Pharmacokinetics of 4′-O-tetrahydropyranyladriamycin given on a weekly schedule in patients with advanced breast cancer

Improved quality of life has gained importance over shortly lasting remissions in yet incurable metastatic breast cancer. Fractionation of drug administration is one of the possible approaches to reduce the concentration-dependent toxicity of anthracyclines. We evaluated the pharmacokinetics of 4-O-tetrahydropyranyladriamycin (THP-ADM) under weekly administration in patients with advanced breast cancer (dose escalation, from 20 to 27 mg/m₂ THP-ADM). The concentration-time curves of THP-ADM in plasma were best described by an open three-compartment model [half-life of the first disposition phase (t_1/2), 3.15 min; terminal elimination half-life (t _1/2), 13.9 h] with a mean area under the curve (AUC) of 12.2 ng h ml^–1mg^–1m^–2, resulting in a mean plasma clearance of 86.91 h^–1m^–2. Metabolism included the formation of Adriamycin (ADM), Adriamycinol (ADM-OH), 13-dihydro-4-O-tetrahydropyranyladriamycin (THP-OH), 7-deoxyadriamycinone (7H-ADn), and 7-deoxy-13-dihydroadrimycinone (7H-ADn-OH), with maximal plasma concentrations ranging from 2.8 to 5.5 ng/ml. The mean total amount of cytotoxic anthracyclines excreted into urine, mainly as the parent drug, was 5% of the delivered dose. ADM and ADM-OH, but not the parent drug, were observed in urine at up to 4 weeks after the last therapeutic cycle. There was a significant correlation between the leukocyte nadir under therapy and the AUC of ADM-OH (r=0.800,P<0.05). Since no shift in the plasma kinetics was observed from the first to the sixth cycle, the favorable ratio of the AUCs of THP-ADM and ADM after fractionation of THP-ADM suggests lower toxic side effects attributable to ADM. This hypothesis was confirmed in a clinical study, where no severe cardiotoxicity and only mild alopecia were observed in 19 patients. Thus, pharmacokinetics studies might be helpful in both individualization of therapy with THP-ADM and optimization of the administration schedule.     

Trastuzumab‐Related Cardiotoxicity in Early Breast Cancer: A Cohort Study

Background.

Concerns have been raised about the cardiac safety profile of trastuzumab for the adjuvant treatment of early stage breast cancer in clinical practice. We assessed trastuzumab-related cardiotoxicity and its predictors in a large cohort of Italian women.

Methods.

Through a record linkage between four regional health care databases, we identified the rate of severe cardiac adverse events among women treated with trastuzumab for early breast cancer in Lombardy. The cumulative risk of cardiotoxicity was estimated using the Kaplan-Meier method, and independent predictors were assessed using the Cox model.

Results.

Of 2,046 trastuzumab users, 53 (2.6%) experienced at least one hospitalization for a cardiac event, and there were two cardiac deaths. The cumulative risk of cardiotoxicity increased up to 2 years after starting treatment, reaching a plateau at 2.8%. The risk was low (0.2%) among young women, whereas the incidence was approximately 10% in women aged ≥70 years, irrespective of cardiovascular risk factors. Age and history of cardiac disease were strong predictors of cardiotoxicity, with a hazard ratio of 11.3 (95% confidence interval [CI]: 3.5–36.6) for women aged ≥70 years as compared with those <50 years of age. Hazard ratio was 4.4 (95% CI: 2.1–9.5) for women with a history of cardiac disease compared with those without a history of cardiac disease.

Conclusions.

Cardiotoxicity of trastuzumab varies considerably across subgroups of patients. The long-term safety profile was less favorable than in the largest clinical trial. Strategies to reduce cardiotoxicity in high-risk women should be investigated.     

Bleomycin, vinorelbine and trofosfamide in relapsed stage IV cutaneous malignant melanoma patients

Purpose  To evaluate the efficacy of bleomycin, vinorelbine, and trofosfamide (BVT) in 28 patients with pretreated relapsed AJCC stage IV cutaneous malignant melanoma. Methods  Patients in relapse after first- or second-line therapy received 8 mg/m² intravenous (i.v.) bleomycin, 25 mg/m² i.v. vinorelbine, on days 1 and 6, each, and oral (p.o.) trofosfamide 60 mg/m²/day, days 1–7. BVT therapy was repeated every 5 weeks until progression of disease occurred. A maximum of six BVT cycles (mean, 2.2 cycles) was administered per patient. Results  Three patients (11%) reached a partial response; 5 (18%) patients showed stable disease, and 20 (71%) patients progressed upon BVT therapy. Median overall survival of all 28 patients was 6 months (6-month survival rate, 52%). Patients with partial remission or stable disease (n = 8) exhibited a median overall survival of 10 months (6-month survival rate, 75%), while patients with disease progression (n = 20) showed a median overall survival of 3 months (6-month survival rate, 43%). Most side effects were limited to WHO grade I/II mild anemia, leucocytopenia, fatigue, nausea/vomiting, pain, and anorexia. WHO grade III/IV side effects occurred in 7% (anorexia) and 4% (fatigue) of patients. Conclusion  Treatment with BVT was efficient in 29% of pretreated relapsed stage IV cutaneous melanoma patients, with overall good tolerability and safety.     

Cutaneous manifestations of hematologic malignancies the experience of an Italian dermatology department

In recent years, dermatologic manifestations in oncohematologic patients have become more common. The aim of our study was to determine the incidence and heterogeneity of skin manifestations in patients followed at our Hematology Department. This observational monocentrical study was conducted on 60 patients. We divided the observed conditions in exanthematous, purpuric, vesicular‐bullous, papulonodular, urticarial, and eczematous manifestations. Moreover, all lesions were classified according to pathogenesis, in (a) specific skin manifestations, caused by neoplastic skin infiltration; (b) immune‐mediated manifestations, based on immunological mechanisms; and (c) skin lesions due to immunodeficiency. Altogether, 73 clinical manifestations were reported. Specific manifestations (a) were detected in 15.1% of the cases, mainly with papulonodular appearance. Immune‐mediated manifestations (b) were found in 37 cases (50.7%), particularly with eczematous or exanthematous appearance, and leukemia was the malignancy most frequently reported in these patients. Eventually, lesions due to immunosuppression (c) were reported in 34.2% of the cases. They were represented by infections and cutaneous malignancies, and usually manifested with papulonodular lesions. Skin lesions in oncohematologic patients are a common event. A multidisciplinary approach based on the collaboration between the hematologist and the dermatologist is crucial to achieve a proper diagnosis, and correctly manage these manifestations.     

Prodrug suicide gene therapy for cancer targeted intracellular by mesenchymal stem cell exosomes

The natural behavior of mesenchymal stem cells (MSCs) and their exosomes in targeting tumors is a promising approach for curative therapy. Human tumor tropic mesenchymal stem cells (MSCs) isolated from various tissues and MSCs engineered to express the yeast cytosine deaminase::uracil phosphoribosyl transferase suicide fusion gene (yCD::UPRT-MSCs) released exosomes in conditional medium (CM). Exosomes from all tissue specific yCD::UPRT-MSCs contained mRNA of the suicide gene in the exosome's cargo. When the CM was applied to tumor cells, the exosomes were internalized by recipient tumor cells and in the presence of the prodrug 5-fluorocytosine (5-FC) effectively triggered dose-dependent tumor cell death by endocytosed exosomes via an intracellular conversion of the prodrug 5-FC to 5-fluorouracil. Exosomes were found to be responsible for the tumor inhibitory activity. The presence of microRNAs in exosomes produced from naive MSCs and from suicide gene transduced MSCs did not differ significantly. MicroRNAs from yCD::UPRT-MSCs were not associated with therapeutic effect. MSC suicide gene exosomes represent a new class of tumor cell targeting drug acting intracellular with curative potential.     

Variant classification in precision oncology

Next-generation sequencing has become a cornerstone of therapy guidance in cancer precision medicine and an indispensable research tool in translational oncology. Its rapidly increasing use during the last decade has expanded the options for targeted tumor therapies, and molecular tumor boards have grown accordingly. However, with increasing detection of genetic alterations, their interpretation has become more complex and error-prone, potentially introducing biases and reducing benefits in clinical practice. To facilitate interdisciplinary discussions of genetic alterations for treatment stratification between pathologists, oncologists, bioinformaticians, genetic counselors and medical scientists in specialized molecular tumor boards, several systems for the classification of variants detected by large-scale sequencing have been proposed. We review three recent and commonly applied classifications and discuss their individual strengths and weaknesses. Comparison of the classifications underlines the need for a clinically useful and universally applicable variant reporting system, which will be instrumental for efficient decision making based on sequencing analysis in oncology. Integrating these data, we propose a generalizable classification concept featuring a conservative and a more progressive scheme, which can be readily applied in a clinical setting.     

Analysis of mdm2 and p53 Gene Alterations in Glioblastomas and its Correlation with Clinical Factors

Malignant gliomas are the most frequent primary brain tumors. Recent studies defined several genetic markers, which might characterize molecular-biological subsets of glioblastomas with probably prognostic implications. To elucidate the involvement of murine-double-minute (mdm)2 gene amplifications and mutations of the tumor suppressor gene p53 in the tumorigenesis of malignant gliomas we analyzed a series of 75 glioblastomas. The p53 mutations occur in one-third of glioblastomas, mdm2 amplifications were found in 13% of cases. Our analysis revealed a hot spot in the p53 gene locus in codon 156, the same point mutation was detected in 4 tumor samples. None of the mdm2 amplified tumors had p53 mutations, supporting the hypothesis, that mdm2 amplifications are alternative mechanisms for p53 inactivation. Patients with p53 mutated tumors were significantly younger characterized by a mean age of 44 years. Additionally association with longer overall survival could be detected for this subgroup of patients. In our study, survival estimation revealed a significant correlation of mdm2 gene amplification with shorter survival time, and support the hypothesis, that mdm2 oncogene activation appears to occur late in tumor progression and may be characteristic as negative prognostic marker.     

Activity of abiraterone in rechallenging two AR-expressing salivary gland adenocarcinomas,resistant to androgen-deprivation therapy

Androgen-deprivation therapy (ADT) has been reported to be active in androgen receptor (AR)-expressing, relapsed/metastatic (RM), salivary gland cancers (SGCs). Abiraterone, an inhibitor of androgen synthesis, has recently been approved as a second-line treatment in hormone-resistant (HR) prostate cancer (PCa) patients. Two patients with AR-positive HR-RM adenocarcinoma, NOS of the salivary glands have been treated with abiraterone. This is the first time that this agent has been reported to be active in tumors other than HRPCa. Immunohistochemical analysis showed overexpression of EGFR, HER2, and HER3 in both untreated primary tumors. Sequencing analysis revealed a TP53 non-functional mutation in one case and a PIK3CA-activating mutation in the other. In conclusion, second line activity of ADT in AR-expressing, adenocarcinoma, NOS of salivary glands further strengthens the pathogenic and therapeutic role of AR signaling in AR-positive SGCs.