Pulmonary metastases from a low-grade endometrial stromal sarcoma confirmed by chromosome aberration and fluorescence in-situ hybridization approaches: a case of recurrence 13 years after hysterectomy

Pulmonary metastasis from low-grade endometrial stromal sarcomas (ESSs) occasionally are found after long, disease-free periods, mostly as incidental histological or radiological discoveries. We describe a case of low-grade ESS presenting as nodular pulmonary metastases finally diagnosed by estrogen-receptor staining, cytogenetic and fluorescence in situ hybridization (FISH) analyses, and perusal of the histology of hysterectomy material. An abnormal nodule in the lung field was discovered by means of chest X-ray of a 47-year-old woman. She had been disease free for 13 years after hysterectomy for an alleged leiomyoma. A computed tomographic scan revealed nodules, with fluctuation in size over the 2-year period, in both lungs. Finally the lesion in the left lung was resected, and pulmonary endometriosis was suspected because of the lack of stromal cell nuclear atypia and positive immunohistochemical reactions for estrogen and progesterone receptors. However, a characteristic karyotype was identified cytogenetically: 46, XX, t(7;17)(p15;q11), the translocation of which, specific to ESS, was confirmed by FISH analysis. A final diagnosis of pulmonary metastases from an ESS could be made by reviewing the histology of the previous uterine tumor. In this case, metastatic lesions from an ESS showed a decrease as well as an increase in size, despite the malignant potential. Immunostaining for estrogen and progesterone receptors and cytogenetic and FISH analyses, together with clinical information on the past gynecological history, are valuable diagnostic keys.     

Low-voltage-activated potassium channels underlie the regulation of intrinsic firing properties of rat vestibular ganglion cells

Individual primary vestibular afferents exhibit spontaneous activity the regularity of which can vary from regular to irregular. Different aspects of vestibular responsiveness have been associated with this dimension of regularity of resting discharge. Isolated rat vestibular ganglion cells (VGCs) showed heterogeneous intrinsic firing properties during sustained membrane depolarization: some neurons exhibited a strong adaptation generating just a single or a few spikes (phasic type), whereas other neurons showed moderate adaptation or tonic firing (tonic type). Tonic discharging VGCs were rare at postnatal days 5–7 and increased up to 60% of neurons during postnatal 2–3 wk. To explore the major factors responsible for the discharge regularity of primary vestibular afferents, we investigated the contribution of K⁺ channels to the firing properties of isolated rat VGCs. Phasic firing became tonic firing in the presence of 4-aminopyridine or -dendrotoxin, indicating that Kv1 potassium channels control the firing pattern of the phasic VGCs. Tetraethylammonium decreased the number of spikes during step current stimuli in all types. Blockade of Ca²⁺-activated K⁺ channels decreased the number of spikes in tonic VGCs. Our results suggest that Kv1 channels are critical both in determining the pattern of spike discharge in rat vestibular ganglion neurons and in their proportional change during maturation.     

Immunohistochemistry and K-ras sequence of pancreatic carcinosarcoma

Herein is presented a case of carcinosarcoma of the pancreas in an 82-year-old woman, analyzed on immunohistochemistry and K-ras sequence. The tumor, which arose in the pancreas head, was removed on pancreaticoduodenectomy. The patient died, however, of disseminated intravascular coagulation syndrome from postoperative sepsis 13 days later. Microscopically, the tumor consisted of malignant epithelial (well-differentiated adenocarcinoma cells) and mesenchymal (spindle-shaped tumor cells) components. The adenocarcinoma cells had positive immunostaining for cytokeratin AE1/AE3, cytokeratin 7, epithelial membrane antigen (EMA), CEA and carbohydrate antigen 19-9 (CA 19-9), while focal staining of these proteins was observed in the sarcomatous cells. In contrast, the sarcomatous cells had diffuse immunostaining for vimentin, CD10 and p53, while these proteins were not expressed in the ductal adenocarcinoma cells. These findings support the dual characteristics of a carcinosarcoma. DNA sequencing of the present case indicated point mutations of K-ras in both codons 12 and 34 on exon 2. The latter mutation is likely to correlate with the sarcomatous characteristics of this tumor. The tumor cells had specific and diffuse positive staining for CD10 and p53, with features characteristic of rapid growth.     

Comprehensive analysis of loss of heterozygosity events in glioblastoma using the 100K SNP mapping arrays and comparison with copy number abnormalities defined by BAC array comparative genomic hybridization

We have undertaken an extensive high-resolution analysis of loss of heterozygosity (LOH) in 30 high grade gliomas using the Affymetrix 100K SNP mapping array. Only 70% of LOH events were accompanied by a copy number loss (CNA(loss)), and of the other 30%, the distal region of 17p preferentially showed copy number neutral (CNN)-associated LOH. Combined analysis of CNA(loss) and LOH using MergeLevels analysis software predicts whether the observed losses occurred on a diploid or tetraploid background. In a side-by-side comparison between SNP and bacterial artificial chromosome (BAC) arrays, the overall identification of CNAs was similar on both platforms. The resolution provided by the SNP arrays, however, allowed a considerably more accurate definition of breakpoints as well as defining small events within the cancer genomes, which could not be detected on BAC arrays. CNN LOH was only detected by the SNP arrays, as was ploidy prediction. From our analysis, therefore, it is clear that simultaneously defining CNAs and CNN-LOH using the SNP platform provides a higher resolution and more complete analysis of the genetic events that have occurred within tumor cells. Our extensive analysis of SNP array data has also allowed an objective assessment of threshold LOH scores that can accurately predict LOH. This capability has important implications for interpretation of LOH events since they have consistently been used to localize potential tumor suppressor genes within the cancer genome.     

Relationship between GST Yp induction and hepatocyte proliferation in rats treated with phase II drug metabolizing enzyme inducers

Butylated hydroxyanisole (BHA) and 1,2-bis(2-pyridyl)ethylene (2PY-e) are phase II drug metabolizing enzyme inducers which cause hepatomegaly without hepatocyte hypertrophy and induce glutathione S-transferase Yp (GST Yp, pi-class GST), which is known as a tumor marker. To evaluate the relationship between GST Yp induction and hepatocyte proliferation, male F344/DuCrj rats were treated with BHA, 2PY-e, or phenobarbital (PB) for three or seven days. All three chemicals caused increases in liver weight after three and seven days. Immunohistochemical examinations revealed that BHA and 2PY-e induced GST Yp in the hepatocytes of the periportal and centrilobular areas at three and seven days, respectively, whereas PB did not. Significant increases in the BrdU labeling indices were found in the livers of rats in each of the three-day treatment groups, but the labeling index of rat livers treated with BHA was decreased to the control level at seven days, although the high labeling indices of 2PY-e and PB persisted at seven days. Double immunostaining confirmed that BrdU-positive nuclei corresponded to GST Yp-positive hepatocytes in both BHA and 2PY-e treated rats. These results suggest that the GST Yp induction caused by BHA or 2PY-e has some kind of relationship with hepatocyte proliferation.     

PX-RICS mediates ER-to-Golgi transport of the N-cadherin/beta-catenin complex

Cadherins mediate Ca2+-dependent cell-cell adhesion. Efficient export of cadherins from the endoplasmic reticulum (ER) is known to require complex formation with beta-catenin. However, the molecular mechanisms underlying this requirement remain elusive. Here we show that PX-RICS, a beta-catenin-interacting GTPase-activating protein (GAP) for Cdc42, mediates ER-to-Golgi transport of the N-cadherin/beta-catenin complex. Knockdown of PX-RICS expression induced the accumulation of the N-cadherin/beta-catenin complex in the ER and ER exit site, resulting in a decrease in cell-cell adhesion. PX-RICS was also required for ER-to-Golgi transport of the fibroblast growth factor-receptor 4 (FGFR4) associated with N-cadherin. PX-RICS-mediated ER-to-Golgi transport was dependent on its interaction with beta-catenin, phosphatidylinositol-4-phosphate (PI4P), Cdc42, and its novel binding partner gamma-aminobutyric acid type A receptor-associated protein (GABARAP). These results suggest that PX-RICS ensures the efficient entry of the N-cadherin/beta-catenin complex into the secretory pathway, and thereby regulates the amount of N-cadherin available for cell adhesion and FGFR4-mediated signaling.     

What do clinicians derive from partnering with their patients?: A reliable and valid measure of “personal meaning in patient care”

Objective

Burnout is high among clinicians and may relate to loss of “meaning” in patient care. We sought to develop and validate a measure of “personal meaning” that practitioners derive from patient care.

Methods

As part of a larger study of well-being among genetics professionals, we conducted three focus groups of clinical genetics professionals: physicians, nurses and genetic counselors (N = 29). Participants were asked: “What gives you meaning in patient care?” Eight themes were identified, converted into Likert items, and included in a questionnaire. Next, we mailed the questionnaire to clinical geneticists, genetic counselors and genetic nurses (N = 480) randomly selected from mailing lists of their professional associations. Results were subjected to exploratory factor analysis. The survey also included validated scales of burnout and professional satisfaction, and a 1-item measure of gratitude, to assess predictive validity.

Results

214 eligible providers completed the survey out of an estimated 348 eligible (61% response rate). Factor analysis resulted in a unidimensional scale consisting of 6-items with an alpha of 0.82 and an eigen value of 3.2. Factor loadings ranged from 0.69–0.77. The mean total score was 18.1 (S.D. 3.7) out of a possible high score of 24. Higher meaning scores were associated with being female (p = 0.044), a nurse (p < 0.001), and in practice longer (p = 0.006). Meaning scores were inversely correlated with burnout (p < 0.001), and positively correlated with gratitude (p < 0.001) and professional satisfaction (p < 0.022).

Conclusion

The 6-item “personal meaning in patient care” scale demonstrates high reliability and predictive validity in a select group of health professionals. Future research should validate this scale in a broader population of clinicians.

Practice implications

The scale could be useful in identifying providers at risk of burnout, and in evaluating interventions designed to counteract burnout, enhance meaning and improve communication and partnership between providers and patients.     

The importance of parent artery geometry in intra-aneurysmal hemodynamics

We show the importance of arterial geometry in intra-aneurysmal hemodynamics. Using a new geometric parameterized saccular aneurysm model including parameters for parent artery shape and the configuration of the aneurysm in the parent artery, we performed a parametric computational fluid dynamics study. We examined lateral saccular aneurysm models with different aneurysm shapes (i.e., the ratio of aneurysm height to aneurysm neck diameter) and different configurations (i.e., the torsion angle of the aneurysm to the upstream part of the parent artery). The aneurysm lateral to the curve of the parent artery had significantly higher wall shear stress than the aneurysm inside or outside the curve of the artery, even with the same shape of the aneurysm. Our findings suggest the important role played by the configuration of the aneurysm relative to the parent artery in intra-aneurysmal hemodynamics.     

46,XY gonadal dysgenesis: evidence for autosomal dominant transmission in a large kindred

46,XY gonadal dysgenesis is characterized by abnormal testicular determination. We describe a large kindred in which various disorders of sexual development were observed, ranging from completely female phenotype without ambiguities of the external genitalia (five cases) to men with isolated penile or perineal hypospadias (four cases), including two cases with moderate virilization and one case with ambiguity of the external genitalia. Histologic examination of gonadal tissue was performed on seven subjects. These findings were suggestive of complete gonadal dysgenesis in one patient, partial gonadal dysgenesis in three patients, and mixed gonadal dysgenesis in three patients. Four patients developed gonadal tumors (two gonadoblastoma, two dysgerminoma, and one immature teratoma, i.e., one patient had a dysgerminoma with some areas of gonadoblastoma). All affected subjects had no other congenital anomalies or dysmorphic features. Analysis of families with several affected individuals with 46,XY gonadal dysgenesis implied an X-linked mode of inheritance because of the apparent absence of male-to-male transmission. However, a sex-limited autosomal dominant mode of inheritance affecting only XY individuals could not be ruled out. Analysis of the pedigree we report indicated an autosomal dominant mode of inheritance because of male-to-male transmission. This kindred supports the involvement of at least one autosomal gene in non-syndromic 46,XY gonadal dysgenesis.     

Effects of spouses on distress experienced by BRCA1 mutation carriers over time

Concerns about psychological distress have arisen regarding genetic testing for susceptibility to late-onset diseases such as breast and/or ovarian cancer. Early results do not show large-scale psychological distress among those tested; therefore, research is now focusing on identifying subgroups that may be at risk for negative outcomes. Social support has been shown to buffer both negative physical and psychological outcomes in health research. The role of spouses as part of the tested person's social support system is shown to be significant in a sample of 57 BRCA1 mutation carriers. Separately, the tested person's perception of his/her spouse's anxiety and his/her perception of the spouse's support at the time of testing are predictive of the tested person's psychological distress up to 2 years after testing. The interaction of the two variables is even more predictive. For those tested who perceived their spouse to be both anxious and nonsupportive at the time of testing, distress levels reached clinically significant levels 1 week after results were received and remained above clinical threshold measured 4 months, 1 year, and 2 years after testing. While the effects were greatest for women, they were significant for both male and female carriers. These findings are an important addition to the literature and will augment clinicians' ability to identify individuals potentially at risk for negative responses to adverse genetic test results.