Advanced Adrenocortical Carcinoma: Current Perspectives on Medical Treatment.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. For stage I and II tumors, surgery is a curative option, but even in these cases recurrence is frequent. Practical guidelines advocate a combination of mitotane with etoposide, doxorubicin, and cisplatin as first-line therapy for metastatic adrenocortical carcinoma. However, this scheme presents limited efficacy and high toxicity. The use of Immune Checkpoint Inhibitors (ICI) and multi-Tyrosine Kinase Inhibitors (mTKI) has modified the approach of multiple malignancies. The expectation of their applicability on advanced adrenocortical carcinoma is high but the role of these new therapies persists unclear. This article provides a short summary of last years' findings targeting outcomes, limitations, and adverse effects of these new therapeutic approaches. The results of recent trials and case series pointed pembrolizumab as the most promising drug among these new therapies. It is the most often used ICI and the one presenting the best results with less related adverse effects when in comparison to the standard treatment with mitotane. Hereafter, the identification of specific molecular biomarkers or immune profiles associated with ICI or mTKI good response will facilitate the selection of candidates for these therapies. So far, microsatellite instability and Lynch Syndrome related germline mutations are suggested as predictive biomarkers of good response. Contrarywise, cortisol secretion has been associated with more aggressive ACC tumors and potentially poor responses to immunotherapy.

Mechanistic Rationales Guiding Combination Hepatocellular Carcinoma Therapies Involving Immune Checkpoint Inhibitors.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers because of late symptom manifestation leading to delayed diagnosis, which limits patients with HCC in terms of receiving curative surgical treatment. There are only a few therapeutic options for patients with advanced HCC. The emergence of immune checkpoint inhibitors (ICIs) brings HCC treatment to a stage at which nivolumab, an anti-programmed cell death protein 1 monoclonal antibody, achieves a 20% response rate. However, the large proportion of unresponsive patients drives the exploration of therapeutic strategies to improve ICIs' efficacy. Recent preclinical and clinical studies have suggested that ICIs, when used in combinations or when used with other cancer therapies, might elicit synergistic antitumor effects. However, the mechanistic rationales guiding different drug combinations to maximize this synergy remain largely ambiguous. In this review, we discuss different drug combinations used in HCC and the underlying mechanistic rationales, aiming to enhance the understanding of how these treatments can achieve synergy. This knowledge sets the foundation for the development of more effective and promising combination therapies for HCC.

[An orally administered glucagon-like peptide 1 (GLP1) analogue: A landmark in the treatment of type 2 diabetes]. / Un analogue du glucagon-like peptide 1 (GLP1) administré par voie orale - Une nouveauté dans le traitement du diabète de type 2.

Semaglutide is the first peptide to receive European marketing authorization for oral administration in the treatment of type 2 diabetes. The active molecule is the same as the one marketed for weekly subcutaneous administration. It is associated with a new excipient, which protects it from degradation by gastric pepsin and allows its absorption in the stomach. This article presents the pharmacological characteristics of this drug, as well as a critical analysis of the results of the main phase III clinical trials.

TITLE: Un analogue du glucagon-like peptide 1 (GLP1) administré par voie orale - Une nouveauté dans le traitement du diabète de type 2. ABSTRACT: Le sémaglutide est le premier peptide à avoir reçu une autorisation européenne de mise sur le marché, pour une administration quotidienne par voie orale dans le traitement du diabète de type 2. La molécule active est identique à celle qui est déjà commercialisée pour une administration hebdomadaire par voie sous-cutanée. Elle est associée à un nouvel excipent, qui la protège de la dégradation par la pepsine gastrique et permet son absorption dans l'estomac. Cet article présente les caractéristiques pharmacologiques du médicament dans sa nouvelle formulation, ainsi qu'une analyse critique des résultats des principaux essais cliniques de phase III dans lesquels elle a été testée.

Re-Sensitizing Tumor Cells to Cancer Drugs with Epigenetic Regulators.

Cancer drug resistance is a major problem for cancer therapy. While many drugs can be effective in first-line treatments, cancer cells can become resistant due to genetic (mutations and chromosomal aberrations) but also epigenetic changes. Hence, many research studies addressed epigenetic drugs in circumventing resistance to conventional therapeutics in different tumor entities and in increasing the efficiency of immune checkpoint therapies. Furthermore, repositioning of already approved drugs in combination with epigenetic modifiers could potentiate their efficacy and thus could be an attractive strategy for cancer treatment. Summarizing, we recapitulate current data on epigenetic drugs and their targets in modulating sensitivity towards conventional and immune therapies, providing evidence that altering expression profiles by epigenetic modifiers holds great potential to improve the clinical outcome of cancer patients.

Rational Cancer Treatment Combinations: An Urgent Clinical Need.

We are witnessing several revolutionary technological advances in cancer. These innovations have not only contributed to a growing understanding of the tumor and its microenvironment but also uncovered an increasing array of new therapeutic targets. For most advanced cancers, therapy resistance limits the benefit of single-agent therapies. Therefore, some 5,000 clinical trials are ongoing globally to probe the clinical benefit of new combination treatments. However, the possibilities to combine individual treatments dramatically outnumber the patients available to enroll in clinical trials. This comes at a potential cost of missed opportunities, clinical failure, avoidable toxicity, insufficient patient accrual, and financial loss. A solution may be to design combination therapies more rationally, which are informed by fundamental biological and mechanistic insight. We will discuss some successes and failures of current treatment combinations, as well as interesting emerging preclinical concepts that warrant clinical exploration.

[Advances in Combination Therapy of Immune Checkpoint Inhibitors for Lung Cancer].

Immune checkpoint inhibitors (ICIs) therapy is the most commonly used immunotherapy regimen at present. It has been approved for clinical treatment of melanoma, kidney cancer, head and neck cancer, bladder cancer and other tumors. It has made a breakthrough in the treatment of lung cancer and become a new pillar of comprehensive treatment of lung cancer. However, ICIs alone is less effective in non-selective patients, and combination therapy has become a hot topic of exploration. This article focuses on the development of combined immune checkpoint inhibitors and describes how immunotherapy can be used to treat early stage cancer.

Diabetic retinopathy, a vascular and inflammatory disease: Therapeutic implications.

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of visual impairment in the working-age population in the Western world. Diabetic macular oedema (DME) is one of the major complications of DR. Therapy with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs has become the gold standard treatment for DR and its complications. However, these drugs have no effect on the pathogenesis of DR and must be administered frequently via invasive intravitreal injections over many years. Thus, there is a pressing need to develop new therapeutic strategies to improve the treatment of this devastating disease. Indeed, an increasing volume of data supports the role of the inflammatory process in the pathogenesis of DR itself and its complications, including both increased retinal vascular permeability and neovascularization. Inflammation may also contribute to retinal neurodegeneration. Evidence that low-grade inflammation plays a critical role in the pathogenesis of DME has opened up new pathways and targets for the development of improved treatments. Anti-inflammatory compounds such as intravitreal glucocorticoids, topical non-steroidal anti-inflammatory drugs (NSAIDs), antioxidants, inflammatory molecule inhibitors, renin-angiotensin system (RAS) blockers and natural anti-inflammatory therapies may all be considered to reduce the rate of administration of antineovascularization agents in the treatment of DR. This report describes the current state of knowledge of the potential role of anti-inflammatory drugs in controlling the onset and evolution of DR and DME.

Oral medical dissolution of gallstones in patients with gallstone disease

Being the main treatment for cholelithiasis, laparoscopic cholecystectomy does not always solve the problem. It often entails postcholecystectomy syndrome (PCS). Oral medication to dissolve gallstones with bile acids is alternative therapy for some patients. However, lack of efficacy and limited medical indications make it necessary to apply combination treatment tactics. This study was conducted to investigate the dissolution of gallstones during the combined effects of ursodeoxycholic acid (UDCA) and rosuvastatin as well as to assess the results of eradication therapy in the presence of H. pylory as a measure to prevent cholelithiasis in the course of treatment.

Polypharmacy, defined as taking five or more drugs, is inadequate in the cardiovascular setting.

BACKGROUND: By how much polypharmacy (defined by number of drugs) differs from polyactive ingredient use (defined by the number of pharmacologically active ingredients) has not been assessed. OBJECTIVES: To compare the extent of polypharmacy vs. polyactive ingredients among patients taking cardiovascular (CV) medicines. METHODS: Prospective, 10-year follow-up study conducted among 880 participants of the CoLaus study taking CV drugs at baseline. Polypharmacy was defined as the use of five or more CV medicines; polyactive ingredient use was defined as the use of five or more pharmacologically active CV ingredients. RESULTS: The prevalence of polypharmacy increased from 1.4% (0.7-2.4) (prevalence rate [95% confidence interval]) at baseline to 11.9% (9.9-14.3) at follow-up, and the prevalence of polyactive ingredients increased from 2.4% (1.5-3.6) at baseline to almost 17.6% (15.2-20.3) at follow-up. The prevalence of combination drugs increased from 15.7% (13.3-18.3) at baseline to 25.9% (23-28.9) at follow-up, and the prevalence of three-component combination use increased from 0.1% (0.0-0.6) at baseline to 2.3% (1.4-3.5) at follow-up. At baseline, nine of 21 participants on polyactive ingredients were not considered as being on polypharmacy; at follow-up, the rate was 50 of 155 participants. CONCLUSION: Among individuals taking CV drugs, polypharmacy as defined by the number of drugs underestimates the prevalence of individuals taking five or more pharmacologically active drugs. Polypharmacy should no longer be based on the number of drugs but on the number of pharmacologically active drugs.

Tissue selective estrogen complex (TSEC): a review.

OBJECTIVE: This review describes historical development of selective estrogen receptor modulators (SERMs) and their combination with estrogens, termed a tissue selective estrogen complex (TSEC), and considers the potential for future TSEC development. METHODS: This narrative review is based on literature identified on PubMed and the TSEC research and development experience of the authors. RESULTS: SERMs have estrogenic and antiestrogenic effects in various tissues; however, no single agent has achieved an optimal balance of agonist and antagonist effects for the treatment of menopausal symptoms. Clinically, a number of SERMs protect against osteoporosis and breast cancer but can exacerbate vasomotor symptoms. Estrogens alleviate menopausal hot flushes and genitourinary symptoms as well as reduce bone loss, but the addition of a progestogen to menopausal hormone therapy to protect against endometrial cancer increases vaginal bleeding risk, breast tenderness, and potentially breast cancer. The search for an effective menopausal therapy with better tolerability led to the investigation of TSECs. Clinical development of a TSEC consisting of conjugated estrogens/bazedoxifene increased understanding of the importance of a careful consideration of the combination's components and their respective doses to balance safety and efficacy. Bazedoxifene is an estrogen receptor agonist in bone but an antagonist/degrader in the endometrium, which has contributed to its success as a TSEC component. Other oral TSEC combinations studied thus far have not demonstrated similar endometrial safety. CONCLUSIONS: Choice of SERM, selection of doses, and clinical trial data evaluating safety and efficacy are key to ensuring safety and adequate therapeutic effect of TSECs for addressing menopausal symptoms.

A Clinical Update and Global Economic Burden of Rheumatoid Arthritis.

BACKGROUND AND OBJECTIVE: Rheumatoid arthritis (RA) is a predominant inflammatory autoimmune disorder. The incidence and prevalence of RA is increasing with considerable morbidity and mortality worldwide. The pathophysiology of RA has become clearer due to many significant research outputs during the last two decades. Many inflammatory cytokines involved in RA pathophysiology and the presence of autoantibodies are being used as potential biomarkers via the use of effective diagnostic techniques for the early diagnosis of RA. Currently, several disease-modifying anti-rheumatic drugs are being prescribed targeting RA pathophysiology, which have shown significant contributions in improving the disease outcomes. DISCUSSION: Even though innovations in treatment strategies and monitoring are helping the patients to achieve early and sustained clinical and radiographic remission, the high cost of drugs and limited health care budgets are restricting the easy access of RA treatment. Both direct and indirect high cost of treatment are creating economic burden for the patients and affecting their quality of life. CONCLUSION: The aim of this review is to describe the updated concept of RA pathophysiology and highlight current diagnostic tools used for the early detection as well as prognosis - targeting several biomarkers of RA. Additionally, we explored the updated treatment options with side effects besides discussing the global economic burden.

Locally advanced pancreatic cancer: An emerging entity.

Pancreatic adenocarcinoma (PDAC) remains a highly fatal disease that is increasing in incidence. PDAC can be classified according to resectability status with 3 nonmetastatic groups defined: resectable, borderline resectable, and locally advanced PDAC (LAPC). Delineating these subtypes is important with the optimal treatment approach dictated by high-quality CT imaging and multidisciplinary team discussion. Patients with LAPC are thought unresectable and are therefore rarely cured. In these patients, chemotherapy remains the mainstay of treatment. Aggressive approaches in this cohort are increasingly employed. Local therapies after induction chemotherapy including standard fractionation radiation, stereotactic body radiotherapy (SBRT), and irreversible electroporation (IRE) are being investigated in an attempt to improve long-term control. In some cases, responses to neoadjuvant therapy may facilitate surgical resection. Biomarkers that can select patients most likely to benefit from these options are urgently needed. This review aims to highlight the emerging treatment of patients with LAPC and to discuss current trials.

An Insight on the Pathogenesis and Treatment of Systemic Lupus Erythematosus.

BACKGROUND AND OBJECTIVE: Systemic lupus erythematosus (SLE) is a diverse autoimmune disorder, evoked in response to self-immune system that leads to immune complex depositions and organ damage. The exact mechanism of SLE pathogenesis is still unclear but certain genetic and environmental factors have been suggested that could influence its pathogenesis. DISCUSSION: The modulation in B- and T- cell responses and genetic variations could lead to abnormal lymphocyte functions and the production of antibodies against the indigenous proteins and the immune complex depositions. CONCLUSION: The present review highlights the various causatives of SLE, particularly the genetic alteration in B- and T-cell-related proteins. We have also delineated some of the available therapeutic strategies for the treatment of SLE.

Emerging therapies for acute myeloid leukemia.

Acute myeloid leukemia (AML) is characterized by clinical and biological heterogeneity. Despite the advances in our understanding of its pathobiology, the chemotherapy-directed management has remained largely unchanged in the past 40 years. However, various novel agents have demonstrated clinical activity, either as single agents (e.g., isocitrate dehydrogenase (IDH) inhibitors, vadastuximab) or in combination with standard induction/consolidation at diagnosis and with salvage regimens at relapse. The classes of agents described in this review include novel cytotoxic chemotherapies (CPX-351 and vosaroxin), epigenetic modifiers (guadecitabine, IDH inhibitors, histone deacetylase (HDAC) inhibitors, bromodomain and extraterminal (BET) inhibitors), FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors, and antibody-drug conjugates (vadastuximab), as well as cell cycle inhibitors (volasertib), B-cell lymphoma 2 (BCL-2) inhibitors, and aminopeptidase inhibitors. These agents are actively undergoing clinical investigation alone or in combination with available chemotherapy.

Role of Probiotics in Managing of Helicobacter Pylori Infection: A Review.

Background:Helicobacter pylori is a prevalent pathogen which is considered as an etiological cause for gastroduodenal ulcers, and a substantial risk factor for gastric malignancies. The vital factor to take into account is that roughly half of the world's population is infected with this bacterium. However, most subjects colonized remain asymptomatic and do not require any treatment. Several antimicrobial agents such as amoxicillin, clarithromycin and metronidazole are used to eradicate the infection. However, these drug regiments do not eradicate H. pylori in all patients because of the anti-drug resistance. Aim: In this review we aim to discuss the role and mechanisms of probiotics, as supportive medicines, in management of H. pylori infection. Methods: We have reviewed the published articles in PubMed and Medline databases. Also, abstracts presented in international conferences on the management of H. pylori infections and treatment protocol, have been thoroughly reviewed. Results: The overall trend in the literature indicates the usefulness of probiotics in controlling H. pylori infection. This bacterium is among the most studied human pathogens regarding the efficacy of probiotics for treating its infection. Nevertheless, some studies suggest that probiotics do not efficiently eradicate H. pylori but retain the number of this bacterium at low levels inside the human stomach. Conclusion: The analyzed literature suggest that when probiotics are consumed in conjunction with antibiotics, the eradication rate may be improved through modulating the immune response and decreasing the adverse effects of routine drugs leading to gastroprotection.