Molecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers.

The dysregulation of the phosphatidylinositol-3-kinase (PI3K) pathway can lead to uncontrolled cellular growth and tumorigenesis. Targeting PI3K and its downstream substrates has been shown to be effective in preclinical studies and phase III trials with the approval of several PI3K pathway inhibitors by the Food and Drug Administration (FDA) over the past decade. However, the limited clinical efficacy of these inhibitors, intolerable toxicities, and acquired resistances limit the clinical application of PI3K inhibitors. This review discusses the PI3K signaling pathway, alterations in the PI3K pathway causing carcinogenesis, current and novel PI3K pathway inhibitors, adverse effects, resistance mechanisms, challenging issues, and future directions of PI3K pathway inhibitors.

Molecular Targeting of the Human Epidermal Growth Factor Receptor-2 (HER2) Genes across Various Cancers.

Human epidermal growth factor receptor 2 (HER2) belongs to the ErbB family, a group of four transmembrane glycoproteins with tyrosine kinase activity, all structurally related to epidermal growth factor receptor (EGFR). These tyrosine kinases are involved in the transmission of cellular signals controlling normal cell growth and differentiation. If this transmission goes awry, it can lead to dysregulated growth of the cell. HER2 specifically can be implicated in the pathogenesis of at least eight malignancies. HER2 positivity quickly became a well-characterized indicator of aggressiveness and poor prognosis, with high rates of disease progression and mortality. After realizing the implication of HER2, it first became investigated as a target for treatment in breast cancer, and later expanded to areas of research in other cancer types. To this day, the most therapeutic advancements of anti-HER2 therapy have been in breast cancer; however, there have been strong advancements made in the incorporation of anti-HER2 therapy in other cancer types as well. This comprehensive review dissects HER2 to its core, incorporating the most up to date information. The topics touched upon are discussed in detail and up to 200 published sources from the most highly recognized journals have been integrated. The importance of knowing about HER2 is exemplified by the groundbreaking advancements that have been made, and the change in treatment plans it has brought to the oncological world in the last twenty years. Since its groundbreaking discovery there have been significant breakthroughs in knowledge regarding the actual receptor, the receptors biology, its mechanism of action, and advancements in tests to detect HER2 and significant strides on how to best incorporate targeted treatment. Due to the success of this field thus far, the review concludes by discussing the future of novel anti-HER2 therapy currently in development that everyone should be aware of.

Molecular Targeting of the Fibroblast Growth Factor Receptor Pathway across Various Cancers.

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that are involved in the regulation of cell proliferation, survival, and development. FGFR alterations including amplifications, fusions, rearrangements, and mutations can result in the downstream activation of tyrosine kinases, leading to tumor development. Targeting these FGFR alterations has shown to be effective in treating cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid neoplasms, and there are currently four FGFR inhibitors approved by the Food and Drug Administration (FDA). There have been developments in multiple agents targeting the FGFR pathway, including selective FGFR inhibitors, ligand traps, monoclonal antibodies, and antibody-drug conjugates. However, most of these agents have variable and low responses, with some intolerable toxicities and acquired resistances. This review will summarize previous clinical experiences and current developments in agents targeting the FGFR pathway, and will also discuss future directions for FGFR-targeting agents.

Molecular Targeting of the BRAF Proto-Oncogene/Mitogen-Activated Protein Kinase (MAPK) Pathway across Cancers.

The mitogen-activated protein kinase (MAPK) pathway is essential for cellular proliferation, growth, and survival. Constitutive activation of this pathway by BRAF mutations can cause downstream activation of kinases, leading to uncontrolled cellular growth and carcinogenesis. Therefore, inhibition of BRAF and the downstream substrate MEK has been shown to be effective in controlling tumor growth and proliferation. Over the last decade, several BRAF and MEK inhibitors have been investigated, ranging from primarily melanoma to various cancer types with BRAF alterations. This subsequently led to several Food and Drug Administration (FDA) approvals for BRAF/MEK inhibitors for melanoma, non-small cell lung cancer, anaplastic thyroid cancer, colorectal cancer, histiocytosis neoplasms, and finally, tumor-agnostic indications. Here, this comprehensive review will cover the developments of BRAF and MEK inhibitors from melanomas to tumor-agnostic indications, novel drugs, challenges, future directions, and the importance of those drugs in personalized medicine.

A Mysterious Paratracheal Mass: Parathyroid Carcinoma.

Parathyroid carcinoma is a rare cause of primary hyperparathyroidism. We detail a 60-years-old gentleman who was otherwise healthy presented to the hospital due to acute encephalopathy. He was subsequently found to have parathyroid carcinoma as the cause of the acute encephalopathy with impressive serum calcium and parathyroid hormone levels. The parathyroid carcinoma was later surgically resected with the diagnosis confirmed via pathology specimen. The patient was safely discharged from the hospital with recommendations of close routine outpatient followup.

A Silent Fatal Presentation of Pulmonary Embolism: Reflection and Discussion.

Acute pulmonary embolism is a common medical condition that clinicians face in practice. It is important to have a prompt diagnosis with proper management as it is associated with high morbidity and mortality. However, a timely diagnosis is often difficult to obtain especially when the presenting symptoms are atypical, but the consequence could be fatal. We present an 80-year-old gentleman who presented with a near-syncope episode who subsequently was found to have acute extensive bilateral pulmonary embolisms after a code blue event.

An Exceedingly Rare Presentation of Severe Folate Deficiency-Induced Non-Immune Hemolytic Anemia.

Macrocytic anemia is usually associated with vitamin B12 or folate deficiency. However, folate deficiency was rarely reported as a cause of hemolytic anemia. We present a case of a young man with a history of alcohol abuse who initially presented with an acute on chronic abdominal pain and was found to have jaundice and scleral icterus. His liver enzymes were unremarkable, and his abdominal imaging did not reveal any acute pathology. However, he was found to have a severe non-immune hemolytic anemia secondary to folate deficiency.

A Mysterious Paratracheal Mass: Pulmonary Agenesis.

A 35-year-old lady with a history of possible tuberculosis infection 15 years ago presented to the clinic with the chief complaint of cough. Incidental chest CT showed a right paratracheal and medial right apical heterogeneous soft tissue mass with central areas of calcification that warranted further investigation. A routine endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) discovered isolated lobar pulmonary agenesis as the underlying cause of the mass without findings of malignancy on pathology reports.

A Rare Case Report and Literature Review of Anabolic-Androgenic Steroids (AAS)-Induced Acute Myocardial Infarction.

Anabolic-androgenic steroids (AAS) abuse is common in competitive athletes in order to enhance athletic performances. However, AAS abuse is often associated with deleterious side effects including but not limited to cardiovascular diseases, depression, hormonal abnormalities, and cancer. We present a case of a 31-year-old male with a history of Crohn's disease on infliximab and chronic AAS use who had persistent retrosternal chest pain found to have an acute myocardial infarction (MI) without obvious cardiovascular risk factors.

Iron Deficiency Anemia: An Unexpected Cause of an Acute Occipital Lobe Stroke in an Otherwise Healthy Young Woman.

A 29-year-old caucasian woman who presented to the hospital with an acute onset of right eye visual disturbance and headache was found to have an acute left occipital lobe infarction. Past medical history was significant for iron deficiency anemia (IDA) secondary to menorrhagia. Her initial hemoglobin level was 7.8 G/DL, and her symptoms improved after iron and blood transfusions. Hypercoagulable studies were completed in the outpatient setting, and the results were unremarkable. Her acute stroke was most likely related to IDA as she had low cardiovascular risk factors along with a negative complete stroke workup.

Anosmia and Ageusia as the Only Indicators of Coronavirus Disease 2019 (COVID-19).

The patient is a 60-year-old woman with a history of vertigo and seasonal allergies who presented to the hospital with the chief complaint of headache. Radiological findings were negative for intracranial abnormalities. The headache was due to trigeminal neuralgia. She had concurrent complaints of anosmia and ageusia without fever, respiratory symptoms, or obvious risk factors. However, it was determined to test the patient for coronavirus disease 2019 (COVID-19) infection despite extremely low clinical suspicion. Unfortunately, she was found to be COVID-19 positive after she was discharged from the hospital while she remained asymptomatic. There is currently a lack of published case reports describing COVID-19 patients with the sole symptoms of anosmia and ageusia in the United States of America.

A Rare Presentation of Coronavirus Disease 2019 (COVID-19) Induced Viral Myositis With Subsequent Rhabdomyolysis.

A 38-year-old gentleman with no significant past medical history but had recent COVID-19 exposure presented to the hospital with the chief complaints of fever, shortness of breath, and generalized myalgia. He was unfortunately found to be severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive. Laboratory findings showed creatine kinase (CK) >42,670 U/L along with elevated inflammatory markers and unremarkable creatinine, cardiac troponin level. The cause of his rhabdomyolysis was discovered to be due to COVID-19 as he had no evidence of other viral infections, strenuous exercise, seizure, or other nontraumatic exertional etiologies. He received aggressive fluid resuscitation while we trended his CK levels along with other inflammatory markers throughout his hospitalization course. His diffuse myalgia improved with treatments, and he was found to maintain stable hemodynamics and was subsequently discharged home.

A Rare Case of Coronary Artery Thrombosis in a Patient With Recently Diagnosed Giant Cell Arteritis: Is Anticardiolipin Antibody Involved?

Giant cell arteritis (GCA) is an immune-mediated systemic inflammation of large-sized arteries that predominantly affects elderly women. It may be considered as one of the risk factors for acute coronary syndrome (ACS). Moreover, patients with GCA may have increased anticardiolipin antibodies (aCL). However, its relationship with antiphospholipid syndrome (APS) is not clear. We present a case of a unique presentation of GCA with a connection to both ACS and APS. A 76-year-old woman who initially presented to the hospital with a chief complaint of intermittent unilateral headache, blurry vision along with transient aphasia was found to have a biopsy confirmed GCA and subsequently developed left anterior descending artery (LAD) thrombosis. Her hypercoagulability workup was negative except for significantly elevated aCL.