Intensity of Cyclophosphamide-Based Bridging Therapy Before Chimeric Antigen Receptor T Cell Therapy in Myeloma.

Patients receiving autologous chimeric antigen receptor T cell (CAR-T) therapy for multiple myeloma (MM) may require bridging therapy (BT) before CAR-T infusion to maintain some level of disease control. Alkylators, such as cyclophosphamide (Cy), are often used in regimens, either in high-intensity regimens, such as modified hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), or once-weekly regimens, such as KCd (carfilzomib, cyclophosphamide, and dexamethasone). However, there is no consensus regarding the optimal BT alkylator dose intensity in MM. We performed a single-center analysis of all instances of BT before planned autologous CAR-T for MM during a 5-year period ending in April 2022. We classified bridging regimens into 3 cohorts: (1) hyperfractionated Cy (HyperCy) with inpatient Cy every 12 to 24 hours or as a continuous i.v. infusion; (2) less intensive Cy dosing (WeeklyCy), such as KCd; and (3) NonCy, in which no alkylators were used in BT. Demographic, disease-related, and treatment-related characteristics were collected for all patients. The 3 BT cohorts were compared using the Fisher exact test, Kruskal-Wallis test, and log-rank test, as appropriate. We identified 70 discrete BT instances among 64 unique patients, including 29 (41%) with HyperCy, 23 (33%) with WeeklyCy, and 18 (26%) with NonCy. The median total Cy dosing during BT in the 3 groups were 2100 mg/m2, 615 mg/m2, and 0 mg/m2, respectively. Age, number of prior lines of therapy, triple-class refractory status, presence of high-risk cytogenetics, extramedullary disease, bone marrow plasma cell burden, involved free light chain (iFLC) kinetics before collection, and other measures of disease aggressiveness were comparable across the 3 cohorts. iFLC levels rose ≥25% and ≥100 mg/L during BT (approximating progressive disease) in comparable proportions (P = .25) among the cohorts: 52% for HyperCy, 39% for WeeklyCy, and 28% for NonCy. All BT instances without subsequent CAR-T were due to manufacturing failures. Among 61 instances of BT followed by CAR-T, vein-to-vein times were slightly longer (P = .03) with HyperCy (45 days) compared with WeeklyCy (39 days) and NonCy (46.5 days). Neutrophil recovery times were similar in the 3 cohorts, but platelet recovery took longer with HyperCy (64 days) compared with WeeklyCy (42 days) and NonCy (12 days). Progression-free survival was comparable among the cohorts, but median overall survival (OS) was not: 15.3 months with HyperCy, versus 30.0 months with WeeklyCy and not reached with NonCy. In our retrospective analysis of BT before CAR-T therapy in MM, HyperCy did not result in superior disease control than WeeklyCy despite a 3-fold higher dose of Cy. In contrast, HyperCy was associated with longer post-CAR-T platelet recovery and worse OS despite comparable measurements of disease aggressiveness and tumor burden. Study limitations include our small sample size, as well as confounding from gestalt markers of MM aggressiveness that might have led to poorer outcomes as well as physicians' decision to prescribe HyperCy. Given the rarity of objective disease responses to chemotherapy in relapsed/refractory MM, our analysis suggests that hyperfractionated Cy regimens do not outperform once-weekly Cy regimens for most patients who require BT before CAR-T therapy.

Acquired Amegakaryocytic Thrombocytopenic Purpura: A Review of Therapeutic Options.

Acquired amegakaryocytic thrombocytopenic purpura (AATP) is a rare bone marrow disorder characterized by either a marked decrease or a complete absence of megakaryocytes with the preservation of all other cell lines. To date, more than 60 cases of AATP have been reported in the literature. Due to the rarity of this disease, no standard treatment guidelines have been established, and therapy is based on a handful of case studies and expert opinions. Herein, we provide a comprehensive review of currently utilized therapeutic options for AATP.

Eculizumab in the management of drug-induced thrombotic microangiopathy: A scoping review of the literature.

Drug-induced TMA (DI-TMA) is a thrombotic microangiopathy (TMA) caused by certain drugs, usually managed by drug discontinuation and supportive measures. Data on the use of complement-inhibition with eculizumab in DI-TMA is scarce, and its benefit in cases of severe or refractory DI-TMA is unclear. We conducted a comprehensive search in PubMed, Embase and MEDLINE databases (2007-2021). We included articles that reported on DI-TMA patients treated with eculizumab and its clinical outcomes. All other causes of TMA were excluded. We evaluated the outcomes of hematologic recovery, renal recovery, and a composite of both (complete TMA recovery). 35 studies fulfilled our search criteria, which included 69 individual cases of DI-TMA treated with eculizumab. Most cases were secondary to chemotherapeutic agents, and the most implicated drugs were gemcitabine (42/69), carfilzomib (11/69), and bevacizumab (5/69). The median number of eculizumab doses given was 6 (range 1-16). 55/69 (80 %) patients achieved renal recovery, after 28-35 days (5-6 doses). 13/22 (59 %) patients were able to discontinue hemodialysis. 50/68 (74 %) patients achieved complete hematologic recovery after 7-14 days (1-2 doses). 41/68 (60 %) patients met criteria for complete TMA recovery. Eculizumab was safely tolerated in all cases, and appeared to be effective in achieving both hematologic and renal recovery in DI-TMA refractory to drug discontinuation and supportive measures, or with severe manifestations associated with significant morbidity or mortality. Our findings suggest that eculizumab may be considered as a potential treatment for severe or refractory DI-TMA that does not improve after initial management, although larger studies are needed.

The Impact of Atrial Fibrillation on hospitalization Outcomes for Patients With Chronic Lymphocytic Leukemia Using the National Inpatient Sample Database.

BACKGROUND: The incidence of atrial fibrillation (AF) in patients with chronic lymphocytic leukemia (CLL) has been on the rise. However, the excess burden added by AF to the morbidity and mortality of CLL patients especially in the hospitalized setting is undetermined. METHODS: The National Inpatient Sample (NIS) database was accessed to gather data of hospitalized CLL patients with AF from 2009 to 2018. Propensity-score matching (PSM) and logistic regression model were performed to control for baseline patient factors to match 7265 CLL patient admissions with AF and 7265 CLL patient admissions without AF. The primary outcome was all-cause mortality (ACM), while the secondary outcomes included acute coronary syndrome (ACS), acute myocardial infarction (AMI), and the need for percutaneous coronary intervention (PCI), acute heart failure (AHF), acute hypoxic respiratory failure (AHRF), cardiac arrest (CA), cardiogenic shock (CS), stroke, and the total cost of hospitalization. RESULTS: CLL patients with AF had a higher rate of ACM (6.06% vs 4.47%; odds ratio [OR] 1.39, 95% confidence interval [CI] 1.19-1.61; P =< .001). All other secondary outcomes including ACS, AMI, PCI, AHRF, CA, CS, and stroke were observed at a significantly higher rate in the AF group as well. The median total hospital cost was also higher in the AF group ($9097 vs. $7646; P value < .0001) CONCLUSION: CLL patients with AF are at a significantly increased risk of all-cause mortality, cardiac-related mortality, and stroke. For this population, a multidisciplinary approach should be orchestrated for better management and outcomes.

Low-cost production and application of lipopeptide for bioremediation and plant growth by Bacillus subtilis SNW3.

At present time, every nation is absolutely concern about increasing agricultural production and bioremediation of petroleum-contaminated soil. Hence, with this intention in the current study potent natural surfactants characterized as lipopeptides were evaluated for low-cost production by Bacillus subtilis SNW3, previously isolated from the Fimkessar oil field, Chakwal Pakistan. The significant results were obtained by using substrates in combination (white beans powder (6% w/v) + waste frying oil (1.5% w/v) and (0.1% w/v) urea) with lipopeptides yield of about 1.17 g/L contributing 99% reduction in cost required for medium preparation. To the best of our knowledge, no single report is presently describing lipopeptide production by Bacillus subtilis using white beans powder as a culture medium. Additionally, produced lipopeptides display great physicochemical properties of surface tension reduction value (SFT = 28.8 mN/m), significant oil displacement activity (ODA = 4.9 cm), excessive emulsification ability (E24 = 69.8%), and attains critical micelle concentration (CMC) value at 0.58 mg/mL. Furthermore, biosurfactants produced exhibit excellent stability over an extensive range of pH (1-11), salinity (1-8%), temperature (20-121°C), and even after autoclaving. Subsequently, produced lipopeptides are proved suitable for bioremediation of crude oil (86%) and as potent plant growth-promoting agent that significantly (P < 0.05) increase seed germination and plant growth promotion of chili pepper, lettuce, tomato, and pea maximum at a concentration of (0.7 g/100 mL), showed as a potential agent for agriculture and bioremediation processes by lowering economic and environmental stress.

Adenovirus-Associated Disseminated Intravascular Coagulation.

A 21-year-old previously healthy Caucasian female presented to the emergency department (ED) in the pre-COVID-19 era for evaluation of thrombocytopenia after a flu-like illness. The patient reported fever, cough, headache and myalgias for one week. She was on oral contraceptive pills (OCPs) for five years but discontinued one week ago. She was found to be in disseminated intravascular coagulation (DIC) and her hospital course was complicated by intraparenchymal hemorrhage, deep vein thrombus (DVT) in the right arm veins, bilateral pulmonary embolus (PE) and multiple splenic infarcts. An extensive workup was negative but nasopharyngeal swab came back positive for adenovirus by polymerase chain reaction (PCR).

Anaplastic Large Cell Lymphoma Presenting as Haemophagocytic Lymphohistiocytosis with Underlying Coxiella burnetii and Bartonella henselae Seropositivity.

A 44-year-old woman with no significant medical history presented with a 3-week history of high-grade fevers, fatigue and shortness of breath. Laboratory investigation was significant for lymphopenia and thrombocytopenia which progressively worsened during her hospital stay, along with new-onset anaemia, and elevated ferritin, transaminase and triglycerides. A computerized tomography (CT) scan of the abdomen revealed retroperitoneal lymphadenopathy. A bone marrow biopsy confirmed the diagnosis of haemophagocytic lymphohistiocytosis (HLH). Extensive infectious work-up revealed high IgG titres for Bartonella henselae and Coxiella burnetii. Interestingly, the left supraclavicular node was negative for both microbes by polymerase chain reaction (PCR), but the biopsy revealed anaplastic large T-cell lymphoma. LEARNING POINTS: Haemophagocytic lymphohistiocytosis (HLH) is an important differential diagnosis to consider for fever of unknown origin in adults, especially in the setting of pancytopenia and hyperferritinaemia.Q fever resulting from Coxiella burnetii can cause HLH and is also postulated to increase the risk of lymphoma.Bartonella henselae infection can also trigger HLH, but the risk of lymphoma following infection by B. henselae is unknown.

Interventions to improve resident reporting of patient safety events: a quality improvement initiative.

BACKGROUND: Patient safety events (PSE) are opportunities to improve patient care but physicians rarely report them. In a previous study, residents identified knowledge regarding what constitutes a PSE, perceived lack of time, complexity of the reporting process, lack of feedback, and perceived failure to resolve the issue despite reporting to be barriers limiting their PSE reporting. The residency programs and system patient safety and quality improvement departments created targeted interventions to address identified barriers. OBJECTIVE: Assess effectiveness of targeted interventions on improving PSE reporting rates amongst residents. METHODS: As part of a multi-residency patient safety project, interventions were created to focus on the removal of barriers to reporting PSE identified previously. Post-interventions, an identical cross-sectional survey of the residents at the same two community teaching hospitals was conducted from Sept to Dec 2018 through an online questionnaire tool. RESULTS: 78 out of 149 residents (52.3%) completed the survey. We found a significant improvement in the number of residents who endorsed reporting a PSE in the past 1 year (51.2% vs 23.5%, p = 0.001), as well as during the course of their training (52.6% vs 26.5%, P = 0.001). There was also a significant decrease in the number of residents who were unsure of how to report a PSE (p = 0.031) as well as those who viewed medical error as a sign of incompetence (p = 0.036). CONCLUSION: Our study demonstrates that simplifying the PSE reporting process, improving knowledge and acceptance of patient safety/quality improvement principles and promotion of a just culture improves resident PSE reporting.

A presumed case of Darbepoetin-induced myocardial infarction in the patient with MDS-RARS.

Our case is only the 2nd such reported case of atherothrombosis from ESAs and highlights the increased risk of cardiovascular events in patients receiving erythropoietin-stimulating agents specially patients with underlying MDS where targeting a lower hemoglobin goal and optimizing other cardiovascular risk factors might be beneficial in preventing future cardiovascular mortality.

Multiple myocardial abscesses secondary to late stent infection.

A 53-year-old woman presented to our hospital with dizziness and low-grade fever. She underwent percutaneous coronary intervention to the obtuse marginal artery with a drug-eluting stent 20 months prior to this presentation. Physical examination was remarkable for bradycardia. Electrocardiogram showed a junctional rhythm with heart rate of 35 bpm. Blood and urine cultures were negative. Despite successful urgent pacemaker placement, she had cardiac arrest the following day with unsuccessful cardiopulmonary resuscitation attempt. Cardiac autopsy report revealed multiple abscesses involving the obtuse marginal and left anterior descending arteries as well as the adjacent myocardial regions.

Non-functional paraganglioma of the mediastinum.

Paragangliomas are rare tumours which have the ability to secrete neuropeptide and catecholamines. Frequently, the clinical presentation of these tumours is ill defined and some may have no symptoms whatsoever until the tumour is large enough to cause symptoms secondary to local invasion and mass effect, hence making paragangliomas a challenge to diagnose and manage surgically. We report a case of a 55 year old female who presented with shortness of breath and chest pain for 3 years. Further investigations led to the demonstration of a mass along the left side of the mediastinum which was suggestive of a neoplasm. Complete surgical resection of the tumour was achieved and the patient was discharged uneventfully.

Huge carcinoid tumour causing complete obstruction of the left main bronchus and destruction of left lung.

Carcinoid tumours arise from the neuroendocrine cells of the bronchial epithelium known as Kulchitsky cells and comprise 4% of all lung malignancies. We report a case of a 16- year-old male who presented with a 1-month history of fever, cough, left-side chest pain and shortness of breath. Chest X -ray showed loss of lung volume on the left side with cystic spaces and air fluid levels. Computed tomography scan chest demonstrated a homogenous mass extending into the left main bronchus causing its complete obstruction along with extensive bronchiectatic changes in the left lung. Bronchoscopy and bronchial biopsy confirmed the diagnosis of typical carcinoid tumour. A pneumonectomy was performed. This case is unusual due to the large size of the tumour, its location and associated destruction of the entire left lung.