Impact of age, obesity, and renal impairment on outcomes after autologous stem cell transplantation for patients with newly diagnosed multiple myeloma.

INTRODUCTION: There remains a need to determine whether certain subgroups of newly diagnosed multiple myeloma (NDMM) derive the same benefit from high-dose chemotherapy-autologous stem cell transplant (HDT-ASCT). We describe our institutional experience highlighting the impact of age, obesity, and renal impairment on outcomes after HDT-ASCT for patients with NDMM in a real-world setting. METHODS: A total of 449 consecutive patients were included in this retrospective analysis. RESULTS: No difference in median progression free survival or overall survival was seen for patients with age > 65, body mass index (BMI) > 30 kg/m2, or estimated glomerular filtration rate < 60 mL/min/1.73 m2 when compared to those without these characteristics. From a safety standpoint, there were no differences in the incidence of transplant-related mortality or secondary malignancy among subgroups. CONCLUSION: For patients with NDMM undergoing HDT-ASCT, there is no difference in outcomes based on age, BMI, or renal function, and the presence of one or more of these factors should not preclude patients from HDT-ASCT.

Impact of race and ethnicity on outcomes after autologous stem cell transplantation for patients with newly diagnosed multiple myeloma.

Non-Hispanic Black patients are disproportionally affected by multiple myeloma (MM) and whether efficacy outcomes after autologous stem cell transplant (ASCT) differ by race and ethnicity remains an area of active investigation. This study included 449 patients enriched with a large proportion of non-Hispanic Black patients and sought to highlight the impact of race and ethnicity on outcomes after HDT-ASCT for patients with newly diagnosed MM. We found induction chemotherapy followed by high-dose therapy-ASCT and maintenance chemotherapy is associated with long-term PFS and OS, regardless of race or ethnicity.

Treatments and challenges in advanced prostate cancer.

PURPOSE OF REVIEW: This review is designed to highlight recent research examining treatment progress in advanced prostate cancer while identifying ongoing challenges to clinical outcomes. RECENT FINDINGS: Recent randomized trials suggest an overall survival advantage to treating some men with newly identified metastatic prostate cancer with a "triplet" of androgen deprivation therapy, docetaxel, and an androgen receptor axis-targeted agent. Questions remain about which men are best served by these combinations. Additional treatment success is being identified with prostate-specific membrane antigen positron emission tomography (PSMA)-radiopharmaceuticals, combinations involving targeted therapies, and novel manipulations of the androgen receptor axis. Challenges remain in selecting between available therapies, harnessing immune therapies, and treating tumors with emergent neuroendocrine differentiation. SUMMARY: An expanding number of therapeutics are becoming available for men with advanced prostate cancer improving outcomes but at the same time making treatment selection more demanding. Ongoing research will be required to continue to hone treatment paradigms.

Impact of Cytogenetic Abnormalities, Induction and Maintenance Regimens on Outcomes After High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients With Newly Diagnosed Multiple Myeloma: A Decade-Long Real-World Experience.

Background: High-dose chemotherapy and autologous stem cell transplant (HDT-ASCT) has become a standard of care for transplant eligible newly diagnosed multiple myeloma (NDMM) patients. While cytogenetic abnormalities have been shown to affect outcomes after HDT-ASCT in clinical trials, these trials often exclude or underrepresent elderly patients with comorbidities and those belonging to ethnic minorities. We describe our institutional experience highlighting the impact of high-risk cytogenetic abnormalities (HRCAs) on outcomes after HDT-ASCT for NDMM patients. Methods: A total of 449 patients with NDMM who underwent HDT-ASCT between February 2012 and August 2022 were included in this retrospective analysis. HRCAs included the presence of one or more of: deletion 17p, t(14;16), t(4;14), and amplification 1q. Survival analyses, including progression-free survival (PFS) and overall survival (OS), were performed using Kaplan-Meier estimator. Results: With a median follow-up of 29 (1 - 128) months for the entire patient population, the best overall response rate for the patients with HRCAs was lower compared to those with standard risk cytogenetics (90% vs. 96%; P = 0.01). Patients with HRCAs had an inferior PFS compared to patients with standard-risk cytogenetics (29 vs. 58 months; P < 0.001) without a difference in OS (70 months vs. not reached; P = 0.13). Conclusions: In a multivariable analysis adjusting for factors including age, race, and comorbidities, HRCAs, non-lenalidomide-based maintenance, non-proteasome inhibitor-based maintenance, and age greater than 65 were associated with inferior PFS. Amongst these factors, only non-lenalidomide-based maintenance was associated with inferior OS.

Can Discord Domain-Containing Receptor 2 Mutation Act as a Disease Modifier for PRKAR1A Associated Melanotic Schwannoma?

Melanotic Schwannomas are rare neural sheath tumors with distinctive findings of both Schwann cells and melanocytic cells. Recognition of this entity has prompted the importance of distinction from similar tumor types such as melanomas. Early diagnosis facilitates removal of the mass with less risk of local invasion and metastasis. Although previously known as mostly benign lesions, malignant conversion and recurrence are recognized. This paper presents a patient with melanotic schwannoma, describes the distinctive features that will separate it from melanoma, and addresses the possibility of further guided therapy through next-generation sequencing.

Thoracic Osteomyelitis and Eustachian Valve Endocarditis: A Case Report and Literature Review.

Infective endocarditis and vertebral osteomyelitis are rare infections, most commonly caused by methicillin-sensitive Staphylococcus aureus (MSSA). The eustachian valve is an embryological remnant of the inferior vena cava that has the potential to harbor a nidus leading to infective endocarditis. Eustachian valve endocarditis has been documented in the literature on less than 50 occasions and has yet to be documented in the presence of concomitant vertebral osteomyelitis. In this case, we present a 43-year-old male presenting with vertebral osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA). Persistent bacteremia prompted the identification of vegetative growth on a eustachian valve remnant. This case helps mend the gap in the literature by documenting the treatment considerations in a patient with eustachian valve endocarditis in the presence of osteomyelitis caused by MRSA.

Understanding the Differences in COVID-19 Case Fatality Rates Observed Across Alabama Counties.

To understand county-level variation in case fatality rates of COVID-19, a statewide analysis of COVID-19 incidence and fatality data was performed, using publicly available incidence and case fatality rate data of COVID-19 for all 67 Alabama counties and mapped with health disparities at the county level. A specific adaptation of the Shewhart p-chart, called a funnel chart, was used to compare case fatality rates. Important differences in case fatality rates across the counties did not appear to be reflective of differences in testing or incidence rates. Instead, a higher prevalence of comorbidities and vulnerabilities was observed in high fatality rate counties, while showing no differences in access to acute care. Funnel charts reliably identify counties with unexpected high and low COVID-19 case fatality rates. Social determinants of health are strongly associated with such differences. These data may assist in public health decisions including vaccination strategies, especially in southern states with similar demographics.

IV Lipid Emulsion Infusion in the Treatment of Severe Diphenhydramine Overdose.

BACKGROUND Diphenhydramine is a commonly available over-the-counter antihistamine; however, there are few documented cases of treatment when ingested in toxic quantities, where it can cause a sodium channel blockade leading to wide-complex tachycardia, seizures, and death. Conventional treatment includes sodium bicarbonate infusion, but few cases have documented the addition of lipid emulsion therapy. CASE REPORT A 24-year-old African American female ingested 18 g (360 pills of 50 mg) over-the-counter diphenhydramine. She presented comatose, with hemodynamic instability and hypotension, intubated with pupil dilation to 6 to 7 mm, and initial electrocardiography findings showing a type 1 AV block with a QT/QTc of 360/402 ms which progressed into sinus tachycardia with widened QRS intervals of 134 ms and prolonged QT/QTc intervals of up to 638/759 ms. Treatment using sodium bicarbonate and magnesium was initiated; however, the intraventricular conduction delay persisted. Infusion of 20% intravenous lipid emulsion was administered; following this, the patient developed narrow complex QRS with sinus rhythm and shortened the QT/QTc interval to 448/516 ms. She recovered quickly and was transferred to inpatient psychiatric unit for further evaluation, and discharged 1 month later. CONCLUSIONS Lipid emulsion therapy has been utilized in treatment of various medication overdoses, but there are few documented cases in the treatment of diphenhydramine overdose. With the amount of diphenhydramine ingested by the patient in this case report, the use of combined conventional and lipid emulsion therapy was utilized in the stabilization and management of the patient, and should be considered in scenarios where conventional treatments have not improved the clinical outcome.

A Case of Levofloxacin-Induced Hepatotoxicity.

BACKGROUND Levofloxacin covers a broad spectrum of pathogens and is readily prescribed by clinicians. Hepatotoxicity is a known but unusual complication of levofloxacin use. Here, we present a case of severe transaminitis caused by levofloxacin. CASE REPORT A young man in his thirties with a history of asthma, chronic alcoholism, methamphetamine intravenous drug abuse (IVDA), and non-compliant insulin-dependent diabetes mellitus (IDDM) presented to an emergency department with suicidal ideation. Vital signs were stable and the patient was noted to have cellulitis of the right forearm, for which cultures were drawn, and he received IV clindamycin. He was admitted to behavioral medicine for further care. Blood cultures were positive for gram-negative rods and he was transferred to the medicine ward. Cultures eventually grew Brevundimonas diminuta. Clindamycin was discontinued and he was started on levofloxacin. Transaminase levels measured soon after levofloxacin administration showed aminotransferase levels raised to approximately 50 times baseline within a few days. Levofloxacin was discontinued due to concern about drug-induced hepatotoxicity. After discontinuation, transaminase levels decreased immediately. Work-up for other causes of transaminitis revealed no other etiology. CONCLUSIONS Clinicians should remain mindful that levofloxacin can induce hepatotoxicity in rare cases. In patients presenting with acute liver injury who have recently taken levofloxacin, it would be wise to remain cognizant of the possibility of levofloxacin-induced hepatotoxicity.

Comorbidities, Sociodemographic Factors, and Hospitalizations in Outpatients With Heart Failure and Preserved Ejection Fraction.

Patients with heart failure and preserved ejection fraction (HFpEF) tend to be older and have a high co-morbidity burden. The impact of co-morbid conditions and sociodemographic risk factors on outcomes in these patients has not been quantified. We evaluated 445 consecutive outpatients with HFpEF, defined as established diagnosis of heart failure (HF) with left ventricular ejection fraction at presentation >40% and no previous left ventricular ejection fraction ≤40%. Patients with specific cardiomyopathies, congenital heart disease, primary right-sided disease, valvular disease, or previous advanced HF therapies were excluded. After 2 years, there were 44 deaths and 609 all-cause hospitalizations; of these, 260 (42.7%) were cardiovascular hospitalizations, including HF, and 173 (28.4%) were specifically for HF. The highest attributable risk for hospitalizations was associated with marital status (single, divorced, and widowed had higher hospitalization rates compared with married patients), hypoalbuminemia, diabetes, atrial fibrillation, and renal dysfunction. The proportion of hospitalizations potentially attributable to these factors was 66.6% (95% confidence interval [CI] 56.4 to 74.4) for all-cause hospitalizations, 76.9% (95% CI 65.2 to 84.6) for cardiovascular hospitalizations, and 83.0% (95% CI 70.3 to 90.3) for HF hospitalizations. For composite end points, the proportion was 46.9% (95% CI 34.0% to 57.3%) for death or all-cause hospitalization, 45.7% (95% CI 29.3% to 58.2%) for death or cardiovascular hospitalization, and 43.7% (95% CI 24.2% to 58.2%) for death or HF-related hospitalization. In conclusion, among outpatients with HFpEF, most hospitalizations could be attributed to co-morbidities and sociodemographic factors. Effects of HF therapies on hospitalizations and related end points may be difficult to demonstrate in these patients. Multidisciplinary approaches are more likely to impact hospitalizations in HFpEF.

Leiomyosarcoma of the Inferior Vena Cava in an HIV-Positive Adult Patient: A Case Report and Review of the Literature.

BACKGROUND Leiomyosarcoma is the most common primary malignancy of the inferior vena cava (IVC), and represents approximately 10% of primary retroperitoneal sarcomas. Leiomyosarcoma presents with non-specific symptoms, including abdominal pain or back pain. There is an increased incidence in immunosuppressed individuals. CASE REPORT An unusual presentation of IVC leiomyosarcoma is reported in a 46-year-old female patient infected with human immunodeficiency virus (HIV) who was on highly active antiretroviral therapy (HAART) and who had a normal CD4 count of 934, who presented with back pain. Magnetic resonance imaging (MRI) of the lumbar spine showed a mass of the IVC. Initial computed tomography (CT)-guided biopsy of the IVC mass was non-diagnostic. An IVC filter was inserted, and the patient was discharged home, but 20 days later, she returned to the hospital with worsening right flank pain. Laboratory tests showed acute renal failure, and a repeat CT scan showed IVC thrombus extending 5 cm superiorly. When compared with the previous CT, there was an extension of thrombus into both renal veins. Histopathology of a transjugular needle core biopsy showed a moderately differentiated leiomyosarcoma. The patient was transferred to a multidisciplinary sarcoma center for surgical resection, chemotherapy, and radiation therapy. CONCLUSIONS This report is of a rare case of IVC leiomyosarcoma in a middle-aged HIV-positive woman with a normal CD4 count. Leiomyosarcoma of the IVC is extremely rare, is often detected when advanced, and has a poor prognosis. This case report describes the clinical, imaging, surgical and histopathological findings of leiomyosarcoma of the IVC.

Update on pulmonary arterial hypertension pharmacotherapy.

Pulmonary artery hypertension (PAH) refers to several subgroups of disease in which the mean pulmonary artery pressure (mPAP) is elevated to more than 25 mm Hg, pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and an elevated pulmonary vascular resistance (PVR) > 3 Wood units as confirmed by right heart catheterization. The prevalence and geographic distribution of PAH vary depending on the type and etiology of the disease. Despite enormous efforts in the research and development of therapeutic agents in the last twenty years, the disease remains relatively incurable and the overall prognosis remains guarded. Median survival for an untreated patient is 2.8 years. In the last three decades, there have been dramatic advances in understanding the molecular mechanisms and signaling pathways involved in the disease, resulting in emerging new treatment strategies. In the following pages, we will review currently approved treatments for PAH, as well as a new generation of investigational drugs.

Promising new therapies for the treatment of hypercholesterolemia.

INTRODUCTION: Statins are currently the most commonly used agents for treatment of hypercholesterolemia in patients with atherosclerotic cardiovascular disease. However, some patients on statins do not achieve their treatment goals or are intolerant to statins. Therefore, new therapies for treatment of hypercholesterolemia are under investigation. AREAS COVERED: This article reviews the new emerging medications for the treatment of hypercholesterolemia and discusses their efficacy and safety profile based on literature searches that included human studies published on PubMed and reported clinical trials. EXPERT OPINION: Inhibition of the PCSK9 protein by monoclonal antibodies results in a dramatic 40%-60% lowering of serum low-density lipoprotein cholesterol (LDL-C). This is in addition to LDL-C lowering achieved by statins. Multiple clinical studies have demonstrated the high selectivity of these antibodies for the PCSK9 pathway and their long-term safety and efficacy. Alirocumab and evolocumab have been approved by the FDA for the treatment of patients with heterozygous familial hypercholesterolemia and patients with clinical atherosclerotic cardiovascular disease) who do not achieve their LDL-C target on maximal tolerated statin treatment and dietary modification. In addition, evolocumab has been approved by the FDA for homozygous familial hypercholesterolemia. However, the long-term efficacy and safety of PCSK9 inhibitors are unknown.

Identification of miRNAs that modulate glucocerebrosidase activity in Gaucher disease cells.

Gaucher disease is an autosomal recessive disorder caused by deficiency of the enzyme glucocerebrosidase. Although it is a monogenic disease, there is vast phenotypic heterogeneity, even among patients with the same genotype. MicroRNAs (miRNAs) are small non-coding RNAs involved in many biological processes and diseases. To determine whether miRNAs can affect glucocerebrosidase activity, we performed a screen of 875 different miRNA mimics. The screen was performed using Gaucher fibroblasts, and glucocerebrosidase activity was used as the initial outcome parameter. We found several miRNAs that either up- or down-regulated glucocerebrosidase activity. In follow-up assays, we confirmed that one specific miRNA (miR-127-5p) down-regulated both glucocerebrosidase activity and protein levels by down-regulation of LIMP-2, the receptor involved in proper trafficking of glucocerebrosidase from the endoplasmic reticulum to the lysosome. A conditioned media assay demonstrated that cells treated with this miRNA secreted glucocerebrosidase into the extracellular environment, supporting impaired LIMP-2 function. Two other miRNAs, miR-16-5p and miR-195-5p, were found to up-regulate glucocerebrosidase activity by greater than 40% and to enhance expression and protein levels of the enzyme. In conclusion, we show that miRNAs can alter glucocerebrosidase activity in patient cells, indicating that miRNAs can potentially act as modifiers in Gaucher disease.

Saposin C protects glucocerebrosidase against α-synuclein inhibition.

Mutations in GBA1, the gene for glucocerebrosidase (GCase), are genetic risk factors for Parkinson disease (PD). α-Synuclein (α-Syn), a protein implicated in PD, interacts with GCase and efficiently inhibits enzyme activity. GCase deficiency causes the lysosomal storage disorder Gaucher disease (GD). We show that saposin C (Sap C), a protein vital for GCase activity in vivo, protects GCase against α-syn inhibition. Using nuclear magnetic resonance spectroscopy, site-specific fluorescence, and Förster energy transfer probes, Sap C was observed to displace α-syn from GCase in solution and on lipid vesicles. Our results suggest that Sap C might play a crucial role in GD-related PD.

New development of cardiac tamponade on underlying effusive-constrictive pericarditis: an uncommon initial presentation of scleroderma.

A 40-year-old man with a medical history of hypertension was admitted for weight loss, generalised weakness, joint pains and mottling of fingertips. The initial laboratory data revealed microangiopathic haemolytic anaemia, thrombocytopenia and acute renal failure. Intravenous steroids were started for possible diagnosis of systemic lupus erythematosus based on admission assessment. Intravenous immunoglobulin and plasmapharesis were subsequently added to the treatment plan to cover thrombotic thrombocytopenic purpura while his autoimmune panel was pending. The echocardiogram study on day 2 revealed cardiac tamponade for which he underwent pericardiocentesis and right heart catheterisation. The atrial waveforms postpericardiocentesis demonstrated effusive-constrictive pericarditis. His clinical condition kept on deteriorating with reaccumulation of pericardial effusion and further complicated by hemoperitoneum and colonic obstruction. He had cardiorespiratory arrest on his fourth admission day and was not revived. Anti-Scl-70 antibody came back positive. Autopsy findings confirmed the presence of fibrinous pericarditis and hemoperitoneum.

Membrane-bound α-synuclein interacts with glucocerebrosidase and inhibits enzyme activity.

Mutations in GBA, the gene encoding glucocerebrosidase, the lysosomal enzyme deficient in Gaucher disease increase the risk for developing Parkinson disease. Recent research suggests a relationship between glucocerebrosidase and the Parkinson disease-related amyloid-forming protein, α-synuclein; however, the specific molecular mechanisms responsible for association remain elusive. Previously, we showed that α-synuclein and glucocerebrosidase interact selectively under lysosomal conditions, and proposed that this newly identified interaction might influence cellular levels of α-synuclein by either promoting protein degradation and/or preventing aggregation. Here, we demonstrate that membrane-bound α-synuclein interacts with glucocerebrosidase, and that this complex formation inhibits enzyme function. Using site-specific fluorescence and Förster energy transfer probes, we mapped the protein-enzyme interacting regions on unilamellar vesicles. Our data suggest that on the membrane surface, the glucocerebrosidase-α-synuclein interaction involves a larger α-synuclein region compared to that found in solution. In addition, α-synuclein acts as a mixed inhibitor with an apparent IC(50) in the submicromolar range. Importantly, the membrane-bound, α-helical form of α-synuclein is necessary for inhibition. This glucocerebrosidase interaction and inhibition likely contribute to the mechanism underlying GBA-associated parkinsonism.

Discovery of a novel noniminosugar acid α glucosidase chaperone series.

Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the lysosomal enzyme acid α-glucosidase (GAA). Many disease-causing mutated GAA retain enzymatic activity but are not translocated from endoplasmic reticulum (ER) to lysosomes. Enzyme replacement therapy (ERT) is the only treatment for Pompe disease but remains expensive, inconvenient, and does not reverse all disease manifestations. It was postulated that small molecules which aid in protein folding and translocation to lysosomes could provide an alternate to ERT. Previously, several iminosugars have been proposed as small-molecule chaperones for specific LSDs. Here we identified a novel series of noniminosugar chaperones for GAA. These moderate GAA inhibitors are shown to bind and thermostabilize GAA and increase GAA translocation to lysosomes in both wild-type and Pompe fibroblasts. AMDE and physical properties studies indicate that this series is a promising lead for further pharmacokinetic evaluation and testing in Pompe disease models.

Discovery, structure-activity relationship, and biological evaluation of noninhibitory small molecule chaperones of glucocerebrosidase.

A major challenge in the field of Gaucher disease has been the development of new therapeutic strategies including molecular chaperones. All previously described chaperones of glucocerebrosidase are enzyme inhibitors, which complicates their clinical development because their chaperone activity must be balanced against the functional inhibition of the enzyme. Using a novel high throughput screening methodology, we identified a chemical series that does not inhibit the enzyme but can still facilitate its translocation to the lysosome as measured by immunostaining of glucocerebrosidase in patient fibroblasts. These compounds provide the basis for the development of a novel approach toward small molecule treatment for patients with Gaucher disease.