Improved Accuracy and Sensitivity in Diagnosis and Staging of Lung Cancer with Systematic and Combined Endobronchial and Endoscopic Ultrasound (EBUS-EUS): Experience from a Tertiary Center.

BACKGROUND: Combined endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided tissue acquisition (EUS-TA) are accurate procedures for the diagnosis and staging of mediastinal lymph nodes (MLNs) in lung cancer. However, the respective contribution of separate and combined procedures in diagnosis and staging has not been fully studied. The aim of this study was to assess their respective performances. METHODS: Patients with suspected malignant MLNs in lung cancer or recurrence identified by PET-CT who underwent combined EBUS-TBNA and EUS-TA were retrospectively reviewed. RESULTS: A total of 141 patients underwent both procedures. Correct diagnosis was obtained in 82% with EBUS-TBNA, 91% with EUS-TA, and 94% with the combined procedure. The overall sensitivity, specificity, and positive and negative predictive values (PPV and NPV) of EBUS-TBNA, EUS-TA, and the combined procedure for diagnosing malignancy were [75%, 100%, 100%, 58%], [87%, 100%, 100%, 75%], and [93%, 100%, 100%, 80%], respectively, with a significantly better sensitivity of the combined procedure (p < 0.0001). Staging (82/141 patients) was correctly assessed in 74% with EBUS-TBNA, 68% with EUS-TA, and 85% with the combined procedure. The overall sensitivity, specificity, PPV, and NPV of EBUS-TBNA, EUS-TA, and the combined procedure for lung cancer staging were [62%, 100%, 100%, 55%], [54%, 100%, 100%, 50%], and [79%, 100%, 100%, 68%], respectively, significantly better in terms of sensitivity for the combined procedure (p < 0.001). CONCLUSION: The combined EBUS-EUS approach in lung cancer patients showed better accuracy and sensitivity in diagnosis and staging when compared with EBUS-TBNA and EUS-TA alone.

Uterine embryonal rhabdomyosarcoma in adult women: a case report on the challenging diagnosis and treatment.

BACKGROUND: Uterine embryonal rhabdomyosarcoma (uERMS) in adult women is a very rare malignant entity. The study aim was to report a case of adult uERMS and to discuss the implications of histopathological diagnosis on the treatment and prognosis. CASE PRESENTATION: We present here the clinicopathological features of a uERMS case in an adult woman. The study has been approved by the institutional Ethics Committee and an informed consent has been obtained (IJB∕CE3005). A 45-year-old woman presented to her gynecologist with intermenstrual bleedings and polypoid cervical mass (initially interpreted as benign polyp). A second biopsy was sent to our Department of Pathology at the Jules Bordet Institute, Brussels, Belgium for revision and was reinterpreted as botryoid-type uERMS. The patient underwent a total hysterectomy. The final pathology confirms a 3 cm cervical ERMS, and a simple surveillance was decided by our multidisciplinary team. Six months later, pelvic magnetic resonance imaging control showed a recurrence in the right pelvic lymph nodes. Multi-drug chemotherapy and radiotherapy were done before surgical resection. Pathological examination of the resected pelvic mass confirmed uERMS recurrence of 60 mm, with large zones of necrosis and the presence of cartilaginous structures. The patient is free of disease 60 months after diagnosis. CONCLUSIONS: Adult uERMS is rare and the pathological examination is the main element for diagnosis and treatment. It is often confused with other benign entities, at least at the time of diagnosis. ERMS should be included in the differential diagnosis of cervical and uterine polyp of adult women. Long-term survival is possible with a multimodal therapy approach.

Systemic Inflammation/Nutritional Status Scores Are Prognostic but Not Predictive in Metastatic Non-Small-Cell Lung Cancer Treated with First-Line Immune Checkpoint Inhibitors.

Biomarkers of systemic inflammation/nutritional status have been associated with outcomes in advanced-stage non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). However, most of them were not tested in cohorts of patients treated with ICIs in combination with chemotherapy (CT) (ICI + CT) or with CT alone, making it impossible to discriminate a predictive from a prognostic effect. We conducted a single-center retrospective study to search for associations between various baseline biomarkers/scores that reflected the systemic inflammation/nutritional status (Lung Immune Prognostic Index, Modified Lung Immune Prognostic Index, Scottish Inflammatory Prognostic Score, Advanced Lung Cancer Inflammation Index, EPSILoN, Prognostic Nutritional Index, Systemic Immune-Inflammation Index, Gustave Roussy Immune Score, Royal Marsden Hospital Prognostic Score, Lung Immuno-oncology Prognostic Score 3, Lung Immuno-oncology Prognostic Score 4, score published by Holtzman et al., and Glasgow Prognostic Score) and outcomes in metastatic NSCLC treated in a first-line setting either with ICI in monotherapy (cohort 1; n = 75), ICI + CT (cohort 2; n = 56), or CT alone (cohort 3; n = 221). In the three cohorts, the biomarkers/scores were moderately associated with overall survival (OS) and progression-free survival (PFS). Their prognostic performance was relatively poor, with a maximum c-index of 0.66. None of them was specific to ICIs and could help to choose the best treatment modality. The systemic inflammation/nutritional status, associated with outcomes independently of the treatment, is therefore prognostic but not predictive in metastatic NSCLC.

Interobserver variability in the assessment of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative invasive breast carcinoma influences the association with pathological complete response: the IVITA study.

High stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC) are associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Histopathological assessment of sTILs in TNBC biopsies is characterized by substantial interobserver variability, but it is unknown whether this affects its association with pCR. Here, we aimed to investigate the degree of interobserver variability in an international study, and its impact on the relationship between sTILs and pCR. Forty pathologists assessed sTILs as a percentage in digitalized biopsy slides, originating from 41 TNBC patients who were treated with NAC followed by surgery. Pathological response was quantified by the MD Anderson Residual Cancer Burden (RCB) score. Intraclass correlation coefficients (ICCs) were calculated per pathologist duo and Bland-Altman plots were constructed. The relation between sTILs and pCR or RCB class was investigated. The ICCs ranged from -0.376 to 0.947 (mean: 0.659), indicating substantial interobserver variability. Nevertheless, high sTILs scores were significantly associated with pCR for 36 participants (90%), and with RCB class for eight participants (20%). Post hoc sTILs cutoffs at 20% and 40% resulted in variable associations with pCR. The sTILs in TNBC with RCB-II and RCB-III were intermediate to those of RCB-0 and RCB-I, with lowest sTILs observed in RCB-I. However, the limited number of RCB-I cases precludes any definite conclusions due to lack of power, and this observation therefore requires further investigation. In conclusion, sTILs are a robust marker for pCR at the group level. However, if sTILs are to be used to guide the NAC scheme for individual patients, the observed interobserver variability might substantially affect the chance of obtaining a pCR. Future studies should determine the 'ideal' sTILs threshold, and attempt to fine-tune the patient selection for sTILs-based de-escalation of NAC regimens. At present, there is insufficient evidence for robust and reproducible sTILs-guided therapeutic decisions.

Morphological intratumor heterogeneity in ductal carcinoma in situ of the breast.

Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous disease in terms of morphological characteristics, protein expression profiles, genetic abnormalities, and potential for progression. Molecular heterogeneity has been extensively studied in DCIS. Yet morphological heterogeneity remains relatively undefined. This study investigated morphological intratumor heterogeneity in a series of 51 large DCIS. Nuclear atypia, DCIS architecture, necrosis, calcifications, stromal architecture, and stromal inflammation were assessed in one biopsy slide and three representative slides from each corresponding resection. For each histopathological feature, a histo-score was determined per slide and compared between the biopsy and the resection, as well as within a single resection. Statistical analysis comprised of Friedman tests, post hoc Wilcoxon tests with Bonferroni corrections, Mann-Whitney U tests, and chi-square tests. Despite substantial morphological heterogeneity in around 50% of DCIS, the histopathological assessment of the biopsy did not statistically significantly differ from the resection. Morphological heterogeneity was not significantly associated with patient age, DCIS size, or type of surgery, except for a weak association between heterogeneous stromal inflammation and smaller DCIS size. At the group level, the degree of heterogeneity did not significantly affect the representativity of a biopsy. At the individual patient level, however, the presence of necrosis, intraductal calcifications, myxoid stromal changes, and high-grade nuclear atypia was underestimated in a minority of DCIS patients. This study confirms the presence of morphological heterogeneity in DCIS for all six evaluated histopathological features. This should be kept in mind when taking biopsy-based treatment decisions for DCIS patients.

Fibrin hydrogels promote scar formation and prevent therapeutic angiogenesis in the heart.

Therapeutic angiogenesis is the delivery of factors to promote vascular growth and holds promise for the treatment of ischemic heart conditions. Recombinant protein delivery to the myocardium by factor-decorated fibrin matrices is an attractive approach, thanks to the ability to precisely control both dose and duration of the treatment, the use of a clinically approved material like fibrin, and the avoidance of genetic modification. Here, we investigated the feasibility of inducing therapeutic angiogenesis in the rat myocardium by a state-of-the-art fibrin-based delivery platform that we previously optimized. Engineered versions of murine vascular endothelial growth factor A (VEGF164 ) and platelet-derived growth factor BB (PDGF-BB) were fused with an octapeptide substrate of the transglutaminase coagulation factor fXIIIa (TG) to allow their covalent cross-linking into fibrin hydrogels and release by enzymatic cleavage. Hydrogels containing either 100 µg/mL TG-VEGF alone or in combination with 10 µg/mL TG-PDGF-BB or no factor were injected into rat myocardium. Surprisingly, vascular density was severely reduced in all conditions, both in and around the injection site, where large fibrotic scars were formed. Scar formation was not due to the presence of growth factors, adaptive immunity to human proteins, damage from injection, nor to mechanical trauma from the hydrogel stiffness or volume. Rather scar was induced directly by fibrin and persisted despite hydrogel degradation within 1 week. These results caution against the suitability of fibrin-based platforms for myocardial growth factor delivery, despite their efficacy in other tissues, like skeletal muscle. The underlying molecular mechanisms must be further investigated in order to identify rational targets to prevent this serious side effect.

The daily practice reality of PD-L1 (CD274) evaluation in non-small cell lung cancer: A retrospective study.

Treatment with pembrolizumab, an anti-programmed cell death-1 (PDCD-1) monoclonal antibody for the treatment of non-small cell lung cancers (NSCLCs) requires prior immunohistochemical (IHC) analysis of the expression of the programmed death-ligand 1 (PD-L1) (also known as CD274 molecule) which is a heterogeneous and complex marker. The present study aimed to investigate how pathological and technical factors (such as tumor location and sampling type, respectively) may affect the PD-L1 evaluation in patients with NSCLC in the daily practice of pathology laboratories. The current study was retrospective, and included 454 patients with NSCLC, for whom PD-L1 expression analysis by IHC was prospectively performed between November 2016 and January 2018. The association between PD-L1 expression and the clinicopathological characteristics of patients was statistically investigated using either the χ2 and Fisher exact tests or the Mann-Whitney and Kruskal-Wallis tests, depending on whether PD-L1 expression was assessed in three large categories (<1, 1-49, ≥50%) or in more precise percentages. Furthermore, the same statistical methodology was used to analyze the heterogeneity of PD-L1 expression according to its sampling type (cytology, biopsy or surgical specimen) and its location (primary tumor, lymph node or distant metastasis). Intra- and inter-observer discrepancies were also studied using double-blind evaluation and concordance analyses based on the weighted κ coefficient. The results demonstrated a significant association between PD-L1 expression and sample location (P=0.005), histological type (P=0.026), total number of mutations (P=0.004) and KRAS proto-oncogene, GTPase mutations (P=0.024). In addition, sampling type did not influence PD-L1 expression. The inter- and intra-observer discrepancies were 15% and between 16 and 17.5%, respectively. The present study confirmed that evaluation of PD-L1 expression by IHC can be performed on all types of samples. In addition, the results from the current study highlighted the heterogeneity of PD-L1 expression among the different types of sample location. In complex cases, a second evaluation of PD-L1 expression by IHC would be performed due to intra- and inter-observer discrepancies.

Interobserver variability in upfront dichotomous histopathological assessment of ductal carcinoma in situ of the breast: the DCISion study.

Histopathological assessment of ductal carcinoma in situ, a nonobligate precursor of invasive breast cancer, is characterized by considerable interobserver variability. Previously, post hoc dichotomization of multicategorical variables was used to determine the "ideal" cutoffs for dichotomous assessment. The present international multicenter study evaluated interobserver variability among 39 pathologists who performed upfront dichotomous evaluation of 149 consecutive ductal carcinomas in situ. All pathologists independently assessed nuclear atypia, necrosis, solid ductal carcinoma in situ architecture, calcifications, stromal architecture, and lobular cancerization in one digital slide per lesion. Stromal inflammation was assessed semiquantitatively. Tumor-infiltrating lymphocytes were quantified as percentages and dichotomously assessed with a cutoff at 50%. Krippendorff's alpha (KA), Cohen's kappa and intraclass correlation coefficient were calculated for the appropriate variables. Lobular cancerization (KA = 0.396), nuclear atypia (KA = 0.422), and stromal architecture (KA = 0.450) showed the highest interobserver variability. Stromal inflammation (KA = 0.564), dichotomously assessed tumor-infiltrating lymphocytes (KA = 0.520), and comedonecrosis (KA = 0.539) showed slightly lower interobserver disagreement. Solid ductal carcinoma in situ architecture (KA = 0.602) and calcifications (KA = 0.676) presented with the lowest interobserver variability. Semiquantitative assessment of stromal inflammation resulted in a slightly higher interobserver concordance than upfront dichotomous tumor-infiltrating lymphocytes assessment (KA = 0.564 versus KA = 0.520). High stromal inflammation corresponded best with dichotomously assessed tumor-infiltrating lymphocytes when the cutoff was set at 10% (kappa = 0.881). Nevertheless, a post hoc tumor-infiltrating lymphocytes cutoff set at 20% resulted in the highest interobserver agreement (KA = 0.669). Despite upfront dichotomous evaluation, the interobserver variability remains considerable and is at most acceptable, although it varies among the different histopathological features. Future studies should investigate its impact on ductal carcinoma in situ prognostication. Forthcoming machine learning algorithms may be useful to tackle this substantial diagnostic challenge.

The impact of breast MRI workup on tumor size assessment and surgical planning in patients with early breast cancer.

BACKGROUND: The size and focality of the primary tumor in breast cancer (BC) influence therapeutic decision making. The purpose of this study was to evaluate whether preoperative breast magnetic resonance imaging (MRI) is helpful for the assessment of tumor size and surgical planning in early BC. METHODS: We performed a retrospective review of a prospectively collected database of 174 patients treated at a single institution for invasive BC who had complete documentation of the tumor size from mammography (MMG), ultrasonography (US), and MRI. RESULTS: A total of 186 breast tumors were analyzed. Mean tumor size varied by imaging method: 14.7 mm by MMG, 13.8 mm by US, and 17.9 mm by MRI. The concordance between breast imaging techniques (BIT) and final pathology with a cutoff ≤ 2 mm was 34.8% for MRI, 32.1% for US, and 27.2% for MMG. US and MMG underestimated while MRI and MMG overestimated the real tumor size. Concordance was the same in premenopausal women for MRI and US at 35%, while concordance was higher in postmenopausal women for MRI. Correlations between size determined by BIT and histopathological size were best with MRI (0.59), compared to US (0.56) or MMG (0.42). Intrinsic subtypes of BC had different concordances according to imaging method, but no significant associations were found. MRI examination revealed additional lesions in 13.8% of patients, 69% of these lesions were malignant. MRI changed the surgical plan in 15 patients (8.6%), and the rate of mastectomy increased by 6.9%. CONCLUSIONS: MRI estimates BC tumor size more accurately than US or MMG, but a significant overestimation exists. Complementary MRI examination improved the concordance for tumor size between BIT and final pathology in 16.7%. MRI did not alter surgical planning for most patients and allowed more appropriate treatment for 8% of them.