Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer.

BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.

Performance insights of endobronchial ultrasonography (EBUS) and mediastinoscopy for mediastinal lymph node staging in lung cancer.

INTRODUCTION: Endobronchial Ultrasonography (EBUS) and mediastinoscopy are used for mediastinal lymph node staging in patients with suspected non-small cell lung carcinoma (NSCLC). In our hospital, confirmatory mediastinoscopy has been largely abandoned, which may reduce the number of surgical interventions and health care costs. This study provides insight into EBUS and mediastinoscopy performance in patients with proven NSCLC from January 2007 until January 2019. METHODS: This is a single-centre, retrospective study, evaluating unforeseen N2 rates, negative predictive value and survival, providing insight into the diagnostic yield of EBUS and mediastinoscopy. Surgical lung resection with lymph node dissection was used as reference. RESULTS: A total of 418 patients with proven NSCLC after lung resection (mean age: 66 years; 61 % male) and 118 patients who underwent mediastinoscopy, have been included in the study. The overall prevalence of N2 metastases after lung resection was 10.5 %. The percentage of unforeseen N2 cases after negative EBUS was 14.5 %, and 14.3 % after negative mediastinoscopy. Over the past nine years, none of the confirmatory mediastinoscopies were tumor positive after negative EBUS results. The median survival in patients with surgically confirmed N2 metastases was 33 months, compared to 23 months in patients with EBUS/mediastinoscopy-proven N2 metastases. CONCLUSION: Despite optimisation of mediastinal staging procedures, it remains difficult to identify all patients with N2 metastases in the workup of NSCLC. In our institute, confirmatory mediastinoscopy has no added value after tumor-negative EBUS procedures, and has been abandoned as standard procedure.

Minimally invasive breast cancer excision using the breast lesion excision system under ultrasound guidance.

PURPOSE: To assess the feasibility of completely excising small breast cancers using the automated, image-guided, single-pass radiofrequency-based breast lesion excision system (BLES) under ultrasound (US) guidance. METHODS: From February 2018 to July 2019, 22 patients diagnosed with invasive carcinomas ≤ 15 mm at US and mammography were enrolled in this prospective, multi-center, ethics board-approved study. Patients underwent breast MRI to verify lesion size. BLES-based excision and surgery were performed during the same procedure. Histopathology findings from the BLES procedure and surgery were compared, and total excision findings were assessed. RESULTS: Of the 22 patients, ten were excluded due to the lesion being > 15 mm and/or being multifocal at MRI, and one due to scheduling issues. The remaining 11 patients underwent BLES excision. Mean diameter of excised lesions at MRI was 11.8 mm (range 8.0-13.9 mm). BLES revealed ten (90.9%) invasive carcinomas of no special type, and one (9.1%) invasive lobular carcinoma. Histopathological results were identical for the needle biopsy, BLES, and surgical specimens for all lesions. None of the BLES excisions were adequate. Margins were usually compromised on both sides of the specimen, indicating that the excised volume was too small. Margin assessment was good for all BLES specimens. One technical complication occurred (retrieval of an empty BLES basket, specimen retrieved during subsequent surgery). CONCLUSIONS: BLES allows accurate diagnosis of small invasive breast carcinomas. However, BLES cannot be considered as a therapeutic device for small invasive breast carcinomas due to not achieving adequate excision.

Reliability of MRI tumor size measurements for minimal invasive treatment selection in small breast cancers.

INTRODUCTION: Due to the shift towards minimal invasive treatment, accurate tumor size estimation is essential for small breast cancers. The purpose of this study was to determine the reliability of MRI-based tumor size measurements with respect to clinical, histological and radiomics characteristics in small invasive or in situ carcinomas of the breast to select patients for minimal invasive therapy. MATERIALS AND METHODS: All consecutive cases of cT1 invasive breast carcinomas that underwent pre-operative MRI, treated in two hospitals between 2005 and 2016, were identified retrospectively from the Dutch cancer registry and cross-correlated with local databases. Concordance between MRI-based measurements and final pathological size was analyzed. The influence of clinical, histological and radiomics characteristics on the accuracy of MRI size measurements were analyzed. RESULTS: Analysis included 343 cT1 breast carcinomas in 336 patients (mean age, 55 years; range, 25-81 years). Overall correlation of MRI measurements with pathology was moderately strong (ρ = 0.530, P < 0.001), in 42 cases (12.2%) MRI underestimated the size with more than 5 mm. Underestimation occurs more often in grade 2 and grade 3 disease than in low grade invasive cancers. In DCIS the frequency of underestimation is higher than in invasive breast cancer. Unfortunately, none of the patient, imaging or biopsy characteristics appeared predictive for underestimation. CONCLUSION: Size measurements of small breast cancers on breast MRI are within 5 mm of pathological size in 88% of patients. Nevertheless, underestimation cannot be adequately predicted, particularly for grade 2 and grade 3 tumors, which may hinder patient selection for minimal invasive therapy.

Incremental value of transition zone and midline apical biopsy at baseline TRUS-guided biopsy for prostate cancer detection.

PURPOSE: To determine the diagnostic yield of transition zone (TZB) and midline apical biopsies (MAB) in baseline transrectal ultrasound (TRUS)-guided biopsies and to establish whether TZB and MAB for the diagnosis of prostate cancer (PCa) add clinical relevant information. METHODS: We performed baseline 9-core TRUS-guided biopsy in 412 consecutive subjects using sextant biopsies of the PZ (PZB), with an additional TZB on either side and a MAB at the prostatic apex. We determined the incremental diagnostic value of additional TZB an MAB to sextant PZB. RESULTS: Within a cohort of 412 patients with a median PSA of 7.5 ng/ml, 178 (43.2 %) patients were diagnosed with PCa upon baseline TRUS-guided biopsies. In 102 cases, at least one TZB was positive for PCa, with 6/412 (1.4 %) cases displaying PCa in the TZB only. MAB alone was positive for PCa in 4/412 (1.0 %) cases. One case (1/412; 0.2 %) had only a TZB and a MAB positive for PCa without positive PZB. Thus, 11/412 (2.7 %) of cases would not have been diagnosed with PCa at baseline TRUS-guided biopsy had only sextant PZ biopsy been performed. TZB detected a high-grade Gleason component (Gleason 4 and/or 5) not present in the PZB in 2.4 % of PCa cases. CONCLUSIONS: There is limited value for TZB and MAB in the context of sextant PZB at baseline TRUS-guided biopsies for PCa.

The predictive value of endorectal 3 Tesla multiparametric magnetic resonance imaging for extraprostatic extension in patients with low, intermediate and high risk prostate cancer.

PURPOSE: We determined the positive and negative predictive values of multiparametric magnetic resonance imaging for extraprostatic extension at radical prostatectomy for different prostate cancer risk groups. MATERIALS AND METHODS: We evaluated a cohort of 183 patients who underwent 3 Tesla multiparametric magnetic resonance imaging, including T2-weighted, diffusion weighted magnetic resonance imaging and dynamic contrast enhanced sequences, with an endorectal coil before radical prostatectomy. Pathological stage at radical prostatectomy was used as standard reference for extraprostatic extension. The cohort was classified into low, intermediate and high risk groups according to the D'Amico criteria. We recorded prevalence of extraprostatic extension at radical prostatectomy and determined sensitivity, specificity, positive predictive value and negative predictive value of multiparametric magnetic resonance imaging for extraprostatic extension in each group. Univariate and multivariate analyses were performed to identify predictors of extraprostatic extension at radical prostatectomy. RESULTS: The overall prevalence of extraprostatic extension at radical prostatectomy was 49.7% ranging from 24.7% to 77.1% between low and high risk categories. Overall staging accuracy of multiparametric magnetic resonance imaging for extraprostatic extension was 73.8%, with sensitivity, specificity, positive predictive value and negative predictive value of 58.2%, 89.1%, 84.1% and 68.3%, respectively. Positive predictive value of multiparametric magnetic resonance imaging for extraprostatic extension was best in the high risk cohort with 88.8%. Negative predictive value was highest in the low risk cohort with 87.7%. With an odds ratio of 10.3 multiparametric magnetic resonance imaging is by far the best preoperative predictor of extraprostatic extension at radical prostatectomy. CONCLUSIONS: For adequate patient counseling, knowledge of predictive values of multiparametric magnetic resonance imaging for extraprostatic extension is of utmost importance. High negative predictive value, important for decisions on nerve sparing strategies at radical prostatectomy, is only reached in low risk subjects.

Perinatal asphyxia results in changes in presynaptic bouton number in striatum and cerebral cortex-a stereological and behavioral analysis.

Deficits in cognitive function have been related to quantitative changes in synaptic population, particularly in the cerebral cortex. Here, we used an established model of perinatal asphyxia that induces morphological changes, i.e. neuron loss in the cerebral cortex and striatum, as well as behavioural deficits. We hypothesized that perinatal asphyxia may lead to a neurodegenerative process resulting in cognitive impairment and altered presynaptic bouton numbers in adult rats. We studied cognitive performance at 18 months and presynaptic bouton numbers at 22 months following perinatal asphyxia. Data of the spatial Morris water escape task did not reveal clear memory or learning deficits in aged asphyctic rats compared to aged control rats. However, a memory impairment in aged rats versus young rats was observed, which was more pronounced in asphyctic rats. We found an increase in presynaptic bouton density in the parietal cortex, whereas no changes were found in striatum and frontal cortex in asphyctic rats. An increase of striatal volume was observed in asphyctic rats, leading to an increase in presynaptic bouton numbers in this area. These findings stress the issue that volume measurements have to be taken into account when determining presynaptic bouton density. Furthermore, perinatal asphyxia led to region-specific changes in presynaptic bouton numbers and it worsened the age-related cognitive impairment. These results suggest that perinatal asphyxia induced neuronal loss, which is compensated for by an increase in presynaptic bouton numbers.

Effects of hypothermia and gender on survival and behavior after perinatal asphyxia in rats.

Previous studies in rats have demonstrated that perinatal asphyxia (PA) produces long-term morphological alterations, particularly affecting hippocampus. neostriatum, and cerebral cortex. These changes were prevented by applying hypothermia during the asphyctic insult. Because these cerebral areas are involved in cognitive and motor functions, the aim of the present study was to determine whether periods of PA during normothermia or hypothermia produces long-term behavioral impairments in rats of both sexes. The cognitive and motor functions were studied using the spatial Morris water maze (MWM) task at 1.5 months, and the open field at 5 months, respectively. The present study revealed that female rats had a higher survival rate than males after PA in normothermic conditions (p < 0.014). and that hypothermia drastically prolonged the time of survival in both sexes (p < 0.001). There were no differences in learning and memory functions between groups or male and female rats when tested with MWM. Rats subjected to hypothermia treatment did not show differences in the MWM compared to controls. A lower locomotor activity in the open field test was only observed in male rats that suffered 15 and 20 min of PA in normothermia (p < 0.05). Hypothermia treatment prevented this hypoactivity. PA in females, even if severe, did not affect the motor activity. The data of both behavioral tests showed differences between sexes, i.e., the female rats learned the MWM task slower, and were more active in the open field. This work lends further support for the hypothesis that hypothermia can prevent mortality as well as long-term sequelae induced by PA.