Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis.

Anaphylaxis is an acute, potential life-threatening systemic allergic reaction that may have a wide range of clinical manifestations. Severe anaphylaxis and/or the need for repeated doses of epinephrine to treat anaphylaxis are risk factors for biphasic anaphylaxis. Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis, although evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy. Evidence is lacking to support the role of antihistamines and/or glucocorticoid routine premedication in patients receiving low- or iso-osmolar contrast material to prevent recurrent radiocontrast media anaphylaxis. Epinephrine is the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis. After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully resolved. All patients with anaphylaxis should receive education on anaphylaxis and risk of recurrence, trigger avoidance, self-injectable epinephrine education, referral to an allergist, and be educated about thresholds for further care.

Outcomes of Immune Checkpoint Inhibitor Administration in Hospitalized Patients With Solid Tumor Malignancies.

PURPOSE: More oncologists desire to treat their patients with immune checkpoint inhibitors (ICIs) in the inpatient setting as their use has become more widespread for numerous oncologic indications. This is cost-prohibitive to patients and institutions because of high drug cost and lack of reimbursement in the inpatient setting. We sought to examine current practice of inpatient ICI administration to determine if and in which clinical scenarios it may provide significant clinical benefit and therefore be warranted regardless of cost. METHODS: We conducted a retrospective chart review of adult patients who received at least one dose of an ICI for treatment of an active solid tumor malignancy during hospitalization at a single academic medical center between January 2017 and June 2018. Patient, disease, and admission characteristics including mortality data were examined, and cost analysis was performed. RESULTS: Sixty-five doses of ICIs were administered to 58 patients during the study period. Nearly 40% and 80% of patients died within 30 days and 180 days of ICI administration, respectively. There was a trend toward longer overall survival in patients with good prognostic factors including positive programmed death-ligand 1 (PD-L1) expression or microsatellite instability-high (MSI-H) status. Slightly over 70% of patients were discharged within 7 days of ICI administration. The total cost of inpatient ICI administration over the 18-month study period was $615,016 US dollars. CONCLUSION: Inpatient ICI administration is associated with high costs and poor outcomes in acutely ill hospitalized patients with advanced solid tumor malignancies and therefore should largely be avoided. Careful discharge planning to expedite outpatient treatment after discharge will be paramount in ensuring patients with good prognostic features who will benefit most from ICI therapy can be promptly treated in the outpatient setting as treating very close to discharge in the inpatient setting appears to be unnecessary, regardless of tumor features.

The utility of procalcitonin for diagnosing bacteremia and bacterial pneumonia in hospitalized oncology patients.

PURPOSE: Procalcitonin (PCT) is an inflammatory marker elevated in bacteremia and bacterial pneumonia. We aimed to assess the real-world diagnostic accuracy of PCT in hospitalized patients with malignancy. METHODS: A retrospective cohort of 715 patients with cancer who had PCT measured during 750 admissions was analyzed. Diagnosis of bacteremia was determined using blood culture data. Diagnosis of bacterial pneumonia was based on radiographic infiltrate and/or sputum culture. PCT's performance was assessed using receiver operating characteristic (ROC) curves, sensitivity, and specificity. RESULTS: Patients had bacteremia, bacterial pneumonia, or both during 210 admissions (28%). PCT elevation above 0.5 ng/mL was significantly associated with diagnosed infection in the overall population (p < 0.0001) and in subgroups with solid tumor malignancies (p < 0.0001) and hematologic malignancies (p = 0.008). PCT was associated with infectious status in patients with any metastases, but not those with primary lung cancer, lung metastases, neuroendocrine tumors, febrile neutropenia, or history of bone marrow transplant (BMT). The area under the ROC curve for PCT in the overall population was 0.655. An ideal cutoff of 0.21 ng/mL led to a sensitivity of 60% and specificity of 59%. At cutoffs of 0.5 ng/mL and 0.05 ng/mL, PCT's sensitivity was 39% and 94%, while specificity was 79% and 17%, respectively. CONCLUSION: In this large cohort of hospitalized oncology patients, PCT elevation was associated with diagnosed bacteremia and/or bacterial pneumonia. However, specificity was limited, and PCT elevation was not associated with diagnosed infection in some subpopulations. While PCT may have some diagnostic utility for hospitalized oncology patients, values must be interpreted cautiously and considering clinical context.

Hidden Dangers: A Gastrointestinal Stromal Tumor Concealed Inside of a Meckel's Diverticulum.

Meckel's diverticulum (MD) is one of the most common congenital abnormalities of the gastrointestinal tract, affecting approximately two percent of the population. Rarely, Meckel's diverticula have been found to harbor various tumors, which go unnoticed until later in their course. The clinical presentation varies among each individual, and tumors have often metastasized or caused diverticular rupture at the time of diagnosis. This is a case of a 55-year-old male with a past medical history of alcohol abuse and asthma who presented to the emergency department with abdominal pain. He denied any fever, chills, chest pain, nausea, changes in urinary patterns, recent travel, or sick contacts. He is a non-smoker but has been a heavy drinker for many years. On physical exam, he was found to have diffuse abdominal tenderness with pain greatest in the epigastric region and no bowel sounds. He was afebrile but tachycardic at 112 bpm, hypertensive at 168/98 mmHg, and tachypneic at 38 bpm. Labs showed a markedly elevated white blood cell count, hemoglobin and platelet count, as well as metabolic acidosis and elevated lactate levels. Abdominal CT showed a mechanical small bowel obstruction with unclear etiology. Of note was a 7.2 cm thick-walled collection in the right lower quadrant having no clear communication with any bowel loops. Despite aggressive hydration and supportive care, his abdominal exam continued to worsen, prompting an exploratory laparotomy. During the laparotomy, a perforated MD with frank succus was found. On pathology, the affected segment of the bowel revealed a CD117 and CD34 positive spindle cell gastrointestinal stromal tumor (GIST) with mild cytological atypia, no necrosis, and no regional lymph node involvement. Cultures of peritoneal fluid were positive for Klebsiella oxytoca, and the patient was started on meropenem and doxycycline. The patient showed significant improvement with the appropriate administration of antibiotics and was eventually discharged to follow-up with hematology/oncology as an outpatient for further management and monitoring of his GIST tumor. This case is unique as there are only a few reported cases of patients developing GIST inside of MDs. Despite the high five-year survival rate of typically localized GIST tumors, the complications (such as perforation in the case of our patient) caused by tumor growth inside a MD are detrimental if not diagnosed promptly. Not only does perforation increase the risk of metastasis but also the risk of peritonitis and other complications. This case calls for more research on standardization of care for patients who have MD to prevent malignant transformations as well as potential prophylactic excision of incidental MD findings in adult patients.

The Homeobox gene, HOXB13, Regulates a Mitotic Protein-Kinase Interaction Network in Metastatic Prostate Cancers.

HOXB13, a homeodomain transcription factor, is linked to recurrence following radical prostatectomy. While HOXB13 regulates Androgen Receptor (AR) functions in a context dependent manner, its critical effectors in prostate cancer (PC) metastasis remain largely unknown. To identify HOXB13 transcriptional targets in metastatic PCs, we performed integrative bioinformatics analysis of differentially expressed genes (DEGs) in the proximity of the human prostate tumor-specific AR binding sites. Unsupervised Principal Component Analysis (PCA) led to a focused core HOXB13 target gene-set referred to as HOTPAM9 (HOXB13 Targets separating Primary And Metastatic PCs). HOTPAM9 comprised 7 mitotic kinase genes overexpressed in metastatic PCs, TRPM8, and the heat shock protein HSPB8, whose levels were significantly lower in metastatic PCs compared to the primary disease. The expression of a two-gene set, CIT and HSPB8 with an overall balanced accuracy of 98.8% and a threshold value of 0.2347, was sufficient to classify metastasis. HSPB8 mRNA expression was significantly increased following HOXB13 depletion in multiple metastatic CRPC models. Increased expression of HSPB8 by the microtubule inhibitor Colchicine or by exogenous means suppressed migration of mCRPC cells. Collectively, our results indicate that HOXB13 promotes metastasis of PCs by coordinated regulation of mitotic kinases and blockade of a putative tumor suppressor gene.

Targeting the BRD4-HOXB13 Coregulated Transcriptional Networks with Bromodomain-Kinase Inhibitors to Suppress Metastatic Castration-Resistant Prostate Cancer.

Resistance to androgen receptor (AR) antagonists is a significant problem in the treatment of castration-resistant prostate cancers (CRPC). Identification of the mechanisms by which CRPCs evade androgen deprivation therapies (ADT) is critical to develop novel therapeutics. We uncovered that CRPCs rely on BRD4-HOXB13 epigenetic reprogramming for androgen-independent cell proliferation. Mechanistically, BRD4, a member of the BET bromodomain family, epigenetically promotes HOXB13 expression. Consistently, genetic disruption of HOXB13 or pharmacological suppression of its mRNA and protein expression by the novel dual-activity BET bromodomain-kinase inhibitors directly correlates with rapid induction of apoptosis, potent inhibition of tumor cell proliferation and cell migration, and suppression of CRPC growth. Integrative analysis revealed that the BRD4-HOXB13 transcriptome comprises a proliferative gene network implicated in cell-cycle progression, nucleotide metabolism, and chromatin assembly. Notably, although the core HOXB13 target genes responsive to BET inhibitors (HOTBIN10) are overexpressed in metastatic cases, in ADT-treated CRPC cell lines and patient-derived circulating tumor cells (CTC) they are insensitive to AR depletion or blockade. Among the HOTBIN10 genes, AURKB and MELK expression correlates with HOXB13 expression in CTCs of mCRPC patients who did not respond to abiraterone (ABR), suggesting that AURKB inhibitors could be used additionally against high-risk HOXB13-positive metastatic prostate cancers. Combined, our study demonstrates that BRD4-HOXB13-HOTBIN10 regulatory circuit maintains the malignant state of CRPCs and identifies a core proproliferative network driving ADT resistance that is targetable with potent dual-activity bromodomain-kinase inhibitors.

Leukemia Therapy: Mechanisms of Drug Resistance and Investigational Strategies.

Certain types of leukemia are amongst the first neoplasias to be “cured” with relatively high 5-year remission rates. This is largely due to targeted therapeutics. However, considerable resistance to tumor-specific targeting drugs has developed due to the presence of abundant cancer stem cells, profound genetic diversity, redundant growth/survival pathways and residual disease. Although these issues propose a challenge, they also provide the opportunity for novel innovations of therapy which currently include the development of multi-target kinase inhibitors, multiple drugs acting on multiple targets, key upstream targets covering multiple downstream targets and the future direction of hybrid molecules targeting two or more targets in different pathways.

Flavanols, mild cognitive impairment, and Alzheimer's dementia.

Alzheimer's disease (AD) is a dementing neurological disorder that results in progressive memory loss and cognitive decline thought to be associated with buildup of amyloid plaques and neurofibrillary tangles in the brain. Vascular Dementia (VaD) is another common dementing disorder characterized by decreased brain perfusion. Together, AD and VaD constitute mixed dementia, an extremely common type of dementia associated with aging. Neuroimaging research suggests that brain vascular atrophy results in mild cognitive impairment (MCI), a possible precursor for AD. Additionally, literature suggests that attention to cardiovascular risk factors such as hypertension could reduce or delay the incidence of mixed dementia. Furthermore, foods and beverages rich in natural antioxidant flavanoids (i.e. epicatechin and catechin) are currently being advocated as possible preventative agents for a number of pathological conditions ranging from coronary heart disease to dementia. Experimental evidence is mounting that oxidative stress is involved in the pathophysiology of AD, and numerous studies are indicating that polyphenolic antioxidants found in fruits and vegetables can be useful in countering this and blocking neuronal death. More specifically, several cocoa studies suggest that daily intake of cocoa flavanols leads to cardiovascular benefits including vasodilatation via a nitric oxide mechanism and increased brain perfusion. The following text will consider an important question that thus arises regarding the potential of flavanols as effective agents for the prevention and delay of the onset of brain vascular atrophy and subsequently MCI and AD. It will also review the molecular mechanisms through which flavanols operate to accomplish their protective effects.