The utility of intraoperative retroareolar margin frozen section assessment and the management of atypical epithelial proliferative lesions at the retroareolar margin in nipple-sparing mastectomies

ObjectivesNipple-sparing mastectomy (NSM) has become more frequently utilized due to superior psychological and cosmetic outcomes. The aim of this study was to evaluate the accuracy and utility of intraoperative frozen section evaluation of the retroareolar margin (RAM) in NSM. The management of atypical epithelial proliferative lesions at the RAM was also reviewed and discussed.MethodsA single institution, retrospective analysis was performed on all therapeutic NSM patients with intraoperative evaluation of the RAM from 2014 to 2018. Patient demographics, tumor characteristics, pathologic assessment of the RAM, surgical management, and clinical follow-up were reviewed.ResultsSeventy-four nipple-sparing mastectomies with intraoperative evaluation of RAMs were identified. Concordance was 95% between frozen and permanent section diagnoses with 4 cases representing false negatives and no false positives. There were no instances of nipple-areolar complex (NAC) recurrence in all cases with preserved NACs (mean follow up: 750 days). In the 9 cases where NACs were excised based on intraoperative RAM evaluation, the findings in the excised NACs were negative in 6 and ductal carcinoma in situ in 3 cases. Postoperative measurement of the tumor to nipple distance was the only statistically significant variable associated with a positive RAM by multivariable logistic regression (OR 0.475; 95% CI 0.238–0.946).ConclusionsIntraoperative RAM evaluation demonstrated high concordance with permanent histology. Negative RAM, including atypical epithelial proliferative lesions, led to NAC preservation without recurrence. Positive RAM alone did not predict NAC involvement, although pagetoid spread of ductal carcinoma in situ along nipple ducts may predict NAC positivity.     

Accuracy and interobserver agreement of retroareolar frozen sections in nipple-sparing mastectomies

In the last decades, surgical treatment of breast cancer has enormously changed. As a result, nipple-sparing mastectomy (NSM) has evolved as an oncologically safe and cosmetic approach. NSM includes a subareolar frozen section to evaluate malignancy. We determined the accuracy of subareolar frozen section diagnosis, analyzed the discrepancy factor, and estimated the interobserver agreement of frozen section in NSM. A retrospective review of all NSMs at our institution from 2009 to 2015 was performed. Frozen sections were compared to the final diagnoses to analyze the accuracy of subareolar frozen sections. Discordant results were rigorously evaluated to identify discrepancy factors. Some cases were randomly chosen to assess the interobserver agreement (kappa) among pathologists. The agreement results were evaluated with and without knowledge of the tumor morphology. Among 34 NSMs, the frozen section false-negative and false-positive rate was 5.9% and 8.8%, respectively. The sensitivity and specificity was 77.8% and 88.0%, respectively. Sampling errors and diathermy artifacts explained our false-negative diagnoses. Freezing artifacts and an intraductal papilloma explained our false-positive diagnoses. The interobserver agreement between breast and general pathologists was 0.87 (p < 0.0001) and 0.31 (p = 0.0001), respectively. The interobserver agreement increased to 0.35 (p < 0.0001) in general pathologists with knowledge of the tumor morphology. Subareolar frozen section showed to be a specific test with moderate sensitivity. Papillary lesions can mimic atypical cells and influence the frozen section interpretation. Frozen section in NSM had a better performance in breast pathologists (almost perfect) versus general pathologists (fair). Interobserver agreement may improve with knowledge of tumor morphology.     

Postoperative pain assessment of robotic nipple-sparing mastectomy with immediate prepectoral prosthesis breast reconstruction: a comparison with conventional nipple-sparing mastectomy

Aims: Nipple-sparing mastectomy (NSM) is a surgical procedure for patients with breast cancer without nipple-areolar complex (NAC) involvement. Robotic NSM (RNSM) with immediate breast reconstruction has been recently introduced; however, reports regarding RNSM are still lacking. Therefore, this study aimed to evaluate the postoperative assessment with a focus on postoperative pain of RNSM with prepectoral immediate prosthesis breast reconstruction (IPBR) compared with conventional NSM (CNSM) in patients with breast cancer without NAC invasion.Methods: This retrospective study included 81 patients who underwent RNSM (n = 40) or CNSM (n = 41) with prepectoral IPBR using direct-to-implant or tissue expander between January 2018 and June 2020. The primary endpoint was to compare postoperative pain intensity based on a numerical rating scale (NRS). The secondary endpoint was to evaluate the postoperative recovery profile, including postoperative nausea/vomiting (PONV) and complications.Results: A statistical difference was observed in the resting NRS scores at 0-6 postoperative hours between the RNSM and CNSM groups (3.2 ± 1.5 versus 4.2 ± 1.6, respectively; Bonferroni corrected P = 0.005), however, no difference was shown at other time periods. Also, no between-group difference was found in the NRS scores for acting pain within 48 postoperative hours and the number of patients requiring additional analgesics.Conclusions: Despite a statistical difference in the resting NRS scores during the early postoperative phase, the absence of any significant difference in the requirement of additional analgesics between the groups suggested that RNSM does not significantly attenuate postoperative pain intensity.     

Optimization and evaluation of landmark-based image correlation.

Image correlation methods enable the complementary use of information from different medical images of a patient. These images can be obtained from different imaging devices (CT, MR, PET), or, from one imaging device taken at different times. Unfortunately, there are few cases in which the requirements for later image correlation are taken into account at the time of image acquisition. There is therefore a need for correlation techniques requiring no preparation in advance. We have developed two correlation methods, both based on three or more anatomical or artificial landmarks, to be defined in corresponding image data sets. These methods have been evaluated with phantom data as well as with patient data. We have improved these correlation methods by using more landmarks and special selection criteria. They are applicable to all medical tomograms and to x-ray pictures taken under stereotactical conditions. The results obtained have error ranges in the order of the three-dimensional image resolution.     

Psychological implications of mastectomy

The adjustment of a group of mastectomy patients to their operation was assessed at an interval of between 18 months and 5 years after surgery. They were found to be significantly more depressed and anxious than a control group of cholecystectomy patients; they tended to have lower self-esteem; and they described themselves as being more introverted in their behaviour. These differences were attributed to concern about both the loss of the breast and the possibility of recurrence of the cancer.     

直肠癌远端切缘c—myc、k—ras基因表达与术后局部复发的相关性研究

目的：探讨c-myc、k-ras基因在直肠癌远端切缘表达与直肠癌术后局部复发的相关性。方法采用免疫组织化学 SP 法检测山西医科大学附属肿瘤医院（山西省肿瘤医院）2008年1月至2011年12月间行直肠癌前切除术的47例术后局部复发患者（复发组）和50例术后未复发患者（未复发组,随访2年未发现复发）的瘤组织、近端切缘组织、远端切缘组织c-myc基因和k-ras基因表达情况,并进行比较。结果（1）复发组中k-ras基因在瘤体、近端切缘及远端切缘的表达阳性率分别为76.6%、53.2%、68.1%,在未复发组中的阳性率分别为62.0%、54.0%、66.0%;复发组、未复发组瘤组织、近端切缘组织、远端切缘组织k-ras基因表达情况两组比较差异均无统计学意义（P〉0.05）;（2）复发组中c-myc基因在瘤组织、近端切缘及远端切缘的表达阳性率分别为66.0%、74.5%、93.6%,在未复发组中的阳性率分别为54.0%、70.0%、58.0%;两组瘤组织、近端切缘组织c-myc基因表达情况比较差异无统计学意义（P〉0.05）;而远端切缘组织c-myc基因表达情况比较,复发组表达阳性率明显高于未复发组,差异具有统计学意义（P〈0.05）。结论c-myc基因在远端切缘组织中的过度表达与直肠癌术后局部复发存在某种相关性。     

A new method of margin evaluation in breast conservation surgery using an adjustable mould during fixation

AIMS: We have developed a new method of breast resection margin assessment in quadrantectomy using an adjustable mould to prevent the three-dimensional specimen from distorting during fixation. METHODS AND RESULTS: The new method has been applied to 10 consecutive quadrantectomies (six invasive duct carcinomas, four duct carcinoma in situ with or without microinvasion). The precise configuration of the fixed specimen enabled pathologists to examine the side slices, the 5 mm thick slices cut parallel to the flat lateral margins of the specimen, permitting the separation of margin evaluation from tumour characterization. Eight cases with negative margins by our method would also be negative by assessment of inked margins since the margin widths were estimated to be from 5 to 30 mm (average 16.3 mm); two cases with positive margins would also be positive by inked margins. CONCLUSIONS: Our new method was as reliable as the inked margins employing sequential slicing of the entire tissue, although it reduced the number of blocks by more than half in invasive carcinomas. A further advantage of this method is that the accuracy in margin evaluation is not influenced by the extent of tumour sampling. In addition, our system can pinpoint the positive margins facilitating re-excision to obtain tumour-free margins.     

Development of a spatially offset Raman spectroscopy probe for breast tumor surgical margin evaluation

The risk of local recurrence for breast cancers is strongly correlated with the presence of a tumor within 1 to 2 mm of the surgical margin on the excised specimen. Previous experimental and theoretical results suggest that spatially offset Raman spectroscopy (SORS) holds much promise for intraoperative margin analysis. Based on simulation predictions for signal-to-noise ratio differences among varying spatial offsets, a SORS probe with multiple source-detector offsets was designed and tested. It was then employed to acquire spectra from 35 frozen-thawed breast tissue samples in vitro. Spectra from each detector ring were averaged to create a composite spectrum with biochemical information covering the entire range from the tissue surface to ～2 mm below the surface, and a probabilistic classification scheme was used to classify these composite spectra as "negative" or "positive" margins. This discrimination was performed with 95% sensitivity and 100% specificity, or with 100% positive predictive value and 94% negative predictive value.     

Steroid receptors in benign mastectomy tissue

Estrogen and progesterone receptors (ERs and PRs, respectively) were measured in both cancerous and noncancerous components of 104 modified radical mastectomy specimens. In addition, ER and PR levels were determined for 14 benign breast specimens obtained by reduction mammoplasty. The receptor levels were measured by scatchard method. Each of these groups--cancerous, corresponding noncancerous, and mammoplasty specimens--were divided into subgroups according to their receptor levels. Fourteen of the 104 noncancerous specimens were found to be ER positive (ER+). Most cases of ER+ noncancerous tissue (13 of 14 cases) were associated with ER+ tumors. The reverse was not true because only 13 of 64 cases of the ER+ tumors were associated with positive ER in their noncancerous counterparts. Comparable results were obtained for PR. The average ER-PR level of the noncancerous mastectomy tissue was significantly higher than that of the mammoplasty specimens despite the similar histologic findings in both groups.     

Systematic ophthalmologic evaluation in cardio-facio-cutaneous syndrome: A genotype–endophenotype correlation

Cardio-facio-cutaneous syndrome (CFCS) is a rare genetic disorder belonging to the RASopathies, a group of developmental syndromes caused by upregulated RAS/MAPK signaling. Pathogenic variants affecting four genes, KRAS, BRAF, MAP2K1 and MAP2K2, encoding core signal transducers of the pathway, underlie the condition. Major clinical features include a distinctive facies, ectodermal and cardiac anomalies, reduced postnatal growth, intellectual disability, and musculoskeletal abnormalities. Similar to other RASopathies, reports of visual impairment, high refractive error, optic nerve pallor, and other ocular abnormalities have been anecdotally reported in the literature. The aim of our study is to report the prevalence of ophthalmologic abnormalities in a large monocentric cohort of individuals affected by CFCS and explore the occurrence of genotype–endophenotype correlations in this series of patients. We observed that BRAF mutations are associated to a higher prevalence of anisometropia >3D (11.8% vs. 0%) and high astigmatism (29.4% vs. 0%; both p < 0.001) while patients with mutations in other genes had a significantly higher prevalence of myopia >6 D (60% vs. 5.9%; p = 0.012). Pale optic disc was associated with higher prevalence of inferior oblique muscle (IO) overaction (33.3% vs. 0%) and lower prevalence of ptosis (0% vs. 11.8%; both p < 0.001). Combined exotropia, IO overaction and nystagmus were frequent in patients with pale optic nerve. Our findings might suggest the need for earlier ophthalmologic referral for CFCS patients due to high risk of amblyopia, especially those expressing BRAF mutations.     

Utilisation of prophylactic mastectomy in 10 European centres

Increasingly women at high risk of breast cancer are opting for prophylactic surgery to reduce their risks. Data from 10 European centres that offer a risk counselling and screening service to women at risk show different approaches to the option of preventive surgery, although most centres adhere to a protocol including at least two risk counselling sessions and a psychological assessment. Thus far the combined centres have data on 174 women who have undergone prophylactic mastectomy with in excess of 400 women years of follow up. Operations were carried out on women with lifetime risks of 25-80%, with an average annual expected incidence rate of 1% per women. No breast cancers have occurred in this cohort. Long term follow up on an extended group of women will be necessary to truly address the risk of subsequent breast cancer and the psychological sequelae.     

Positive correlation between in vivo and in vitro assays for the evaluation of Pseudomonas virulence

Some bacterial phenotypes measured in vitro can be used to access bacterial virulence, on the premise that they are positively correlated with data from in vivo experiments. We show here that in vitro assessment of bacterial phenotypes, such as adherence and cytotoxicity, are positively correlated with data from in vivo experiments in Drosophila and can be used to assess bacterial virulence in vivo. Manipulation of environmental parameters, such as iron availability, induced changes in the phenotypes measured in vitro that correlated with changes in vivo virulence of all strains tested. Applying these assays, we demonstrate the pathogenic potential of a Pseudomonas fluorescens strain, initially isolated as a non-pathogenic milk contaminant. This strain displayed adherence and cytotoxicity comparable to those of the Pseudomonas aeruginosa pathogenic strain PAK, and colonized the infected flies as rapidly as the PAK strain. These results indicate that this "a priori" non-pathogenic bacterium is capable of escaping the host immune response, supporting the use of in vitro tests for screening of potential pathogens.     

Olfaction evaluation and correlation with brain atrophy in Bardet‐Biedl syndrome

Bardet‐Biedl syndrome (BBS) is a well‐recognized ciliopathy characterized by cardinal features namely: early onset retinitis pigmentosa, polydactyly, obesity, hypogonadism, renal and cognitive impairment. Recently, disorders of olfaction (anosmia, hyposmia) have been also described in BBS patients. Moreover, morphological brain anomalies have been reported and prompt for further investigations to determine whether they are primary or secondary to peripheral organ involvement (i.e. visual or olfactory neuronal tissue). The objective of this article is to evaluate olfactory disorders in BBS patients and to investigate putative correlation with morphological cerebral anomalies. To this end, 20 BBS patients were recruited and evaluated for olfaction using the University of Pennsylvania Smell Identification Test (UPSIT). All of them underwent a structural magnetic resonance imaging (MRI) scan. We first investigated brain morphological differences between BBS subjects and 14 healthy volunteers. Then, we showed objective olfaction disorders in BBS patients and highlight correlation between gray matter volume reduction and olfaction dysfunction in several brain areas.     

Differential color coding of surgical margins in mastectomy specimens

Abstract

Application of suture marks or clips for specimen orientation is routine for operating surgeons. However, it is impossible for a pathologist to reproduce these in the final sections. In most laboratories a single dye is employed to paint the surgical margins. It helps to assess complete/incomplete excision of a tumor. However, many times, several margins need to be studied together, especially in larger resection specimens. This study was undertaken to assess fabric dyes, which can be employed for marking surgical margins, for their reproducibility, safety, reliability, ease of application and cost. Multiple color coding was done on 24 mastectomy specimens and the results recorded and compared.     

Radial partition fluorescent immunoassay of thyrotropin. Analytic evaluation and clinical correlation

The authors evaluated the analytic and clinical performance of a sensitive radial partition fluorescent enzyme immunoassay for thyrotropin (TSH) performed on Stratus and compared it with a nonsensitive radioimmunoassay (RIA) method. Sensitivity of 0.15 mIU/L was obtained, and precision, specificity, and linearity were acceptable. A good correlation was observed between the two assays in samples from 311 hospitalized patients (r = 0.976). Stratus TSH results were outside the reference range for 20% of clinically euthyroid patients (n = 126), and 2.4% had undetectable levels. The clinically hyperthyroid group (n = 11) with the exception of one patient had TSH values below 0.2 mIU/L. Only 39% of hypothyroid patients on thyroid hormone replacement (n = 74) had TSH values in the reference range, with 38% and 23% exhibiting low and high values, respectively. All untreated primary hypothyroid patients (n = 8) had elevated TSH concentrations. The authors conclude that this sensitive TSH assay is useful for diagnosing hyperthyroidism when there is a clinical suspicion but cannot be recommended for thyroid screening in hospitalized patients.     

The correlation evaluation of a tumor tracking system using multiple external markers

The purpose of this study is to evaluate the correlations between external markers and internal targets for radiation therapy of lung cancer patients. Using an infrared camera system coupled with a clinical simulator, the simultaneous motions of multiple external markers and an internal target were obtained. The correlation between external and internal signals was analyzed using a cross-covariance function. A linear regression model was employed to generate a composite signal from multiple external markers in order to predict the internal target motion. The external and internal signals, and their correlations, demonstrated a wide range of variation with respect to marker location, motion dimension, and breathing pattern. The performance of the composite signal indicates that when more external signals were taken into account, the mean correlation between the composite signal and internal signal was improved. This implies that a combination of multiple external signals might be an improved way to predict internal target motion. Also, since the characteristics of respiratory signals can vary significantly, certain methods of preprocessing and external signal combination are necessary.