Conservative management of early endometrial adenocarcinoma with repeat curettage and hormone therapy under assistance of hysteroscopy and laparoscopy

We report a rare case of early-stage endometrial adenocarcinoma in a 22 year old nullipara with polycystic ovaries undergoing conservative treatment. Pretreatment evaluation including tumour grade, depth of myometrial invasion, tumour size, hormone receptor status and flow cytometric analysis indicated a favourable prognosis. The patient underwent repeat endometrial curettage and a 6 month period of therapy with megestrol acetate and tamoxifen. A combination contraceptive pill was then prescribed to ensure withdrawal of the menstrual cycle thereafter. Now, 1 year after the last curettage, there is no evidence of disease. During the treatment period, hysteroscopy allowed for a more precise approach in panoramically examining the tumour nest in the endometrial cavity, and the subsequent endometrial response to hormone therapy. Laparoscopy using bulldog clamps applied to the isthmic portion of the Fallopian tubes prevented i.p. spread of endometrial tissue from retrograde regurgitation during hysteroscopy. Laparoscopic ovarian electrocautery resulted in the reduction of abnormal hypervascularization on the surface of polycystic ovaries postoperatively but caused a peri-ovarian adhesion complication. It is interesting that this case posed a unique opportunity to demonstrate the tumour regression under the assistance of laparoscopy and hysteroscopy.      

Correlation of MIC with outcome for Candida species tested against caspofungin, anidulafungin, and micafungin: analysis and proposal for interpretive MIC breakpoints

The CLSI Antifungal Subcommittee followed the M23-A2 “blueprint” to develop interpretive MIC breakpoints for anidulafungin, caspofungin, and micafungin against Candida species. MICs of ≤2 μg/ml for all three echinocandins encompass 98.8 to 100% of all clinical isolates of Candida spp. without bisecting any species group and represent a concentration that is easily maintained throughout the dosing period. Data from phase III clinical trials demonstrate that the standard dosing regimens for each of these agents may be used to treat infections due to Candida spp. for which MICs are as high as 2 μg/ml. An MIC predictive of resistance to these agents cannot be defined based on the data from clinical trials due to the paucity of isolates for which MICs exceed 2 μg/ml. The clinical data set included only three isolates from patients treated with an echinocandin (caspofungin) for which the MICs were >2 μg/ml (two C. parapsilosis isolates at 4 μg/ml and one C. rugosa isolate at 8 μg/ml). Based on these data, the CLSI subcommittee has decided to recommend a “susceptible only” breakpoint MIC of ≤2 μg/ml due to the lack of echinocandin resistance in the population of Candida isolates thus far. Isolates for which MICs exceed 2 μg/ml should be designated “nonsusceptible” (NS). For strains yielding results suggestive of an NS category, the organism identification and antimicrobial-susceptibility test results should be confirmed. Subsequently, the isolates should be submitted to a reference laboratory that will confirm the results by using a CLSI reference dilution method.     

Differentiating between Burkitt lymphoma and CD10+ diffuse large B-cell lymphoma: the role of commonly used flow cytometry cell markers and the application of a multiparameter scoring system

The goal of this study was to evaluate routine flow cytometric (FC) immunophenotypic markers in differentiating between Burkitt lymphoma (BL) and CD10+ diffuse large B-cell lymphoma (DLBCL). We performed retrospective analysis of FC data from 55 patients. We evaluated 9 FC parameters: forward and side scatter (FSC and SSC); mean fluorescent intensity (MFI) for CD20, CD10, CD38, CD79b, CD43, and CD71; and the percentage of neoplastic cells positive for CD71 (%CD71). The FSC; MFIs of CD10, CD43, CD79b, and CD71; and %CD71 cells were significantly different between BL and CD10+ DLBCL (P < .05; Student t test). A 5-point scoring system (FSC, %CD71, and MFIs of CD43, CD79b, and CD71) was devised, and 6 (60%) of 10 BLs scored 3 or greater and 1 (10%) of 10 CD10+ DLBCLs scored 3 (P = .04; χ(2)). Our findings indicate that routine FC parameters can aid in differentiating BL from CD10+ DLBCL.     

HER-2/neu oncogene amplification by fluorescence in situ hybridization in epithelial tumors of the ovary

HER-2/neu gene amplification and protein overexpression have been associated with prognosis in breast, lung and prostate cancers but have not been extensively studied in ovarian carcinoma. For the study, we selected 5-micron-thick, formalin-fixed, paraffin-embedded tissue sections from 74 cases of ovarian epithelial tumors of low malignant potential and ovarian carcinoma. Tumors were graded and staged and evaluated for amplification of the HER-2/neu gene by fluorescence in situ hybridization. HER-2/neu amplifications was present in 3 of 13 serous, mucinous, and endometrioid epithelial tumors of low malignant potential and in 40 of 61 epithelial carcinomas. In the carcinoma group, amplification did not correlate with stage, grade, or tumor type. Mean follow-up was 31 months; 1 patient with a low malignant potential tumor and 32 patients with carcinomas died of disease. On univariate and multivariate analysis, survival correlated with stage of disease but not with HER-2/neu amplification. HER-2/neu amplification by fluorescence in situ hybridization can be performed on tissue sections of ovarian neoplasms; amplification is uncommon in ovarian tumors of low malignant potential, but is present in 66% of ovarian epithelial carcinomas. HER-2/neu amplification did not predict outcome in ovarian epithelial neoplasia but may have an important role in tumor development.     

Reciprocal modulation of C/EBP‐α and C/EBP‐β by IL‐13 in activated microglia prevents neuronal death

In response to aggravation by activated microglia, IL‐13 can significantly enhance ER stress induction, apoptosis, and death via reciprocal signaling through CCAAT/enhancer‐binding protein alpha (C/EBP‐α) and C/EBP‐beta (C/EBP‐β). This reciprocal signaling promotes neuronal survival. Since the induction of cyclooxygenase‐2 (COX‐2) and peroxisome proliferator‐activated receptor gamma/heme oxygenase 1 (PPAR‐γ/HO‐1) by IL‐13 plays a crucial role in the promotion of and protection from activated microglia, respectively; here, we investigated the role of IL‐13 in regulating C/EBPs in activated microglia and determined its correlation with neuronal function. The results revealed that IL‐13 significantly enhanced C/EBP‐α/COX‐2 expression and PGE₂ production in LPS‐treated microglial cells. Paradoxically, IL‐13 abolished C/EBP‐β/PPAR‐γ/HO‐1 expression. IL‐13 also enhanced ER stress‐evoked calpain activation by promoting the association of C/EBP‐β and PPAR‐γ. SiRNA‐C/EBP‐α effectively reversed the combined LPS‐activated caspase‐12 activation and IL‐13‐induced apoptosis. In contrast, siRNA‐C/EBP‐β partially increased microglial cell apoptosis. By NeuN immunochemistry and CD11b staining, there was improvement in the loss of CA3 neuronal cells after intrahippocampal injection of IL‐13. This suggests that IL‐13‐enhanced PLA2 activity regulates COX‐2/PGE₂ expression through C/EBP‐α activation. In parallel, ER stress‐related calpain downregulates the PPAR‐γ/HO‐1 pathway via C/EBP‐β and leads to aggravated death of activated microglia via IL‐13, thereby preventing cerebral inflammation and neuronal injury.     

The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1–2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex‐influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre‐symptomatic diagnosis has the greatest clinical utility.     

Effect of PD-L1 testing on the cost-effectiveness and budget impact of pembrolizumab for advanced urothelial carcinoma of the bladder in the United States

Purpose

Our purpose was to evaluate the effect of PD-L1 testing on the cost-effectiveness of pembrolizumab for second-line treatment of advanced urothelial carcinoma in the bladder from the U.S. societal perspective.

Does preoperative needle localization lead to an increase in local breast cancer recurrence?

Between 1978 and 1981, 74 women with nonpalpable breast cancer underwent surgery after localization guides were placed. In 72 patients, guides were introduced parallel to the chest wall; in two the needle was positioned anteroposteriorly under computed tomographic guidance. Fifty-six cases (76%) were infiltrating cancer; 13 (17%), intraductal cancers; two (3%), inflammatory; and three (4%), lobular carcinoma in situ. Surgery was not used to treat the latter five patients. In the remaining 69 women, 42 (61%) were treated by means of modified radical mastectomy; six (9%), total mastectomy; 12 (17%), local excision and radiation therapy; and seven (10%), local excision alone; exact therapy for two women (3%) was unknown. At a minimum follow-up of 5 years, none of the 67 women in whom the parallel approach was used had a local recurrence. The authors conclude that preoperative placement of guides parallel to the chest wall does not appear to increase the risk of local breast cancer recurrence.     

A Monte Carlo approach for improving transient dopamine release detection sensitivity

Current methods using a single PET scan to detect voxel-level transient dopamine release—using F-test (significance) and cluster size thresholding—have limited detection sensitivity for clusters of release small in size and/or having low release levels. Specifically, simulations show that voxels with release near the peripheries of such clusters are often rejected—becoming false negatives and ultimately distorting the F-distribution of rejected voxels. We suggest a Monte Carlo method that incorporates these two observations into a cost function, allowing erroneously rejected voxels to be accepted under specified criteria. In simulations, the proposed method improves detection sensitivity by up to 50% while preserving the cluster size threshold, or up to 180% when optimizing for sensitivity. A further parametric-based voxelwise thresholding is then suggested to better estimate the release dynamics in detected clusters. We apply the Monte Carlo method to a pilot scan from a human gambling study, where additional parametrically unique clusters are detected as compared to the current best methods—results consistent with our simulations.