Reviews on Recent Clinical Trials - Volume 11, Issue 2, 2016

The combination of immune checkpoint inhibitors ipilimumab and nivolumab has been recently been FDA approved for first line treatment of unresectable and metastatic BRAF wild type melanoma. The approval came following the impressive results of the CheckMate 067, where the combination of ipilimumab and nivolumab appeared to outperform each as a single agent in regards to response rate and progression free survival. Though we await final overall survival data, the combination will likely be adapted by many oncologists and integrated into the ever changing melanoma treatment algorithm. In this article we aim to summarize the data leading up to the recent FDA approval and publication by Larkin et al. that presents the results from the CheckMate 067 trial. We will also further explore the feasibility, challenges, and applicability of combination immune checkpoint inhibitor therapy.

Lung cancer is a major public health problem worldwide and the leading cause of cancerrelated mortality in developed countries. Significant advances have been made especially with the discovery of targeted agents. However, only a small proportion of patients carry activating mutations; until recently conventional chemotherapy and angiogenesis inhibitors were the preferred treatment for the vast majority of patients. Now, the successful experience of anti-PD-1 agents may have opened the door to a novel and previously unexplored dimension in the treatment of lung cancer: immunotherapy. In this mini-review we will discuss the current applications and future consequences related this topic, paying special attention to the clinical studies that constitute the scientific evidence to supports its use.

Colon cancer is a leading cause of cancer related mortality. Until very recently the only existing options that medical oncologists had to treat metastatic colon cancer were a combination of chemotherapy, anti-EGFR and anti-angiogenic agents. We currently have the first proof that immune therapies could be an effective approach to battle colorectal cancers that carry a mismatch repair machinery deficient phenotype. It is expected that as our knowledge of the different mechanisms of immune-resistance grows, this therapeutic modality might soon be applicable to all patients. However, due to the continuous increase in the cost of oncological drugs, some treatment overheads may soon become prohibitive for many. In this review we will examine the current evidence related to this topic with the objective to provide the reader with concise but practical information about the potential role of immunotherapy in CRC.

Background: The clarification of several molecular pathways underlying the tumorigenesis has led to the development of several targeted drugs that have substantially improved the treatment of Non-Small-Cell Lung Cancer (NSCLC). The Epidermal Growth Factor Receptor (EGFR) is the target of several Tyrosine-Kinase Inhibitors (TKIs), some of them approved for treatment and others currently in clinical development. EGFR-TKIs markedly improve progression-free survival of patients with advanced NSCLC with EGFR mutations compared with chemotherapy. Methods: We undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question. Results: Although first- and second-generation agents offer in target population (with EGFR mutations) a substantial improvement of outcomes compared with standard chemotherapy, unfortunately, drug resistance develops after initial benefit, through a variety of mechanisms. Novel- (third) generation EGFR inhibitors have a selective mechanism of action and are currently in advanced clinical development, producing encouraging results in patients with acquired resistance to previous generation agents. Conclusion: The search for new drugs or strategies to overcome the TKI resistance in patients with EGFR mutations is to be considered a priority for the improvement of outcomes in the treatment of advanced NSCLC, and third-generation EGFR inhibitors are the most promising approach to the issue.

Type 1 diabetes represents 5-10% of patients with diabetes worldwide. The importance of tight glycemic control has been demonstrated definitively in the Diabetes Control and Complications Trial but is often elusive for patients because of the associated risk of hypoglycemia. Care for these patients requires coordination amongst a variety of health professionals including primary care providers, endocrinologists, nephrologists, ophthalmologists, pharmacists, podiatrists and others. The 21st century is witnessing emerging and exciting treatment options for this disease. Previous attempts at curative therapy have included pancreas or islet transplantation, but limitations of organ availability and the risk associated with immunosuppression have resulted in renewed efforts for novel methods of insulin replacement. Advancement in technology has resulted in several versions of an artificial pancreas—technology that uses a continuous glucose monitor to sense the blood sugar, transmit those numbers to a control algorithm that then doses insulin ± glucagon in response to changes in blood sugar. Free living experiments with two versions of the artificial pancreas have recently been published. A quest for a bioartificial pancreas has been ongoing as well. In this system, islets (porcine, human, or embryonic stem cell derived) are encapsulated in a biocompatible device that is either a macrocapsule or a microcapsule. The benefits of this system allows for replacement therapy without immunosuppression. Human trials with encapsulation are currently ongoing. This review will provide a detailed review of artificial and bioartificial pancreas systems with a focus on human trials.

The introduction of novel drugs in multiple myeloma therapy has changed disease survivals in last 15 years. Besides to be more effective in this disease new agents have been utilized in novel strategies such as consolidation and maintenance therapy. Lenalidomide has been one of the favourite in clinical trials because of its oral administration, and bortezomib has been utilized too after the drug has been proved to be effective subcutaneously. Advances in the understanding of disease biology and genetics could give a risk stratification to identify those patients who can benefit more and to better drive maintenance therapy in the future.

Background: Associated co-morbidities with psoriasis are treated with concomitant medications apart from the antipsoriatic therapy and the resulting Drug-Drug Interactions (DDI) may affect therapeutic outcome. Objective: To assess the DDI in psoriatic patients with co-morbidities. Method: In this prospective observational analysis, 150 prescriptions of psoriatic patients, receiving two or more drugs were analysed using drug interaction checker software. DDI was classified into minor, moderate, major and pharmacokinetic & pharmacodynamic. Result: Of 150 patients, 77.3% (n=116) had cardiovascular comorbities; diabetes mellitus (49.3%), psoriatic arthritis (20.7%), hyperlipidemia (46%), infections (28.7%), neurologic conditions (24.7%) and dermatologic conditions (37.3%) were other reported comorbidities. Of these, 138 (92%) patients had 612 DDI (4.49 interactions/patient). More number of interactions were seen in 45-60 yrs (n=311, 50.8%). Moderate DDI (79.9%) were higher; 306 (50%) were pharmacokinetic interactions. Frequent interactions were due to non-steroidal anti-inflammatory drugs (n=229, 37.4%) and antibiotics (n=176, 28.8%). Monitoring of the signs & symptoms was the advised intervention in 67.2% of patients. Mean DDI per patient was more in those who received >10 drugs (9.67). There was an increased number of DDI with an increase in the number of medications which was statistically significant (p<0.01), with greater number of (n=458, 74.8%) interactions seen in those who received 5-10 drugs. Conclusion: There was an increased number of DDI in those who received more number of drugs. Careful monitoring with appropriate timely laboratory investigations, and a rational drug prescription for the comorbid conditions can prevent the occurrence of harmful DDIs.

Background: This manuscript addresses the multilevel role of dietary nitrate and nitrite in health and diseases because of increased interest in dietary supplementation. Method: Review of research devoted to both beneficial but also possible deleterious effects of uncontrolled indigestion of red beet-root juice and other sources of high concentrated nitrate and nitrite. Results: The body of evidence strongly suggested that persons using nitrate/nitrite supplementation and particularly patients treated with sodium nitrite, having kidney disease or impaired methemoglobin reeducates activity, should closely monitor nitrate/nitrite indigestion. Conclusion: Oral intake of red beet-root juice, green leaved veggies, cured meat, as well as urine excretion of nitrate/ nitrite, methemoglobin reeducates activity should be carefully assessed especially in patients treated with sodium nitrite.

Introduction: Breast cancer and pregnancy is rare. It is defined by the discovery of breast cancer during pregnancy or within one year after delivery. Throughout this study, we analyzed the characteristics of this entity with review of the literature. Materials and Methods: We report through a retrospective study of breast cancer in pregnant women, a series of 11 cases collected at the oncology department in Sfax between 1994 and 2012. Result: The average age of our patients at diagnosis was 35 years. The average term of pregnancy was 22 weeks. Nine cases were diagnosed during pregnancy. The pregnancy outcome was well with babies in a good health, in 10 cases. The prognosis was excellent with complete remission after a mean follow of 39 months in 7 cases (2years-9years). Conclusion: The diagnosis of breast cancer in pregnant women is often delayed because of physiological changes of pregnancy and the young age which explain the poor prognosis of this entity. The prognosis was excellent in our series compared to the literature.

After long defeats-almost no marked breakthrough in HIV vaccination campaign has been observed during the past two decades, and we still have not lost our faiths for the development of highly effective and low risk HIV vaccines. Many effective vaccines have been discovered and will certainly enter into the markets within the next 5 to 10 years. In order to promote HIV vaccine developments and clinical HIV therapeutic improvements, this perspective addresses the good and bad sides of currently available HIV vaccines, discusses many subjects of medical significance and finally provides up-to-date information in the field of HIV studies, in particular regarding vaccine developments and HIV pathogenesis.

Background: Non-Cirrhotic Portal Hypertension (NCPH) is a rare but potentially fatal liver disorder described in patients treated with anti-retroviral therapy for Human Immunodeficiency Virus (HIV). In particular, the most important predisposing factor to its development has been identified as prolonged exposure to Didanosine (ddI). The clinical entity of NCPH is characterized by an increase in portal pressure due to pre- or intra-hepatic causes, in absence of liver cirrhosis. However, the exact pathogenesis remains poorly understood, and due to its rarity, the diagnosis is often delayed. Objective: We herein report a case in which ddI administration, with concomitant spontaneous bacterial peritonitis by Streptococcus agalactiae, has induced NCPH in a HIV male patient. Conclusion: NPCH should be suspected when HIV patient with an history of ddI treatment presents liver decompensation.