Tenofovir versus entecavir on the prognosis of hepatitis B virus-related hepatocellular carcinoma: a reconstructed individual patient data meta-analysis.

Background: Hepatitis B, often leading to Hepatocellular carcinoma (HCC), poses a major global health challenge. While Tenofovir (TDF) and Entecavir (ETV) are potent treatments, their comparative effectiveness in improving recurrence-free survival (RFS) and overall survival (OS) rates in HBV-related HCC is not well-established. Methods: We conducted an individual patient data meta-analysis using survival data from randomized trials and high-quality propensity score-matched studies to compare the impact of Tenofovir (TDF) and Entecavir (ETV) on RFS and OS in HBV-related HCC patients. Data from six databases and gray literature up to 30 August 2023, were analyzed, utilizing Kaplan-Meier curves, stratified Cox models, and shared frailty models for survival rate assessment and to address between-study heterogeneity. The study employed restricted mean survival time analysis to evaluate differences in RFS and OS between TDF-treated and ETV-treated patients. Additionally, landmark analyses compared early (<2 years) and late (≥2 years) tumor recurrence in these cohorts. Results: This study incorporated seven research articles, covering 4,602 patients with HBV-related HCC (2,082 on TDF and 2,520 on ETV). Within the overall cohort, TDF recipients demonstrated significantly higher RFS (p = 0.042) and OS (p < 0.001) than those on ETV. The stratified Cox model revealed significantly improved OS for the TDF group compared to the ETV group (hazard ratio, 0.756; 95% confidence interval, 0.639-0.896; p = 0.001), a result corroborated by the shared frailty model. Over a follow-up period of 1-8 years, no significant difference was noted in the mean time to death between the TDF and ETV groups. The rates of early recurrence did not significantly differ between the groups (p = 0.735). However, TDF treatment was significantly associated with a reduced risk of late recurrence compared to ETV (p < 0.001). In the HCC resection subgroup, the disparities in OS, early, and late recurrence rates between the two treatments paralleled those seen in the overall cohort. Conclusion: Compared to ETV, TDF may enhance OS and reduce late tumor recurrence risk in HBV-related HCC patients receiving curative treatment. However, there was no statistically significant distinction in the timing of tumor recurrence and mortality between patients administered TDF and those prescribed ETV. Systematic Review Registration: http://www.crd.york.ac.uk/prospero/.

Imatinib­induced gynecomastia: A case report.

Chronic myeloid leukemia is a myeloproliferative neoplasm characterized by the unregulated and abnormal proliferation of both mature and immature granulocytes, which results in the proliferation of peripheral blood leukocytes. Imatinib, a tyrosine kinase inhibitor, is the first-line treatment for patients diagnosed with chronic myeloid leukemia. However, despite its favorable safety profile, imatinib use is associated with a number of side effects. Gynecomastia is a rare adverse effect of imatinib treatment and may be associated with an imbalance in sex hormones. The present study reports the case of a patient with chronic myeloid leukemia diagnosed with gynecomastia after imatinib treatment. The aim of the present report was to highlight to clinicians this adverse reaction to imatinib treatment and investigate a treatment strategy with fewer side effects.

Secondary Polycythemia May Be an Early Clinical Manifestation of Multiple Myeloma: A Case Report.

Multiple myeloma (MM) is a malignancy of plasma cells that can cause anemia due to renal failure and bone marrow failure. Secondary polycythemia (SE) is a clinically rare disease that involves the overproduction of red blood cells. To our knowledge, the association of multiple myeloma and polycythemia has been reported, but the association of SE and multiple myeloma is rare and has been infrequently reported in literature. In contrast to anemia, the presence of polycythemia in multiple myeloma patients is a rare finding. A patient of IgA-λ multiple myeloma with secondary erythrocytosis recently admitted to our department is now reported as follows and relevant literature is reviewed to improve clinicians' awareness of such rare comorbidities.

Acute promyelocytic leukemia with additional chromosome abnormalities in a patient positive for HIV: A case report and literature review.

Acute promyelocytic leukemia (APL), especially cases of high-risk with complex chromosomes (CK), is rare in individuals infected with human immunodeficiency virus (HIV), making the establishment of therapeutic approaches challenging; often the treatment is individualized. This report describes a 49-year-old female patient with HIV who was diagnosed with high-risk APL with a new CK translocation and presents a literature review. At diagnosis, the patient presented with typical t(15;17)(q24;q21) with additional abnormalities, including add(5)(q15), add(5)(q31), add(7)(q11.2) and add(12) (p13). The results of acute myeloid leukemia mutation analysis suggested positivity for calreticulin and lysine methyltransferase 2C genes. The patient received all-trans retinoic acid combined with arsenic trioxide and chemotherapy, with morphologically complete remission after the first cycle of chemotherapy. The present report provided preliminary data for future clinical research.

Multiple myeloma in a patient with chronic myeloid leukemia: A case report.

Chronic myeloid leukemia (CML), a clonal myeloproliferative disorder of pluripotent hematopoietic stem cells, results from the Philadelphia chromosome (Ph) chromosome. The Ph is from a translocation, t(9;22)(q34q11), that creates a BCR-ABL fusion gene, which is transcribed into proteins with abnormal tyrosine kinase activity, driving the abnormal proliferation of white blood cells. Multiple myeloma (MM) is a proliferation disorder of plasma cells derived from a single clone, which may lead to uncontrolled growth, kidney injury, destructive bone lesions, hypercalcemia and anemia. It is extremely rare that MM and CML should occur in the same patient either synchronously or metachronously. To date, MM accompanied with CML has only been reported in limited studies, and the the cause behind the occurrence of both malignancies together is not understood. With the advent of novel therapies, the survival time in patients with CML and MM has improved. Therefore, the further investigation of the pathophysiology and clinical characteristics of these cases is valuable. The present study reports the case of a 79-year-old male who had been diagnosed with CML and treated with tyrosine kinase inhibitor, and then developed immunoglobulin G-κ MM after 6 years. This report should provide valid raw data for clinical research.

Targeting RNA Exonuclease XRN1 Potentiates Efficacy of Cancer Immunotherapy.

Despite the remarkable clinical responses achieved with immune checkpoint blockade therapy, the response rate is relatively low and only a subset of patients can benefit from the treatment. Aberrant RNA accumulation can mediate IFN signaling and stimulate an immune response, suggesting that targeting RNA decay machinery might sensitize tumor cells to immunotherapy. With this in mind, we identified an RNA exoribonuclease, XRN1, as a potential therapeutic target to suppress RNA decay and stimulate antitumor immunity. Silencing of XRN1 suppressed tumor growth in syngeneic immunocompetent mice and potentiated immunotherapy efficacy, while silencing of XRN1 alone did not affect tumor growth in immunodeficient mice. Mechanistically, XRN1 depletion activated IFN signaling and the viral defense pathway; both pathways play determinant roles in regulating immune evasion. Aberrant RNA-sensing signaling proteins (RIG-I/MAVS) mediated the expression of IFN genes, as depletion of each of them blunted the elevation of antiviral/IFN signaling in XRN1-silenced cells. Analysis of pan-cancer CRISPR-screening data indicated that IFN signaling triggered by XRN1 silencing is a common phenomenon, suggesting that the effect of XRN1 silencing may be extended to multiple types of cancers. Overall, XRN1 depletion triggers aberrant RNA-mediated IFN signaling, highlighting the importance of the aberrant RNA-sensing pathway in regulating immune responses. These findings provide the molecular rationale for developing XRN1 inhibitors and exploring their potential clinical application in combination with cancer immunotherapy. SIGNIFICANCE: Targeting XRN1 activates an intracellular innate immune response mediated by RNA-sensing signaling and potentiates cancer immunotherapy efficacy, suggesting inhibition of RNA decay machinery as a novel strategy for cancer treatment.

Dendritic cell therapy with CD137L-DC-EBV-VAX in locally recurrent or metastatic nasopharyngeal carcinoma is safe and confers clinical benefit.

INTRODUCTION: Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), and provides a target for a dendritic cell (DC) vaccine. CD137 ligand (CD137L) expressed on antigen presenting cells, costimulates CD137-expressing T cells, and reverse CD137L signaling differentiates monocytes to CD137L-DC, a type of DC, which is more potent than classical DC in stimulating T cells. METHODS: In this phase I study, patients with locally recurrent or metastatic NPC were administered CD137L-DC pulsed with EBV antigens (CD137L-DC-EBV-VAX). RESULTS: Of the 12 patients treated, 9 received full 7 vaccine doses with a mean administered cell count of 23.9 × 106 per dose. Treatment was well tolerated with only 4 cases of grade 1 related adverse events. A partial response was obtained in 1 patient, and 4 patients are still benefitting from a progression free survival (PFS) of currently 2-3 years. The mean pre-treatment neutrophil: lymphocyte ratio was 3.4 and a value of less than 3 was associated with prolonged median PFS. Progressors were characterized by a high frequency of naïve T cells but a low frequency of CD8+ effector T cells while patients with a clinical benefit (CB) had a high frequency of memory T cells. Patients with CB had lower plasma EBV DNA levels, and a reduction after vaccination. CONCLUSION: CD137L-DC-EBV-VAX was well tolerated. The use of CD137L-DC-EBV-VAX is demonstrated to be safe. Consistent results were obtained from all 12 patients, indicating that CD137L-DC-EBV-VAX induces an anti-EBV and anti-NPC immune response, and warranting further studies in patients post effective chemotherapy. PRECIS: The first clinical testing of CD137L-DC, a new type of monocyte-derived DC, finds that CD137L-DC are safe, and that they can induce an immune response against Epstein-Barr virus-associated nasopharyngeal carcinoma that leads to tumor regression or prevents tumor progression.

PRL3-zumab as an immunotherapy to inhibit tumors expressing PRL3 oncoprotein.

Tumor-specific antibody drugs can serve as cancer therapy with minimal side effects. A humanized antibody, PRL3-zumab, specifically binds to an intracellular oncogenic phosphatase PRL3, which is frequently expressed in several cancers. Here we show that PRL3-zumab specifically inhibits PRL3+ cancer cells in vivo, but not in vitro. PRL3 antigens are detected on the cell surface and outer exosomal membranes, implying an 'inside-out' externalization of PRL3. PRL3-zumab binds to surface PRL3 in a manner consistent with that in classical antibody-dependent cell-mediated cytotoxicity or antibody-dependent cellular phagocytosis tumor elimination pathways, as PRL3-zumab requires an intact Fc region and host FcγII/III receptor engagement to recruit B cells, NK cells and macrophages to PRL3+ tumor microenvironments. PRL3 is overexpressed in 80.6% of 151 fresh-frozen tumor samples across 11 common cancers examined, but not in patient-matched normal tissues, thereby implicating PRL3 as a tumor-associated antigen. Targeting externalized PRL3 antigens with PRL3-zumab may represent a feasible approach for anti-tumor immunotherapy.

Correction: Role of novel histone modifications in cancer.

[This corrects the article DOI: 10.18632/oncotarget.23356.].

Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma.

Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM.

Major hepatectomy for primary hepatolithiasis: a comparative study of laparoscopic versus open treatment.

BACKGROUND: Due to higher technical requirements, laparoscopic major hepatectomy (LMH) for primary hepatolithiasis have been limited to a few institutions. This retrospective study was performed to evaluate the therapeutic safety, and perioperative and long-term outcomes of LMH versus open major hepatectomy (OMH) for hepatolithiasis. METHODS: From January 2012 to December 2016, 61 patients with hepatolithiasis who underwent major hepatectomy were enrolled, including 29 LMH and 32 OMH. The perioperative outcomes and postoperative complications, as well as long-term outcomes, including the stone clearance and recurrence rate, were evaluated. RESULTS: There was no difference of surgical procedures between the two groups. The mean operation time was (262 ± 83) min in the LMH group and (214 ± 66) min in the OMH group (p = 0.05). There is no difference of intra-operative bleeding (310 ± 233) ml versus (421 ± 359) ml (p = 0.05). In the LMH group, there were shorter time to postoperative oral intake ((1.1 ± 0.6) days versus (3.1 ± 1.8) days, p = 0.01) and shorter hospital stay [(7.2 ± 2.3) days versus (11.8 ± 5.5) days, p = 0.03] than the open group. The LMH group had comparable stone clearance rate with the OMH group during the initial surgery (82.8% vs. 84.4%, p = 0.86). CONCLUSIONS: LMH could be an effective and safe treatment for selected patients with hepatolithiasis, with an advantage over OMH in the field of less intra-operative blood loss, less intra-operative transfusion, less overall complications, and faster postoperative recovery.

Role of novel histone modifications in cancer.

Oncogenesis is a multistep process mediated by a variety of factors including epigenetic modifications. Global epigenetic post-translational modifications have been detected in almost all cancers types. Epigenetic changes appear briefly and do not involve permanent changes to the primary DNA sequence. These epigenetic modifications occur in key oncogenes, tumor suppressor genes, and transcription factors, leading to cancer initiation and progression. The most commonly observed epigenetic changes include DNA methylation, histone lysine methylation and demethylation, histone lysine acetylation and deacetylation. However, there are several other novel post-translational modifications that have been observed in recent times such as neddylation, sumoylation, glycosylation, phosphorylation, poly-ADP ribosylation, ubiquitination as well as transcriptional regulation and these have been briefly discussed in this article. We have also highlighted the diverse epigenetic changes that occur during the process of tumorigenesis and described the role of histone modifications that can occur on tumor suppressor genes as well as oncogenes, which regulate tumorigenesis and can thus form the basis of novel strategies for cancer therapy.

Study protocol: phase 1 dose escalating study of Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) with oxaliplatin in peritoneal metastasis.

BACKGROUND: Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is a novel laparoscopic intraperitoneal chemotherapy technique, with advantages such as homogeneous distribution of aerosol and deeper tissue penetration. Thus far, PIPAC oxaliplatin has been administered at an arbitrary dose of 92 mg/m2. AIM: We aim to determine the dose-related safety profile and tolerability of PIPAC oxaliplatin using an evidence-based approach. The secondary aim is to evaluate clinic-pathologic response and the pharmacokinetic profile. METHODS: This is a phase I 3+3 dose escalation study for gastric and colorectal cancer with predominant peritoneal metastasis starting at a dose of 45 mg/m2. Safety is assessed according to Clavien-Dindo Classification and Common Terminology Criteria for Adverse Events (version 4.0). Clinico-pathologic response is assessed using the Peritoneal Regression Grading Score, Peritoneal Cancer Index, and Response Evaluation Criteria In Solid Tumour criteria (version 1.1). Pharmacokinetic analysis is performed using Inductively Coupled Plasma-Mass Spectrometry assay. This trial is registered on ClinicalTrials.gov (NCT03172416). CONCLUSIONS: This phase I study can provide the scientific basis to identify the optimal dose for PIPAC with oxaliplatin such that the benefits of this novel and promising intraperitoneal chemotherapy delivery technique can be maximized.

A Sustained Activation of Pancreatic NMDARs Is a Novel Factor of ß-Cell Apoptosis and Dysfunction.

Type 2 diabetes, which features ß-cell failure, is caused by the decrease of ß-cell mass and insulin secretory function. Current treatments fail to halt the decrease of functional ß-cell mass. Strategies to prevent ß-cell apoptosis and dysfunction are highly desirable. Recently, our group and others have reported that blockade of N-methyl-d-aspartate receptors (NMDARs) in the islets has been proposed to prevent the progress of type 2 diabetes through improving ß-cell function. It suggests that a sustained activation of the NMDARs may exhibit deleterious effect on ß-cells. However, the exact functional impact and mechanism of the sustained NMDAR stimulation on islet ß-cells remains unclear. Here, we identify a sustained activation of pancreatic NMDARs as a novel factor of apoptotic ß-cell death and function. The sustained treatment with NMDA results in an increase of intracellular [Ca2+] and reactive oxygen species, subsequently induces mitochondrial membrane potential depolarization and a decrease of oxidative phosphorylation expression, and then impairs the mitochondrial function of ß-cells. NMDA specifically induces the mitochondrial-dependent pathway of apoptosis in ß-cells through upregulation of the proapoptotic Bim and Bax, and downregulation of antiapoptotic Bcl-2. Furthermore, a sustained stimulation of NMDARs impairs ß-cell insulin secretion through decrease of pancreatic duodenal homeobox-1 (Pdx-1) and adenosine triphosphate synthesis. The activation of nuclear factor-κB partly contributes to the reduction of Pdx-1 expression induced by overstimulation of NMDARs. In conclusion, we show that the sustained stimulation of NMDARs is a novel mediator of apoptotic signaling and ß-cell dysfunction, providing a mechanistic insight into the pathological role of NMDARs activation in diabetes.

Ascochlorin Enhances the Sensitivity of Doxorubicin Leading to the Reversal of Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma.

Increasing evidence has indicated that epithelial-to-mesenchymal transition (EMT) at the advanced stage of liver cancer not only has the ability to self-renew and progress cancer, but also enables greater resistance to conventional chemo- and radiotherapies. Here, we report that ascochlorin (ASC), an isoprenoid antibiotic, could potentiate the cytotoxic effect of doxorubicin on HCCLM3, SNU387, SNU49, and SK-Hep-1 hepatocellular carcinoma cells, which had a predominantly mesenchymal signature with low expression of E-cadherin but high expression of N-cadherin. Co-administration of ASC reduced doxorubicin-induced invasion/migration and modulated EMT characteristics in mesenchymal cells. This process was probably mediated by the E-cadherin repressors Snail and Slug. In addition, ASC increased sensitivity to doxorubicin treatment by directly inhibiting STAT3 binding to the Snail promoter. We also observed that ASC significantly enhanced the effect of doxorubicin against tumor growth and inhibited metastasis in an HCCLM3_Luc orthotopic mouse model. Collectively, our data demonstrate that ASC can increase sensitivity to doxorubicin therapy and reverse the EMT phenotype via the downregulation of STAT3-Snail expression, which could form the basis of a novel therapeutic approach against hepatocellular carcinoma. Mol Cancer Ther; 15(12); 2966-76. ©2016 AACR.

Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI.

BACKGROUND: Irinotecan toxicity correlates with UGT1A1 activity. We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods. METHODS: Twenty-four Asian cancer patients received irinotecan as part of the FOLFIRI regimen. Subjects took raltegravir 400 mg orally and intravenous midazolam 1 mg. Pharmacokinetic analyses were performed using WinNonLin and NONMEM. Genomic DNA was isolated and screened for the known genetic variants in UGT1A1 and CYP3A4/5. RESULTS: SN-38G/SN-38 AUC ratio correlated well with Raltegravir glucuronide/ Raltegravir AUC ratio (r = 0.784 p<0.01). Midazolam clearance correlated well with irinotecan clearance (r = 0.563 p<0.01). SN-38 AUC correlated well with Log10Nadir Absolute Neutrophil Count (ANC) (r = -0.397 p<0.05). Significant correlation was found between nadir ANC and formation rate constant of raltegravir glucuronide (r = 0.598, P<0.005), but not UGT1A1 genotype. CONCLUSION: Raltegravir glucuronide formation is a good predictor of nadir ANC, and can predict neutropenia in East Asian patients. Prospective studies with dose adjustments should be done to develop raltegravir as a probe to optimize irinotecan therapy. TRIAL REGISTRATION: Clinicaltrials.gov NCT00808184.

[Protein composition analysis and cytotoxicity of gulbulin hydrolysates of Brucea javanica seeds].

To analyze the protein composition of Brucea javanica seeds and evaluate the cytotoxicity of its gulbulin hydrolysates. Four protein fractions of albumin, gulbulin, prolamin and glutelin were sequentially extracted and then quantified by Kjeldahl method. Different kinds of proteases were applied to hydrolyze B.javanica gulbulin, and MTT assay was used to evaluate the cytotoxicity of low molecular weight hydrolysates (≤3 kDa) on human breast cancer MCF-7 cell. The results showed that： the total protein content of B.javanica seeds was 17.47%, albumin, gulbulin, coxin, glutelin and residue protein accounted for 15.01%, 8.11%, 2.47%, 44.92% and 23.62% of the total protein content, respectively. The hydrolysates (≤3 kDa) of B.javanica globulin produced by pepsin showed significant growth inhibitory activity on MCF-7 cells, and the IC50 value was（6.52±0.01） mg•L⁻¹ after 72 h of incubation. Protein was abundant in B.javanica seeds, and its peptides demonstrated specific cytotoxicity on MCF-7 cell line in vitro, suggesting antitumor active ingredient can be further generated from B.javanica seeds.

Concomitant non-Hodgkin's lymphoma in colon and liver: report of a rare case and review of literature.

A 58-year-old male patient was admitted with right upper abdominal pain. Initial hematologic evaluation revealed mildly elevated serum carcinoembryonic antigen and carbohydrate antigen (CA) 19-9 tests, while an abdominal CT-scan showed a circumferential mass along the distal ascending colon and the right flexure of colon, simultaneously a liver lesion in segment 8 is considered metastases from colorectal. colonoscopic examination revealed a circumferential growth tumor in the right flexure of colon and the colonoscopy can not reach the proximal of the tumor. We performed a right hemihepatoectomy and a right hemicolectomy associated with loco-regional lymphadenectomy. Histological examination showed diffuse large B-cell lymphomas in resected right colon as well as liver tumors. The patient received six courses of chemotherapy with CHOP-based regimens. At 14-month follow-up before this report, the patient is still alive and free of disease.

Validation of a rapid and sensitive LC-MS/MS method for determination of exemestane and its metabolites, 17ß-hydroxyexemestane and 17ß-hydroxyexemestane-17-O-ß-D-glucuronide: application to human pharmacokinetics study.

A novel, rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the evaluation of exemestane pharmacokinetics and its metabolites, 17ß-dihydroexemestane (active metabolite) and 17ß-dihydroexemestane-17-O-ß-D-glucuronide (inactive metabolite) in human plasma. Their respective D3 isotopes were used as internal standards. Chromatographic separation of analytes was achieved using Thermo Fisher BDS Hypersil C18 analytic HPLC column (100 × 2.1 mm, 5 µm). The mobile phase was delivered at a rate of 0.5 mL/min by gradient elution with 0.1% aqueous formic acid and acetonitrile. The column effluents were detected by API 4000 triple quadrupole mass spectrometer using electrospray ionisation (ESI) and monitored by multiple reaction monitoring (MRM) in positive mode. Mass transitions 297 > 121 m/z, 300 > 121 m/z, 299 > 135 m/z, 302 > 135 m/z, 475 > 281 m/z, and 478 > 284 m/z were monitored for exemestane, exemestane-d3, 17ß-dihydroexemestane, 17ß-dihydroexemestane-d3, 17ß-dihydroexemestane-17-O-ß-D-glucuronide, and 17ß-dihydroexemestane-17-O-ß-D-glucuronide-d3 respectively. The assay demonstrated linear ranges of 0.4-40.0 ng/mL, for exemestane; and 0.2-15.0 ng/mL, for 17ß-dihydroexemestane and 17ß-dihydroexemestane-17-O-ß-D-glucuronide, with coefficient of determination (r2) of > 0.998. The precision (coefficient of variation) were ≤10.7%, 7.7% and 9.5% and the accuracies ranged from 88.8 to 103.1% for exemestane, 98.5 to 106.1% for 17ß-dihydroexemestane and 92.0 to 103.2% for 17ß-dihydroexemestane-17-O-ß-D-glucuronide. The method was successfully applied to a pharmacokinetics/dynamics study in breast cancer patients receiving exemestane 25 mg daily orally. For a representative patient, 20.7% of exemestane in plasma was converted into 17ß-dihydroexemestane and 29.0% of 17ß-dihydroexemestane was inactivated as 17ß-dihydroexemestane-17-O-ß-D-glucuronide 24 hours after ingestion of exemestane, suggesting that altered 17-dihydroexemestane glucuronidation may play an important role in determining effect of exemestane against breast cancer cells.