Granular cell tumor of the scrotum in a child with Noonan syndrome

Abstract:  Granular cell tumor is a rare neoplasm thought to be of neural origin, composed of cells with distinctive granular cytoplasm. Granular cell tumors most often arise on the tongue, but can occur at any body site, and therefore initial presentation to dermatologists is common. We report a granular cell tumor of the scrotum in a child with Noonan syndrome, known to have a mutation in the PTPN11 gene. No previous reports of granular cell tumor of the scrotum in a child are found. The tumor is usually benign; however, it can have a high local recurrence rate (variable between 2% and 50% dependent on whether initial excision is complete and on the occurrence of an infiltrative growth pattern) and therefore long-term follow-up is necessary. This case highlights the occurrence of granular cell tumor, a diagnosis not to be missed by the dermatologist. In addition, we postulate the possible role of PTPN11 mutations in the development of granular cell tumor.     

New models and online calculator for predicting non-sentinel lymph node status in sentinel lymph node positive breast cancer patients

Background

Genetically engineered mouse models of mammary gland cancer enable the in vivo study of molecular mechanisms and signaling during development and cancer pathophysiology. However, traditional whole mount and histological imaging modalities are only applicable to non-viable tissue.

Methods

We evaluated three techniques that can be quickly applied to living tissue for imaging normal and cancerous mammary gland: reflectance confocal microscopy, green fluorescent protein imaging, and ultrasound imaging.

Results

In the current study, reflectance confocal imaging offered the highest resolution and was used to optically section mammary ductal structures in the whole mammary gland. Glands remained viable in mammary gland whole organ culture when 1% acetic acid was used as a contrast agent. Our application of using green fluorescent protein expressing transgenic mice in our study allowed for whole mammary gland ductal structures imaging and enabled straightforward serial imaging of mammary gland ducts in whole organ culture to visualize the growth and differentiation process. Ultrasound imaging showed the lowest resolution. However, ultrasound was able to detect mammary preneoplastic lesions 0.2 mm in size and was used to follow cancer growth with serial imaging in living mice.

Conclusion

In conclusion, each technique enabled serial imaging of living mammary tissue and visualization of growth and development, quickly and with minimal tissue preparation. The use of the higher resolution reflectance confocal and green fluorescent protein imaging techniques and lower resolution ultrasound were complementary.     

Immunopotentiation of DNA vaccine against herpes simplex virus via co-delivery of plasmid DNA expressing CCR7 ligands

The CCR7 ligands, secondary lymphoid tissue chemokine (SLC) and Epstein–Barr virus-induced molecule 1 ligand chemokine (ELC), were recently recognized as key molecules in establishing functional microenvironments for the initiation of immune responses in secondary lymphoid tissue. Here, we investigated the effect of CCR7 ligands-DNA administration on systemic and mucosal immune responses to plasmid DNA encoding gB of herpes simplex virus (HSV). Systemic co-transfer of both CCR7 ligands enhanced serum gB-specific IgG Ab but failed to elicit enhancement of distal mucosal IgA responses. In contrast, mucosal co-transfer provided significant increases of distal mucosal IgA responses. CCR7 ligands also enhanced T cell-mediated immunity as measured by CD4+ T helper cell proliferation and CD8+ T cell-mediated CTL activity. Of particular interest, is the observation that SLC significantly increased the production of Th1-type cytokines (IL-2 and IFN-γ) (P<0.05), whereas ELC increased the production of both Th1-type and Th2-type (IL-4) cytokines (P<0.05). Moreover, co-vaccination of CCR7 ligands increased the number of dendritic cells in secondary lymphoid tissue. These data indicate that CCR7 ligands may prove to be useful adjuvants for genetic vaccination against intracellular infection as well as cancer.     

Characterization of Apolipoprotein C3 (Apo C3) LNA/DNA Impurities and Degradation Products by LC-MS/MS

Apolipoprotein C3 (Apo C3) LNA/DNA gapmer was evaluated under various stress and formulation conditions for the purpose of its development as a potential biotherapeutic for low density lipoprotein (LDL) lowering. Using ion-pairing (IP) reversed-phase (RP) liquid chromatography ultra-high resolution (UHR) tandem mass spectrometry (IP-RPLC-MS/MS), a combination of accurate mass measurements and collision-induced dissociation enabled in-depth characterization of Apo C3 LNA/DNA oligonucleotide, in particular the inherent impurities following synthesis and degradation products after exposure to stress conditions. In this study, oligonucleotide samples were stressed under different pH and UV exposure conditions. The primary impurities in Apo C3 LNA/DNA were losses of nucleotide moieties from both the 5′- and 3′-terminus leading to n-1, n-2, etc. species. Desulfurization and depurination were observed in Apo C3 LNA/DNA after a week under UV light stress conditions at low pH. Guanine oxidation and dimerization were the primary degradation products detected under UV light exposure for 1 week at high pH. The effect of antioxidants on the levels of these degradation products was evaluated under neutral pH conditions. In the presence of all antioxidants, levels of guanine oxidation and desulfurization under tested conditions were the same as those in the unstressed sample, except for sodium ascorbate. The thorough understanding of the Apo C3 LNA/DNA oligonucleotide structure, its impurities, and degradation products laid the foundation for the successful formulation development of this novel biotherapeutic modality.     

Diagnostic accuracy of focused appendiceal CT in clinically equivocal cases of acute appendicitis.

PURPOSE: To determine the diagnostic accuracy of modified focused appendiceal computed tomography (CT) to exclude or confirm appendicitis in patients who presented with equivocal symptoms and signs of appendicitis. MATERIALS AND METHODS: One hundred patients (age range, 14-81 years; mean age, 30.6 years) with equivocal symptoms and signs of acute appendicitis were included in this prospective study. Patients were given 30 mL of diatrizoate meglumine and diatrizoate sodium and 60 mL of sorbitol mixed in 1 L of water orally over 1 hour. CT was performed 1.5 hours after the commencement of oral contrast material administration. The criteria used for the diagnosis of appendicitis were (a) appendix greater than 6 mm in maximum diameter, (b) no contrast material in the appendiceal lumen, and (c) inflammatory changes in the periappendiceal fat. CT results were compared with histopathologic findings at appendectomy. Patients with negative CT findings were followed up by telephone or clinically. RESULTS: Of 100 cases, 30 were positive at CT and 70 were negative. There were 28 true-positive cases; two false-positive cases, one cecal diverticulitis and one pelvic peritonitis with periappendicitis; and two false-negative cases, one perforated appendix and one mucosal and submucosal inflammation of the appendix but no transmural inflammation. Sensitivity was 93%, specificity was 97%, and accuracy was 96%. CONCLUSION: Focused appendiceal CT in which oral contrast material is used alone yields high levels of accuracy in clinically equivocal cases of acute appendicitis.     

Screening for gestational diabetes mellitus in the subsequent pregnancy: is it worthwhile?

OBJECTIVE: The purpose of this study was to determine, among women without evidence of gestational diabetes mellitus during their first pregnancy, the likelihood of, and associated risk factors for, the development of gestational diabetes mellitus in the subsequent pregnancy. STUDY DESIGN: This was a retrospective cohort study, with a time frame of 1991 to 1999. RESULTS: Of 3710 women without gestational diabetes mellitus in the first pregnancy, 1% (37 women) were subsequently diagnosed with gestational diabetes mellitus in the second pregnancy. These 37 women, when compared (by means) to women without gestational diabetes mellitus in their second pregnancy, were more likely to be older (age 21 years vs 19 years) and obese (first visit body mass index, 28 kg/m(2) vs 25 kg/m(2)) and to have an interpregnancy weight gain of >5 kg (93% vs 49%) and a longer mean interpregnancy interval (33 months vs 24 months). Regression analysis revealed that, during the first pregnancy, a first visit body mass index of >29 kg/m(2) (odds ratio, 2.2; 95% CI, 1.1-4.5) and a serum glucose screen of >101 mg/dL (odds ratio, 8.3; 95% CI, 2.5-27.9) were associated significantly with the development of gestational diabetes mellitus in the second pregnancy, as was an interpregnancy weight gain of >5 kg (odds ratio, 10.8; 95% CI, 2.5-46.3). All women who subsequently had gestational diabetes mellitus had at least one of these risk factors. CONCLUSION: Among women without gestational diabetes mellitus in the first pregnancy, the risk of gestational diabetes mellitus in a second pregnancy is low. Therefore, screening all such women in the second pregnancy may not be justified.     

Gender and spatial patterns in metal concentrations in brown anoles (Anolis sagrei) in southern Florida, USA

Comparatively little is known about heavy metal levels in reptiles, particularly for lizards. Yet lizards often are common predators that could serve as bioindicators of contamination on a small spatial scale. This study examined the differences in metal concentrations of adult brown anoles (Anolis sagrei) for arsenic, cadmium, chromium, lead, manganese, mercury, and selenium in six locations in southern Florida, USA, from Lake Okeechobee (Pahokee) south to Key West. We predicted that levels of contaminants would be higher in the industrialized ports (Port Everglades, Port of Miami) and at a landfill (in Key West) compared to a campground, tropical garden, and marine laboratory. Males were significantly larger than females, as expected. Although there were significant locational differences in metal concentrations, they did not fit a consistent pattern, either among sites or between reference and study sites. However, the lowest levels were generally found at Everglades Marina and Campground (except for selenium) and at Fairchild Tropical Garden (except for manganese). For females, size was significantly correlated with cadmium, lead, and mercury levels, while for males, there were significant correlations between length and arsenic, chromium, and manganese concentrations. Where there were gender differences in metal levels, females had significantly higher levels than males even though they were smaller. We attribute these gender differences to differences in diet due to microhabitat differences in foraging locations. Females spend more time feeding near the ground and males spend more time feeding on tree trunks and branches where they consume more flying insects. This is the first study that examines concentrations of metals in lizards in the United States, and suggests that nonnative lizards may be useful in toxicological studies.     

Re-organizing services for the management of upper gastrointestinal cancers: patterns of care and problems with change

The 'Calman-Hine' report (1995) recommended that cancer surgery should be limited to specialist high-volume units. National guidance from the National Health Service (NHS) Executive in 2001 stated that specialist oesophagogastric cancer centres should 'aim to draw patients from catchment areas with a population of 1-2 million.' For pancreatic cancers, the catchment areas should be between 2 and 4 million, reflecting the relatively lower incidence of disease. For the West Midlands region, these recommendations would suggest that four or five centres might be required to provide specialist surgical management for oesophagogastric cancer, and one or two centres for pancreatic disease. We used Hospital Episode Statistics to analyse trends in management patterns for these tumours within the West Midlands during the period 1992-2000. Over 20 different units were involved in the management of oesophagogastric and pancreatic disease, and we were unable to discern any clear and consistent move towards the centralisation of the upper gastrointestinal work in high-volume units since the publication of the Calman-Hine report in 1995. Although the drive for centralisation might be anticipated to increase following the publication of the NHS Executive's guidance, there is a substantial way to go before the provision of surgical services for upper gastrointestinal cancers is limited to a small number of high-volume specialist units.     

Institutional Commitment to Rectal Cancer Screening Results in Earlier-Stage Cancers on Diagnosis

Background: The Veterans Administration hospitals underwent an institutional directive in 1998 to meet a colorectal cancer screening (CRCS) standard. This intervention should result in an increase in the hospitals screening rate and percentage of early-stage rectal cancers diagnosed.Methods: A retrospective review, from 1991 to 2002, of our institutions pathology and cancer registry databases for rectal cancers. CRCS data were obtained from the Veterans Administration Prevention Disease Index. Cancer stage at diagnosis was compared before and after the directive and was compared with the National Cancer Data Base and the Surveillance, Epidemiology, and End Results data.Results: The rate of CRCS was 55% in 1998 and increased to 75% in 2003. During the 11 years studied, a total of 147 rectal cancers were diagnosed. After the Veterans Administration directive, there was a significant increase in stage 0 cancers (P < .02) and an overall migration to earlier-stage cancers. Our Veterans Administration hospital had a significantly greater percentage of stage 0 cancers both before (P < .007) and after the directive (P < .00) and had fewer stage 3 cancers after the directive (P < .03) compared with National Cancer Data Base data. Compared with Surveillance, Epidemiology, and End Results data, the Palo Alto Veterans Affairs Health Care System had more local disease (P < .03) and less regional disease (P < .006).Conclusions: These data suggest that a monitored institutional directive may significantly increase early detection of rectal cancers. This should result in a greater survival rate and lower local recurrence rate, because survival is predicated on stage at presentation. This may serve as a model for other health-care systems.     

DNA containing CpG motifs induces angiogenesis

New blood vessel formation in the cornea is an essential step in the pathogenesis of a blinding immunoinflammatory reaction caused by ocular infection with herpes simplex virus (HSV). By using a murine corneal micropocket assay, we found that HSV DNA (which contains a significant excess of potentially bioactive "CpG" motifs when compared with mammalian DNA) induces angiogenesis. Moreover, synthetic oligodeoxynucleotides containing CpG motifs attract inflammatory cells and stimulate the release of vascular endothelial growth factor (VEGF), which in turn triggers new blood vessel formation. In vitro, CpG DNA induces the J774A.1 murine macrophage cell line to produce VEGF. In vivo CpG-induced angiogenesis was blocked by the administration of anti-mVEGF Ab or the inclusion of "neutralizing" oligodeoxynucleotides that specifically oppose the stimulatory activity of CpG DNA. These findings establish that DNA containing bioactive CpG motifs induces angiogenesis, and suggest that CpG motifs in HSV DNA may contribute to the blinding lesions of stromal keratitis.