Leukemic stem cells and advances in hematopoietic stem cell transplantation for acute myeloid leukemia: a narrative review of clinical trials.

Objective: The purpose of this literature review is to summarize and provide a brief overview of our current understanding of acute myeloid leukemia (AML) and the role of stem cell transplantation (SCT) in its management. Background: AML is a malignant hematological disorder that is characterized by the uncontrolled proliferation of myeloid blood cells. This disease has been associated with various risk factors such as ionizing radiation, cigarette smoke, pesticides/herbicides, and chemotherapy. SCT remains the most beneficial treatment for medically fit AML patients due to superior survival outcomes. Methods: A thorough search was conducted on PubMed, Scopus, ClinicalTrials.gov, Embase and Web of Science using related keywords. Current articles on the uses of stem cell therapy in AML patients were selected. Conclusions: Long term exposure to ionizing radiation and other harmful substances such as benzene, cigarette smoke and chemotherapeutic drugs plays an important role in AML carcinogenesis. Mutations in certain genes (e.g., ASXL1, RUNX1, KIT, TP53, BCR-ABL1) seem to accelerate the process as they affect normal cellular proliferation and cell death. These events may give rise to a small subpopulation of leukemic stem cells (LSC) which continuously sustain tumor development and growth. Patients who are deemed to be medically "fit" should receive an allogenic hematopoietic stem cell transplantation (allo-HSCT) due to improved overall survival (OS) (~50%) and decreased relapsed risk (32% vs. 59%). Several studies have revealed that the medically "unfit" may benefit from more conventional agents such as azacytidine, decitabine, venetoclax or sorafenib.

Miliary Tuberculosis: A Case Report Highlighting the Diagnostic Challenges Associated With the Condition.

End-stage renal disease requiring chronic dialysis is an immunocompromised state which increases the risk of tuberculosis development and its spread. Due to the high frequency of non-specific or "decoy" symptoms at presentation and frequent extrapulmonary involvement, diagnosis of tuberculosis is a significant challenge. Therefore, it is correctly labeled as 'Tuberculosis; the great imitator' as it can mimic various other disease processes, causing confusion and testing of subsystems involved in the disease process, which come back as abnormal, leading to a vicious cycle. Missing the diagnosis leads to grave consequences, especially in a patient with a miliary form of tuberculosis, as the prognosis with any delay in treatment is poor. High diagnostic suspicion is required to promptly diagnose and treat the condition, especially in a resource-rich setting where tuberculosis is uncommon. Here, we report a patient with miliary tuberculosis who presented with a chief complaint of chronic diarrhea and fecal continence, with prior recent negative interferon-gamma release assay testing. Due to every organ system involved, multiple subspecialties were on board, with a broad differential in mind, including malabsorption syndromes, neoplasia, infections, amyloidosis, and autoimmune disorders, and therefore, numerous tests were performed. However, despite all efforts, the diagnosis was delayed significantly, leading to the unfortunate demise of the patient. The case report sheds light on unique clinical features of miliary tuberculosis, diagnostic findings, and a reminder to always keep tuberculosis high in the differential in an appropriate clinical setting.

A Rare Case of an Exploratory Laparotomy to Treat a Liver Abscess Secondary to Foreign Body Ingestion.

A 49-year-old female presented to the hospital with complaints of generalized weakness, subjective fevers, and chills. In the emergency department (ED), she was found to be hypotensive and tachycardic and met the sepsis criteria. A CT scan of the abdomen and pelvis (CT A/P) with contrast revealed a liver abscess and a foreign body (FB) that was suspected to be the cause of the liver abscess. Of note, the patient had undergone a recent dental procedure due to an infected root canal, which had involved a dental screw. The patient was uncertain whether the dental screw had been removed, but she felt as though it was no longer there. At this time, the clinical suspicion was high for FB secondary to this dental procedure. The patient underwent interventional radiology (IR)-guided liver abscess drainage and magnetic resonance cholangiopancreatography (MRCP) for the evaluation of the FB. An esophagogastroduodenoscopy (EGD) was performed, but no evidence of the FB was found. This warranted an exploratory laparotomy (EL) to ensure the successful removal of the FB. Upon gross visualization by surgery, the FB was revealed to be a bone that the patient did not recall ingesting. However, surgical pathology evaluation revealed that the FB was actually a plastic stick. This rare case highlights the clinical approach to FB ingestion when complicated by liver abscess, as well as successful treatment with EL as opposed to laparoscopy which is the procedure of choice.

Large-Cell Esophageal Neuroendocrine Tumor Leading to Hepatorenal Syndrome.

Neuroendocrine tumors are tumors that arise from the enterochromaffin cells in the neuroendocrine tissue found throughout the body, particularly the digestive tract, pancreas, and thymus. Neuroendocrine tumors of the esophagus are extremely rare and highly aggressive in nature. We present the case of a 55-year-old Hispanic male who initially presented to the emergency department with right-sided abdominal pain. Imaging revealed innumerable lesions occupying half of the liver parenchyma. Subsequent endoscopy with biopsy of the esophageal and liver lesions along with immunohistochemistry staining was suggestive of a large cell neuroendocrine tumor. He later presented with generalized weakness and right-sided abdominal pain with worsening hepatic and renal function. Over the course of the patient's stay in the hospital, his mental status progressively deteriorated. Given the deranged hepatic and renal function, chemotherapy could not be initiated. The patient's family decided against hemodialysis considering his poor prognosis and the patient expired on day 15 of admission. The case report highlights the aggressiveness of one of the rare esophageal malignancies. It is crucial to establish diagnosis at the earlier stages of the disease with prompt treatment in order to avoid serious complications such as hepatorenal syndrome, which resulted in rapid deterioration of our patient's clinical status. More research is necessary in order to establish guidelines to treat neuroendocrine tumors of the esophagus.

Cabozantinib-Induced Severe Cardiac Dysfunction: A Case Report and a Systematic Review of the Literature.

Cabozantinib is a novel multitargeted receptor tyrosine kinase inhibitor commonly used to treat advanced renal cell carcinoma. Cardiotoxicity is not a previously well-described adverse effect of cabozantinib. We present a rare case of a 74-year-old male with a history of renal cell carcinoma who underwent partial nephrectomy. The patient had been recently started on cabozantinib for advanced metastatic renal cell carcinoma. He developed acute onset of heart failure and subclinical hypothyroidism within nine months of treatment. Our case report postulates a causal relationship between cabozantinib and the development of non-ischemic cardiomyopathy.

Understanding pancreatic cancer stem cells and their role in carcinogenesis: a narrative review.

OBJECTIVE: The purpose of this review article is to describe the pathogenesis of pancreatic cancer and to better understand the role of abnormal stem cells in the development of pancreatic cancer. BACKGROUND: Pancreatic cancer is a highly fatal disease that is caused by the uncontrolled proliferation of pancreatic exocrine or neuroendocrine glands. It is believed that pancreatic cancers arise from a small population of abnormal cancer stem cells (CSCs) that promote tumorigenesis, tumor metastasis and therapeutic resistance. The molecular markers CD133, CXCR4, DCLK1, c-MET, ABCG2 and Lgr5 are routinely used to detected and observe the behaviours of pancreatic cancer stem cells (PCSCs). METHODS: A comprehensive search was performed on PubMed, Google Scholar, Scopus, Clinicaltrials.gov and Web of Science using related keywords. Articles focusing on PCSCs and pancreatic cancer pathogenesis, biochemistry and clinical trials were selected. CONCLUSIONS: Although very little is known about the exact cause of pancreatic cancer, PCSCs seem to play an important role in carcinogenesis. Mutated biochemical cascades include Sonic Hedgehog, K-RAS-JNK, DLL4/Notch and Nodal/Activin. Several clinical trials are trying to determine if the transplantation of hematopoietic stem cell or peripheral stem cells could be useful for the treatment of such an aggressive tumor.

Aggressive Natural Killer Cell Leukemia: A Brief Overview of Its Genomic Landscape, Histological Features, and Current Management.

Aggressive natural killer-cell leukemia (ANKL) is a rare hematological malignancy characterized by the abnormal proliferation of natural killer (NK) cells. There are currently no therapies approved by the US Food and Drug Administration (FDA) for the treatment of ANKL, but advancements in genomics are assisting in the unraveling of this rare malignancy. We selected 37 articles that contained information on genomics, immunohistochemistry, and/or current clinical trials relating to the treatment and survival of ANKL. Current therapeutic strategies have been subdivided into (1) concurrent chemoradiation, (2) sequential chemoradiation, and (3) sandwich chemoradiation. These methods have been developed to reduce toxicity while still producing a pathologic response. Concurrent chemoradiation with VIDL (etoposide, ifosfamide, dexamethasone, and L-asparaginase) produced an excellent clinical response, while sequential chemoradiation with SMILE (steroid dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) showed an adequate response, but with severe hematologic toxicity. The efficacy of L-asparaginase in chemotherapeutic regimens and its association with NK-cell apoptosis have led to its inclusion in all standard regimens. Future studies are focusing on the addition of a programmed death-ligand 1 (PD-L1) inhibitor and hematopoietic stem cell transplant (HSCT).

Advancements in the Treatment of Triple-Negative Breast Cancer: A Narrative Review of the Literature.

Triple-negative breast cancers (TNBCs) are aggressive tumors that are more common in young women, African American populations, and those with hereditary mutations. These tumors are notable for their high recurrence rate and predilection for chemoresistance. The goal of this narrative review is to describe the current treatment options for patients diagnosed with TNBC and to review the studies that have put forward these recommendations. We searched PubMed and Cochrane databases for free full-text, English-language studies published within the last several years pertaining to the search items "triple negative breast cancer" and "treatment". We included clinical trials and retrospective reviews that had clear designs and assessed their findings against a gold standard or placebo and included evidence of overall response and/or survival outcomes.  Patients with early-stage (I-III) TNBC still benefit from treatment with chemotherapeutic regimens involving anthracyclines, taxanes, and antimetabolites. Platinum-based therapies have been shown to improve the overall pathologic complete response (pCR), but there is conflicting evidence with regard to their contribution to disease-free survival (DFS) and overall survival (OS), even with the addition of a poly (ADP-ribose) polymerase (PARP) inhibitor. Patients with residual disease after neoadjuvant chemotherapy and surgical intervention have shown a significant improvement in OS when treated with adjuvant capecitabine. The high mutation burden in metastatic TNBC (mTNBC) allows for targeted therapies and immune checkpoint inhibitors. mTNBCs that express programmed death ligand-1 (PD-L1) receptors may achieve improved response and survival if their regimen includes a monoclonal antibody. Antibody-drug conjugates (ADCs) can deliver high doses of chemotherapy and significantly impact survival in mTNBC regardless of the level of biomarkers expressed by the tumor cells. PARP inhibitors significantly improve survival in newly diagnosed, treatment-naive mTNBC, but have shown mixed results in patients with a history of previous therapy. PARP inhibitors may also target patients with somatic breast cancer (BRCA) and partner and localizer of BRCA-2 (PALB2) mutations, which would allow for more options in this subset of patients. While other rare targets have shown mixed results, the future of treatment may lie in anti-androgen therapy or the development of cancer vaccinations that may increase the immunogenicity of the tumor environment. The management of TNBC includes treatment with multimodal chemotherapy, immune checkpoint inhibitors, and ADCs. The optimal approach depends on a multitude of factors, which include the stage of the tumor, its unique mutational burden, comorbid conditions, and the functional status of the patient. Physicians should be familiar with the advantages and disadvantages of each therapy in order to appropriately counsel and guide their patients.

Ivosidenib for IDH1 Mutant Cholangiocarcinoma: A Narrative Review.

Cholangiocarcinoma is an uncommon gastrointestinal neoplasm characterized by the abnormal proliferation of cholangiocytes within the biliary duct. This type of malignancy can be subdivided into three major classes: intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA), and distal cholangiocarcinoma (dCCA). Based on the results of various clinical trials, ivosidenib was approved for acute myeloid leukemia harboring the IDH1 mutation. It has also been shown that ivosidenib was effective in patients with IDH1 mutated cholangiocarcinoma. In this article, we briefly review the genomics and prognosis of cholangiocarcinoma with a special focus on ivosidenib and the mechanisms by which its approval was met.

Unraveling the Role of STK11/LKB1 in Non-small Cell Lung Cancer.

There are two major groups of lung cancer: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLCs can be further separated into three different categories: lung adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Pulmonary adenocarcinomas represent nearly half of all lung cancer cases and are known to be caused by smoking, certain occupational exposures, and specific genetic mutations. Scientists have noticed that most NSCLCs are driven by defects in the following genes: EGFR, BRAF, ALK, MET, and HER. Abnormalities in the STK11/LKB1 gene have also been shown to induce lung adenocarcinoma. LKB1-deficient cancer cells contain an overactive AMPK "energy sensor," which inhibits cellular death and promotes glucose, lipid, and protein synthesis via the mTOR protein complex. Studies have also discovered that the loss of STK11/LKB1 favors oncogenesis by creating an immunosuppressive environment for tumors to grow and accelerate events such as angiogenesis, epithelial-mesenchymal transition (EMT), and cell polarity destabilization. STK11/LKB1-mutant lung cancers are currently treated with radiotherapy with or without chemotherapy. Recent clinical trials studying the effects of glutaminase inhibitors, mTOR inhibitors, and anti-PD-L1 therapy in lung cancer patients have yielded promising results. This narrative review provides an overview of the STK11/LKB1 gene and its role in cancer development. Additionally, a summary of the LKB1/APMK/mTOR is provided.

Clostridium difficile Infection Complicated by Transformation of Myelodysplastic Syndrome to Acute Myeloid Leukemia With Leukostasis and Sweet's Syndrome.

Myelodysplastic syndrome (MDS) is a premalignant condition characterized by clonal proliferation and ineffective hematopoiesis. The subtype of MDS associated with deletion in the long arm of chromosome 5 is generally associated with older females and carries a good prognosis as it rarely transforms to acute myeloid leukemia. The mechanisms of leukemic transformation are still poorly understood and likely involve a variety of somatic mutations and epigenetic modifications. We present the case of a 70-year-old female with known MDS with deletion 5(q) who presented with anemia, thrombocytopenia, and guaiac positive stool who was subsequently found to be positive for Clostridium difficile infection. During the course of her treatment, she developed significant leukocytosis, splenic infarction, and acute hypoxic respiratory failure requiring high flow nasal cannula. Flow cytometry returned positive for increased blasts of more than 30%. She was transferred to a tertiary care facility for cytoreductive therapy and developed leukostasis and Sweet's syndrome.

The Role of Avapritinib for the Treatment of Systemic Mastocytosis.

Systemic mastocytosis is a rare hematologic disorder characterized by the clonal proliferation of mast cells in extra-cutaneous organs. This disease can be further subdivided into five different phenotypes: indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN) and mast cell leukemia (MCL). The tyrosine kinase inhibitor (and also potent KIT D816V inhibitor) avapritinib, initially approved for the treatment of gastrointestinal stromal tumors (GISTs) bearing a PDGFRA exon 18 mutation, also showed great promise in patients with systemic mastocytosis, a disease known to be driven by a mutation in KIT (D816V). We present an overview of this rare disorder, including a review of the current understanding of the genetic mechanisms which lead to the disease state, the action of the tyrosine kinase inhibitors, as well as the latest clinical trial data which led to the current recommendations for the use of avapritinib.

Hemophagocytic Lymphohistiocytosis Induced by Epstein-Barr Virus Infection and Newly Diagnosed Hodgkin Lymphoma.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, but life-threatening disorder of pathologic immune system activation which results in a hyperinflammatory state. Previous studies have suggested that hematologic malignancies are often inciting factors for HLH and portend a poorer prognosis. However, the substantial overlap between features of hematologic malignancies and HLH makes recognition and prompt diagnosis of HLH a complex and difficult task. We present a case of a young male who presented with acute dyspnea on exertion, unintentional weight loss, and fatigue. He was found to have pancytopenia, fever, splenomegaly, and Epstein-Barr viremia and was subsequently diagnosed with nodular sclerosing Hodgkin lymphoma. Five of eight 2004-HLH criteria were met and the patient was started on intravenous dexamethasone (10 mg/m2 daily), acyclovir, and AAVD (brentuximab, doxorubicin, vinblastine, dacarbazine) chemotherapy protocol with improvement in his symptoms and laboratory findings.

Current systematic reviews and meta-analyses of COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has left a significant impact on the world's health, economic and political systems; as of November 20, 2020, more than 57 million people have been infected worldwide, with over 1.3 million deaths. While the global spotlight is currently focused on combating this pandemic through means ranging from finding a treatment among existing therapeutic agents to inventing a vaccine that can aid in halting the further loss of life. AIM: To collect all systematic reviews and meta-analyses published related to COVID-19 to better identify available evidence, highlight gaps in knowledge, and elucidate further meta-analyses and umbrella reviews that are yet to be performed. METHODS: We explored studies based on systematic reviews and meta-analyses with the key-terms, including severe acute respiratory syndrome (SARS), SARS virus, coronavirus disease, COVID-19, and SARS coronavirus-2. The included studies were extracted from Embase, Medline, and Cochrane databases. The publication timeframe of included studies ranged between January 01, 2020, to October 30, 2020. Studies that were published in languages other than English were not considered for this systematic review. The finalized full-text articles are freely accessible in the public domain. RESULTS: Searching Embase, Medline, and Cochrane databases resulted in 1906, 669, and 19 results, respectively, that comprised 2594 studies. 515 duplicates were subsequently removed, leaving 2079 studies. The inclusion criteria were systematic reviews or meta-analyses. 860 results were excluded for being a review article, scope review, rapid review, panel review, or guideline that produced a total of 1219 studies. After screening articles were categorized, the included articles were put into main groups of clinical presentation, epidemiology, screening and diagnosis, severity assessment, special populations, and treatment. Subsequently, there was a second subclassification into the following groups: gastrointestinal, cardiovascular, neurological, stroke, thrombosis, anosmia and dysgeusia, ocular manifestations, nephrology, cutaneous manifestations, D-dimer, lymphocyte, anticoagulation, antivirals, convalescent plasma, immunosuppressants, corticosteroids, hydroxychloroquine, renin-angiotensin-aldosterone system, technology, diabetes mellitus, obesity, pregnancy, children, mental health, smoking, cancer, and transplant. CONCLUSION: Among the included articles, it is clear that further research is needed regarding treatment options and vaccines. With more studies, data will be less heterogeneous, and statistical analysis can be better applied to provide more robust clinical evidence. This study was not designed to give recommendations regarding the management of COVID-19.

Atypical Carcinoid Tumor of the Mediastinum Presenting as Cushing's Syndrome in an Otherwise Healthy Young Male.

Primary neuroendocrine tumors (NETs) are rare types of malignancies that can have a variety of presentations due to the ubiquitous distribution of neuroendocrine cells within the body. While mediastinal masses are not uncommon, NETs arising from the anterior mediastinum are rare and often originate from the thymus gland. A subset of NETs, atypical carcinoids, are more commonly seen in the lungs or gastrointestinal organs and often present with endocrine syndromes, chiefly Cushing's syndrome. The behavior of atypical carcinoid tumors within the mediastinum is often aggressive and clinical presentations vary widely. In this report, we describe a case of an atypical carcinoid tumor within the anterior mediastinum in an otherwise healthy young male with signs and symptoms of Cushing's syndrome.

Racial disparities in hematopoietic stem cell transplant: a systematic review of the literature.

BACKGROUND: Hematopoietic stem cell transplant (HSCT) is an expensive and complex treatment regimen that can be curative in many diseases of the bone marrow, including malignant and non-malignant conditions. The introduction of the Affordable Care Act increased access to potential candidates and removed or reduced many barriers previously identified in the literature, however, racial disparities continue to persist. As HSCT expands its utilization and indications, there is a continued need to understand the multifactorial barriers which lead to inequalities in transplant referral, utilization, and survival. The objective of this systematic review is to summarize these racial disparities, expand the current understanding of the literature, and determine whether the increases in insurance status from Medicaid expansion have played a role in HSCT utilization and survival rates by race. METHODS: We explored studies based on retrospective reviews, literature reviews, and focus groups with the key-terms of 'race', 'hematopoietic stem cell transplant', and 'disparities'. The included studies were extracted from Cochrane and Medline databases. After screening for relevancy to research aims and objectives, 10 articles were utilized for background information and discussion, while 30 articles were categorized into main groups of outcomes, chiefly, (I) access/referral to transplant and (II) survival. RESULTS: Eight of the eleven retrospective reviews found substantial variation in access to HSCT by ethnic minorities (Black, Hispanic, or Asian) when compared to their Caucasian counterparts. Thirteen of the fourteen publications found racial disparities in either overall survival, progression free survival, treatment related mortality, relapse, or combinations of these outcomes. The majority of the studies evaluated African American patients with six of eight studies showing significantly elevated mortality compared to Caucasian patients. DISCUSSION: Substantial variation exists in access to HSCT, particularly in black patients. Having less generous insurance coverage was previously hypothesized to reduce the likelihood of HSCT utilization. Studies performed after full implementation of the Affordable Care Act continue to show poorer survival among ethnic minorities, particularly black patients, despite this increased coverage. Perceived racial bias and health-related stigma, as well as physician decisions and delay in referral process are likely contributing factors.

Impact of the AYA HOPE Comorbidity Index on Assessing Health Care Service Needs and Health Status among Adolescents and Young Adults with Cancer.

BACKGROUND: Existing comorbidity indices were not developed for adolescent and young adults (AYA) 15 to 39 years of age. The aim of this study was to assess impact of comorbidities on health care service needs and health status among AYA cancer survivors using the newly developed AYA HOPE comorbidity index in comparison with the existing indices. METHODS: Data on comorbid conditions were obtained from medical records and service needs and health status were from a survey of AYA cancer survivors. Prevalence of comorbidities was based on the AYA HOPE index. Charlson and NCI indices were compared. Multivariable logistic regression was used. RESULTS: Of the 485 patients, 14.6% had ≥2 comorbidities based on the AYA HOPE Index. Prevalence of mental illness and obesity/overweight, which were not included in existing indices, were 8.2% and 5.8%, respectively. Prevalence of cardiovascular, endocrine, gastrointestinal, and neurologic conditions were higher with the AYA HOPE Index than the other two indices. Forty percent of AYA patients reported service needs, particularly for mental health services (25.2%) and support groups (17.7%). Having ≥2 comorbidities on the AYA index was associated with higher mental health service needs [OR, 2.05; 95% confidence interval (CI), 1.10-3.82] adjusting for demographic and clinical factors. Comorbidities were associated with fair/poor self-reported health status. CONCLUSION: The AYA HOPE Index is a more comprehensive comorbidity index for AYA cancer patients than existing indices, and the number of comorbidities is associated with service needs and health status. IMPACT: The AYA HOPE index could identify patients' additional service needs early in therapy.