Treatment of Cesarean Scar and Cervical Pregnancies Using the Ovum Aspiration Set for Intrachorial Methotrexate Injection as a Conservative, Fertility-Preserving Procedure.

Background and Objectives: Cesarean scar and cervical pregnancies are rare forms of ectopic pregnancies, occurring in 1 in 2000 and 1 in 9000 pregnancies, respectively. Both entities are medically challenging due to their high morbidity and mortality potential. Materials and Methods: In this retrospective study, we analyzed all cesarean scar and cervical pregnancies from 2010 to 2019 in the Department of Gynecology and Obstetrics of the University Hospital Freiburg, treated with both intrachorial (using the ovum aspiration set) and systemic methotrexate application. Results: We identified seven patients with a cesarean scar and four patients with cervical pregnancies. At diagnosis, the median gestational age was 7 + 1 (range: 5 + 5-9 + 5) weeks and the mean value of ß-hCG was 43,536 (range: 5132-87842) mlU/mL. On average, one dose of intrachorial and two doses of systemic methotrexate were administered per patient. The efficacy rate was 72.7% with three patients (27.3%) needing an additional surgical or interventional procedure. The uterus was preserved in 100% of the patients. Out of the eight patients with follow-up data, five reported subsequent pregnancies (62.5%) that resulted in six live births. None had recurrent cesarean scars or cervical pregnancies. In the subgroup analyses, when comparing cesarean scar pregnancies to cervical pregnancies, patient characteristics, treatment modality, and the outcome did not differ significantly, except for parity (2 versus 0, p = 0.02) and the duration since the last pregnancy (3 vs. 0.75 years, p = 0.048). When comparing cases with successful and failed methotrexate-only treatments, the maternal age was significantly higher in the successful group (34 vs. 27 years, p = 0.02). Localization of the gestation, gestational and maternal age, ß-hCG, and history of preceding pregnancies were non-predictive for the efficacy of the treatment. Conclusions: The combined application of intrachorial and systemic methotrexate for the treatment of cesarean scar and cervical pregnancies has been proven effective, well-tolerated, organ- and fertility-conserving with a low complication rate.

Evaluation of circulating microRNAs as non-invasive biomarkers in the diagnosis of ovarian cancer: a case-control study.

PURPOSE: Ovarian cancer is the seventh most frequent form of malignant diseases in women worldwide and over 150,000 women die from it every year. More than 70 percent of all ovarian cancer patients are diagnosed at a late-stage disease with poor prognosis necessitating the development of sufficient screening biomarkers. MicroRNAs displayed promising potential as early diagnostics in various malignant diseases including ovarian cancer. The presented study aimed at identifying single microRNAs and microRNA combinations detecting ovarian cancer in vitro and in vivo. METHODS: Intracellular, extracellular and urinary microRNA expression levels of twelve microRNAs (let-7a, let-7d, miR-10a, miR-15a, miR-15b, miR-19b, miR-20a, miR-21, miR-100, miR-125b, miR-155, miR-222) were quantified performing quantitative real-time-PCR. Therefore, the three ovarian cancer cell lines SK-OV-3, OAW-42, EFO-27 as well as urine samples of ovarian cancer patients and healthy controls were analyzed. RESULTS: MiR-15a, miR-20a and miR-222 showed expression level alterations extracellularly, whereas miR-125b did intracellularly across the analyzed cell lines. MicroRNA expression alterations in single cell lines suggest subtype specificity in both compartments. Hypoxia and acidosis showed scarce effects on single miRNA expression levels only. Furthermore, we were able to demonstrate the feasibility to clearly detect the 12 miRNAs in urine samples. In urine, miR-15a was upregulated whereas let-7a was down-regulated in ovarian cancer patients. CONCLUSION: Intracellular, extracellular and urinary microRNA expression alterations emphasize their great potential as biomarkers in liquid biopsies. Especially, miR-15a and let-7a qualify for possible circulating biomarkers in liquid biopsies of ovarian cancer patients.

Structured reporting ensures complete content and quick detection of essential data in pathology reports of oncological breast resection specimens.

There is increasing evidence that not only the way of data acquisition but also the design of data visualization (i.e., the format) has impact on the quality of pathology reports. Therefore, we investigated the correlation between the format of pathology reports and the amount as well as the detection time of transmitted data. All reports of oncological breast resection specimens referred to the Institute for Surgical Pathology, University Medical Center Freiburg, between 2003 and 2011 (n = 4181) were classified into descriptive reports (DR, n = 856), structured reports (SR, n = 2455), or template-based synoptic reports (TBSR, n = 870). The reports were screened regarding the content of nine organ-specific essential data. The amount of recorded essential data per report was summarized in an essential data score (EDS) and the format types were statistically compared regarding their EDS. Additionally, we measured the time a gynecologist needed to detect all nine essential data within a subset of reports and compared the format types regarding the detection times statistically. A full-score EDS of 9 was seen in 28.4 % of all reports, in 4 % of DRs, in 21.4 % of SRs, and in 72.3 % of TBSRs (p < 0.0001). Median EDS of DRs was 7, of SRs 8, and of TBSRs 9 (p < 0.0001). Data regarding tumor localization, tumor size, specific grading, angioinvasion, hormone receptor status, and additional findings were mentioned more frequently in TBSRs compared to other format type reports with a statistically highly significant difference (p < 0.0001). Mean data detection time decreased significantly from 26 to 20 and 14 s in DRs, SRs, and TBSRs, respectively. Our results clearly show that due to the use of TBSRs reporting of oncological breast resection specimens are improved regarding the content of essential data and the clarity of the data layout resulting in a rapid detection of essential data by clinicians.

Real-World Data Analysis of CDK4/6 Inhibitor Therapy-A Patient-Centric Single Center Study.

BACKGROUND: The quest to comprehend the real-world efficacy of CDK4/6 inhibitors (CDKis) in breast cancer continues, as patient responses vary significantly. METHODS: This single-center retrospective study evaluated CDKi use outside the trial condition from November 2016 to May 2020. Progression-free survival (PFS), time-to-treatment failure (TTF), short-term and prolonged treatment benefit (≥4 and ≥10 months), as well as prognostic and predictive markers were assessed with Kaplan-Meier and multivariate regression analyses. RESULTS: Out of 86 identified patients, 58 (67.4%) had treatment failure of which 40 (46.5%) were due to progression. Median PFS and TTF were 12 and 8.5 months, respectively. A total of 57 (66.3%) and 42 (48.8%) patients experienced short-term and prolonged treatment benefit. Independent, significant predictors for PFS were progesterone receptor expression (HR: 0.88), multiple metastatic sites (HR: 2.56), and hepatic metastasis (HR: 2.01). Significant predictors for TTF were PR expression (HR: 0.86), multiple sites (HR: 3.29), adverse events (HR: 2.35), and diabetes (HR: 2.88). Aside from tumor biology and adverse events, treatment modifications like pausing and switching of CDKi were predictive for short-term (OR: 6.73) and prolonged (OR: 14.27) therapeutic benefit, respectively. CONCLUSIONS: These findings emphasize the importance of tailored treatment strategies, highlighting the role of PR expression, metastatic burden, and therapeutic adjustments in optimizing patient outcomes in real-world breast cancer management.

In Vitro microRNA Expression Profile Alterations under CDK4/6 Therapy in Breast Cancer.

BACKGROUND: Breast cancer is the most common type of cancer worldwide. Cyclin-dependent kinase inhibition is one of the backbones of metastatic breast cancer therapy. However, there are a significant number of therapy failures. This study evaluates the biomarker potential of microRNAs for the prediction of a therapy response under cyclin-dependent kinase inhibition. METHODS: This study comprises the analysis of intracellular and extracellular microRNA-expression-level alterations of 56 microRNAs under palbociclib mono as well as combination therapy with letrozole. Breast cancer cell lines BT-474, MCF-7 and HS-578T were analyzed using qPCR. RESULTS: A palbociclib-induced microRNA signature could be detected intracellularly as well as extracellularly. Intracellular miR-10a, miR-15b, miR-21, miR-23a and miR-23c were constantly regulated in all three cell lines, whereas let-7b, let-7d, miR-15a, miR-17, miR-18a, miR-20a, miR-191 and miR301a_3p were regulated only in hormone-receptor-positive cells. Extracellular miR-100, miR-10b and miR-182 were constantly regulated across all cell lines, whereas miR-17 was regulated only in hormone-receptor-positive cells. CONCLUSIONS: Because they are secreted and significantly upregulated in the microenvironment of tumor cells, miRs-100, -10b and -182 are promising circulating biomarkers that can be used to predict or detect therapy responses under CDK inhibition. MiR-10a, miR-15b, miR-21, miR-23a and miR-23c are potential tissue-based biomarkers.

Relevance of Molecular Profiling in Patients With Low-Grade Endometrial Cancer.

Importance: Patients with low-grade (ie, grade 1-2) endometrial cancer (EC) are characterized by their favorable prognosis compared with patients with high-grade (ie, grade 3) EC. With the implementation of molecular profiling, the prognostic relevance of tumor grading might lose attention. As most patients present with low-grade EC and have an excellent outcome, the value of molecular profiling for these patients is unclear. Objective: To determine the association of molecular profiling with outcomes among patients with low-grade EC. Design, Setting, and Participants: This retrospective cohort study included a multicenter international European cohort of patients diagnosed with EC between 1994 and 2018, with a median follow-up of 5.9 years. Molecular subgroups were determined by next-generation sequencing using single-molecule molecular inversion probes and by immunohistochemistry. Subsequently, tumors were classified as polymerase epsilon (POLE)-altered, microsatellite instable (MSI), tumor protein p53 (TP53)-altered, or no specific molecular profile (NSMP). Patients diagnosed with any histological subtypes and FIGO (International Federation of Gynecology and Obstetrics) stages of EC were included, but patients with early-stage EC (FIGO I-II) were only included if they had known lymph node status. Data were analyzed February 20 to June 16, 2022. Exposures: Molecular testing of the 4 molecular subgroups. Main Outcomes and Measures: The main outcome was disease-specific survival (DSS) within the molecular subgroups. Results: A total of 393 patients with EC were included, with a median (range) age of 64.0 (31.0-86.0) years and median (range) body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 29.1 (18.0-58.3). Most patients presented with early-stage (290 patients [73.8%]) and low-grade (209 patients [53.2%]) disease. Of all patients, 33 (8.4%) had POLE-altered EC, 78 (19.8%) had MSI EC, 72 (18.3%) had TP53-altered EC, and 210 (53.4%) had NSMP EC. Across all molecular subgroups, patients with low-grade EC had superior 5-year DSS compared with those with high-grade EC, varying between 90% to 100% vs 41% to 90% (P < .001). Multivariable analysis in the entire cohort including age, tumor grade, FIGO stage, lymphovascular space invasion, and the molecular subgroups as covariates found that only high-grade (hazard ratio [HR], 4.29; 95% CI, 2.15-8.53; P < .001), TP53-altered (HR, 1.76; 95% CI, 1.04-2.95; P = .03), and FIGO stage III or IV (HR, 4.26; 95% CI, 2.50-7.26; P < .001) disease were independently associated with reduced DSS. Conclusions and Relevance: This cohort study found that patients with low-grade EC had an excellent prognosis independent of molecular subgroup. These findings do not support routine molecular profiling in patients with low-grade EC, and they demonstrate the importance of primary diagnostic tumor grading and selective profiling in low-grade EC to increase cost-effectiveness.

Gastrin-Releasing Peptide Receptor Antagonist [68Ga]RM2 PET/CT for Staging of Pre-Treated, Metastasized Breast Cancer.

BACKGROUND: Positron emission tomography (PET)/computed tomography (CT) using the gastrin-releasing peptide receptor antagonist [68Ga]RM2 has shown to be a promising imaging method for primary breast cancer (BC) with positive estrogen receptor (ER) status. This study assessed tumor visualization by [68Ga]RM2 PET/CT in patients with pre-treated ER-positive BC and suspected metastases. METHODS: This retrospective pilot study included eight female patients with initial ER-positive, pre-treated BC who underwent [68Ga]RM2 PET/CT. Most of these patients (seven out of eight; 88%) were still being treated with or had received endocrine therapy. [68Ga]RM2 PET/CTs were visually analyzed by two nuclear medicine specialists in consensus. Tumor manifestations were rated qualitatively (i.e., RM2-positive or RM2-negative) and quantitatively using the maximum standardized uptake value (SUVmax). SUVmax values were compared between the two subgroups (RM2-positive vs. RM2-negative). RESULTS: Strong RM2 binding was found in all metastatic lesions of six patients (75%), whereas tracer uptake in all metastases of two patients (25%) was rated negative. Mean SUVmax of RM2-positive metastases with the highest SUVmax per patient (in lymph node and bone metastases; 15.8 ± 15.1 range: 3.7-47.8) was higher than mean SUVmax of the RM2-negative metastases with the highest SUVmax per patient (in bone metastases; 1.6 ± 0.1, range 1.5-1.7). CONCLUSIONS: Our data suggest that RM2 binding is maintained in the majority of patients with advanced disease stage of pre-treated ER-positive BC. Thus, [68Ga]RM2 PET/CT could support treatment decision in these patients, radiotherapy planning in oligometastatic patients or selection of patients for RM2 radioligand therapy. Further studies with larger patient cohorts are warranted to confirm these findings.

Anticarcinogenic Effects of Odorant Substances Citral, Citrathal R and Cyclovertal on Breast Cancer in vitro.

PURPOSE: In 2020, breast cancer still represents the most common type of cancer in women worldwide. Depending on the specific molecular subtype, clinical breast cancer management comprises surgery, radiotherapy, chemotherapy and targeted therapy. Furthermore, there are some therapeutic approaches from the field of complementary and alternative medicine. Current research focuses on the elucidation of new therapeutic targets for treatment development. Odorant substances affect apoptosis, proliferation and cell cycle in healthy and cancerous cells. Exact signalling pathways involved are not entirely clear. The present study aims to analyse their therapeutic potential in breast cancer. METHODS: This study focuses on the effect of commonly used odorant substances (citral, citrathal R, cyclovertal, para-cymol, hexylacetat, herbavert, dihydromyrcerol and limonen) on the breast cancer cell lines MDA-MB-231, T47-D and BT474. Methodologically, this study applied cell culturing, MTT assay for detection of IC50 of the odorant substance, RNA purification followed by qRT-PCR, protein isolation and Western Blot, as well as immunocytochemistry. Further, this study investigates the role of transient receptor potential channel V1 (TRPV1), involved in the mechanisms of action for some odorant substances. Therefore, capsazepine, a TRPV1 antagonist, was used. RESULTS: The odorant substances citral, citrathal R and cyclovertal have significant pro-apoptotic (p < 0.001), anti-proliferative (p < 0.001) and cell cycle-arresting effects measurable in RNA expression as well as in protein levels and immunocytochemical staining. The combination of citral and capsazepine no longer showed significant pro-apoptotic, antiproliferative, and cell cycle inhibitory effects compared to the compounds alone. This indicates that TRPV1 is necessary for the signal transduction of citral. CONCLUSION: This present study reveals three odorant substances with effects on cell viability, indicating their potential use in breast cancer therapy.

Endoxifen and fulvestrant regulate estrogen-receptor α and related DEADbox proteins.

Breast cancer (BC) represents the most common type of cancer in females worldwide. Endocrine therapy evolved as one of the main concepts in treatment of hormone-receptor positive BC. Current research focuses on the elucidation of tumour resistance mechanisms against endocrine therapy. In a translational in vitro approach, potential regulatory effects of clinically implemented BC anti-oestrogens on ERα, its coactivators DDX5, DDX17 and other DEADbox proteins as well as on the proliferation markers cyclin D1 and Ki67 were investigated on both the RNA and protein level. BC in vitro models for hormone-receptor positive (MCF-7, T-47D) and hormone-receptor negative cells (BT-20) were subjected to endocrine therapy. Anti-oestrogen-dependent expression regulation of target genes on the transcriptional and translational level was quantified and statistically assessed. Endocrine therapy decreases the expression levels of Ki67, cyclin D1 and ERα in hormone-receptor positive cells. In the hormone-receptor negative cells, the three parameters remained stable after endocrine therapy. Endoxifen triggers a downregulation of DDX5 and DDX23 in MCF-7 cells. Fulvestrant treatment downregulates the expression levels of all investigated DEADbox proteins in MCF-7 cells. In T-47D cells, endoxifen and fulvestrant lead to a decrease of all target gene expression levels. Interestingly, endocrine therapy affects DEADbox RNA expression levels in BT-20 cells, too. However, this result could only be confirmed for DDX1, immunocytologically. The investigated DEADbox proteins appear to correlate with the oestrogen-dependent tumourigenesis in hormone-receptor positive BC and show expression alterations after endocrine treatment.

Association between gastrin-releasing peptide receptor expression as assessed with [68Ga]Ga-RM2 PET/CT and histopathological tumor regression after neoadjuvant chemotherapy in primary breast cancer.

INTRODUCTION: The gastrin-releasing peptide receptor is overexpressed in breast cancer (BC) tissue and can be visualized by positron emission tomography (PET) using the GRPR antagonist [68Ga]Ga-RM2. This study assessed tumor binding of RM2 before and after neoadjuvant chemotherapy (NAC) in primary BC with reference to residual tumor size in the resected specimen. MATERIALS AND METHODS: In this retrospective study, five female patients with biopsy-confirmed estrogen receptor (ER)-positive primary BC (one with bilateral tumors) underwent [68Ga]Ga-RM2 PET/CT before and after NAC. PET/CT was acquired 1 h after injection of 143-224 MBq [68Ga]Ga-RM2. Time from pre-NAC PET to beginning of NAC was 23 ±â€¯4.9 days, from end of NAC to post-NAC PET 18.7 ±â€¯6.3 days, and from post-NAC PET to surgery 9.5 ±â€¯10.8 days. In vivo tumor uptake of [68Ga]Ga-RM2 was assessed before and after NAC and correlated with histopathological response. RESULTS: All tumors (6/6) showed strongly increased [68Ga]Ga-RM2 uptake compared to normal breast tissue on pre-NAC PET (mean SUVmax 13.2 ±â€¯7.3; mean SUVpeak 9.4 ±â€¯4.4). [68Ga]Ga-RM2 uptake was significantly reduced on post-NAC PET in all primary tumors (mean SUVmax 2.3 ±â€¯0.8, -79 ±â€¯11%; p = 0.0125; mean SUVpeak 1.6 ±â€¯0.4, -79 ±â€¯10%; p = 0.0096). Residual tumor size in resected specimens correlated well with SUVmax (r = 0.91, p = 0.0057) and SUVpeak (r = 0.88, p = 0.0196) on [68Ga]Ga-RM2 PET/CT after NAC. CONCLUSION AND IMPLICATIONS FOR PATIENT CARE: In this pilot study, residual uptake of [68Ga]Ga-RM2 in ER-positive primary BC correlated well with residual vital tumor size after NAC. This suggests that [68Ga]Ga-RM2 PET/CT merits further investigation for response assessment to NAC in patients with ER-positive BC.

Mutually distinguishing microRNA signatures of breast, ovarian and endometrial cancers in vitro.

Early diagnosis and therapy in the first stages of a malignant disease is the most crucial factor for successful cancer treatment and recovery. Currently, there is a high demand for novel diagnostic tools that indicate neoplasms in the first or pre­malignant stages. MicroRNAs (miRNA or miR) are small non­coding RNAs that may act as oncogenes and downregulate tumor­suppressor genes. The detection and mutual discrimination of the three common female malignant neoplasia types breast (BC), ovarian (OC) and endometrial cancer (EC) could be enabled by identification of tumor entity­specific miRNA expression differences. In the present study, the relative expression levels of 25 BC, EC and OC­related miRNAs were assessed by reverse transcription­quantitative PCR and determined using the 2­ΔΔCq method for normalization against the mean of four housekeeping genes. Expression levels of all miRNAs were analyzed by regression against cell line as a factor. An expression level­based discrimination between BC and OC cell types was obtained for a subgroup of ten different miRNA types. miR­30 family genes, as well as three other miRNAs, were found to be uniformly upregulated in OC cells compared with BC cells. BC and EC cells could be distinguished by the expression profiles of six specific miRNAs. In addition, four miRNAs were differentially expressed between EC and OC cells. In conclusion, miRNAs were identified as a potential novel tool to detect and mutually discriminate between BC, OC and EC. Based on a subset of 25 clinically relevant human miRNA types, the present study could significantly discriminate between these three female cancer types by means of their expression levels. For further verification and validation of miRNA­based biomarker expression signatures that enable valuable tumor detection and characterization in routine screening or potential therapy monitoring, additional and extended in vitro analyses, followed by translational studies utilizing patients' tissue and liquid biopsy materials, are required.

Discovery of potential serum and urine-based microRNA as minimally-invasive biomarkers for breast and gynecological cancer.

BACKGROUND: Deregulated microRNAs (miRNAs) in breast and gynecological cancer might contribute to improve early detection of female malignancies. OBJECTIVE: Specification of miRNA types in serum and urine as minimally-invasive biomarkers for breast (BC), endometrial (EC) and ovarian cancer (OC). METHODS: In a discovery phase, serum and urine samples from 17 BC, five EC and five OC patients vs. ten healthy controls (CTRL) were analyzed with Agilent human miRNA microarray chip. Selected miRNA types were further investigated by RT-qPCR in serum (31 BC, 13 EC, 15 OC patients, 32 CTRL) and urine (25 BC, 10 EC, 10 OC patients, 30 CTRL) applying two-sample t-tests. RESULTS: Several miRNA biomarker candidates exhibited diagnostic features due to distinctive expression levels (serum: 26; urine: 22). Among these, miR-518b, -4719 and -6757-3p were found specifically deregulated in BC serum. Four, non-entity-specific, novel biomarker candidates with unknown functional roles were identified in urine (miR-3973; -4426; -5089-5p and -6841). RT-qPCR identified miR-484/-23a (all p⩽ 0.001) in serum as potential diagnostic markers for EC and OC while miR-23a may also serve as an endogenous control in BC diagnosis. CONCLUSIONS: Promising miRNAs as liquid biopsy-based tools in the detection of BC, EC and OC qualified for external validation in larger cohorts.

Circulating non­coding RNA­biomarker potential in neoadjuvant chemotherapy of triple negative breast cancer?

Due to the positive association between neoadjuvant chemotherapy (NACT) and the promising early response rates of patients with triple negative breast cancer (TNBC), including probabilities of pathological complete response, NACT is increasingly used in TNBC management. Liquid biopsy­based biomarkers with the power to diagnose the early response to NACT may support established monitoring tools, which are to a certain extent imprecise and costly. Simple serum­ or urine­based analyses of non­coding RNA (ncRNA) expression may allow for fast, minimally­invasive testing and timely adjustment of the therapy regimen. The present study investigated breast cancer­related ncRNAs [microRNA (miR)­7, ­9, ­15a, ­17, ­18a, ­19b, ­21, ­30b, ­222 and ­320c, PIWI­interacting RNA­36743 and GlyCCC2] in triple positive BT­474 cells and three TNBC cell lines (BT­20, HS­578T and MDA­MB­231) treated with various chemotherapeutic agents using reverse transcription­quantitative PCR. Intracellular and secreted microvesicular ncRNA expression levels were analysed using a multivariable statistical regression analysis. Chemotherapy­driven effects were investigated by analysing cell cycle determinants at the mRNA and protein levels. Serum and urine specimens from 8 patients with TNBC were compared with 10 healthy females using two­sample t­tests. Samples from the patients with TNBC were compared at two time points. Chemotherapeutic treatments induced distinct changes in ncRNA expression in TNBC cell lines and the BT­474 cell line in intra­ and extracellular compartments. Serum and urine­based ncRNA expression analysis was able to discriminate between patients with TNBC and controls. Time point comparisons in the urine samples of patients with TNBC revealed a general rise in the level of ncRNA. Serum data suggested a potential association between piR­36743, miR­17, ­19b and ­30b expression levels and an NACT­driven complete clinical response. The present study highlighted the potential of ncRNAs as liquid biopsy­based biomarkers in TNBC chemotherapy treatment. The ncRNAs tested in the present study have been previously investigated for their involvement in BC or TNBC chemotherapy responses; however, these previous studies were restricted to patient tissue or in vitro models. The data from the present study offer novel insight into ncRNA expression in liquid samples from patients with TNBC, and the study serves as an initial step in the evaluation of ncRNAs as diagnostic biomarkers in the monitoring of TNBC therapy.

Targeted Proteomics Identifies Proteomic Signatures in Liquid Biopsies of the Endometrium to Diagnose Endometrial Cancer and Assist in the Prediction of the Optimal Surgical Treatment.

Purpose: Endometrial cancer (EC) diagnosis relies on the observation of tumor cells in endometrial biopsies obtained by aspiration (i.e., uterine aspirates), but it is associated with 22% undiagnosed patients and up to 50% of incorrectly assigned EC histotype and grade. We aimed to identify biomarker signatures in the fluid fraction of these biopsies to overcome these limitations.Experimental Design: The levels of 52 proteins were measured in the fluid fraction of uterine aspirates from 116 patients by LC-PRM, the latest generation of targeted mass-spectrometry acquisition. A logistic regression model was used to assess the power of protein panels to differentiate between EC and non-EC patients and between EC histologic subtypes. The robustness of the panels was assessed by the "leave-one-out" cross-validation procedure performed within the same cohort of patients and an independent cohort of 38 patients.Results: The levels of 28 proteins were significantly higher in patients with EC (n = 69) compared with controls (n = 47). The combination of MMP9 and KPYM exhibited 94% sensitivity and 87% specificity for detecting EC cases. This panel perfectly complemented the standard diagnosis, achieving 100% of correct diagnosis in this dataset. Nine proteins were significantly increased in endometrioid EC (n = 49) compared with serous EC (n = 20). The combination of CTNB1, XPO2, and CAPG achieved 95% sensitivity and 96% specificity for the discrimination of these subtypes.Conclusions: We developed two uterine aspirate-based signatures to diagnose EC and classify tumors in the most prevalent histologic subtypes. This will improve diagnosis and assist in the prediction of the optimal surgical treatment. Clin Cancer Res; 23(21); 6458-67. ©2017 AACR.

BMI and Pathologic Complete Response to Neoadjuvant Chemotherapy in Breast Cancer: A Study and Meta-Analysis.

INTRODUCTION: There is only limited data from clinical practice on the relevance of body mass index (BMI) on pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) in patients with breast cancer (BC). PATIENTS AND METHODS: The impact of BMI on pCR and survival outcome was examined in 324 patients with primary non-metastatic BC. An additional meta-analysis was performed on the current data and relevant previously published studies in clinical practice. RESULTS: Multivariable regression analysis identified lymph vascular invasion (odds ratio [OR], 0.05; 95% confidence interval [CI], 0.01-0.18; P = .0000), grading 3 (OR, 3.12; 95% CI, 1.59-6.12; P = .0009), and HER2/neu status (OR, 4.76; 95% CI, 1.86-12.18; P = .011) as independent factors for pCR after NAC. There was no association between pCR and continuous or categorical BMI. Various additional subgroup analyses of molecular BC subtypes (triple-negative, luminal-like, HER2-luminal, HER2-like) and BMI also showed no association. These findings were confirmed by the meta-analysis. Except for one subgroup analysis in which overweight and obese patients were combined as one group, no association between BMI and pCR as well as survival outcome was found. CONCLUSIONS: BMI was not established as a relevant clinical factor. Only lymph vascular invasion, grading 3, luminal-like, and HER2/like BC subtype showed predictive and prognostic impact in patients with BC receiving NAC.