Abdo Haddad

The pharmacological importance of cytochrome CYP3A4 in the palliation of symptoms: review and recommendations for avoiding adverse drug interactions

BackgroundAdverse drug interactions are major causes of morbidity, hospitalizations, and mortality. The greatest risk of drug interactions occurs through in the cytochrome system. CYP3A4, the most prevalent cytochrome, accounts for 30–50% of drugs metabolized through type I enzymes.Materials and methodsPalliative patients received medications for symptoms and co-morbidities, many of which are substrate, inhibitors, or promoters of CYP3A4 activity and expression. A literature review on CYP3A4 was performed pertinent to palliative medicine.DiscussionIn this state of the art review, we discuss the CYP3A4 genetics, and kinetics and common medications, which are substrates or inhibitor/promoters of CYP3A4.ConclusionWe made some recommendations for drug choices to avoid clinically important drug interaction.

Single nucleotide polymorphism arrays complement metaphase cytogenetics in detection of new chromosomal lesions in MDS

Single nucleotide polymorphism arrays complement metaphase cytogenetics in detection of new chromosomal lesions in MDS

Hypocupremia and bone marrow failure

Copper deficiency associated with neurological disorders is a well-documented condition. However, hypocupremia is less often recognized as a cause of cytopenias or bone marrow failure. We report an illustrative series of three new cases of bi-lineage cytopenia associated with copper deficiency. We have analyzed clinical features of current and historical cases to identify clues that could facilitate application of appropriate laboratory testing and heighten the level of clinical suspicion. By maintaining an appropriately high level of suspicion for potential copper deficiency and obtaining a serum copper level, bone marrow failure due to this condition can be correctly diagnosed and treated. We suggest that copper deficiency be included in the differential diagnosis of reversible causes of bone marrow failure syndromes including myelodysplastic syndrome.

Components of the anorexia–cachexia syndrome: gastrointestinal symptom correlates of cancer anorexia

IntroductionCancer-related anorexia is traditionally considered part of a complex but ill-defined anorexia–cachexia syndrome in which anorexia is intimately associated with other gastrointestinal (GI) symptoms and weight loss. We surveyed cancer patients with anorexia to learn more about the relationship between anorexia and these symptoms.Materials and methodsA 22-item GI questionnaire assessed the severity of anorexia and the prevalence of concurrent GI symptoms, including taste changes, food aversions, altered sense of smell, and diurnal food intake changes. The relationship between anorexia severity and anticancer therapy and prior menstrual or pregnancy-related appetite changes was also assessed.ResultsNinety-five of 101 patients with anorexia surveyed had complete data. Seventy-eight percent of them had moderate or severe anorexia. Abnormal diurnal appetite variation, taste changes, and food aversions were present in over 50% of all those with anorexia. Judged by the numerical rating scale, the worse the anorexia, the more prevalent were early satiety, constipation, vomiting, and food aversions. Those with more severe anorexia had greater weight loss, and worse performance status. Anorexia severity did not correlate with that during prior menses/pregnancy or antitumor therapy.ConclusionsEvaluation of multiple other GI symptoms is important in understanding the total experience of cancer anorexia. Early satiety, taste changes, food aversions, and altered sense of smell are important accompanying GI symptoms. Most validated anorexia tools do not assess these commonly associated GI symptoms. Future research should develop a comprehensive anorexia symptom questionnaire.

Primary Cardiac Sarcoma: 25-Year Cleveland Clinic Experience.

Background:Cardiac sarcomas are rare and have a poor prognosis. The median overall survival remains dismal and has been reported ranging from 6 months to a few years. Primary cardiac sarcoma is the most common malignant tumor comprising approximately 95% of all malignant tumors of the heart. Methods:We conducted a retrospective chart review in a single institution of patients diagnosed between March 1988 and April 2013. A total of 42 patients were identified. The following variables were studied: age at diagnosis, year of diagnosis, sex, stage, site of tumor involvement, tumor histology, grade, treatment modality, type of chemotherapy, and survival outcome. The overall median follow-up time was 49.5 months. Results:The most common histologic type was angiosarcoma. Overall estimated median survival (EMS) was 25 months. Tumors involving the left side of the heart and pericardium demonstrated better survival. Patients who received multimodality treatment (any combination of surgery, radiation therapy, and chemotherapy) had an EMS of 36.5 months compared with 14.1 months for patients treated with surgery, radiation therapy, or chemotherapy only (P=0.05). Conclusions:Cardiac sarcoma is a lethal tumor with an EMS of 25 months. The tumor histology could be a possible predictor of better survival. Although selection bias may have been present, multimodality therapy (surgery, radiation therapy, and chemotherapy) was associated with improved survival.

Targeted therapy for lung cancer.

Lung cancer is considered the number one killer among all cancers. Recent observations have altered the treatment paradigm for non-small-cell lung cancer (NSCLC). The discovery of activating mutations in the epidermal growth factor receptor and anaplastic lymphoma kinase positivity has made personalized treatment for NSCLC more feasible. Both erlotinib and crizotinib have been shown to be effective and safe for subgroup populations, and now personalized treatment for nonsquamous NSCLC has progressed even further. New tyrosine kinase inhibitors are being tested, resistant mutations are being studied, and new detection systems are being incorporated; all these developments will make the detection and treatment of the deadliest cancer more affordable, practical, and effective. The National Comprehensive Cancer Network has already incorporated these new developments into their guidelines for advanced nonsquamous NSCLC.

Gene expression profiling for early-stage NSCLC

Lung cancer is the leading cause of cancer-related death in both developed and developing countries with unacceptably high mortality even for early-stage cancers. Present guidelines do not recommend adjuvant chemotherapy for stage I non–small cell lung carcinoma and prompts a search for a prognostic marker that would separate stage I patients into 2 groups, those who would benefit and those who would not benefit from adjuvant treatment. Studies during the last decade showed that the gene expression profiling can be the biomarker being sought. Many gene expression profiling have been found and reported from the analysis of surgical specimens of resected lung cancers during the last decade, and many of them had been shown to have an excellent predictive accuracy. These profiles used in the studies had not only different gene combinations but also different number of genes and methods of identification. Researchers have used microarray assays, RT-quantitative polymerase chain reaction, and more recently microRNA-based techniques to achieve this goal. Unfortunately, most of the profiles were not sufficiently validated and/or were not used in prospective phase III studies. This review focuses on major studies in the field, future prospects, as well as the lessons learned so far. It is shown that the gene expression profiles have a good chance of being implemented in future everyday practice.

Geriatric Oncology and Palliative Medicine

People age 65 years and older are the fastest growing segment of the US population. Cancer is one of the leading causes of death in the elderly. Geriatric oncology has developed since most cancer cases are diagnosed in elderly patients and the majority of cancer deaths occur in elderly patients. Little is known on how to best treat elderly patients with cancer and deal with treatment side effects and palliative care. Most recommendations have focused on the need for clinical trials specifically for the elderly with cancer, and a short, easy tool to predict chemotherapy toxicity. The focus of geriatric oncologists has been to integrate geriatric assessment into the care of the elderly cancer patient and find new assessment tools to predict chemotherapy tolerance, toxicity, and outcomes. Understanding the importance of supportive management during antineoplastic treatment and developing an intentional approach to palliative care issues (which are an important part of treating elderly patients with cancer) will help patients complete a full treatment course and maintain quality of life.

Complete Durable Response From Carboplatin and Olaparib in a Heavily Pretreated Triple-Negative Metastatic Breast Cancer With Germline BRCA2 and “BRCAness” Mutations

Case Presentation, Management, and Outcome The patient is a 62-year-old female with stage IV triple-negative invasive ductal carcinomaof the left breast, cT3N1M1, nuclear grade3,diagnosed in July2013(Fig 1A). She was treated with dose-dense doxorubicin 60 mg/mandcyclophosphamide600mg/m for four cycles followed by paclitaxel once per week starting in November 2013. She had a good response in the left breast and pulmonary nodules per scans. After discussion, she had a simple mastectomy in January 2014. Pathology revealed two foci of residual invasive ductal carcinomawith treatment effect (0.11 cm and 0.1 cm) and ductal carcinoma in situ with comedo necrosis. Three sentinel lymph nodes were negative. In July 2014, progression was found in the lung, and the largest pulmonary nodule was 6.4 mm. While undergoing restaging work-up in August, magnetic resonance imaging scans of the brain showed a 3-cm mass in the left frontal lobe. The resected lesion showed metastatic adenocarcinoma positive for PTEN loss, BRCA2 9435_9436delGT,MYC amplification, TP53 R196*, FAS loss, and RB1 loss according to a next-generation sequencing-based assay from FoundationOne. The left frontal area was treated with Gamma Knife surgery in September. Gemcitabine 800 mg/m on days 1 and 8 every 3 weeks was started in October. Because of progression in January 2015, the patient was considered for the Study of Glembatumumab Vedotin (CDX-011) in Patients With Metastatic, gpNMB Over-Expressing, Triple Negative Breast Cancer (METRIC) trial. She was tested for BRCA at the same time, and Integrated BRCAnalysis confirmed germline BRCA2 mutation of 9663delGT. Her breast tumor had glycoprotein NMB overexpression, but she was randomly assigned to the control arm with capecitabine 1,250 mg/m. On the basis of scans, she had stable disease by mid-March. In May, capecitabine was stopped because of progression (Fig 1B). With rapid

New anticoagulants in cancer patient treatments.

Venous thromboembolism (VTE) is a common complication of cancer patients. Initiation of anticoagulant treatment is of vital importance once a diagnosis of VTE has been established. Unfractionated heparin and low-molecular-weight heparins (LMWH) have been the mainstay for in-hospital-based prophylaxis, both postsurgically and on medicine floors, and for the acute management of VTE. The current international guidelines, including American Society of Clinical Oncology, the American College of Chest Physicians, the European Society of Medical Oncology, and the International Society of Thrombosis and Hemostasis, recommend the use of LMWH monotherapy for the long-term management of cancer patients with established acute symptomatic VTE. Although LMWHs have become the preferred treatment for patients with cancer, problems with its use have prompted clinicians to seek newer antithrombotic agents.