Case report: emapalumab treatment for a pediatric Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) patient with cytokine storm enabling allogeneic hematopoietic cell transplantation.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by excessive immune activation and inflammatory response. Conventional immunotherapy and molecular targeted drugs demonstrate varying efficacy. Cytokine storm, the primary pathogenic mechanism of HLH, is driven by interferon-gamma (IFN-γ), interleukin (IL)-2, IL-18, etc., in which IFN-γ plays a critical role in the development of the disease. Emapalumab, a potent IFN-γ inhibitor, effectively reduces the occurrence of cytokine storms in refractory and relapsed HLH. Case Description: A pediatric patient, 5 years old, female, with relapsed and refractory Epstein-Barr virus-associated HLH (EBV-HLH) showed no response to conventional chemotherapy or molecular-targeted drug treatment. However, after treatment with emapalumab, the patient achieved hematological remission. Subsequently, the patient underwent allogeneic hematopoietic cell transplantation (allo-HCT) and remains without HLH to date. Conclusions: To the best of our knowledge, this is the first case report using emapalumab to control EBV-HLH before HCT in mainland China. This case highlights the potential efficacy of emapalumab for treating relapsed and refractory EBV-HLH and providing a stable physical status for HCT. Further research is necessary to confirm the efficacy and safety of emapalumab in this setting.

B-cell prolymphocytic leukemia with P53 abnormalities successfully treated with bendamustine and rituximab: a report of three cases.

Background: B-cell prolymphocytic leukemia (B-PLL) is a rare mature B-cell tumor with an aggressive clinical course and poor prognosis. It is characterized by prominent splenomegaly and prolymphocytes exceeding 55% of the lymphoid cells in the blood. Purine analog-based chemo-immunotherapy is the first-line therapy for B-PLL. Owing to its rarity, there are few reports on the efficacy of bendamustine and rituximab (BR) regimen. Our study presents three cases of BR being effective in the treatment of B-PLL and provides experience for clinical treatment. Case Description: This report describes the cases of three male patients (median age: 66 years old) who initially presented with abdominal discomfort. Physical examinations and imaging revealed splenomegaly, while a peripheral blood (PB) smear revealed a prolymphocyte count exceeding 70% of the lymphoid cells. Therefore, the three patients were diagnosed with B-PLL. Further molecular detection showed that they harbored P53 abnormalities (17p deletion/TP53 mutation) associated with resistance to conventional chemotherapies. In addition, one of the patients had a highly complex karyotype and multiple gene mutations. All patients underwent four cycles of BR, and two of them received two further cycles of rituximab monotherapy. Ultimately, the patients achieved a complete response (CR) that lasted for 25, 33, and 34 months, respectively, with a median follow-up time of 34 months. The adverse events of the BR mainly included a grade 3 haematological toxicities. Also, the treatment was well-tolerated. Conclusions: This case series suggests that BR regimen is promising for bringing deep remission to patients with B-PLL. Prospective trials are still required for further elucidation.

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.

Biliary Anastomosis Using T-tube Versus No T-tube for Liver Transplantation in Adults: A Review of Literature.

The T-tube-directed biliary anastomosis in orthotopic liver transplantation (OLT) aims to minimize preventable biliary complications, including bile leaks and strictures. Biliary complications in patients with OLT increase the risk of morbidity and mortality. This review paper evaluated the current evidence on the routine use of T-tube reconstruction in OLT cases. A review of prospective, retrospective, observational, cohort studies as well as systematic reviews, meta-analyses, review papers, and opinion papers has been conducted to evaluate the therapeutic potential of T tube-based biliary anastomosis in cases of OLT. Our finding showed a bile leak incidence of 16.6% and 6.6% in T-tube and non-T-tube groups, respectively. The results indicated a lower incidence of anastomotic fistulae in the non-T-tube group (0.6%) compared to the T-tube group (4%). The findings negated statistically significant differences in the three-year actuarial survival rates based on biliary anastomosis with and without T-tube intervention (62.5% vs. 69.8%). The studies revealed a 6-11% and 2-11% incidence of cholangitis in OLT patients with T-tube-based reconstruction and those without a T-tube, respectively, and 26% and 20% incidence of total biliary complications in OLT patients with and without T-tube, respectively. In addition, the findings ruled out the influence of a T-tube on the incidence of perioperative complications, endoscopies, and reoperations in OLT cases. The current evidence correlates the increased incidence of bile leaks, cholangitis, and overall biliary complications with the use of a T-tube during OLT. In addition, T-tube-guided reconstruction has no impact on perioperative complications, overall survival, endoscopies, and reoperations in OLT cases.

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.

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.

Cannabis and Its Potential Protective Role Against Inflammatory Bowel Disease: A Scoping Review.

Globally, around 15%-40% of patients suffering from inflammatory bowel disease (IBD) use Cannabis for pain reduction, increased appetite, and reduced need for other medications. Although many patients report having benefited by using Cannabis in IBD, there is still a lack of consensus regarding the use of Cannabis in IBD. The aim is to identify, explore and map literature on the potential protective role of Cannabis against IBD through this scoping review. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed during the search to answer the focal question: (1) Does Cannabis play a protective role against IBD as assessed by clinical remission; (2) If yes, what is the mechanism of action for this protective role. There were only three randomized controlled trials (RCTs) and three observational studies that satisfied the selection criteria of this scoping review. Although promising results including the improvement in general well-being/ Harvey-Bradshaw Index, health perception enhancement [4.1±1.43 to 7±1.42 (p = 0.0002)], weight gain, Crohn's Disease Activity Index (CDAI) score<150, Mayo scores (4-10), and reduction in clinical complications have been found in some studies, its medical use in IBD is still questionable due to the lack of high-quality evidence. Future RCTs studies should determine the cannabis treatment parameters and validate its safety and effectiveness in the IBD setting. The highlights include: the current literature provides inconclusive evidence concerning the protective role of cannabis for IBD patients; limited research evidence regarding the therapeutic use of cannabinoids for IBD warrants future investigation via RCTs; cannabis provides some benefits to IBD patients by improving their general well-being perceptions, Harvey-Bradshaw Index, Mayo scores, and minimizing their clinical complications.

New-Onset Diabetes in the Setting of Beta-Cell Dysfunction in a Young Patient With COVID-19 Infection.

Reciprocal relationships between viral illness and chronic diseases have been established. Such relationships augment one another and increase the potential harm. The coronavirus 2019 pandemic proved that the most vulnerable populations are the ones with underlying chronic diseases, especially diabetes mellitus. As new data are evolving, viral illnesses, like COVID-19, have been speculated to potentially induce diabetes mellitus. Here we report a 20-year-old male with no past medical history who presented with polyuria, polydipsia, and dry mouth. He was found to have significant hyperglycemia. He had COVID-19-like symptoms a few weeks prior to admission and was tested positive for COVID-19, but the symptoms had resolved prior to his presentation. He was managed with intravenous fluids (IVFs), electrolytes replacement, and insulin. He was diagnosed with new-onset diabetes mellitus likely secondary to a recent COVID-19 infection and was discharged home on insulin, oral antidiabetic medications, and outpatient follow-up with primary care clinic and endocrinology clinic.

Thyroid Storm-Induced Acute Liver Dysfunction and Disseminated Intravascular Coagulation.

Thyroid storm-induced disseminated intravascular coagulation (DIC) is a very rare complication of untreated/undertreated Graves' disease. It is considered to be a medical emergency as it can rapidly lead to hemodynamic instability in patients due to multi-organ failure. Although the exact pathogenesis of this hematological phenomenon remains poorly understood, it is believed to be triggered by the uncontrolled release of pro-inflammatory cytokines, which in turn prematurely activates the coagulation cascade. In this report, we present the case of a 48-year-old female who presented with symptoms of abdominal pain, dyspnea, and unintentional weight loss for the past several weeks. Her vital signs, overall clinical picture, and laboratory tests confirmed thyroid storm complicated by DIC and acute liver injury. The patient made a significant recovery after the initiation of methimazole therapy.

Acquired Thrombotic Thrombocytopenic Purpura in a Newly Diagnosed HIV Patient: A Case Report and Literature Review.

Thrombotic thrombocytopenic purpura (TTP) is a rare but a potentially fatal condition. Although the majority of TTP cases are of unknown etiology, certain viral infections, malignancies, and medications have been linked to the acquired form of the illness. Regardless of the underlying etiology, TTP remains a great challenge diagnostically and therapeutically. TTP remains a very uncommon complication of HIV. We reviewed the current literature to better understand the relationship between HIV and TTP and address some of the major obstacles that may impede or delay the correct diagnosis. Here, we present a case of a 28-year-old male with complaints of light-headedness, fatigue, and gingival bleeding. He was found to have severe anemia and thrombocytopenia. He tested positive for the HIV and was then diagnosed with TTP. Despite needing endotracheal intubation for airway protection, he clinically improved with packed red blood cells, plasmapheresis, and highly active antiretroviral therapy.

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.

An Unusual Case of Prostate Carcinoma With Metastasis to the Iliopsoas Muscle and Nerve Root Impingement.

The majority of prostate cancer cases carry a favorable prognosis due to various screening protocols and the progression of surgical/medical techniques. Prostate cancers that metastasize to the skeletal system bear worse five-year survival rates as they are indicative of widespread dissemination. There are very few cases of prostate cancer invading the iliopsoas muscle described in the medical literature. Here, we present the case of a 61-year-old male who was diagnosed with prostate cancer with metastasis to the bones and iliopsoas muscle. Given the advanced presentation of his disease, the patient underwent a prostate biopsy. He was initiated on bicalutamide and transitioned to leuprolide and docetaxel with eventual radiation therapy.

A Case of Rapidly Proliferative Glomerulonephritis Secondary to Syphilis That Responded to Treatment With Penicillin.

The involvement of kidneys in syphilis has been reported in the literature with the majority of cases presenting with nephrotic-range proteinuria. We report a case of rapidly proliferative glomerulonephritis in a patient with secondary syphilis. A 40-year-old male with a history of human immunodeficiency virus (HIV), chronic hepatitis B virus, and chronic kidney disease stage 2 presented with fatigue, anorexia, weight loss, arthralgia, chills, and rash throughout the body. The patient was non-compliant with HIV medication and had unprotected sexual intercourse. Labs showed blood urea nitrogen of 57 mg/dL (range: 7-23 mg/dL), creatinine 8.2 mg/dL (range: 0.5-1.3 mg/dL), and high titers of rapid plasma reagin. The biopsy showed crescentic glomerulonephritis with c3 deposition in mesangium and basement membrane. The patient responded to treatment with penicillin therapy with gradual improvement in kidney function.

Heroin-Induced Leukoencephalopathy.

Heroin-induced leukoencephalopathy (HLE) is a rare but potentially debilitating and sometimes fatal neurological disorder. Despite the widely practiced heroin use via different routes and modalities, the syndrome is said to be rare and mostly associated with inhaling rather than injecting or snorting practices. We reviewed the literature to address the latest diagnostic, therapeutic, and prognostic measures related to the condition. Here, we present a case of a 35-year-old male who admitted to inhaling heroin 18 days ago and has been experiencing ongoing neurological symptoms for the past 17 days. Imaging was consistent with extensive white matter disease at multiple levels and different anatomical regions. Although there is no known cure for HLE, the patient benefited, somewhat, from antioxidants and physical rehabilitation.