Isolation of acute myeloid leukemia blasts from blood using a microfluidic device.

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and associated with poor prognosis. Unfortunately, most of the patients that achieve clinical complete remission after the treatment will ultimately relapse due to the persistence of minimal residual disease (MRD), that is not measurable using conventional technologies in the clinic. Microfluidics is a potential tool to improve the diagnosis by providing early detection of MRD. Herein, different designs of microfluidic devices were developed to promote lateral and vertical mixing of cells in microchannels to increase the contact area of the cells of interest with the inner surface of the device. Possible interactions between the cells and the surface were studied using fluid simulations. For the isolation of leukemic blasts, a positive selection strategy was used, targeting the cells of interest using a panel of specific biomarkers expressed in immature and aberrant blasts. Finally, once the optimisation was complete, the best conditions were used to process patient samples for downstream analysis and benchmarking, including phenotypic and genetic characterisation. The potential of these microfluidic devices to isolate and detect AML blasts may be exploited for the monitoring of AML patients at different stages of the disease.

Home Ultrasound: A Contemporary and Valuable Tool for Palliative Medicine.

This narrative review explores the application of point-of-care ultrasound (POCUS) in palliative care and its feasibility in home care settings. POCUS has the potential to streamline diagnostic strategies without patient transfer to the hospital, expedite timely symptomatic relief, and reduce complications from specific palliative interventions. The advent of handheld ultrasound devices has made it an attractive diagnostic and interventional adjunct in acute palliative care. POCUS has gained widespread acceptance as part of routine care in emergency medicine and intensive care, guiding certain procedures and increasing their safety. The modernization and miniaturization of ultrasound equipment have made ultra-portable devices available, allowing for better-quality images at affordable prices. Handheld devices have the potential to revolutionize everyday clinical practice in home-based palliative care, contributing to important bedside clinical decisions. Palliative care patients often require diagnostic examinations in the last months of their lives, with CT being the most frequently performed imaging procedure. However, CT imaging is associated with high costs and burdens, leading to increased suffering and impaired quality of life. Clinical ultrasound, a dialogic imaging modality, offers a safer and more efficient approach to palliative care. POCUS applications, which are cost-effective, non-invasive, and well-tolerated, can be used to improve patient satisfaction and diagnostic understanding. POCUS is a valuable tool in palliative care, improving diagnostic accuracy and reducing the time to diagnosis for various pathologies. It is a standard of care for many procedures and improves patient safety. However, there are limitations to POCUS in palliative care, such as operator-dependent examination variability and limited availability of trained professionals. To overcome these limitations, palliative care physicians should receive mandatory training in POCUS, which can be incorporated into the core curriculum. Additionally, ultrasound teleconsulting can assist less experienced examiners in real-time examinations. The literature on POCUS in palliative care is limited, but research on patient-oriented outcomes is crucial. POCUS should be considered a supplement to good clinical reasoning and regulated radiological evaluations.

Response to therapy in Richter syndrome: a systematic review with meta-analysis of early clinical trials.

Introduction and aims: Richter syndrome (RS) represents the clonal evolution of chronic lymphocytic leukemia with histological transformation into a high-grade B cell lymphoma (diffuse large B cell lymphoma - DLBCL) or Hodgkin lymphoma. Considering that RS is an uncommon condition with poor prognosis, few high-quality evidence is available. To overcome this unmet need, this meta-analysis aimed to pool efficacy of early clinical trials in Richter syndrome (DLBCL subtype). Methods: MEDLINE, Scopus and Web of Science were searched up to May of 2023 to identify clinical trials decoying efficacy. The pooled complete response, objective response and intension-to-treat failure rates were calculated by pharmacological categories (classical chemotherapy, immunochemotherapy, immunotherapy, Bruton-tyrosine kinase inhibitors, targeted approaches, cell-based therapies and combinatorial regimens) using the Der-Simonian and Laird random-effects model. The Freeman-Tukey double arcsine method was used to estimate variance and confidence intervals. Heterogeneity was assessed using the I2 method. Results: Overall, from 1242 studies identified, 30 were included, pooling data from 509 patients. The higher efficacy rates when, cell-based therapies were excluded, were achieved by immunochemotherapeutic regimens followed by combinatorial regimens, with complete response rates of 21.54% (IC95%14.93-28.87) and 23.77% (IC95% 8.70-42.19), respectively. Bispecific antibodies (alone or coupled with a chemotherapy debulking strategy) overtook Bruton tyrosine kinase inhibitors response rates. The latter, although achieving objective response rates above average, presented scarce complete response rates. Checkpoint inhibitors alone usually do not lead to complete responses, but their effectiveness may improve when combined with other agents, unveiling the importance of immune microenvironmental modulation. Conclusion: This is the first meta-analysis of early clinical trials assessing the impact of different therapeutics in RS. By analyzing the pooled efficacy estimates, our work suggests the role of a tailor-made bridging therapy for young patients with RS eligible for allogeneic hematopoietic stem cell transplantation (alloSCT), formally the only curative strategy.

Diagnostic Point-of-Care Ultrasound (POCUS) for Abdominal Pain: A Case of Tumefactive Sludge.

Biliary sludge is an extremely viscous sediment, consisting essentially of calcium bilirubinate granules and cholesterol crystals, which, due to its high viscosity, has poor and slow movement, leading to a mass-like configuration called tumefactive biliary sludge. Tumefactive sludge was first described with the advent of ultrasonography in the 1970s and is an uncommon intraluminal lesion of the gallbladder (GB). The differential diagnoses for an echogenic mass in the GB lumen include GB carcinoma, tumefactive sludge, and gangrenous cholecystitis. Ultrasonography is the election method for the screening of GB diseases, with diagnostic accuracy exceeding 90%. The point-of-care ultrasound (POCUS) has shown a major improvement in the evaluation of hepatobiliary diseases. POCUS allows the detection of GB wall thickness, pericholestatic fluid, sonographic Murphy's sign, and dilatation of the common bile duct. The authors present a case of abdominal pain caused by the presence of tumefactive sludge in the GB, in which POCUS helped establish the diagnosis and therapeutic guidance.

Ultrasound Assessment in a Pregnant Woman? Not just for the Fetus.

Pericarditis is a relatively common diagnosis worldwide; however, there are few data published on the frequency, diagnosis, and management of pericardial diseases in pregnant women. Ultrasonography has established its utmost importance and is worldwide recognized in pregnancy and fetal evaluation. Moreover, point-of-care ultrasonography of pregnant women, guided by clinical examination and history, can play an equally fundamental role. We present a case of a 37-year-old pregnant woman who presented at the emergency department with pleuritic chest pain, fever, and cough. Bedside point-of-care ultrasonography confirmed pericarditis revealing an organized pericardial effusion, leading to patient hospitalization and initiation of therapy. The importance and acknowledgment of portable and hand-held ultrasonography devices are growing since it enables physicians not only to make a fast and accurate diagnosis but also to access evolution in inpatient and outpatient settings.

Costs, effectiveness, and safety associated with Chimeric Antigen Receptor (CAR) T-cell therapy: Results from a comprehensive cancer center.

Real world effectiveness, toxicity and costs analyses from chimeric antigen receptor (CAR)-T cell therapy are of utmost relevance to determine whether and how to offer patients highly personalized immunotherapy. In this study, we aimed at describing CAR T-cells effectiveness, safety and costs in a Portuguese Comprehensive Cancer Center. We performed a retrospective descriptive study of adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma and transformed follicular lymphoma referred to CAR T-cell therapy, between May 2019 and February 2021. Rates of treatment response, toxicity and survival (Kaplan-Meier method) were analyzed by intention-to-treat. Direct medical costs stratified by inpatient-care, outpatient-care, and diagnostic-therapeutic procedures (DTP) were derived based on resources used and their respective unit costs. In twenty patients (median age 49.5y; 55%male; 70%DLBCL; 50% with primary refractory disease), best overall and complete response rates were 65.0% and 45.0%, respectively. Median overall (OS) and progression-free survivals were 9.2 and 7.3 months; 12-month OS rate was 42.6% (95%CI:23.2-78.3). Grade≥3 cytokine release syndrome and neurotoxicity occurred in 5.6% and 11.1% of patients, respectively. CAR T-cell therapy expenditure, including adverse events costs, was 7 176 196€, or 286 238€ when excluding drug cost. Median cost for treated patient was 355 165€ with CAR T-cell drug cost accounting for 97.0% of the overall expense. Excluding CAR T-cell acquisition cost, inpatient-care and DTP accounted for 57% and 38% of total cost/patient, respectively. Our findings highlight the heavy economic burden of CAR T-cell therapy driven by drug acquisition costs.

Point-of-Care Ultrasound Protocol for Insertion and Confirmation of Central Venous Catheter Placement.

Central venous catheterization is a common procedure in the management of critically ill patients, in the context of medical emergencies, and before surgical interventions. Placing a central venous catheter (CVC) in the internal jugular vein (IJV) using anatomical references is associated with a high risk of complications, in particular pneumothorax and arterial puncture. Thus, the placement of CVCs with ultrasound support is recommended by several medical societies and health regulators at the international level. When compared with chest radiography, ultrasound is accessible, safe, cost-effective, and time efficient. This technical report is meant to detail a point-of-care ultrasound protocol designed for the insertion and confirmation of the correct placement of a CVC in the IJV.

Ultra-low dose radiotherapy in the management of low-grade orbital lymphomas.

Background: Ultra-low dose radiotherapy (ULDRT) (2 × 2 Gy) has been used for symptomatic control of low-grade lymphomas with surprising local control rates, suggesting that these entities could respond to lower doses. These are particularly desirable for the treatment of orbital sites and some publications refer to high rates of complete responses. In this paper, we present our experience with the use of ULDRT for indolent orbital lymphomas. Materials and methods: Electronic files and treatment plans of patients treated with ULDRT for low-grade orbital lymphoma were retrospectively reviewed. Oncological outcomes and toxicities were collected and described for each patient. Results: Seven patients (median age of 75 years) with 8 lesions (3 follicular, 2 MALT, 1 marginal and 1 low-grade non-Hodgkin lymphoma) were considered for analysis. The majority had stage IE disease and one patient had bilateral disease. Six tumors were detected on imaging (median size of 20 mm). Involved orbital sites were periocular, conjunctival and palpebral; there was one case of intraocular (choroid) and one case of lacrimal gland involvement. One patient received consolidative rituximab after RT. The median follow-up time was 22 months. Two patients had partial response, one of them with persistent minimal choroidal disease and the other with partial response on CT. Five (71%) patients had clinical (n = 2) or radiologic (n = 3) complete response on treated sites. Reported late toxicities were minimal and included dry eye and pruritus. Conclusion: In our experience, ULDRT achieved a local control rate of 100% and complete response rate of 71% with minimal toxicity.

Screening a Targeted Panel of Genes by Next-Generation Sequencing Improves Risk Stratification in Real World Patients with Acute Myeloid Leukemia.

Although mutation profiling of defined genes is recommended for classification of acute myeloid leukemia (AML) patients, screening of targeted gene panels using next-generation sequencing (NGS) is not always routinely used as standard of care. The objective of this study was to prospectively assess whether extended molecular monitoring using NGS adds clinical value for risk assessment in real-world AML patients. We analyzed a cohort of 268 newly diagnosed AML patients. We compared the prognostic stratification of our study population according to the European LeukemiaNet recommendations, before and after the incorporation of the extended mutational profile information obtained by NGS. Without access to NGS data, 63 patients (23%) failed to be stratified into risk groups. After NGS data, only 27 patients (10%) failed risk stratification. Another 33 patients were re-classified as adverse-risk patients once the NGS data was incorporated. In total, access to NGS data refined risk assessment for 62 patients (23%). We further compared clinical outcomes with prognostic stratification, and observed unexpected outcomes associated with FLT3 mutations. In conclusion, this study demonstrates the prognostic utility of screening AML patients for multiple gene mutations by NGS and underscores the need for further studies to refine the current risk classification criteria.

Gastric MALT Lymphoma: A 8-Year Experience.

Gastric mucosa-associated lymphoid tissue non-Hodgkin lymphoma (gMALT NHL) is the second most common gastrointestinal lymphoma (50% of all gastric lymphomas), being closely associated with Helicobacter pylori infection, justifying that antibiotic therapy is effective in over 75% of all cases. This is a retrospective study analyzing all adult gMALT NHL cases diagnosed and treated in a single center for 8 years, focusing on demographic features, treatment outcomes, and survival analysis. Sixty patients with a median age of 61 years (53.3% female gender) were analyzed. Most of the cases had localized disease (66.7% were Lugano stage I) and had low IPI scores (median: 1). There was a high prevalence of Helicobacter pylori infection (68.3%). Nearly 97% of the cases received treatment for the disease, a median of one line; 55% of the patients treated endured complete response after first-line therapy (mostly antibiotics). Median overall survival time and median progression-free survival time were not reached. The mean follow-up time was 81.8 months (95% CI: [73.3-90.3]). Thirty-six patients (60%) achieved a 3-year follow-up time; the mortality rate was 15% at the end of the study. Age superior to 65 years and transformation into DLBCL were statistically significant negative prognostic markers for survival in this study (p = 0.006 and p = 0.033, respectively). Our study confirms that gMALT NHL is an indolent disease with long-term survival. Many patients, however, are exposed to several treatment lines along their disease course.

Characteristics and Outcomes of Adult Patients in the PETHEMA Registry with Relapsed or Refractory FLT3-ITD Mutation-Positive Acute Myeloid Leukemia.

This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 + 7. Subsequently, patients received salvage with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care only (n = 80). Active salvage therapy (i.e., intensive or non-intensive therapy) resulted in a complete remission (CR) or CR without hematological recovery (CRi) rate of 42%. More patients achieved a CR/CRi with intensive (48%) compared with non-intensive (19%) salvage therapy (p < 0.001). In the overall population, median overall survival (OS) was 5.5 months; 1- and 5-year OS rates were 25% and 7%. OS was significantly (p < 0.001) prolonged with intensive or non-intensive salvage therapy compared with supportive therapy, and in those achieving CR/CRi versus no responders. Of 280 evaluable patients, 61 (22%) had an allogeneic stem-cell transplant after they had achieved CR/CRi. In conclusion, in this large cohort study, salvage treatment approaches for patients with FLT3-ITD mutated R/R AML were heterogeneous. Median OS was poor with both non-intensive and intensive salvage therapy, with best long-term outcomes obtained in patients who achieved CR/CRi and subsequently underwent allogeneic stem-cell transplant.

Early Lung Ultrasound Findings in Patients With COVID-19 Pneumonia: A Retrospective Multicenter Study of 479 Patients.

OBJECTIVES: Lung ultrasound (LUS) holds the promise of an accurate, radiation-free, and affordable diagnostic and monitoring tool in coronavirus disease 2019 (COVID-19) pneumonia. We sought to evaluate the usefulness of LUS in the diagnosis of patients with respiratory distress and suspicion of interstitial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia, in comparison to other imaging modalities. METHODS: This was a multicenter, retrospective study. LUS was performed, on Emergency Department (ED) arrival of patients presenting for possible COVID-19 evaluation, by trained emergency physicians, before undergoing conventional radiologic examination or while waiting for the report. Scans were performed using longitudinal transducer orientation of the lung regions. CXR was interpreted by radiologists staffing ED radiology. Subjects were divided into two group based on molecular test results. LUS findings were compared to COVID test results, nonlaboratory data, and other imaging for each patient. Categorical variables were expressed as percentages and continuous variables as median ± standard error. RESULTS: A total of 479 patients were enrolled, 87% diagnosed with SARS-CoV-2 by molecular testing. COVID positive and COVID negative patients differed with respect to sex, presence of fever, and white blood cells count. Most common findings on lung point of care ultrasound (POCUS) for COVID-positive patients were B-lines, irregular pleural lines, and small consolidation. Normal chest X-ray was found in 17.89% of cases. CONCLUSIONS: This 479 patient cohort, with COVID-19, found LUS to be noninferior to chest X-ray (CXR) for diagnostic accuracy. In this study, COVID-positive patients are most likely to show B lines and sub-pleural consolidations on LUS examination.

Efficacy and Safety of CT-P10 Versus Rituximab in Untreated Low-Tumor-Burden Follicular Lymphoma: Final Results of a Randomized Phase III Study.

INTRODUCTION: This double-blind, parallel-group, active-controlled phase III trial (NCT02260804) assessed CT-P10 and rituximab safety and efficacy in patients with previously untreated low-tumor-burden follicular lymphoma (LTBFL), including after a single switch from rituximab to CT-P10. PATIENTS AND METHODS: LTBFL patients were randomized (1:1) to receive CT-P10 or rituximab (375 mg/m2 intravenously; day 1 of 4 7-day cycles). Patients achieving disease control entered a 2-year maintenance period. CT-P10 or rituximab were administered every 8 weeks (6 cycles) in year 1; all patients could receive CT-P10 (every 8 weeks; 6 cycles) in year 2. Secondary endpoints (reported here) were overall response rate (ORR) during the study period, progression-free survival (PFS), time to progression (TTP), and overall survival (OS). Safety and immunogenicity were evaluated. RESULTS: Between  November 9, 2015 and  January 4, 2018, 258 patients were randomized (130 for CT-P10; 128 for rituximab). ORR was similar between groups over the study period (CT-P10: 88%; rituximab: 87%). After 29.2 months' median follow-up, median PFS, TTP, and OS were not estimable; 24-month Kaplan-Meier estimates suggested similarity between groups. Overall, 114 (CT-P10: 88%), and 104 (rituximab: 81%) patients experienced treatment-emergent adverse events. The single switch was well tolerated. CONCLUSION: These updated data support therapeutic similarity of CT-P10 and rituximab and support the use of CT-P10 monotherapy for previously untreated LTBFL.

Treatment patterns and outcomes of 2310 patients with secondary acute myeloid leukemia: a PETHEMA registry study.

Secondary acute myeloid leukemia (sAML) comprises a heterogeneous group of patients and is associated with poor overall survival (OS). We analyze the characteristics, treatment patterns, and outcomes of adult patients with sAML in the Programa Español de Tratamientos en Hematología (PETHEMA) registry. Overall, 6211 (72.9%) were de novo and 2310 (27.1%) had sAML, divided into myelodysplastic syndrome AML (MDS-AML, 44%), MDS/myeloproliferative AML (MDS/MPN-AML, 10%), MPN-AML (11%), therapy-related AML (t-AML, 25%), and antecedent neoplasia without prior chemotherapy/radiotherapy (neo-AML, 9%). Compared with de novo, patients with sAML were older (median age, 69 years), had more Eastern Cooperative Oncology Group ≥2 (35%) or high-risk cytogenetics (40%), less FMS-like tyrosine kinase 3 internal tandem duplication (11%), and nucleophosmin 1 (NPM1) mutations (21%) and received less intensive chemotherapy regimens (38%) (all P < .001). Median OS was higher for de novo than sAML (10.9 vs 5.6 months; P < .001) and shorter in sAML after hematologic disorder (MDS, MDS/MPN, or MPN) compared with t-AML and neo-AML (5.3 vs 6.1 vs 5.7 months, respectively; P = .04). After intensive chemotherapy, median OS was better among patients with de novo and neo-AML (17.2 and 14.6 months, respectively). No OS differences were observed after hypomethylating agents according to type of AML. sAML was an independent adverse prognostic factor for OS. We confirmed high prevalence and adverse features of sAML and established its independent adverse prognostic value. This trial was registered at www.clinicaltrials.gov as #NCT02607059.

Ropivacaine:An Unusual Cause of Neuroleptic Malignant-Like Syndrome.

Ropivacaine is commonly used for post-operative pain management. We describe a case of neuroleptic malignant-like syndrome in a woman administered ropivacaine delivered using a drug infusion balloon. The presenting symptoms were confusion, agitation and fever. Blood analysis showed elevated C-reactive protein, leucocytosis and increased creatine phosphokinase. As intoxication was suspected, ropivacaine was suspended and the patient gradually improved. Possible leakage of ropivacaine into the intrathecal space may have resulted in central nervous system toxicity. LEARNING POINTS: It is important to be aware of the secondary effects of common drugs.The differential diagnosis should always include side effects and drug interactions.Intoxication can lead to poor outcomes, so early recognition is key.

Management of ibrutinib treatment in patients with B-cell malignancies: clinical practice in Portugal and multidisciplinary recommendations.

OBJECTIVES: Ibrutinib, a potent inhibitor of the Bruton tyrosine kinase, has revolutionized the treatment of many B-cell malignancies. Ibrutinib has an established favorable toxicity profile with up to 8 years of experience in clinical trials; however, despite ibrutinib's favorable toxicity profile, dose reductions and treatment discontinuations are becoming more evident in clinical practice, particularly in the setting of specific clinical contexts and patient characteristics. This manuscript is set to provide practical recommendations on the management of patients treated with this agent in daily practice. METHODS: A group of multidisciplinary experts from Portugal met to discuss and highlight practical recommendations, supported on both literature and clinical insights, for the management of the treatment with ibrutinib. RESULTS/DISCUSSION: Handling of both toxicities and drug-drug interactions during ibrutinib treatment poses several challenges to healthcare providers and can benefit from a multidisciplinary approach. The involvement of specialties, such as cardiology, infectiology and pharmacology, can bring an added value to patient care, not only in anticipating/managing safety issues and dose adjustments but also in enhancing adherence to treatment, ultimately improving the risk/benefit balance. CONCLUSION: By involving a multidisciplinary group of experts, this work provides a set of key recommendations to optimize care and outcomes for ibrutinib-treated patients. Despite not being a fully comprehensive review on the topic, it is intended as a framework to hematologists and other healthcare professionals who manage these patients in their daily clinical practice.

IgA nephropathy in IgG kappa multiple myeloma.

Multiple myeloma (MM) frequently affects kidney function through multiple mechanisms. Nonetheless, some patients develop kidney injury due to other causes. A 54-year-old woman was diagnosed with IgG kappa MM developed IgA nephropathy without cast nephropathy. Further studies did not show criteria for MM progression or other causes. This case highlights the need for further investigation of kidney injury in MM patients (such as toxicity of previous drugs, infectious events, or immune-mediated disorders).

Loss of erythroblasts in acute myeloid leukemia causes iron redistribution with clinical implications.

Acute myeloid leukemia (AML) is a heterogeneous disease with poor prognosis and limited treatment strategies. Determining the role of cell-extrinsic regulators of leukemic cells is vital to gain clinical insights into the biology of AML. Iron is a key extrinsic regulator of cancer, but its systemic regulation remains poorly explored in AML. To address this question, we studied iron metabolism in patients with AML at diagnosis and explored the mechanisms involved using the syngeneic MLL-AF9-induced AML mouse model. We found that AML is a disorder with a unique iron profile, not associated with inflammation or transfusion, characterized by high ferritin, low transferrin, high transferrin saturation (TSAT), and high hepcidin. The increased TSAT in particular, contrasts with observations in other cancer types and in anemia of inflammation. Using the MLL-AF9 mouse model of AML, we demonstrated that the AML-induced loss of erythroblasts is responsible for iron redistribution and increased TSAT. We also show that AML progression is delayed in mouse models of systemic iron overload and that elevated TSAT at diagnosis is independently associated with increased overall survival in AML. We suggest that TSAT may be a relevant prognostic marker in AML.