Prevalence of Homologous Recombination Deficiency Among Patients With Germline RAD51C/D Breast or Ovarian Cancer.

Importance: RAD51C and RAD51D are involved in DNA repair by homologous recombination. Germline pathogenic variants (PVs) in these genes are associated with an increased risk of ovarian and breast cancer. Understanding the homologous recombination deficiency (HRD) status of tumors from patients with germline PVs in RAD51C/D could guide therapeutic decision-making and improve survival. Objective: To characterize the clinical and tumor characteristics of germline RAD51C/D PV carriers, including the evaluation of HRD status. Design, Setting, and Participants: This retrospective cohort study included 91 index patients plus 90 relatives carrying germline RAD51C/D PV (n = 181) in Spanish hospitals from January 1, 2014, to December 31, 2021. Genomic and functional HRD biomarkers were assessed in untreated breast and ovarian tumor samples (n = 45) from June 2022 to February 2023. Main Outcomes and Measures: Clinical and pathologic characteristics were assessed using descriptive statistics. Genomic HRD by genomic instability scores, functional HRD by RAD51, and gene-specific loss of heterozygosity were analyzed. Associations between HRD status and tumor subtype, age at diagnosis, and gene-specific loss of heterozygosity in RAD51C/D were investigated using logistic regression or the t test. Results: A total of 9507 index patients were reviewed, and 91 patients (1.0%) were found to carry a PV in RAD51C/D; 90 family members with a germline PV in RAD51C/D were also included. A total of 157 of carriers (86.7%) were women and 181 (55.8%) had received a diagnosis of cancer, mainly breast cancer or ovarian cancer. The most prevalent PVs were c.1026+5_1026+7del (11 of 56 [19.6%]) and c.709C>T (9 of 56 [16.1%]) in RAD51C and c.694C>T (20 of 35 [57.1%]) in RAD51D. In untreated breast cancer and ovarian cancer, the prevalence of functional and genomic HRD was 55.2% (16 of 29) and 61.1% (11 of 18) for RAD51C, respectively, and 66.7% (6 of 9) and 90.0% (9 of 10) for RAD51D. The concordance between HRD biomarkers was 91%. Tumors with the same PV displayed contrasting HRD status, and age at diagnosis did not correlate with the occurrence of HRD. All breast cancers retaining the wild-type allele were estrogen receptor positive and lacked HRD. Conclusions and Relevance: In this cohort study of germline RAD51C/D breast cancer and ovarian cancer, less than 70% of tumors displayed functional HRD, and half of those that did not display HRD were explained by retention of the wild-type allele, which was more frequent among estrogen receptor-positive breast cancers. Understanding which tumors are associated with RAD51C/D and HRD is key to identify patients who can benefit from targeted therapies, such as PARP (poly [adenosine diphosphate-ribose] polymerase) inhibitors.

LOXL2-mediated chromatin compaction is required to maintain the oncogenic properties of triple-negative breast cancer cells.

Oxidation of histone H3 at lysine 4 (H3K4ox) is catalyzed by lysyl oxidase homolog 2 (LOXL2). This histone modification is enriched in heterochromatin in triple-negative breast cancer (TNBC) cells and has been linked to the maintenance of compacted chromatin. However, the molecular mechanism underlying this maintenance is still unknown. Here, we show that LOXL2 interacts with RuvB-Like 1 (RUVBL1), RuvB-Like 2 (RUVBL2), Actin-like protein 6A (ACTL6A), and DNA methyltransferase 1associated protein 1 (DMAP1), a complex involved in the incorporation of the histone variant H2A.Z. Our experiments indicate that this interaction and the active form of RUVBL2 are required to maintain LOXL2-dependent chromatin compaction. Genome-wide experiments showed that H2A.Z, RUVBL2, and H3K4ox colocalize in heterochromatin regions. In the absence of LOXL2 or RUVBL2, global levels of the heterochromatin histone mark H3K9me3 were strongly reduced, and the ATAC-seq signal in the H3K9me3 regions was increased. Finally, we observed that the interplay between these series of events is required to maintain H3K4ox-enriched heterochromatin regions, which in turn is key for maintaining the oncogenic properties of the TNBC cell line tested (MDA-MB-231).

Identification of Precise 3D CT Radiomics for Habitat Computation by Machine Learning in Cancer.

Purpose To identify precise three-dimensional radiomics features in CT images that enable computation of stable and biologically meaningful habitats with machine learning for cancer heterogeneity assessment. Materials and Methods This retrospective study included 2436 liver or lung lesions from 605 CT scans (November 2010-December 2021) in 331 patients with cancer (mean age, 64.5 years ± 10.1 [SD]; 185 male patients). Three-dimensional radiomics were computed from original and perturbed (simulated retest) images with different combinations of feature computation kernel radius and bin size. The lower 95% confidence limit (LCL) of the intraclass correlation coefficient (ICC) was used to measure repeatability and reproducibility. Precise features were identified by combining repeatability and reproducibility results (LCL of ICC ≥ 0.50). Habitats were obtained with Gaussian mixture models in original and perturbed data using precise radiomics features and compared with habitats obtained using all features. The Dice similarity coefficient (DSC) was used to assess habitat stability. Biologic correlates of CT habitats were explored in a case study, with a cohort of 13 patients with CT, multiparametric MRI, and tumor biopsies. Results Three-dimensional radiomics showed poor repeatability (LCL of ICC: median [IQR], 0.442 [0.312-0.516]) and poor reproducibility against kernel radius (LCL of ICC: median [IQR], 0.440 [0.33-0.526]) but excellent reproducibility against bin size (LCL of ICC: median [IQR], 0.929 [0.853-0.988]). Twenty-six radiomics features were precise, differing in lung and liver lesions. Habitats obtained with precise features (DSC: median [IQR], 0.601 [0.494-0.712] and 0.651 [0.52-0.784] for lung and liver lesions, respectively) were more stable than those obtained with all features (DSC: median [IQR], 0.532 [0.424-0.637] and 0.587 [0.465-0.703] for lung and liver lesions, respectively; P < .001). In the case study, CT habitats correlated quantitatively and qualitatively with heterogeneity observed in multiparametric MRI habitats and histology. Conclusion Precise three-dimensional radiomics features were identified on CT images that enabled tumor heterogeneity assessment through stable tumor habitat computation. Keywords: CT, Diffusion-weighted Imaging, Dynamic Contrast-enhanced MRI, MRI, Radiomics, Unsupervised Learning, Oncology, Liver, Lung Supplemental material is available for this article. © RSNA, 2024 See also the commentary by Sagreiya in this issue.

Overview of Oral Potentially Malignant Disorders: From Risk Factors to Specific Therapies.

Oral squamous cell carcinoma (OSCC) is a very aggressive cancer, representing one of the most common malignancies worldwide. Oral potentially malignant disorders (OPMDs) regroup a variegate set of different histological lesions, characterized by the potential capacity to transform in OSCC. Most of the risk factors associated with OSCC are present also in OPMDs' development; however, the molecular mechanisms and steps of malignant transformation are still unknown. Treatment of OSCC, including surgery, systemic therapy and radiotherapy (alone or in combination), has suffered a dramatic change in last years, especially with the introduction of immunotherapy. However, most cases are diagnosed during the advanced stage of the disease, decreasing drastically the survival rate of the patients. Hence, early diagnosis of premalignant conditions (OPMDs) is a priority in oral cancer, as well as a massive education about risk factors, the understanding of mechanisms involved in malignant progression and the development of specific and more efficient therapies. The aim of this article is to review epidemiological, clinical, morphological and molecular features of OPMDs, with the purpose to lay the foundation for an exhaustive comprehension of these lesions and their ability of malignant transformation and for the development of more effective and personalized treatments.

Severe SARS-CoV-2 placenta infection can impact neonatal outcome in the absence of vertical transmission.

The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pathophysiology of the placenta and its impact on pregnancy outcome has not yet been fully elucidated. Here, we present a comprehensive clinical, morphological, and molecular analysis of placental tissues from pregnant women with and without SARS-CoV-2 infection. SARS-CoV-2 could be detected in half of placental tissues from SARS-CoV-2-positive women. The presence of the virus was not associated with any distinctive pathological, maternal, or neonatal outcome features. SARS-CoV-2 tissue load was low in all but one patient who exhibited severe placental damage leading to neonatal neurological manifestations. The placental transcriptional response induced by high viral load of SARS-CoV-2 showed an immunopathology phenotype similar to autopsy lung tissues from patients with severe coronavirus disease 2019. This finding contrasted with the lack of inflammatory response in placental tissues from SARS-CoV-2-positive women with low viral tissue load and from SARS-CoV-2-negative women. Importantly, no evidence of vertical transmission of SARS-CoV-2 was found in any newborns, suggesting that the placenta may be an effective maternal-neonatal barrier against the virus even in the presence of severe infection. Our observations suggest that severe placental damage induced by the virus may be detrimental for the neonate independently of vertical transmission.

Sequential immunohistochemistry and virtual image reconstruction using a single slide for quantitative KI67 measurement in breast cancer.

OBJECTIVE: Ki67 is a prognostic and predictive marker in breast cancer (BC). However, manual scoring (MS) by visual assessment suffers from high inter-observer variability which limits its clinical use. Here, we developed a new digital image analysis (DIA) workflow, named KiQuant for automated scoring of Ki67 and investigated its equivalence with standard pathologist's assessment. METHODS: Sequential immunohistochemistry of Ki67 and cytokeratin, for precise tumor cell recognition, were performed in the same section of 5 tissue microarrays containing 329 tumor cores from different breast cancer subtypes. Slides were digitalized and subjected to DIA and MS for Ki67 assessment. The intraclass correlation coefficient (ICC) and Bland-Altman plot were used to evaluate inter-observer reproducibility. The Kaplan-Meier analysis was used to determine the prognostic potential. RESULTS: KiQuant showed an excellent correlation with MS (ICC:0.905,95%CI:0.878-0.926) with satisfactory inter-run (ICC:0.917,95%CI:0.884-0.942) and inter-antibody reproducibilities (ICC:0.886,95%CI:0.820-0.929). The distance between KiQuant and MS increased with the magnitude of Ki67 measurement and positively correlated with analyzed tumor area and breast cancer subtype. Agreement rates between KiQuant and MS within the clinically relevant 14% and 30% cut-off points ranged from 33% to 44% with modest interobserver reproducibility below the 20% cut-off (0.606, 95%CI:0.467-0.727). High Ki67 by KiQuant correlated with worse outcome in all BC and in the luminal subtype (P = 0.028 and P = 0.043, respectively). For MS, the association with survival was significant only in 1 out of 3 observers. CONCLUSIONS: KiQuant represents an easy and accurate methodology for Ki67 measurement providing a step toward utilizing Ki67 in the clinical setting.

Enfermedad relacionada con IgG4 con posible afectación miocárdica / IgG4-related disease with possible myocardial involvement

La enfermedad relacionada con el depósito de IgG4 es una entidad caracterizada por lesiones tumefactas, infiltrado denso linfoplasmocítico con positividad inmunohistoquímica para IgG4, fibrosis estoriforme y, frecuentemente, niveles séricos elevados de IgG4. Puede cursar con afectación multisistémica; sin embargo, la afectación miocárdica, objetivada mediante pruebas de imagen, no ha sido descrita en la literatura médica. Se presenta el caso clínico de un varón afecto de enfermedad relacionada con IgG4 con posible afectación miocárdica, detectada a través de cardiorresonancia magnética, que plantea el diagnóstico diferencial con otras enfermedades como la sarcoidosis y la enfermedad de Fabry, cuyo diagnóstico diferencial es de gran importancia por su repercusión terapéutica

IgG4-related disease is characterized by mass lesions, a dense lymphoplasmacytic infiltrate with immunohistochemical positivity for IgG4, storiform fibrosis and, frequently, elevated serum IgG4 levels. It can be multisystemic; however, myocardial involvement, which is objectively determined by imaging tests, has not been described in the medical literature. We report the case of a man with IgG4-related disease with possible myocardial involvement, detected by cardiac magnetic resonance. This raises the question of a differential diagnosis with other diseases such as sarcoidosis and Fabry disease, the differential diagnosis of which is of great importance due to its therapeutic impact

IgG4-related disease with possible myocardial involvement. / Enfermedad relacionada con IgG4 con posible afectación miocárdica.

IgG4-related disease is characterized by mass lesions, a dense lymphoplasmacytic infiltrate with immunohistochemical positivity for IgG4, storiform fibrosis and, frequently, elevated serum IgG4 levels. It can be multisystemic; however, myocardial involvement, which is objectively determined by imaging tests, has not been described in the medical literature. We report the case of a man with IgG4-related disease with possible myocardial involvement, detected by cardiac magnetic resonance. This raises the question of a differential diagnosis with other diseases such as sarcoidosis and Fabry disease, the differential diagnosis of which is of great importance due to its therapeutic impact.

IgG4-related disease in thymus. A very rare case of chronic fibrosis mimicking sarcoidosis.

IgG4-related disease (IgG4-RD) is a multi-organ immune-mediated chronic fibroinflammatory condition, with unclear certain etiology. It is morphologically characterized by storiform fibrosis, dense IgG4-positive lymphoplasmacytic infiltrate, and obliterative phlebitis. It was recognized as a systemic condition as recently as 2003. IgG4-RD has been described in virtually every organ, forming sclerosing masses, and often mimicking tumors. Clinically, patients present unspecific symptoms and this condition is often recognized incidentally. The epidemiology remains poorly studied, but it has been noted that in the majority of recorded instances, patients are middle-aged men. IgG4-RD could mimic conditions other than tumors, such as infection, inflammation, or other systemic disorders. To ensure accuracy of diagnosis, an exhaustive histopathological analysis is required, together with clinical, radiological, and serological data. Thymic fibrosis in the absence of other primary thymic lesions is a very rare occurrence; in English literature only 1 case has been reported with scattered IgG4 plasma cells infiltrate and focal obliterative phlebitis. We will describe, for the first time, the case of a 49-year-old man displaying an anterior mediastinic, hilar, and intramyocardial mass simulating a sarcoidosis, with a definitive diagnosis of IgG4-related thymic fibrosis extending to the mediastinum and the heart. At the histological examination, we found many features of IgG4-RD in the thymic tissue, such as diffused storiform fibrosis, dense lymphoplasmacytic infiltrate with abundant plasma cells IgG4 positive (ratio IgG/IgG4: 40%), obliterative phlebitis, eosinophilic infiltrate, and Castleman-like lymphoid follicles. We discussed the differential diagnosis and reviewed the literature and the other cases of IgG4-related diseases that had been diagnosed in our department.

Adenoma tubular gigante en una paciente gestante. Presentación de un caso clínico y su diagnóstico diferencial histológico / Giant tubular adenoma in a pregnant woman. Case report and differential histological diagnosis

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RAS/MAPK pathway hyperactivation determines poor prognosis in undifferentiated pleomorphic sarcomas.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) constitutes the most common subtype of soft tissue sarcoma. However, UPS is clinically and molecularly poorly understood, in great extent due to its intrinsic phenotypic and cytogenetic complexity, which in turn results in the absence of specific prognostic or predictive biomarkers. The RAS/mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase inhibitor (PI3K)/mammalian target of rapamycin (mTOR) pathways are considered to be 2 major mechanisms for sarcoma proliferation and survival and to the authors' knowledge their role in UPS remains unclear. The objective of the current study was to investigate whether the RAS/MAPK and PI3K/mTOR pathways are activated in UPS, and whether pathway activation is associated with outcome. METHODS: Records for patients diagnosed and treated for UPS in the study institution between 2000 and 2009 were reviewed. Phosphorylation status of 4E-binding protein (4E-BP1), eukaryotic translation initiation factor 4E (eIF-4E), S6-RP, and ERK 1/2, together with total forms of 4E-BP1 and eIF-4E, were assessed using immunohistochemistry in paraffin-embedded tumor tissue. Mutational analysis for KRAS; NRAS; BRAF; and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) oncogenic mutations was performed as well. RESULTS: Critical lymph nodes within the RAS/MAPK and PI3K/mTOR pathways were found to be activated in >80% of UPS cases. Hyperactivation of the RAS/MAPK pathway, as assessed by expression of phosphorylated ERK 1/2, was found to independently predict a higher risk of disease recurrence and impaired overall survival. Only a KRAS A146V mutation was detected in 1 tumor. CONCLUSIONS: The RAS/MAPK and PI3K/mTOR pathways are activated in the majority of cases of UPS. The RAS/MAPK pathway distinguishes a subgroup of patients with localized UPS with a worse outcome.

Schwannoma de la línea media cervical / Cervical midline schwannoma

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BRAF V600E and KRAS G12S mutations in peripheral nerve sheath tumours.

AIMS: Benign (BPNST) and malignant (MPNST) peripheral nerve sheath tumours occur either sporadically or are related to neurofibromatosis (NF). The mechanisms involved are well known in NF-related tumours, but still remain unclear in sporadic cases. Somatic BRAF and KRAS mutations represent the most frequent genetic events in melanocytic neoplastic lesions. Because melanocytes and Schwann cells both derive from neural crest cells, we hypothesized that BRAF and KRAS mutations might influence BPNST and MPNST development. METHODS AND RESULTS: BRAF exon 15 and KRAS exons 2 and 3 polymerase chain reaction (PCR) sequencing was performed in formalin-fixed/paraffin-embedded samples of 99 BPNST and MPNST, related and non-related to NF types 1 and 2. Oncogenic BRAF V600E mutations were found in four of 40 schwannomas (including one acoustic neuroma) and one of 13 MPNST, not associated with NF. A KRAS G12S mutation was also evident in one sporadic schwannoma. CONCLUSION: Our findings suggest that RAS pathway activation due to BRAF V600E and KRAS mutations is an important event in a subset of peripheral nerve sheath tumours not related to NF.

Immunophenotyping analysis in invasive micropapillary carcinoma of the breast: role of CD24 and CD44 isoforms expression.

We analyzed immunohistochemically the expression of CD24 and spliced variants of CD44v5 and v9 in invasive micropapillary carcinoma (IMPC) of the breast that is a rather aggressive tumor characterized by alteration of cells adhesion molecules, early lymph node metastases and poor prognosis. We analyzed 31 high-grade IMPCs and compared their expression to 22 high grade (G3) invasive ductal carcinomas of the breast (IDCs). We found a higher expression of CD24 in high-grade IMPCs with a peculiar inverted apical localization, compared to IDCs, showing a strong cytoplasmic staining; normal breast tissue resulted completely negative. IMPCs showed reduced expression of CD44v5 and CD44v9 compared with IDCs, but without a statistical significant difference. This study demonstrated that IMPC represents a distinct entity of breast carcinoma with high expression of CD24 with a typical inverted apical membrane pattern and reduction of CD44 isoforms v5 and v9, compared to IDCs. These features could explain the high lymph-vascular invasion propensity and higher metastatic capability of these tumors and could be a useful tool for a future targeted therapy.

Fifth Educational Symposium of the Spanish Lung Cancer Group: report on the Molecular Biology Workshop.

The majority of non-small-cell lung cancer (NSCLC) patients present with locally advanced (35%) or metastatic disease (40%); in this setting, it is of the utmost importance to balance efficacy with toxicity. However, with platinum combinations, survival has reached a "plateau", with median overall survival times of a mere 10-12 months, making it mandatory to search for new strategies and to identify more effective treatment. Molecular characteristics can be more informative than clinical features in predicting clinical benefit, and the identification of molecular markers can help define subgroups of patients who are likely to respond to different treatments, thus avoiding unnecessary toxicities and costs and providing the maximum benefit to each patient. Here we review research on biomarker assessment that was presented during the Molecular Biology Workshop held in Palma de Mallorca on 25 November 2010, during the Fifth Educational Symposium of the Spanish Lung Cancer Group.

Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations.

PURPOSE: Advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations (deletion in exon 19 or L858R) show an impressive progression-free survival of 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. We hypothesized that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways. EXPERIMENTAL DESIGN: We assessed the T790M mutation in pretreatment diagnostic specimens from 129 erlotinib-treated advanced NSCLC patients with EGFR mutations. The expression of eight genes and two proteins involved in DNA repair and four receptor tyrosine kinases was also examined. RESULTS: The EGFR T790M mutation was observed in 45 of 129 patients (35%). Progression-free survival was 12 months in patients with and 18 months in patients without the T790M mutation (P = 0.05). Progression-free survival was 27 months in patients with low BRCA1 mRNA levels, 18 months in those with intermediate levels, and 10 months in those with high levels (P = 0.02). In the multivariate analysis, the presence of the T790M mutation (HR, 4.35; P = 0.001), intermediate BRCA1 levels (HR, 8.19; P < 0.0001), and high BRCA1 levels (HR, 8.46; P < 0.0001) emerged as markers of shorter progression-free survival. CONCLUSIONS: Low BRCA1 levels neutralized the negative effect of the T790M mutation and were associated with longer progression-free survival to erlotinib. We advocate baseline assessment of the T790M mutation and BRCA1 expression to predict outcome and provide alternative individualized treatment to patients based on T790M mutations and BRCA1 expression.

Detection of EGFR mutations with mutation-specific antibodies in stage IV non-small-cell lung cancer.

BACKGROUND: Immunohistochemistry (IHC) with mutation-specific antibodies may be an ancillary method of detecting EGFR mutations in lung cancer patients. METHODS: EGFR mutation status was analyzed by DNA assays, and compared with IHC results in five non-small-cell lung cancer (NSCLC) cell lines and tumor samples from 78 stage IV NSCLC patients. RESULTS: IHC correctly identified del 19 in the H1650 and PC9 cell lines, L858R in H1975, and wild-type EGFR in H460 and A549, as well as wild-type EGFR in tumor samples from 22 patients. IHC with the mAb against EGFR with del 19 was highly positive for the protein in all 17 patients with a 15-bp (ELREA) deletion in exon 19, whereas in patients with other deletions, IHC was weakly positive in 3 cases and negative in 9 cases. IHC with the mAb against the L858R mutation showed high positivity for the protein in 25/27 (93%) patients with exon 21 EGFR mutations (all with L858R) but did not identify the L861Q mutation in the remaining two patients. CONCLUSIONS: IHC with mutation-specific mAbs against EGFR is a promising method for detecting EGFR mutations in NSCLC patients. However these mAbs should be validated with additional studies to clarify their possible role in routine clinical practice for screening EGFR mutations in NSCLC patients.

The levels of the endocannabinoid receptor CB2 and its ligand 2-arachidonoylglycerol are elevated in endometrial carcinoma.

The endocannabinoid system plays protective roles against the growth and the spreading of several types of carcinomas. Because estrogens regulate this system both in physiological states and cancer, in this paper we evaluated its involvement in endometrial carcinoma, a well-known estrogen-dependent tumor. To test whether the endocannabinoid system is expressed in endometrial cancer, tissue samples were collected both from 18 patients undergoing surgical treatment for endometrial adenocarcinoma and 16 healthy age-matched controls, and treated for Western blot and immunohistochemical analysis. Moreover, tissues were dounce homogenized and submitted to endocannabinoid measurement by liquid chromatography-mass spectrometry. To evaluate the physiological role of the endocannabinoid system, a human endometrial cancer cell-line (AN3CA) was used and transiently transfected with a plasmid containing the cDNA for the endocannabinoid receptor CB(2). Cells were incubated for 48 h with an agonist (JWH133) (10 mum) or antagonist (SR144528) (1 mum) of CB(2) 24 h after transfection, and cell proliferation was measured by the 3-[4,5-dimethyltiazol-2yl]-2,5 diphenyltetrazolium bromide formazan assay. In human endometrial carcinoma biopsies the expression of CB(2) receptor and the levels of its ligand, 2-arachidonoylglycerol increased, whereas monoacylglycerol lipase, an enzyme responsible for 2-arachidonoylglycerol degradation, was down-regulated. Immunohistochemical analysis revealed that CB(2) was overexpressed only in malignant endometrial cells. CB(2)-overexpressing AN3CA cells showed a significant reduction in cell vitality compared with parental AN3CA cells: incubation with the selective CB(2) antagonist SR144128 restored the viability of CB(2)-overexpressing cells to that of untransfected cells. In conclusion, the endocannabinoid system seems to play an important role in human endometrial carcinoma, and modulation of CB(2) activity/expression may account for a tumor-suppressive effect.