Druggable targets meet oncogenic drivers: opportunities and limitations of target-based classification of tumors and the role of Molecular Tumor Boards.

The therapeutic landscape of cancer is changing rapidly due to the growing number of approved drugs capable of targeting specific genetic alterations. This aspect, together with the development of noninvasive methods for the assessment of somatic mutations in the peripheral blood of patients, generated a growing interest toward a new tumor-agnostic classification system based on 'predictive' biomarkers. The current review article discusses this emerging alternative approach to the classification of cancer and its implications for the selection of treatments. It is suggested that different types of cancers sharing the same molecular profiles could benefit from the same targeted drugs. Although recent clinical trials have demonstrated that this approach cannot be generalized, there are also specific examples that demonstrate the clinical utility of this alternative vision. In this rapidly evolving scenario, a multidisciplinary approach managed by institutional Molecular Tumor Boards is fundamental to interpret the biological and clinical relevance of genetic alterations and the complexity of their relationship with treatment response.

LKB1 loss is associated with glutathione deficiency under oxidative stress and sensitivity of cancer cells to cytotoxic drugs and γ-irradiation.

The liver kinase B1 (LKB1) gene is a tumor suppressor associated with the hereditary Peutz-Jeghers syndrome and frequently mutated in non-small cell lung cancer and in cervical cancer. Previous studies showed that the LKB1/AMPK axis is involved in regulation of cell death and survival under metabolic stress. By using isogenic pairs of cancer cell lines, we report here that the genetic loss of LKB1 was associated with increased intracellular levels of total choline containing metabolites and, under oxidative stress, it impaired maintenance of glutathione (GSH) levels. This resulted in markedly increased intracellular reactive oxygen species (ROS) levels and sensitivity to ROS-induced cell death. These effects were rescued by re-expression of LKB1 or pre-treatment with the anti-oxidant and GSH replenisher N-acetyl cysteine. This role of LKB1 in response to ROS-inducing agents was largely AMPK-dependent. Finally, we observed that LKB1 defective cells are highly sensitive to cisplatin and γ-irradiation in vitro, suggesting that LKB1 mutated tumors could be targeted by oxidative stress-inducing therapies.

An immediate transcriptional signature associated with response to the histone deacetylase inhibitor Givinostat in T acute lymphoblastic leukemia xenografts.

Despite some success with certain hematological malignancies and in contrast with the strong pro-apoptotic effects measured in vitro, the overall response rate of acute lymphoblastic leukemia (ALL) to histone deacetylase inhibitors (HDACis) is low. With the aim to improve the understanding of how HDACis work in vivo, we investigated the therapeutic efficacy of the clinically approved HDACi Givinostat in a collection of nine pediatric human T-ALL engrafted systemically in NOD/SCID mice. We observed highly heterogeneous antileukemia responses to Givinostat, associated with reduction of the percentage of infiltrating blasts in target organs, induction of apoptosis and differentiation. These effects were not associated with the T-ALL cytogenetic subgroup. Transcriptome analysis disclosed an immediate transcriptional signature enriched in genes involved in cell-cycle regulation and DNA repair, which was validated by quantitative RT-PCR and was associated with in vivo response to this HDACi. Increased phospho-H2AX levels, a marker of DNA damage, were measured in T-ALL cells from Givinostat responders. These results indicate that the induction of the DNA damage response could be an early biomarker of the therapeutic effects of Givinostat in T-ALL models. This information should be considered in the design of future clinical trials with HDACis in acute leukemia.

Calcineurin and GSK-3 inhibition sensitizes T-cell acute lymphoblastic leukemia cells to apoptosis through X-linked inhibitor of apoptosis protein degradation.

The calcineurin (Cn)-nuclear factor of activated T cells signaling pathway is critically involved in many aspects of normal T-cell physiology; however, its direct implication in leukemogenesis is still ill-defined. Glycogen synthase kinase-3ß (GSK-3ß) has recently been reported to interact with Cn in neuronal cells and is implicated in MLL leukemia. Our biochemical studies clearly demonstrated that Cn was able to interact with GSK-3ß in T-cell acute lymphoblastic leukemia (T-ALL) cells, and that this interaction was direct, leading to an increased catalytic activity of GSK-3ß, possibly through autophosphorylation of Y216. Sensitivity to GSK-3 inhibitor treatment correlated with altered GSK-3ß phosphorylation and was more prominent in T-ALL with Pre/Pro immunophenotype. In addition, dual Cn and GSK-3 inhibitor treatment in T-ALL cells promoted sensitization to apoptosis through proteasomal degradation of X-linked inhibitor of apoptosis protein (XIAP). Consistently, resistance to drug treatments in primary samples was strongly associated with higher XIAP protein levels. Finally, we showed that dual Cn and GSK-3 inhibitor treatment in vitro and in vivo is effective against available models of T-ALL, indicating an insofar untapped therapeutic opportunity.

External cephalic version for singleton breech presentation: proposal of a practical check-list for obstetricians.

OBJECTIVE: External cephalic version (ECV) for breech presentation is not routinely performed by obstetricians in many clinical settings. The aim of this work is to assess to what extent the factors involved in performing ECV are relevant for the success and safety of ECV, in order to propose a practical check-list for assessing the feasibility of ECV. METHODS: Review of 214 references. Factors involved in the success and risks of ECV (feasibility of ECV) were extracted and were scored in a semi-quantitative way according to textual information, type of publication, year of publication, number of cases. Simple conjoint analysis was used to describe the relevance found for each factor. RESULTS: Parity has the pivotal role in ECV feasibility (relevance 16.6%), followed by tocolysis (10.8%), gestational age (10.6%), amniotic fluid volume (4.7%), breech variety (1.9%), and placenta location (1.7%). Other factors with estimated relevance around 0 (regional anesthesia, station, estimated fetal weight, fetal position, obesity/BMI, fetal birth weight, duration of manoeuvre/number of attempts) have some role in the feasibility of ECV. Yet other factors, with negative values of estimated relevance, have even less importance. CONCLUSIONS: From a logical interpretation of the relevance of each factor assessed, ECV should be proposed with utmost prudence if a stringent check-list is followed. Such a check-list should take into account: parity, tocolytic therapy, gestational age, amniotic fluid volume, breech variety, placenta location, regional anesthesia, breech engagement, fetal well-being, uterine relaxation, fetal size, fetal position, fetal head grasping capability and fetal turning capability.

Cross talk between EBV and telomerase: the role of TERT and NOTCH2 in the switch of latent/lytic cycle of the virus.

Epstein-Barr virus (EBV)-associated malignancies, as well as lymphoblastoid cell lines (LCLs), obtained in vitro by EBV infection of B cells, express latent viral proteins and maintain their ability to grow indefinitely through inappropriate activation of telomere-specific reverse transcriptase (TERT), the catalytic component of telomerase. Our previous studies demonstrated that high levels of TERT expression in LCLs prevent the activation of EBV lytic cycle, which is instead triggered by TERT silencing. As lytic infection promotes the death of EBV-positive tumor cells, understanding the mechanism(s) by which TERT affects the latent/lytic status of EBV may be important for setting new therapeutic strategies. BATF, a transcription factor activated by NOTCH2, the major NOTCH family member in B cells, negatively affects the expression of BZLF1, the master regulator of viral lytic cycle. We therefore analyzed the interplay between TERT, NOTCH and BATF in LCLs and found that high levels of endogenous TERT are associated with high NOTCH2 and BATF expression levels. In addition, ectopic expression of TERT in LCLs with low levels of endogenous telomerase was associated with upregulation of NOTCH2 and BATF at both mRNA and protein levels. By contrast, infection of LCLs with retroviral vectors expressing functional NOTCH2 did not alter TERT transcript levels. Luciferase reporter assays, demonstrated that TERT significantly activated NOTCH2 promoter in a dose-dependent manner. We also found that NF-κB pathway is involved in TERT-induced NOTCH2 activation. Lastly, pharmacologic inhibition of NOTCH signaling triggers the EBV lytic cycle, leading to the death of EBV-infected cells. Overall, these results indicate that TERT contributes to preserve EBV latency in B cells mainly through the NOTCH2/BAFT pathway, and suggest that NOTCH2 inhibition may represent an appealing therapeutic strategy against EBV-associated malignancies.

Primitive omental leiomyoma: a case report.

Primitive omental leiomyomas are very rare. The primitive omental location of the leiomyoma is quite difficult to determine, with the possible presence of "parasite" myomas and of omental metastasizing myomas. Moreover, omental masses may be primitive or secondary metastasis from neoplasms. In this case report a primitive omental leiomyoma is described, and their diagnosis and management are briefly discussed, in order to improve the knowledge of this very uncommon disease.

Prognostic significance of AMPK activation in advanced stage colorectal cancer treated with chemotherapy plus bevacizumab.

BACKGROUND: AMP-activated protein kinase (AMPK) has a central role in cellular energy sensing and is activated in preclinical tumour models following anti-vascular endothelial growth factor (VEGF) therapy. The possible predictive or prognostic role of AMPK status in cancer patients treated with anti-VEGF drugs has not been investigated so far. METHODS: Expression of components of the AMPK pathway including phosphorylated AMPK (pAMPK), phosphorylated acetyl-Coa carboxylase (pACC) and liver kinase B1 (LKB1) was investigated by immunohistochemistry in 48 colorectal cancers treated with FOLFIRI plus bevacizumab. Correlation between pAMPK and pACC and associations between the AMPK pathway scores and clinico-pathological characteristics were assessed. Overall survival (OS) was estimated through Kaplan-Meier method, whereas hazard ratios were computed to identify prognostic factors. RESULTS: Fourteen patients (29.2%) were included in the pAMPK-negative group (score ≤5), whereas 34 patients (70.8%) were included in the pAMPK-positive group (score >5). The Spearman's coefficient for the correlation between pAMPK and pACC scores in primary tumour samples was 0.514 (P=0.0002). Low pAMPK levels were associated with worse OS (P-value 0.0002) but not with PFS, whereas low pACC levels were associated both with worse OS and PFS (P-value 0.0007 and 0.01, respectively). CONCLUSIONS: Our findings suggest that high tissue AMPK activation is a prognostic biomarker in this cohort of metastatic colorectal cancer patients.

Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia.

Notch signaling deregulation is linked to the onset of several tumors including T-cell acute lymphoblastic leukemia (T-ALL). Deregulated microRNA (miRNA) expression is also associated with several cancers, including leukemias. However, the transcriptional regulators of miRNAs, as well as the relationships between Notch signaling and miRNA deregulation, are poorly understood. To identify miRNAs regulated by Notch pathway, we performed microarray-based miRNA profiling of several Notch-expressing T-ALL models. Among seven miRNAs, consistently regulated by overexpressing or silencing Notch3, we focused our attention on miR-223, whose putative promoter analysis revealed a conserved RBPjk binding site, which was nested to an NF-kB consensus. Luciferase and chromatin immunoprecipitation assays on the promoter region of miR-223 show that both Notch and NF-kB are novel coregulatory signals of miR-223 expression, being able to activate cooperatively the transcriptional activity of miR-223 promoter. Notably, the Notch-mediated activation of miR-223 represses the tumor suppressor FBXW7 in T-ALL cell lines. Moreover, we observed the inverse correlation of miR-223 and FBXW7 expression in a panel of T-ALL patient-derived xenografts. Finally, we show that miR-223 inhibition prevents T-ALL resistance to γ-secretase inhibitor (GSI) treatment, suggesting that miR-223 could be involved in GSI sensitivity and its inhibition may be exploited in target therapy protocols.

Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts.

T-acute lymphoblastic leukemia (T-ALL) is characterized by several genetic alterations and poor prognosis in about 20-25% of patients. Notably, about 60% of T-ALL shows increased Notch1 activity, due to activating NOTCH1 mutations or alterations in the FBW7 gene, which confer to the cell a strong growth advantage. Therapeutic targeting of Notch signaling could be clinically relevant, especially for chemotherapy refractory patients. This study investigated the therapeutic efficacy of a novel anti-Notch1 monoclonal antibody by taking advantage of a collection of pediatric T-ALL engrafted systemically in NOD/SCID mice and genetically characterized with respect to NOTCH1/FBW7 mutations. Anti-Notch1 treatment greatly delayed engraftment of T-ALL cells bearing Notch1 mutations, including samples derived from poor responders or relapsed patients. Notably, the therapeutic efficacy of anti-Notch1 therapy was significantly enhanced in combination with dexamethasone. Anti-Notch1 treatment increased T-ALL cell apoptosis, decreased proliferation and caused strong inhibitory effects on Notch-target genes expression along with complex modulations of gene expression profiles involving cell metabolism. Serial transplantation experiments suggested that anti-Notch1 therapy could compromise leukemia-initiating cell functions. These results show therapeutic efficacy of Notch1 blockade for T-ALL, highlight the potential of combination with dexamethasone and identify surrogate biomarkers of the therapeutic response.

Experience of practitioners and delivery outcome.

BACKGROUND: It is commonly believed that the experience of practitioners (time spent in delivery ward) may be helpful in aiding the spontaneous vaginal birth. AIM: To check if this opinion is true. METHODS: In 995 low-risk, full-term, pregnancies resulting in spontaneous labour, multivariate logistic regression analysis was performed, which considered the age, the years of service of the obstetrician and of the midwife, and of both as independent variables. Results The longer the obstetrician (odds ratio 0.779, C.I. 95% 0.653-0.930, p = 0.006) or the midwife has been practising (odds ratio 0.609, C.I. 95% 0.408-0.909, p = 0.015) the less likely is the occurrence of a spontaneous vaginal birth. The combined years of service of the caring doctor/midwife pair appears to have no influence on the outcome of delivery. The chances of an operative vaginal birth increase with the age of the caring obstetrician (odds ratio 1.362, C.I. 95% 1.138-1.630, p = 0.001). CONCLUSION: The experience of the staff assisting women in labour definitely does not determine the success of deliveries. The skills of each professional category are based on theoretical knowledge that is possibly not being put to use during routine duties, especially by the 'more experienced' practitioners. Additionally, it appears that there is no team work, and decisions are not taken together.

The pathogenesis of endometrial polyps: a systematic semi-quantitative review.

UNLABELLED: The pathogenesis and natural history of endometrial polyps are not very clear. The objective of this study was to assess the opinions of international medical literature regarding the factors involved in the pathogenesis of endometrial polyps and to organize the results consistently with what is known about endometrial physiology. MATERIALS AND METHODS: A systematic review was carried out with the following search engines: PubMed, OVID, Scopus, SCIELO, and AJOL. Two hundreds forty-six abstracts were selected from the literature; of these abstracts, 58 factors were extracted and set as causative, non-causative, unclear or protective link with endometrial polyps. This relation is described through a correspondence analysis and tested with a main effect hierarchical log-linear model. RESULTS: The log-linear model resulted significant for the correspondence found with the following factors: (i) causative link (ageing, bcl-2 protein, excess weight/obesity, tamoxifen regardless of timing, relationship between estrogen receptors and prog-estinics, unbalanced estrogen therapy, estrogen-like effect, and unbalance between estrogens and progestinics), (ii) protective link (progestinics, antiestrogenic action), (iii) unclear link (menopause, ki-67 protein, angiogenesis, tamoxifen for a short time, tamoxifen for a long time, hormone replacement therapy (HRT), endometritis/inflammation), and (iv) non-causative link (none of the factors specifically). DISCUSSION: Subsequently to a review of the physiology of the endometrium, the onsetting of endometrial polyps was suggested through estrogen-related and non-estrogen related ways; the two ways can overlap. The most implied factors in the development of endometrial polyps are linked with one of these or both ways.

Wnt activation promotes neuronal differentiation of glioblastoma.

One of the biggest challenges in tumour research is the possibility to reprogram cancer cells towards less aggressive phenotypes. In this study, we reprogrammed primary Glioblastoma multiforme (GBM)-derived cells towards a more differentiated and less oncogenic phenotype by activating the Wnt pathway in a hypoxic microenvironment. Hypoxia usually correlates with malignant behaviours in cancer cells, but it has been recently involved, together with Wnt signalling, in the differentiation of embryonic and neural stem cells. Here, we demonstrate that treatment with Wnt ligands, or overexpression of ß-catenin, mediate neuronal differentiation and halt proliferation in primary GBM cells. An hypoxic environment cooperates with Wnt-induced differentiation, in line with our finding that hypoxia inducible factor-1α (HIF-1α) is instrumental and required to sustain the expression of ß-catenin transcriptional partners TCF-1 and LEF-1. In addition, we also found that Wnt-induced GBM cell differentiation inhibits Notch signalling, and thus gain of Wnt and loss of Notch cooperate in the activation of a pro-neuronal differentiation program. Intriguingly, the GBM sub-population enriched of cancer stem cells (CD133(+) fraction) is the primary target of the pro-differentiating effects mediated by the crosstalk between HIF-1α, Wnt, and Notch signalling. By using zebrafish transgenics and mutants as model systems to visualize and manipulate in vivo the Wnt pathway, we confirm that Wnt pathway activation is able to promote neuronal differentiation and inhibit Notch signalling of primary human GBM cells also in this in vivo set-up. In conclusion, these findings shed light on an unsuspected crosstalk between hypoxia, Wnt and Notch signalling in GBM, and suggest the potential to manipulate these microenvironmental signals to blunt GBM malignancy.

AMPK inhibition enhances apoptosis in MLL-rearranged pediatric B-acute lymphoblastic leukemia cells.

The serine/threonine kinase AMP-activated protein kinase (AMPK) and its downstream effectors, including endothelial nitric oxide synthase and BCL-2, are hyperactivated in B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) cells with MLL gene rearrangements. We investigated the role of activated AMPK in supporting leukemic cell survival and evaluated AMPK as a potential drug target. Exposure of leukemic cells to the commercial AMPK inhibitor compound C resulted in massive apoptosis only in cells with MLL gene rearrangements. These results were confirmed by targeting AMPK with specific short hairpin RNAs. Compound C-induced apoptosis was associated with mitochondrial membrane depolarization, reactive oxygen species production, cytochrome c release and caspases cleavage, indicating intrinsic apoptosis pathway activation. Treatment with low concentrations of compound C resulted in a strong antileukemic activity, together with cytochrome c release and cleavage of caspases and poly(ADP-ribose) polymerase, also in MLL-rearranged primary BCP-ALL samples. Moreover, AMPK inhibition in MLL-rearranged cell lines synergistically enhanced the antiproliferative effects of vincristine, daunorubicin, cytarabine, dexamethasone and L-asparaginase in most of the evaluated conditions. Taken together, these results indicate that the activation of the AMPK pathway directly contributes to the survival of MLL-rearranged BCP-ALL cells and AMPK inhibitors could represent a new therapeutic strategy for this high-risk leukemia.

Behaviour of lab parameters and neonatal weight loss in relation to neonatal breathing movements and cord clamping time.

BACKGROUND: To date, delaying cord clamping two to three minutes after birth is considered effective for newborn well-being. This time does not consider the newborn's breathing movements, which may also condition neonate well-being. AIM: To investigate the behaviour of neonatal weight loss and of some umbilical vein lab parameters, in relation to timing of newborn breathing and cord clamping. MATERIALS AND METHODS: Time from birth to cord clamping and time from birth to first cry of the newborn were collected in 87 full-term healthy women. First cry is a sign of effective breathing. Birth weight loss at the first, second, and third day from birth and lab parameters were assessed in relation to: time from birth to cord clamping, time from birth to first cry, and cord clamping before or after the first cry. RESULTS: Partial pressure of carbon dioxide (pCO2) decreased if cord clamping was performed after first cry and increased if first cry occurred after cord clamping, independently from the time elapsed from birth to first cry (p = 0.012). Calcium (Ca(2+)) concentration decreased if cord clamping was performed after the first cry and increased if first cry of the baby after birth was delayed (p = 0.021). Each second of delay from birth to cord clamping resulted in an increase in Cl- concentration (p <0.001). Each second of delay in cord clamping resulted in a reduction in the percentage of weight loss at the first day (p = 0.024), at the second day (p = 0.007), and at the third day (p = 0.028) after birth. CONCLUSIONS: Neonate breathing after birth should induce umbilical vein flow from placenta to lungs, conditioning the reduction of birth weight loss after birth and umbilical lab parameters modifications.

Effect of epidural analgesia on labor times and mode of delivery: a prospective study.

PURPOSE: To assess changes in labor times and delivery outcome in low-risk women requesting pain relief and undergoing epidural analgesia, according to the epidural analgesia schemes. MATERIALS AND METHODS: Prospective observational study of 499 low-risk women with epidural analgesia. Speed of dilatation (SD) (centimeters of dilatation / hours), speed of lowering of the fetal head through maternal pelvis (SL) (centimeters in lowering / hours), time of active phase of labor (TA), cesarean section (CS), vacuum application (VA) were dependent variables in multivariable linear and logistic regressions. RESULTS: Dilution of ropivacain, fentanyl amount, and volume of the first dose of epidural analgesia did not seem to affect labor times. Epidural analgesia with schemes used in this study favored both the dilatation and the fetal head lowering through maternal pelvis. Every five minutes from the first dose of epidural to the last top-up, SD decreased by about 13% (p=0.002), SL decreased by about 14% (p<0.001), and TA increased by about 40% (p<0.001). Additionally, every five minutes from the first dose of epidural to the last top-up, the odds of an operative vaginal birth (vacuum) increased by 0.7% (p<0.001). Increasing of number of top-ups independently caused a reduction in odds of undergoing CS (odds ratio 0.434; C.I. 95% 0.219-0.859, p=0.017), without influencing labor times. CONCLUSION: Epidural analgesia in patients requesting pain relief favors normal course of labor if it is not discontinued or delayed.

BMP2 sensitizes glioblastoma stem-like cells to Temozolomide by affecting HIF-1α stability and MGMT expression.

Glioblastoma multiforme (GBM) is the most common brain tumour, characterized by a central and partially necrotic (i.e., hypoxic) core enriched in cancer stem cells (CSCs). We previously showed that the most hypoxic and immature (i.e., CSCs) GBM cells were resistant to Temozolomide (TMZ) in vitro, owing to a particularly high expression of O6-methylguanine-DNA-methyltransferase (MGMT), the most important factor associated to therapy resistance in GBM. Bone morphogenetic proteins (BMPs), and in particular BMP2, are known to promote differentiation and growth inhibition in GBM cells. For this reason, we investigated whether a BMP2-based treatment would increase TMZ response in hypoxic drug-resistant GBM-derived cells. Here we show that BMP2 induced strong differentiation of GBM stem-like cells and subsequent addition of TMZ caused dramatic increase of apoptosis. Importantly, we correlated these effects to a BMP2-induced downregulation of both hypoxia-inducible factor-1α (HIF-1α) and MGMT. We report here a novel mechanism involving the HIF-1α-dependent regulation of MGMT, highlighting the existence of a HIF-1α/MGMT axis supporting GBM resistance to therapy. As confirmed from this evidence, over-stabilization of HIF-1α in TMZ-sensitive GBM cells abolished their responsiveness to it. In conclusion, we describe a HIF-1α-dependent regulation of MGMT and suggest that BMP2, by down-modulating the HIF-1α/MGMT axis, should increase GBM responsiveness to chemotherapy, thus opening the way to the development of future strategies for GBM treatment.

Dynamic changes of live/apoptotic circulating tumour cells as predictive marker of response to sunitinib in metastatic renal cancer.

BACKGROUND: Recently, we developed an apoptotic assay for expanding the monitoring capabilities of the circulating tumour cells (CTC) test during therapy. An automated platform for computing CTCs was integrated with a mAb (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 in early apoptosis; we showed that live CTCs were associated with progression, consistent with enhanced cell migration and invasion. The test was first applied here to mRCC. METHODS: Live/apoptotic CTCs changes were measured in mRCC patients receiving first-line Sunitinib and compared with circulating endothelial cell (CEC) levels. RESULTS: The presence of EpCAM-positive, live CTCs predicts progression in individual mRCC patient, being associated with distant metastasis under first-line Sunitinib. Synchronous detection of CTCs and CEC levels discloses for the first time an association between their dynamic changes and outcome: a rapid increase of the CEC number as early as the first cycle of therapy is associated with CTC decrease in non-progressed patients, whereas a delayed response of CECs is related to higher CTC values in the progressed group indicating treatment failure. CONCLUSION: We demonstrated that a delayed response to antiangiogenic treatment indicated by persistent detection of CECs correlates with persistent live CTCs and more aggressive disease.

Could endometrial cytology be helpful in detecting endometrial malignancies?

This short communication assesses the concordance indexes between hysteroscopic biopsies and endometrial cytology for each endometrial pattern found in a sample of 37 women. Patients underwent endometrial cytology under sonographic guidance. The specimens were obtained with an endocervical brush and were fixed on slides (no liquid-based methods). After endometrial cytology, hysteroscopy with biopsy was performed. The best concordance index was found for endometrial malignancies, suggesting that endometrial cytology is able to detect cancers but not other endometrial diseases, as compared with endometrial hysteroscopic biopsies. Therefore, the overall concordance index suggests a fair concordance between histological and cytological findings. This leads us to conclude that usual endometrial cytology should not be recommended to screen endometrial diseases, but it may be used as an alternative diagnostic tool when hysteroscopic biopsies or other blinded procedures for endometrial sampling are unwanted, because it allows malignancies to be detected as well as hysteroscopic-guided biopsies.