Discovery medicine
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Biliary tract cancers (BTC), which include cholangiocarcinoma (both intra- and extrahepatic) and gallbladder, represent a heterogeneous group of malignancies with relatively low-incidence and poor prognosis. Therapeutic options for BTC patients at advanced stage are severely limited and palliative chemotherapy remains the maintreatment option. ⋯ Thus, in the near term, the individual molecular alterations of the disease rather than the anatomic location will likely drive the design of clinical trials. In this review, we summarize recent molecular discoveries in BTC with a special emphasis on the most promising therapeutic targets, ultimately providing an update on current and future directions in the management of this disease.
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Prescribing medications safely and effectively in older adults is a complex process. This review discusses challenges with medication prescribing in older adults and outlines a holistic approach to medication management in older adults. Well-known challenges including the alterations in pharmacokinetics and pharmacodynamics that often occur with aging are discussed. ⋯ Newer approaches, including deprescribing, pharmacogenomics, and the future potential for senolytic therapy are also discussed. All healthcare providers should consider these challenges when prescribing medications in older adults. Choosing a drug that fits both a patient's pathophysiology and biology, avoiding drugs with significant side effects, titrating doses, and deprescribing are all critical in optimizing medication therapy.
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Review
Promise and pitfalls of immune checkpoint inhibitors in hepato-pancreato-biliary malignancies.
A growing understanding of the immune system and its anti-tumor functions has been imperative for the comprehension of malignant processes and beneficial in the pursuit of effective cancer treatments. To defend the body, immune cells must be able to differentiate between self and foreign cells using checkpoints, allowing the immune cells to attack foreign cells. Among the different types of immune target therapies recently developed, checkpoint inhibitors have come to the forefront in cancer treatment, encouraging their study in numerous different types of cancer, including hepato-pancreato-biliary malignancies (HPB). ⋯ Two classes of checkpoint inhibitors being extensively studied are inhibitors of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) ligand and programmed cell death protein 1 and its ligand (PD-1 and PD-L1). Checkpoint inhibitors have an advantage over other types of immunotherapies, such as cell-based therapies, in that they are commercially available and can be given to patients with a range of pathologies and regardless of HLA status. Herein, we will discuss the application of immune checkpoint inhibitors to HPB malignancies as well as the limitations of these medications in these cancers.
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Review Case Reports
Pathological complete response with anti-PD-1 therapy in a patient with microsatellite instable high, BRAF mutant metastatic colon cancer: a case report and review of literature.
Mismatch repair (MMR) and BRAF mutation status are established independent prognostic factors for colorectal cancer (CRC). MMR deficient tumors are considered to have better prognosis whereas BRAF mutation is associated with poor prognosis. Studies evaluating the combined effect of BRAF and MMR status suggest MSI-high and BRAF mutant patients have a poorer prognosis as compared to MSI-high and BRAF wild type patients. Emerging evidence suggests MMR status predicts the immune response to anti-PD-1 therapy in CRC patients; however little is known about combined MMR and BRAF mutation status in this context. Therefore, it is important to identify whether there is a differential response to anti-PD-1 therapy based on BRAF status in the subset of MSI-high CRC patients. ⋯ The case presented illustrates that anti-PD-1 therapy can be effectively used to treat CRC patients with MSI-high and BRAF mutant status which is usually considered a poor prognostic category as opposed to MSI-high and BRAF wild type tumors. Future studies with anti-PD-1 therapy distinguishing these molecular subgroups will improve our knowledge of whether BRAF status can add to MMR status as a predictive biomarker for anti-PD-1 therapy in patients with metastatic CRC.
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Mitochondrial disorders are now well recognized as an important cause of genetic disease. They exhibit remarkable phenotypic, biochemical, and molecular heterogeneity, and frequently involve multiple organ systems. Their complexity partly relates to the dual expression of mitochondrial proteins by both mitochondrial and nuclear genomic DNA. ⋯ Recent advancements in DNA analysis using next generation sequencing technology have provided an unprecedented expansion in the depth of knowledge concerning both molecular mechanisms and biological pathways which underpin many mitochondrial diseases. This understanding has led to the emergence of many potential targets and treatment strategies for these disorders for which there is currently no cure. This review highlights the challenges to therapy development and clinical trial design and outlines the approaches currently being investigated to treat this diverse group of disorders.