T-cell lymphoma who had received nonanthracycline-containing regimens were collected from an international consortium and retrospectively analyzed. Treatment included single modality (CT and RT), sequential modalities (CT+RT; RT+CT) and concurrent modalities (CCRT; CCRT+CT). The impact of clinicopathologic parameters and types of treatment on complete response (CR) rate, progression-free-survival (PFS) and overall-survival (OS) was evaluated. Results: For CR, stage (P=0.027), prognostic index for NK/T-cell lymphoma (PINK) (P=0.026) and types of initial treatment (P=0.011) were significant prognostic factors on multivariate analysis. On Cox regression analysis, ECOG performance score (P=0.021) and PINK-EBV DNA (PINK-E) (P=0.002) significantly impacted on PFS; whereas ECOG performance score (P=0.008) and stage (P

Aims To describe the outcomes of all babies with gastroschisis managed over a 9 year period at a single surgical unit. Methods Retrospective study of all infants with gastroschisis, repaired between Jan 2007 to Jan 2016. They were analysed according to Simple vs Complex Gastroschisis and the Simple group subdivided into Primary vs Staged Closure. Results We identified 56 babies. There were 45 simple and 10 complex cases. One baby was excluded with a closed gastroschisis. 26 babies with Simple Gastroschisis had primary and 19 had staged closure. No deaths were noted. No significant differences in operative complications and unplanned re-operations were demonstrated. The median length of stay, time to full feeds and parenteral nutrition duration was not significantly different between simple and complex gastroschisis groups. There was a significant difference in days to first feed and parenteral nutrition duration in Simple Gastroschisis managed with Primary closure and Staged closure (table 1). Conclusions Simple vs Complex Gastroschisis: a. There was a higher but non significant risk of operative complications in the complex group. b. No statistically significant difference between the simple and complex groups. A sizable proportion of complex patients were excluded as they did not achieve outcome or were transferred to other units. Primary vs Staged closure in Simple Gastroschisis: a. No statistically significant difference in operative complications between primary and staged groups. b. Patients who underwent primary closure had significantly shorter times to first feed and a shorter durationof parenteral nutrition. This study describes our practice and contributes to the growing pool of data regarding gastroschisis. In the absence of consensus, this may aid management decisions and reduce adverse outcomes.

The MAPK phosphatase MKP1 (DUSP1) is overexpressed in many human cancers, including chemoresistant and radioresistant breast cancer cells, but its functional contributions in these settings are unclear. Here, we report that after cell irradiation, MKP1 translocates into mitochondria, where it prevents apoptotic induction by limiting accumulation of phosphorylated active forms of the stress kinase JNK. Increased levels of mitochondrial MKP1 after irradiation occurred in the mitochondrial inner membrane space. Notably, cell survival regulated by mitochondrial MKP1 was responsible for conferring radioresistance in HER2-overexpressing breast cancer cells, due to the fact that MKP1 serves as a major downstream effector in the HER2-activated RAF–MEK–ERK pathway. Clinically, we documented MKP1 expression exclusively in HER2-positive breast tumors, relative to normal adjacent tissue from the same patients. MKP1 overexpression was also detected in irradiated HER2-positive breast cancer stem-like cells (HER2+/CD44+/CD24−/low) isolated from a radioresistant breast cancer cell population after long-term radiation treatment. MKP1 silencing reduced clonogenic survival and enhanced radiosensitivity in these stem-like cells. Combined inhibition of MKP1 and HER2 enhanced cell killing in breast cancer. Together, our findings identify a new mechanism of resistance in breast tumors and reveal MKP1 as a novel therapeutic target for radiosensitization. Cancer Res; 74(24); 7498–509. ©2014 AACR.

Cutaneous biopsies often heal with little or no scarring. Prior studies have shown an alarming percentage of patients who incorrectly identify biopsy sites at the time of surgery.To investigate the safety and utility of an ultraviolet (UV)-fluorescent tattoo for biopsy site identification.A preclinical proof of concept was established with skin culture. An UV-fluorescent tattoo was applied to discarded neonatal foreskin in culture medium. The stability of the tattooed skin was examined clinically and histologically. One patient with a recurrent basal cell carcinoma in a difficult-to-identify location underwent tattoo application at the time of biopsy to demarcate the site. The patient was monitored for tattoo reaction and referred for surgical excision.The cultured tissue exhibited stable UV fluorescence with daily washing. Tissue histology demonstrated tattoo particles lining the skin edge under fluorescent microscopy. The patient was reluctant to undergo another surgical procedure and instead returned to our clinic at 3 months and 17 months after the biopsy for management of other tumors. The patient had no symptoms of allergic reaction to the tattoo dye. The fluorescent tattoo remains invisible under visible light and visible only under Wood's light.The present study documents the utility of an UV-fluorescent tattoo to locate a biopsy site.

Background: Rituximab has been associated with hepatitis B virus reactivation (HBV-R). However, the characteristics and scope of this association remain largely undefined. Methods: We completed a comprehensive literature search of all published rituximab-associated HBV-R cases and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) MedWatch database. Literature and FDA cases were compared for completeness, and a meta-analysis was completed. Results: One hundred and eighty-three unique cases of rituximab-associated HBV-R were identified from the literature (n = 27 case reports, n = 156 case series). The time from last rituximab to reactivation was 3 months (range 0–12), although 29% occurred >6 months after last rituximab. Within FDA data (n = 118 cases), there was a strong signal for rituximab-associated HBV-R [proportional reporting ratio = 28.5, 95% confidence interval (CI) 23.9–34.1; Empiric Bayes Geometric Mean = 26.4, 95% CI 21.4–31.1]. However, the completeness of data in FDA reports was significantly inferior compared with literature cases (P < 0.0001). Among HBV core antibody (HBcAb(+)) series, the pooled effect of rituximab-based therapy showed a significantly increased risk of HBV-R compared with nonrituximab-treated patients (odds ratio 5.73, 95% CI 2.01–16.33; Z = 3.33, P = 0.0009) without heterogeneity (χ2 = 2.12, P = 0.5473). Conclusions: The FDA AERS provided strong HBV-R safety signals; however, literature-based cases provided a significantly more complete description. Furthermore, meta-analysis of HBcAb(+) series identified a more than fivefold increased rate of rituximab-associated HBV-R.

The introduction of the theory of selective photothermolysis has brought to medicine an entirely new therapeutic modality for treating cutaneous disorders. With ongoing research into existing therapies, cutaneous laser medicine is experiencing an expansion in application and safety profiles for many existing technologies. Additional trials and reports have also deepened our understanding and broadened our use for many existing cutaneous laser applications, such as for the treatment of pigment disorders, scarring, vascular disorders and noninvasive removal of fat. Recent data has demonstrated a valuable role of combined pharmacologic and laser modalities for the treatment of vascular malformations. This article will review recent developments of cutaneous laser science and technologies over the last several years, including such innovations as fractional photothermolysis and cryolipolysis.

BACKGROUND Dermatologists have championed Mohs micrographic surgery (MMS) for its unsurpassed treatment success for skin cancers, safety profile, cost-effectiveness, and tissue-sparing quality. It is unclear whether patients undergoing MMS also value these characteristics. OBJECTIVE To evaluate patients' preoperative expectations of MMS and identify the factors that may influence such expectations METHODS The study prospectively recruited participants who were newly diagnosed with skin cancer and referred for MMS. A questionnaire listing the characteristics of MMS was given to the participants asking them to score the importance of each characteristic on a 10-point scale. The participants were also asked to provide information regarding their gender, age, subjective health status, education level, family annual income, and their referral source RESULTS On average, participants placed the highest value, in descending order, on a treatment that yielded the highest cure rate, reconstruction initiation only after complete tumor removal, and the surgeon being a skin cancer specialist. Overall, participants placed high values on characteristics of MMS that dermatologists have long esteemed. CONCLUSION Our data corroborate that MMS is a valuable procedure that meets the expectations not just of physicians, but also of patients. The authors have indicated no significant interest with commercial supporters.

Background and aim: The pharmacokinetics of clenbuterol in equine urine and blood was investigated.Material and methods: Urine and blood samples were collected following 3-day multiple oral administrations. The samples were examined using enzyme-linked immunosorbent assay and further confirmed by solid phase extraction and capillary electrophoresis.Results: Urinary clenbuterol was detectable until day 14 after the last dose. The urinary excretion of clenbuterol was characterized by a biphasic pattern. The half-lives of the bi-exponential elimination (t1/2α and t1/2β) for urinary clenbuterol were about 12.1 and 48 hours. After a single oral administration (4 μg/kg) of clenbuterol, the half-life of serum clenbuterol was approximately 11.4 hours.

Arginine deprivation as an anticancer therapy has historically been met with limited success. The development of pegylated arginine deiminase (ADI-PEG20) has renewed interest in arginine deprivation for the treatment of some cancers. The efficacy of ADI-PEG20 is directly correlated with argininosuccinate synthetase (ASS) deficiency. CWR22Rv1 prostate cancer cells do not express ASS, the rate-limiting enzyme in arginine synthesis, and are susceptible to ADI-PEG20 in vitro. Interestingly, apoptosis by 0.3 μg/mL ADI-PEG20 occurs 96 hours posttreatment and is caspase independent. The effect of ADI-PEG20 in vivo reveals reduced tumor activity by micropositron emission tomography as well as reduced tumor growth as a monotherapy and in combination with docetaxel against CWR22Rv1 mouse xenografts. In addition, we show autophagy is induced by single amino acid depletion by ADI-PEG20. Here, autophagy is an early event that is detected within 1 to 4 hours of 0.3 μg/mL ADI-PEG20 treatment and is an initial protective response to ADI-PEG20 in CWR22Rv1 cells. Significantly, the inhibition of autophagy by chloroquine and Beclin1 siRNA knockdown enhances and accelerates ADI-PEG20–induced cell death. PC3 cells, which express reduced ASS, also undergo autophagy and are responsive to autophagy inhibition and ADI-PEG20 treatment. In contrast, LNCaP cells highly express ASS and are therefore resistant to both ADI-PEG20 and autophagic inhibition. These data point to an interrelationship among ASS deficiency, autophagy, and cell death by ADI-PEG20. Finally, a tissue microarray of 88 prostate tumor samples lacked expression of ASS, indicating ADI-PEG20 is a potential novel therapy for the treatment of prostate cancer. [Cancer Res 2009;69(2):700–8]

The use of magnetoencephalography (MEG) has become increasingly accepted in the clinical realm as a valid and valuable investigational tool in the assessment of patients with epilepsy and in the mapping of functional and eloquent cortices. The clinical MEG lab at The Hospital for Sick Children, Toronto, Ontario, Canada was established in 2000 and focused specifically on pediatric examinations. The MEG laboratory has established pediatric protocols, based on guidelines from the American Electroencephalography Society. This paper will outline the routine clinical protocols that we have established in our lab for the acquisition of MEG data from pediatric patients with intractable epilepsy.

Distinguishing angioimmunoblastic T-cell lymphoma from peripheral T-cell lymphoma, unspecified, using morphology, immunophenotype and molecular genetics Aims: To identify distinguishing histological, immunophenotypic and molecular genetic features between angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma (PTL). Methods: Nodal T-cell lymphomas examined (n =137), included AITL (n = 89), PTL (n = 22), anaplastic large cell lymphoma (n = 16) and 'AITL/PTL indeterminate' (n = 10) with overlapping features between AITL and PTL, showing morphology typical of AITL but lacking follicular dendritic cell expansion. Immunohistochemistry for CD3, CD20, CD21 and CD10, in situ hybridization for Epstein-Barr virus encoded RNA (EBER) and polymerase chain reaction for T-cell and B-cell clonality analysis were performed. Results: Of the AITLs, 74/89 showed typical morphology, whereas 15/89 showed hyperplastic follicles. AITL and 'AITL/PTL indeterminate' showed a polymorphous infiltrate and prominent vascularity in all cases. In both groups, CD10 was present in the majority and clear cells and EBER positivity were specific (but not universal) features lacking in PTL. Detection of T-cell clonality was significantly higher in AITL (90%) compared with PTLu (59%). Conclusions: Clear cells and EBV infection (when present) are useful distinguishing features and CD10 a sensitive and specific marker of AITL. Hyperplastic follicles are present in a significant minority of AITL. AITL/PTL indeterminate probably falls within the spectrum of AITL rather than PTL.

1Alpha,25-dihydroxyvitamin D3 (1,25D3) displays potent antiproliferative activity in a variety of tumor model systems and is currently under investigation in clinical trials in cancer. Studies were initiated to explore its potential in nonsmall cell lung cancer (NSCLC), as effective approaches to the treatment of that disease are needed. In evaluating factors that may affect activity in NSCLC, the authors found that CYP24 (25-hydroxyvitamin D3-24-hydroxylase), the enzyme that catabolizes 1,25D3, is frequently expressed in NSCLC cell lines but not in the nontumorigenic bronchial epithelial cell line, Beas2B. CYP24 expression by RT-PCR was also detected in 10/18 primary lung tumors but in only 1/11 normal lung tissue specimens. Tumor-specific CYP24 upregulation was confirmed at the protein level via immunoblot analysis of patient-matched normal lung tissue and lung tumor extracts. Enzymatically active CYP24 is expected to desensitize NSCLC cells to 1,25D3. The authors therefore implemented a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay for 1,25D3 and its CYP24-generated metabolites to determine whether NSCLC cells express active enzyme. Analysis of NSCLC cell cultures revealed time-dependent loss of 1,25D3 coincident with the appearance of CYP24-generated metabolites. MK-24(S)-S(O)(NH)-Ph-1, a specific inhibitor of CYP24, slowed the loss of 1,25D3 and increased 1,25D3 half-life. Furthermore, combination of 1,25D3 with MK-24(S)-S(O)(NH)-Ph-1 resulted in a significant decrease in the concentration of 1,25D3 required to achieve maximum growth inhibition in NSCLC cells. These data suggest that increased CYP24 expression in lung tumors restricts 1,25D3 activity and support the preclinical evaluation of CYP24 inhibitors for lung cancer treatment.

4 páginas, 1 figura., Multiple cutaneous and uterine leiomyomata (MCL) is an autosomal dominant disorder characterized by the development of benign smooth muscle tumours (leiomyomas) in the skin and uterus of affected women, and in the skin of affected men. In rare cases, MCL has been associated with a predisposition to the rare type II papillary renal cell cancer, also known as hereditary leiomyomatosis and renal cell cancer. The genetic locus for MCL has been mapped to chromosome 1q42.3–43 and subsequently, germline mutations in the fumarate hydratase (FH) gene have been identified. In addition, analysis of FH in some tumours of MCL patients revealed a second mutation inactivating the wild-type allele, suggesting that FH may function as a tumour suppressor gene. Here, we report two cases of MCL patients with FH mutations, designated as T287P and R190L. T287P represents a novel mutation of a highly conserved amino acid of the FH protein. In addition, a patient with an unusual clinical presentation of MCL was found to have the recurrent mutation, R190L, raising the possibility of incorporating FH sequencing as a diagnostic tool. Our findings extend the allelic series of mutations in FH and support its status as the underlying cause of MCL., This work was supported in part by the Skin Disease Research Center, Department of Dermatology, Columbia University (P30 AR44535) and the Authority for Research and Development, Hebrew University of Jerusalem (to A. Zlotogorski).

Objectives To establish the upper limit for warm ischemia time (WIT) beyond which irreversible renal failure will occur in a single-kidney porcine model. The maximal renal tolerance during WIT is currently under revision. Traditionally, 30 minutes was defined as the safe limit for renal WIT. However, accumulating data have suggested that a WIT of up to 90 minutes may not result in permanent damage. Methods Twenty female pigs weighing 60 to 80 lb at arrival underwent initial right laparoscopic nephrectomy to create a single-kidney model. Twelve days later, the animals were randomized into four groups of 5 animals each: 120 minutes of open WIT, 120 minutes of laparoscopic WIT, 5 open controls, and 5 laparoscopic controls. Renal function was assessed with serial glomerular filtration rate and serum creatinine measurements, which were assessed preoperatively and on postoperative days (PODs) 1, 3, 8, and 15. Results No significant difference existed between the laparoscopic and open groups. The glomerular filtration rate reached the lowest value and the serum creatinine levels peaked on POD 3 and were significantly different from baseline at PODs 1, 3, 8, and 15. Renal function did not return to baseline by POD 15, and 66% of the animals showed significant renal insufficiency (more than 25% decline in glomerular filtration rate) in the study group. Conclusions After 120 minutes of WIT, no difference in renal function recovery was observed between the laparoscopic and open techniques. A WIT of 120 minutes produced significant renal failure and mortality. Thus, 120 minutes of WIT in the single kidney porcine model exceeds the kidney’s tolerance to ischemia.

The technical difficulty of laparoscopic partial nephrectomy (LPN) lies mainly in the steps required during warm ischemia time (WIT), which includes tumor excision and renal reconstruction. We present a renal-suspension traction system to place the tumor in stable optimal view during the critical steps of LPN.Thirty-three patients underwent LPN from October 2002 through December 2003. Eight had a renal sling placed intraoperatively because of difficult access to the tumor. Perioperative parameters were assessed. The renal hilum was dissected and the tumor exposed. To keep the tumor oriented perfectly toward the camera and the working ports, a 2-0 braided polyglactin (Vicryl) traction suture was passed through Gerota's fascia, catching the renal capsule; brought out through the abdominal wall; and secured to the skin with a clamp.All surgical margins were negative. For the traction and nontraction groups, the mean sizes of the tumor were 2.5 cm and 2.2 cm, respectively (P = 0.426). The estimated blood loss was 125 mL and 246 mL respectively (P = 0.041). The WIT average 27.4 minutes and 30.12 minutes (P = 0.470). The surgical time was 192 minutes and 235 minutes respectively, (P = 0.062). Based on our findings, we have devised a renal suspension traction algorithm for specific tumor locations during LPN.The renal suspension traction system allows precision in tumor excision and renal reconstruction during the critical steps of LPN. With the renal suspension system we devised, we are able to simplify LPN for tumors located away from optimal port access.

The aim of the present study was to evaluate the preventive effect of an after-school culturally-based arts program with low-income urban children. The specific objective of this study was to evaluate the changes in adaptive functioning and in problem behaviors for program participants as compared to a comparison group through self-reported, parental-reported, and teacher-reported measures. The main findings indicated that the participating children experienced an increase in self-esteem, social skills, and in leadership competencies as compared to the comparison group.

Since 1999 we have made 2 modifications in the nerve sparing approach to radical retropubic prostatectomy (RRP), namely early release of the neurovascular bundles (NVBs) before division of the posterior membranous urethra and the use of 2.5x optical loupe magnification during NVB preservation. We retrospectively reviewed our results.Between January 1998 and August 2003, 507 men underwent RRP for prostate cancer. All surgeries were performed by a single surgeon (CBB). Bilateral nerve sparing procedures were performed in 313 men. Modifications were introduced sequentially to the surgical technique and potency rates were compared to those of patients operated on before these modifications. Patients were divided into groups based on the technique of nerve sparing as group 1 (standard release of the NVB), group 2 (early release of the NVB) and group 3 (early release with loupe magnification). All patients were followed for a minimum of 5 months. Postoperative potency rates were compared among the 3 groups.Mean followup was 15.9 months. Mean patient age was 56.2 years. The overall potency rate among groups 1, 2 and 3 was 40.5%, 54.8% and 66.1%, respectively. Mean time to potency was 10.7, 8.5 and 2.0 months, respectively. Significant differences were found in the overall potency rate among all groups (p0.05). Mean time to potency was significantly improved between groups 1 and 3 (p0.05) and between groups 2 and 3 (p0.05).Minor modifications in nerve sparing technique lead to improved postoperative potency rates and decreased time to potency in men undergoing RRP.

Sphenoid sinus mucocoele presenting with optic neuropathy and abducens palsy: a late complication of radiotherapy to the head and neck

Autophagy or self-eating is an evolutionarily conserved process whereby cells, in response to stress conditions, use lysosomal-mediated degradation of long-­lived proteins and retired organelles to regenerate energy. It protects cells from harsh conditions and prolongs cell survival. Cancer therapeutics induce a variety of stresses in tumor cells including nutritional starvation, DNA damage, ER stress, and ROS generation. Not surprisingly, the great majority of cancer therapeutics also induce autophagy. As such, autophagy becomes an inseparable part of cancer therapy and its modulation, and thus deserve attention. In this review, we discuss the current prostate cancer therapies, the cell biology and detection method of autophagy, the relationship of autophagy to apoptosis and necroptosis, and autophagy modulation in experimental prostate cancer therapies. Finally, we provide a comprehensive summary of the autophagy characteristics (induction and function) of experimental and clinically tested prostate cancer treatments, as well as current clinical trials involving autophagy modulators.

Background Squamous cell carcinoma (SCC) in situ (SCCIS) is often treated without any pathologic confirmation of tumor clearance. It is unclear how often an invasive SCC is harbored within a lesion in which the initial biopsy demonstrated SCCIS because of inadequate sampling. This study examines the final histologic diagnosis of cases in which the initial biopsies were diagnosed as SCCIS and evaluates factors that may correlate with a histologic upstaging of the diagnosis. Methods We prospectively recruited 29 consecutive patients with biopsy-proven SCCIS sent for Mohs micrographic surgery (MMS). Each tumor underwent MMS, and the central blocks of the Mohs debulking specimens were horizontally sectioned at 30-μm intervals until exhausted. A fellowship-trained Mohs surgeon and a board-certified dermatopathologist processed and examined these sections to determine the final histologic diagnosis of the tumor. Results Of the 29 subjects with biopsy-proven SCCIS, nine were found to harbor invasive SCC on final histology. Of the remaining lesions, seven had residual SCCIS, whereas the rest exhibited only actinic keratoses or scars. Approximately 31% of lesions showed evidence of invasive SCC. Correlating the clinical characteristics of the lesions with their corresponding final histologic diagnoses, the lesions harboring invasive SCC were more likely to demonstrate clinical signs of residual tumor (scales and papular changes) and be larger than 1.4 cm in diameter. Limitations Our experience at a single institution in the northeastern United States may not be reflective of a wider population. There is also a possible referral bias, because only lesions with high clinical suspicion for invasive SCC were referred for MMS. Conclusion Although biopsy-proven SCCIS is often treated with modalities that are best suited for superficial disease and do not involve a final pathologic confirmation of clearance (e.g., cryotherapy, electrodesiccation and curettage), this study demonstrated that up to 31% of biopsy-proven SCCIS lesions may harbor invasive SCC. Clinical signs of residual tumor and a diameter larger than 1.4 cm are statistically significant predictors of underlying invasive SCC. These data suggest that treatment modalities that include histologic control of tumor removal should also be strongly considered for the treatment of select biopsy-proven SCCIS meeting the above criteria.

Background Toxic epidermal necrolysis syndrome (TEN) is a rare, life-threatening, drug-related skin reaction with a high mortality rate. To date, only a few studies with insufficient sample sizes have been conducted to analyse SCORTEN in Asian populations with TEN. Objective To analyse SCORTEN and other related factors that affect TEN patients in Taiwan. Methods A retrospective review of medical records of 101 patients with TEN from 1992 to 2009. Results There were 62 cases of adverse reactions to a single medication and 39 cases of idiopathic reaction, from multiple medications, or infectious pathogens, of 101 TEN patients. Of the seven individual SCORTEN parameters, only associate malignancy, detached or compromised body surface area >10%, serum urea and bicarbonate were statistically significant in the multivariate analysis. Factors such as 1.5 times baseline serum creatinine levels, urine output of less than 0.5 mL/kg for 6 h and acute renal failure were connected with subsequent mortality. Conclusion The SCORTEN score is effective in predicting the outcome in Taiwanese TEN patients. A number of factors are predictors of mortality. In our study, we determine renal insufficiency and failure to be a marker for predicting a poor outcome.

This study attempted to determine ingested porcine epidermal growth factor (pEGF) on the gastrointestinal tract development of early-weaned piglets. Thirty-two piglets (14-day weaned) were randomly allotted to supplemented with 0 (control), 0.5, 1.0, or 1.5 mg pEGF/kg diet. Each treatment consisted of four replicates with two pigs per pen for a 14 days experimental period. Piglets were sacrificed and gastrointestinal tract samples were collected to measure mucosa morphology, mRNA expression and activities of digestive enzymes in the gastrointestinal tract of piglets at the end of the experiment. Diets supplemented with pEGF failed to influence growth performance but tended to increase jejunal mucosa weight (p < 0.09) and protein content (p < 0.07). Piglets supplemental pEGF induced incrementally the gastric pepsin activity (p < 0.05) and stimulated jejunal alkaline phosphatase (ALP) and lactase activities accompanied with the increase of jejunal ALP and maltase mRNA expression. No effect of pEGF on the activities of all enzymes in ileum except the stimulation of ileal aminopeptide N mRNA expression. These results reveal that dietary pEGF supplementation might enhance gene expression and activities of digestive enzymes in the stomach and jejunum of piglets.

Although heat shock protein 70 (HSP70) has been suggested to be a stress marker or to play a protective role in brain injury, the relevance of its pathological expression in epilepsy is unclear. We investigated the expression of HSP70 in brain tissue from human temporal lobe epilepsy (TLE) patients and from kainic acid (KA)-induced seizure-related neuronal damage in vivo and in vitro. The human TLE tissue showed severe neuronal loss and gliosis in hippocampal CA3 area. The KA-induced neuronal damage was similar to pathological changes of the TLE hippocampus. An increased number of TUNEL-positive cells were observed at day 5 when compared with day 2 after seizure induction. Intense HSP70 immunofluorescence was observed in hippocampal CA3 pyramidal neurons of rat, 2 days following KA administration, which then declined in labeling by day 5. No HSP70 expression was found in Fluoro-Jade B positive dying neurons by double staining. Western blot analysis showed an increased level of p53 and Bax expression following KA treatment. In vitro, there was no apparent difference in the degree of apoptosis between HSP70 siRNA- and control empty vector-transfected primary neurons following KA treatment. Our results revealed that HSP70 was a useful indicator of stressed neurons in acute phase of epilepsy, but not associated with neuronal death, thereby suggesting that HSP70 played no role in neuroprotection during an epileptogenic state.

To our knowledge the effects of renal warm ischemia (WI) during laparoscopic vs open surgery have not been investigated. Decreased renal blood flow during pneumoperitoneum may precondition the kidney to tolerate longer WI time. Traditionally 30 minutes has defined the limit of renal WI time in open surgery. However, recent reports show renal function recovery at WI times of 45 to 120 minutes. We assessed renal function recovery after prolonged WI during laparoscopic vs open surgery in a solitary kidney porcine model.A total of 32 female farm pigs underwent right laparoscopic nephrectomy to create a single kidney model. At 12 days later the animals were randomized into open and laparoscopic groups, each with 4 subgroups, namely 30, 60 and 90 minutes of WI, and a 90-minute control. Serum creatinine and the glomerular filtration rate were assessed preoperatively and on postoperative days 1, 3, 8 and 15.There was no statistical difference in renal function between the laparoscopic and open groups. Although the early decrease in renal function (72 hours) was highest in the 60 and 90-minute WI groups, by postoperative day 15 this difference was not statistically significant. Postoperative day 15 glomerular filtration rate and serum creatinine values were not significantly different from baseline in any of the WI groups.We found no difference in renal function recovery when comparing laparoscopic and open WI. Although WI up to 90 minutes resulted in initial renal dysfunction, by 2 weeks postoperatively function normalized. Our results indicate that in a single kidney porcine model the renal unit can fully recover from WI times of up to 90 minutes.

Malignant mesothelioma of the tunica vaginalis is rare, and is usually not diagnosed until surgery is undertaken. Reports on the ultrasound features of this tumour are limited. We present an unusual case with ultrasound features mimicking an adenomatoid tumour.

An association between small bowel resection and stone disease has been noted, which is primarily due to increased gut oxalate absorption and resulting excretion by the kidney. In order to better understand the factors affecting both oxalate absorption and renal excretion, and the resulting renal lesions, we have developed a rodent model of small bowel resection and hyperoxaluria. Using this model, we have studied the renal histology in animals with hyperoxaluria over time spans from 2 weeks to 7 months. The initial lesion appears to be crystal formation along the brush border of the proximal tubule, with eventual crystal deposition in collecting ducts and papillary interstitium, and eventual tubule obstruction, interstitial inflammation and fibrosis. Crystal formation appears to dissociate from urinary supersaturation. We hypothesize that oxalate transporters in the proximal tubule may increase local saturations, leading to crystal formation at this site initially. Further studies are required to better characterize the causes and consequences of hyperoxaluria in this animal model.

Despite hopes that antibiotic and vaccine therapies might one day lead to the complete eradication of infectious disease [1], new and emergent pathogens continue to pose a global threat to public health [2]. Even in the present day, infectious disease remains among the top ten causes of death in the United States for all age groups [3]. In part due to increased virulence of recent strains, but also due to a growing cohort of individuals susceptible to severe infection, the U.S. mortality rate caused by influenza has risen to roughly 36,000 per year, exceeding the current rate of HIV/AIDS related deaths in the country [4, 5]. While the victories over bubonic plague (Yersinia pestis), whooping cough (Bordetella pertussis), polio and smallpox (variola) are clearly significant, new diseases represented by human immunodeficiency virus (HIV), as well as the tragic reality of biological agents used as weapons of terrorism and mass destruction [6] — offer sobering evidence that the battle against infectious disease is far from over [7].

9 páginas, 2 figuras, 2 tablas., Germline mutations in the fumarate hydratase gene (FH) predispose to multiple cutaneous and uterine leiomyoma syndrome (MCL) and MCL associated with renal cell cancer. MCL is inherited in an autosomal dominant pattern, manifesting as skin leiomyoma and uterine fibroids in affected individuals. Fumarate hydratase, a component of the tricarboxylic acid cycle, acts as a tumor suppressor gene in the development of cutaneous and uterine leiomyoma and renal cell cancer in this syndrome. Here we report the clinical and mutational analysis of five families with MCL, with the identification of five new mutations affecting highly conserved residues of the FH protein. These results provide further evidence for the role of the FH gene in the pathogenesis of MCL., This work was supported in part by the Skin Disease Research Center, Department of Dermatology, Columbia University (P30 AR44535); a research grant K01-HG0005501 (to D.G.); and a research grant from the Women's Health Program, supported by HWZOA (to A.Z. and B.G.). G.S.C. is a Medical Student Research Training Fellow of Howard Hughes Medical Institute.

The overall cure rate of primary tumors has been significantly improved in the last three decades; however, metastatic and recurrent tumors with aggressive growth and therapy-resistance remain as the major factors shortening breast cancer patients’ survival. MKP1, a mitogen-activated protein kinase (MAPK) phosphatase, was shown to be linked with chemoresistance in breast cancer cells and was over-expressed in radio-resistant breast cancer cells that survived long-term fractionated irradiation. Herein, we showed that MKP1 is expressed exclusively in HER2 positive clinical breast tumors compared to HER2 negative tumors. Comparison of normal and tumor breast tissue samples from same patients revealed that MKP1 expression is induced in breast tumors along with HER2 expression in patients, who showed low/no expression of MKP1 and HER2 in their normal breast tissue. Most importantly, we have shown that HER2 positive breast cancer cells rely heavily on MKP1 for survival as knocking down MKP1 resulted in a massive cell death. MKP1 was found to translocate into the mitochondria in breast cancer cells upon radiation and mitochondrial MKP1 levels were significantly enhanced in HER2 over-expressing and radio-resistant breast cancer cells, suggesting a survival mechanism where increased MKP1 translocation into the mitochondria functions to attenuate pro-apoptotic signals initiated from mitochondria-localized MAPK, c-Jun N-terminal kinase (JNK). Consistent with this, increased mitochondrial MKP1 levels were correlated with the reduced levels of phosphorylated active JNK in the mitochondria of irradiated cells. Such mitochondrial MKP1-mediated dephosphorylation of JNK was predominantly enhanced in the radio-resistant breast cancer cells that can be sensitized by siRNA-mediated inhibition of MKP1. The identification of cancer stem cells (CSCs) in all human tumors and their involvement in tumor radioresistance encouraged the studies investigating whether MKP1-mediated survival mechanism is present in radio-resistant breast cancer stem cells. Here, we showed that MKP1 is overexpressed in irradiated HER2-positive breast CSCs (HER2+/CD44+/CD24-/low) and knocking down MKP1 in these cells significantly reduced their survival, which was further reduced with radiation treatment. These data provide critical insights on the aggressive phenotype of breast tumors and offer MKP1 as a novel diagnostic and therapeutic target to re-sensitize resistant breast cancer stem cells. Identification of the mechanism of MKP1-mediated survival in these cells may provide additional druggable targets to control breast cancer and its recurrence. Citation Format: Demet Candas, Chung-Ling Lu, Ming Fan, Frank Chuang, Colleen Sweeney, Alexander Borowsky, Jian Jian Li. MKP1-mediated survival of HER2 positive breast cancer stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3029. doi:10.1158/1538-7445.AM2014-3029

Background and aims Lactate as a marker for tissue perfusion and hypoxia is increasingly used in routine point-of-care monitoring in critical care. We investigated the association of pre-operative lactate (PreL) with operative outcomes and mortality in neonatal surgical NEC. Methods 25 infants with NEC confirmed on laparotomy at a tertiary surgical centre were retrospectively evaluated. Maximal PreL was categorised as normal ( 5 mmol/L), and correlated to extent of NEC involvement and mortality. Results Median birth gestation and weight were 27weeks (range 23–33) and 1035g (555–2060). Median PreL was 5.1(range 0.6–16.2)mmol/L. Elevated PreL correlated with NEC severity, with predominance of pan-intestinal and multifocal involvement in severe hyperlactaemia (Table 1). Infants with isolated NEC were observed to have normal or moderate-PreL. Moderate to severe PreL was also associated with increased mortality rate and need for further surgery. Conclusions This preliminary study suggests that pre-operative hyperlactaemia and degree of elevation may be associated with a poor prognosis in infants with surgical NEC. Further larger studies may enable better evaluation of its use an adjunctive monitoring or prognostic tool in guiding early neonatal NEC management.

Background and aims EOS is a major cause of neonatal morbidity and mortality that can progress rapidly with minimal clinical and laboratory signs. Early identification of at risk newborns and prompt antibiotic treatment is therefore crucial. In 2012, National Institute for Health and Care Excellence (NICE) guidelines for EOS were published. Our local guideline includes fetal distress (abnormal cardiotocography) and meconium stained liquor as risk factors. We compare the outcomes with NICE and local guidelines. Methods Retrospective analysis of infants ≥35 weeks gestation admitted to a level-3 NICU over 4 months with suspected sepsis classified to have presumed (PS) or confirmed sepsis (CS). Results Of 81 cases identified, 44(54.3%) had PS and 37(45.7%) CS. 23(28.4%) babies in poor condition at birth received antibiotics on clinical grounds. Of remaining 58 cases, 36(62.1%) had PS and 22(37.9%) CS. Using local guideline in PS, 9(25%) required antibiotics, 13(36.1%) observed and 14(38.9%) were low risk. With NICE guideline, 5(13.9%) received antibiotics, 8(22.2%) observed and 23(63.9%) low risk. Using local guideline in CS, 10(45.5%) required antibiotics, 4(18.2%) observed and 8(36.3%) low risk but with NICE guideline, 3(13.6%) received antibiotics, 8(36.3%) observed and 11(50%) low risk did not require antibiotics or observations. Meconium was more common in CS (12/37; 32.4%) versus PS (6/44; 13.6%). Abnormal cardiotocography was noted in 40.5% CS cases versus 25% in PS. Conclusions Local guidelines with fetal distress as a risk factor may enable earlier identification of EOS risk. Larger study may enable better evaluation of our antibiotic therapy and resource implications.

Background Early onset neonatal infection is becoming an indication for neonatal stay of term babies in the postnatal ward. Interventions like intra-partum intravenous antibiotics (IV-Abs) in women with suspected chorioamnionitis and NICE guidelines on use of empirical neonatal antibiotic aim to reduce morbidity and mortality associated with early neonatal infection. 1, 2 An audit was undertaken to understand the characteristics of women whose babies required empirical antibiotics on the postnatal ward in a tertiary hospital and identify measures that will minimise morbidity of early neonatal infection. Method A prospective audit of newborns requiring prophylactic IV-Abs on the postnatal ward was coupled with a six-month retrospective prescription database review. Results Prospective review of 47 term newborns from August–September 2013 revealed 68% (n = 32) were born to primiparous women. Induction of labour was required for 72% (n = 34) births. 25% (n = 12) received IV-Abs in labour. Primips were more likely to have prolonged rupture of membranes – 50% (n = 16). Retrospective review: Noted an increase in number of neonatal prophylactic IV-Abs prescriptions from 10.7% to 13.5% from 1 st January – 30 th June between the years 2012 and 2013 respectively. Conclusion Majority of babies requiring antibiotics in the early neonatal period are born to first time mums – most of whom had labour induced. Presently, 16 babies per week require empirical antibiotics. This has resulted in an increase in the length of stay of mothers fit for discharge, with a knock-on effect on bed blockage and disruption of activity flows within the maternity service.

To find the best immunohistochemical marker for megakaryocytes in normal marrow, myelodysplastic syndrome (MDS), and chronic myeloproliferative disorders (CMPD), 57 marrow biopsy specimens were studied semiquantitatively with immunohistochemical methods using a panel of 7 antibodies. The staining intensity was graded 0 to 3 for scoring 100 consecutive megakaryocytes in each stained section. The final score for each stain was the sum of these 100 megakaryocytes individually multiplied by their corresponding grade. In normal marrow (11 cases), the average scores for antivon Willebrand factor (vWF) and Ulex europaeus agglutinin-1 (UEA-1) were 177.1 and 195.1, respectively. The scores for the other 5 markers, including anti-platelet-derived growth factor-BB, 2 anti-transforming growth factor-beta 3, anti-CD61, and anti-CD79a ranged from 96.1 to 124.1. In MDS (27 cases), the scores were 200.8 (vWF), 152.6 (UEA-1), and 28.7 to 98.5 (others). In CMPD (19 cases), the scores were 220.5 (vWF), 179.2 (UAE-1), and 64.8 to 101.2 (others). These results show that vWF and UEA-1 are good immunohistochemical markers for megakaryocytes in normal marrow, and vWF is the best marker in MDS and CMPD. For routine practice, vWF is the most reliable marker for identifying atypical megakaryocytes, especially in the cases of 5q-syndrome and agnogenic myeloid metaplasia.