Transplant Outcomes in Myelofibrosis: Impact of Donor Type (Cord Blood Grafts Supported by CD34+ selected Cells [Haplo-Cord] Versus Matched Donors).

Despite the established potentially curative role of allogeneic hematopoietic cell transplantation (allo-HCT) in managing myelofibrosis (MF), the choice of alternative donors for patients lacking matched donors remains a challenge, and the optimal graft source in this disease entity continues to be an ongoing debate. We aimed to evaluate the impact of donor type: umbilical cord blood transplant supported with CD34+ selected haploidentical donor (haplo-cord) versus adult matched related donor (MRD) and matched unrelated donor (MUD) in 40 adult patients with primary or secondary MF, including those progressing to accelerated phase (AP) or blast phase (BP), who underwent their first allo-HCT. The primary objective of this study was to analyze the impact of stem cell source on primary endpoints of overall survival (OS), graft-versus-host disease, and non-relapse mortality (NRM). Median follow-up for all alive patients was 53 months (range 0.3-63 months). Nine patients (22.5%) underwent an MRD allo-HCT, 15 patients (37.5%) underwent a MUD allo-HCT, and 16 patients (40%) underwent a haplo-cord allo-HCT. Four patients died without neutrophil engraftment: 3 (19%) in haplo-cord group and one (4%) in MRD/MUD group. The cumulative incidence of absolute neutrophil engraftment by day 60 was 80% (95% CI 45-94) in the haplo-cord group and 92% (95% CI 65-98) in the MRD/MUD group (P = .09). The cumulative incidence of platelet engraftment by day 60 was 59% (95% CI 27-81) in haplo-cord group and 75% (95% CI 51-88) in MRD/MUD group (P = .4). OS was 62% at 1 year (95% CI 49-79) and 34% at 3 years (95% CI 21-55). The 3-year OS was similar between the haplo-cord group and the MRD/MUD (37% versus 32%, P = .9). The 1-year OS for AP/BP patients was 50% (95% CI 27-93) in the haplo-cord group, compared to 40% (95% CI 19-86) in the MRD/MUD. The 1-year OS for chronic phase CP patients was 83% (95% CI 58-100) in the haplo-cord group, compared to 79% (95% CI 60-100) in the MRD/MUD group. The cumulative incidence of relapse at 3 years in the haplo-cord group was 13% (95% CI 1.8-34), and in the MRD/MUD group was 28% (95% CI 10-49) (P = .36). One-year NRM was 38% (95% CI 15-61) in the haplo-cord group and 33% (95% CI 15-52) in the MRD/MUD group. Three-year NRM was 48% (95% CI 19-72) in the haplo-cord group and 54% (95% CI 29-73) in MRD/MUD group (P = .95). We showed no significant difference in OS, relapse, and NRM outcomes after haplo-cord transplant compared to adult matched donors' grafts (MRD or MUD) in MF patients. However, there were more graft failures in patients transplanted with a haplo-cord transplants and delayed engraftments with inadequate haplo myeloid bridges. Despite the small sample size in our study, considering our findings and the availability of other alternative donors, using haplo-cord platforms may no longer be justified for MF unless the UCB engraftment dynamics can be optimized.

Cardiac Tamponade in Concurrent Sickle Cell Disease and Systemic Lupus Erythematosus: An Unusual Association.

This case report describes a rare occurrence of the coexistence of sickle cell disease (SCD) and systemic lupus erythematosus (SLE) in a 33-year-old female. The overlapping clinical manifestations posed diagnostic challenges, leading to a delayed diagnosis. The patient's presentation with pericardial effusion and tamponade during a concurrent SLE flare highlights the complexity of managing these conditions. The case underscores the importance of heightened clinical awareness and multidisciplinary collaboration for accurate diagnosis and timely intervention in such rare comorbidities.

Role of Checkpoint Inhibitors in the Management of Gastroesophageal Cancers.

PURPOSE: This article reviews the essential clinical trials that have led to these immunotherapy approvals and explores the use of predictive biomarkers, such as PD-L1 expression and MSI status, to identify patients who are most likely to benefit from immunotherapies. METHODS: This case review series describe findings from different clinical trials and contribute to the evolving understanding of the role of CPIs in managing advanced gastroesophageal cancers and may lead to improved treatment options and patient outcomes. Ongoing clinical trials also hold promise for expanding treatment options and improving patient outcomes in the future. METHODS: The systematic review followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The protocol has not been registered. A systematic literature review was conducted to identify relevant clinical trials and studies that describe the role of immune checkpoint inhibitors in managing advanced gastroesophageal cancers. Electronic database (PubMed, Clinicaltrials.gov, Society of Immunotherapy of Cancer, Aliment Pharmacology & Therapeutics, BMC cancer, Molecular Cancer Research, Nature Reviews Molecular Cell Biology, American Association for Cancer Research, Science, Nature, Cancer Discovery, Journal of the National Cancer Institute, Advanced Immunology, Oncotarget, Nature Medicine, Nature Genetics, Gut, Pathology and Oncology Research, Journal of Clinical Oncology, The New England Journal of Medicine, Gastrointestinal oncology, JAMA Oncology, Journal of Gastrointestinal Oncology, Current Oncology, Annals of Oncology, The Lancet, JCO Oncology Practice, Future Oncology, Gastric Cancer, CA: A Cancer Journal for Clinicians, American Journal of Gastroenterology, Gastroenterology, Journal of the National Cancer Institute, International Journal of Epidemiology, Helicobacter, Gastroenterology Review) were searched using a combination of relevant keywords and MESH terms. The search encompassed articles published up to 5/2023. Additionally, manual searches of reference lists of selected articles and pertinent review papers were conducted to ensure comprehensive coverage of relevant studies. Studies were included if they provided insights into clinical trials evaluating the efficacy and safety of CPIs in treating advanced gastroesophageal cancers. Relevant case reviews and trials exploring combination therapies involving CPIs were also considered. Articles discussed in the utilization of predictive biomarkers were included to assess their impact on treatment outcomes. Data from selected studies were extracted to inform the narrative review. Key findings were summarized, including clinical trial designs, patient populations, treatment regimens, response rates, progression-free survival (PFS), overall survival (OS), and adverse events. The role of predictive biomarkers, particularly PD-L1 expression and MSI status, in identifying patients likely to benefit from CPIs was critically evaluated based on study results. Ongoing clinical trials investigating novel combination strategies and exploring the broader scope of CPIs in gastroesophageal cancers were also highlighted. The collected data were synthesized to provide a comprehensive overview of the crucial clinical trials that have contributed to the approval of CPIs for advanced gastroesophageal cancers. The role of CPIs in different lines of therapy, including first-line regimens, was discussed. Furthermore, the evolving landscape of predictive biomarkers was examined, emphasizing their potential significance in optimizing patient selection for CPI therapy. Ongoing clinical trials were reviewed to underscore the continuous efforts in expanding treatment options and improving patient outcomes in the future.

Fat Embolization Syndrome Secondary to Steroid Treatment in a Case of Sickle Cell Vaso-Occlusive Crisis.

Fat embolization syndrome (FES) is often seen as a complication of fractures and has been known to cause respiratory failure, rashes of the skin, thrombocytopenia, and neurological damage. Nontraumatic FES is uncommon and occurs due to bone marrow necrosis. Vaso-occlusive crisis in sickle cell patients secondary to steroid therapy is a rare entity and not widely acknowledged. We report a case of FES secondary to steroid therapy administered for a patient with intractable migraine. FES is an uncommon yet serious complication that occurs due to bone marrow necrosis and is usually associated with increased mortality or damaging neurologic sequelae for the surviving patient. Our patient was initially admitted for intractable migraine and worked up to rule out any acute emergency conditions. She was then given steroids for her migraine which did not subside with the initial treatment. Her condition worsened, and she developed respiratory failure along with altered mental status requiring care in the intensive care unit (ICU). Imaging studies showed microhemorrhages throughout the cerebral hemispheres, brainstem, and cerebellum. The imaging of her lungs confirmed severe acute chest syndrome. The patient also had hepatocellular and renal injuries indicative of multiorgan failure. The patient was treated with a red cell exchange transfusion (RBCx) leading to an almost complete recovery in a few days. The patient, however, had residual neurological sequelae with the presence of numb chin syndrome (NCS). This report thus highlights the need to recognize potential multiorgan failure secondary to steroid treatment and the importance of initiating treatment with red cell exchange transfusions to decrease the risk of such complications secondary to steroids.

Patient-tailored transcranial direct current stimulation to improve stroke rehabilitation: study protocol of a randomized sham-controlled trial.

BACKGROUND: Many patients do not fully regain motor function after ischemic stroke. Transcranial direct current stimulation (TDCS) targeting the motor cortex may improve motor outcome as an add-on intervention to physical rehabilitation. However, beneficial effects on motor function vary largely among patients within and across TDCS trials. In addition to a large heterogeneity of study designs, this variability may be caused by the fact that TDCS was given as a one-size-fits-all protocol without accounting for anatomical differences between subjects. The efficacy and consistency of TDCS might be improved by a patient-tailored design that ensures precise targeting of a physiologically relevant area with an appropriate current strength. METHODS: In a randomized, double-blinded, sham-controlled trial, patients with subacute ischemic stroke and residual upper-extremity paresis will receive two times 20 min of focal TDCS of ipsilesional primary motor hand area (M1-HAND) during supervised rehabilitation training three times weekly for 4 weeks. Anticipated 60 patients will be randomly assigned to active or sham TDCS of ipsilesional M1-HAND, using a central anode and four equidistant cathodes. The placement of the electrode grid on the scalp and current strength at each cathode will be personalized based on individual electrical field models to induce an electrical current of 0.2 V/m in the cortical target region resulting in current strengths between 1 and 4 mA. Primary endpoint will be the difference in change of Fugl-Meyer Assessment of Upper Extremity (FMA-UE) score between active TDCS and sham at the end of the intervention. Exploratory endpoints will include UE-FMA at 12 weeks. Effects of TDCS on motor network connectivity and interhemispheric inhibition will be assessed with functional MRI and transcranial magnetic stimulation. DISCUSSION: The study will show the feasibility and test the efficacy of personalized, multi-electrode anodal TDCS of M1-HAND in patients with subacute stroke patients with upper-extremity paresis. Concurrent multimodal brain mapping will shed light into the mechanisms of action of therapeutic personalized TDCS of M1-HAND. Together, the results from this trial may inform future personalized TDCS studies in patients with focal neurological deficits after stroke.

Short periods of bipolar anodal TDCS induce no instantaneous dose-dependent increase in cerebral blood flow in the targeted human motor cortex.

Anodal transcranial direct current stimulation (aTDCS) of primary motor hand area (M1-HAND) can enhance corticomotor excitability, but it is still unknown which current intensity produces the strongest effect on intrinsic neural firing rates and synaptic activity. Magnetic resonance imaging (MRI) combined with pseudo-continuous Arterial Spin Labeling (pcASL MRI) can map regional cortical blood flow (rCBF). The measured rCBF signal is sensitive to regional changes in neuronal activity due to neurovascular coupling. Therefore, concurrent TDCS and pcASL MRI may reveal the relationship between current intensity and TDCS-induced changes in overall firing rates and synaptic activity in the cortical target. Here we employed pcASL MRI to map acute rCBF changes during short-duration aTDCS of left M1-HAND. Using the rCBF response as a proxy for regional neuronal activity, we investigated if short-duration aTDCS produces an instantaneous dose-dependent rCBF increase in the targeted M1-HAND that may be useful for individual dosing. Nine healthy right-handed participants received 30 s of aTDCS at 0.5, 1.0, 1.5, and 2.0 mA with the anode placed over left M1-HAND and cathode over the right supraorbital region. Concurrent pcASL MRI at 3 T probed TDCS-related rCBF changes in the targeted M1-HAND. Movement-induced rCBF changes were also assessed. Apart from a subtle increase in rCBF at 0.5 mA, short-duration aTDCS did not modulate rCBF in the M1-HAND relative to no-stimulation periods. None of the participants showed a dose-dependent increase in rCBF during aTDCS, even after accounting for individual differences in TDCS-induced electrical field strength. In contrast, finger movements led to robust activation of left M1-HAND before and after aTDCS. Short-duration bipolar aTDCS does not produce consistant instantaneous dose-dependent rCBF increases in the targeted M1-HAND at conventional intensity ranges. Therefore, the regional hemodynamic response profile to short-duration aTDCS may not be suited to inform individual dosing of TDCS intensity.

Calcitonin gene-related peptide induced migraine attacks in patients with and without familial aggregation of migraine.

Background Calcitonin gene-related peptide provokes migraine attacks in 65% of patients with migraine without aura. Whether aggregation of migraine in first-degree relatives (family load) or a high number of risk-conferring single nucleotide polymorphisms contributes to migraine susceptibility to calcitonin gene-related peptide infusion in migraine patients is unknown. We hypothesized that genetic enrichment plays a role in triggering of migraine and, therefore, migraine without aura patients with high family load would report more migraine attacks after calcitonin gene-related peptide infusion than patients with low family load. Methods We allocated 40 previously genotyped migraine without aura patients to receive intravenous infusion of 1.5 µg/min calcitonin gene-related peptide and recorded migraine attacks including headache characteristics and associated symptoms. Information of familial aggregation was obtained by telephone interview of first-degree relatives using a validated semi-structured questionnaire. Results Calcitonin gene-related peptide infusion induced a migraine-like attack in 75% (12 out of 16) of patients with high family load compared to 52% (12 out of 23) with low family load ( P = 0.150). In addition, we found that the migraine response after calcitonin gene-related peptide was not associated with specific or a high number of risk-conferring single nucleotide polymorphisms of migraine without aura. Conclusion We found no statistical association between familial aggregation of migraine and hypersensitivity to calcitonin gene-related peptide infusion in migraine without aura patients. We also demonstrated that the currently known single nucleotide polymorphisms conferring risk of migraine without aura have no additive effect on calcitonin gene-related peptide induced migraine-like attacks.

Long-term use of antiplatelet drugs by patients with transient ischaemic attack.

PURPOSE: To determine the degree of long-term non-persistence to antiplatelet drugs in patients with transient ischaemic attack (TIA) and identify determinants of this drug-use pattern. METHODS: We used community-based prescription registry data to determine antiplatelet drug use in TIA patients presenting to a Danish neurology department in the period 2006-2010. Non-persistence was defined as failure to present a prescription for antiplatelet drugs within 180 days after the dosage of a previous prescription had run out. We used Cox regression to calculate the hazard ratio (HR) for non-persistence and the corresponding 95 % confidence interval (CI) by potential determinants, including a stroke risk score (ABCD2 score). Adherence during follow-up [80 % medication possession ratio (MPR80)] was calculated for antiplatelets, statins and antihypertensive drugs. RESULTS: The cohort comprised 594 (84 % evaluated as in-patients) TIA patients. During follow-up (median 1.7 years, interquartile range 0.9-3.0 years), 140 (23.6 %) patients became non-persistent. Non-persistence was associated with younger age (<55 years: HR 1.9, 95 % CI 1.3-2.8) and delay between TIA onset and neurological evaluation (7+ days: HR 2.0, 95 % CI 1.0-4.1). Among admitted patients, a higher ABCD2 score (4+: HR 1.3, 95 % CI 0.8-2.1) was also indicative of non-persistence. Non-persistent users were less adherent to other preventive medication (MPR80: statins 31.8 vs. 75.3 %, p value < 0.001; antihypertensives 64.3 vs. 79.5 %, p value: 0.02) than persistent users. CONCLUSION: Long-term antiplatelet non-persistence was most pronounced in patients of younger age, those with delayed evaluation of symptoms and those at greater risk of stroke. It was also associated with a lower adherence to preventive medication in general.