Re-evaluating Adjuvant Breast Cancer Trials: Assessing Hormone Receptor Status by Immunohistochemical Versus Extraction Assays

Background: Tumor levels of steroid hormone receptors, a factor used to select adjuvant treatment for early-stage breast cancer, are currently determined with immunohistochemical assays. These assays have a discordance of 10%-30% with previously used extraction assays. We assessed the concordance and predictive value of hormone receptor status as determined by immunohistochemical and extraction assays on specimens from International Breast Cancer Study Group Trials VIII and IX. These trials predominantly used extraction assays and compared adjuvant chemoendocrine therapy with endocrine therapy alone among pre- and postmenopausal patients with lymph node-negative breast cancer. Trial conclusions were that combination therapy provided a benefit to pre- and postmenopausal patients with estrogen receptor (ER)-negative tumors but not to ER-positive postmenopausal patients. ER-positive premenopausal patients required further study. Methods: Tumor specimens from 571 premenopausal and 976 postmenopausal patients on which extraction assays had determined ER and progesterone receptor (PgR) levels before randomization from October 1, 1988, through October 1, 1999, were re-evaluated with an immunohistochemical assay in a central pathology laboratory. The endpoint was disease-free survival. Hazard ratios of recurrence or death for treatment comparisons were estimated with Cox proportional hazards regression models, and discriminatory ability was evaluated with the c index. All statistical tests were two-sided. Results: Concordance of hormone receptor status determined by both assays ranged from 74% (κ = 0.48) for PgR among postmenopausal patients to 88% (κ = 0.66) for ER in postmenopausal patients. Hazard ratio estimates were similar for the association between disease-free survival and ER status (among all patients) or PgR status (among postmenopausal patients) as determined by the two methods. However, among premenopausal patients treated with endocrine therapy alone, the discriminatory ability of PgR status as determined by immunohistochemical assay was statistically significantly better (c index = 0.60 versus 0.51; P = .003) than that determined by extraction assay, and so immunohistochemically determined PgR status could predict disease-free survival. Conclusions: Trial conclusions in which ER status (for all patients) or PgR status (for postmenopausal patients) was determined by immunohistochemical assay supported those determined by extraction assays. However, among premenopausal patients, trial conclusions drawn from PgR status differed—immunohistochemically determined PgR status could predict response to endocrine therapy, unlike that determined by the extraction assa

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Beyond “It Was Great”: Views From Returning Sojourners

This paper builds upon ideas from E. David Wong in examining the use of “It was great” among undergraduates returning from study abroad experiences. Using student voices reflecting upon Wong and their own use of “It was great,” the paper argues that the phrase reveals more about student learning abroad than others have argued. By examining 100 student reflections, representative categories were developed to show the range of meaning student sojourners intended when using that one phrase. The categories demonstrate that “It was great” reflects significant student learning, as well as the need for students to have opportunities to make sense of their study abroad experience

Design and Simulation of Natural Gas Liquid Recovery Process from Rich Natural Gas

Natural gas plays a growing role in the energy mix by displacing coal due to its relative economic and/or environmental advantages A process of natural gas liquid (NGL) recovery utilizing internally generated energy to achieve energy efficiency was designed. The process utilizes heat generated from the compressor end of the turbo-expander to provide heat energy required to maintain the appropriate operating conditions at the intermediate and bottom sections of the demethanizer column, rather than utilizing dedicated steam generators that requires additional construction, installation, operations and maintenance cost. Simultaneously, the temperature of the hot residue gas is also dropped to the required range for export, rather than utilizing dedicated process gas coolers. The various unit operations such as heat exchangers, liquid separators, Joules Thompson Valve coefficient, demethanizer column, reflux condenser, and bottom reboiler were designed, and cost evaluation performed for each unit, while models were solved using MatLab software. The quality and composition of NGL and residue gas produced are consistent with industrial process plant data. In addition, condenser and reboiler showed that the heat removed from the condenser is 3.180.5kW and 1.65m2 area was exchanged, while the heat for the reboiler is 474.5kW at 47.25m2 exchanged area. Also, the temperature profile of the demethanizer column is not uniform as lower temperature is required for the rectifying section (cryogenic absorption). Thus, temperature of -90oC to – 95oC favours the production of sales gas as the top product stream, while a temperature range of 30oC to 36oC at the bottom favours the recovery of NGL product as the bottom stream. The height and diameter of demethanizer column for distillation and absorption sections are 28m and 1.55m and 7.24m and 3m respectively. Keywords: Natural Gas Liquid, Heat Exchanger, Separator, J-T Valve, Demethanizer Column, DOI: 10.7176/CPER/64-04 Publication date: January 31st 202

Staphylococcal scalded skin syndrome in an extremely premature neonate: a case report with a brief review of literature

Staphylococcus aureus can cause a spectrum of exfoliative skin conditions ranging from localised bullous impetigo to generalised cutaneous involvement with systemic illness. Staphylococcal scalded skin syndrome (SSSS) generally affects neonates, infants and children less than 5 years of age. SSSS has been rarely reported in premature neonates. We describe here a case of an extremely premature neonate born at 24 weeks gestation who developed SSSS at 7 weeks of postnatal age

The microscopic complexities of C3 in breast cytology

Background: Fine-needle aspiration (FNA) of difficult breast lesions often results in an atypical (C3) report. The assortment of outcomes generated by C3 reports varies widely, and this has given rise to different clinical management pathways. Objective: To identify and objectively assess microscopic features associated with atypical/C3 breast FNA cases. Materials and Methods: A total of 230 atypical breast FNAs were subjected to a blind microscopic rescreen using a range of robust qualitative and quantitative cytological criteria including cellularity, architectural qualities, cytomorphology and background features. A logistic regression with a receiver operating characteristic (ROC) curve and the resultant forward stepwise analysis were conducted to assess the results. This statistical testing was measured against malignant, benign proliferative and benign non-proliferative outcomes. Results: The malignant and benign proliferative outcomes showed a mixture of opposing protective and predictive individual cytological criteria. The stepwise analysis produced models demonstrating the best combination of individual cytological criteria for malignancy, proliferative and benign non-proliferative entities. In the malignancy model, discohesion, nuclear crowding within sheets, diminished numbers of bare bipolar nuclei and myoepithelial cells, the presence of tubules or necrosis and the absence of a cystic background were important features. The benign proliferative model suggested the same criteria but with the opposite implication and with the addition of several others, such as the presence of apocrine metaplasia, retained polarity and a speckled or coarse chromatin pattern. Age was a significant factor in malignant and proliferative outcomes. The benign non-proliferative stepwise analysis produced a model with fewer criteria (complex sheets, bare bipolar nuclei and a cystic background) limiting clinical application. Conclusion: Atypical/C3 breast cytology remains a legitimate reporting category. However, it is associated with a number of different histological outcomes. The incidence of the C3 category can be significantly reduced by controlling extrinsic factors and understanding the associated microscopic features

Is fertility-sparing treatment for high grade cervical dysplasia conservative enough? (letter)

The new National Health and Medical Research Council (NHMRC) guidelines for the management of women with high grade squamous intraepithelial lesions [cervical intraepithelial neoplasia (CIN) 2 and CIN 3] state that the local ablative or excisional treatment should destroy or remove tissue to a depth of at least 7 mm. It is obvious from our study that gynaecologists at our institution are much more conservative in their approach to the treatment of high grade dysplasia than the NHMRC recommendations. We support this approach and believe cytological surveillance for women who have complete excision of CIN to be appropriate; whereas women with involved margins by CIN at initial LLETZ should have long term colposcopic and cytological follow up. We think top-hat LLETZ would constitute over-treatment in the young age group

An unusual presentation of laryngeal paraganglioma: the first pediatric case reported in Australia

Laryngeal paraganglioma is a rare neuroendocrine neoplasm of neural origin. Most commonly it arises in the supraglottis, in either the false cords or aryepiglottic folds. Generally these neoplasms cause symptoms as they enlarge and cause obstruction. We present a case of this unusual condition with no obstructive symptoms, despite the large size of the tumor