Comprehensive procedure for injecting Evusheld® for hematological diseases in a single institute.

Tixagevimab and cilgavimab (EVA, Evusheld®), monoclonal antibody combination treatments, consisted of two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). EVA showed prophylactic and therapeutic effects against coronavirus disease 2019. The Japanese Society of Hematology recommended EVA for such patients with active treatment, but each institution decided on comprehensive administration. We develop a systematic procedure for comprehensive EVA injection prophylactically in patients with hematological malignancies without any over/under-indication. We listed all patients with the required indications from November 2022 to March 2023. We included 178 cases, 84 females and 94 males, with a median age of 70 (range: 19-90) years. Underlying diseases are myeloid neoplasms in 36 (20%), lymphoid neoplasms in 75 (73%), and others. Indications were intensively hematological malignancy treatment, rituximab treatment within 12 months, burton kinase inhibitor treatment, after chimeric antigen receptor T cell immunotherapy, and after stem cell transplantation in 74 (41%), 73 (41%), 3 (2%), 5 (3%), and 23 (13%) cases, respectively. Of the 178 cases, 22 (12.4%) refused EVA injection. Further, 42 and 136 cases were administered outpatient and inpatient, respectively. Over 95% of the listed cases received EVA injection within 3 months. No severe toxicities were observed among them (N = 156), and 8 (5.2%) cases had breakthrough SARS-CoV-2 infection, which was significantly lower (P = 0.02) than those without EVA (4 [18.2%] of 22 cases). Both groups showed no moderate or severe infection cases. This single-center experience showed that comprehensive EVA injection management effectively generated safer completion with preferable clinical impact.

Graft-versus-host disease after autologous stem cell transplantation in a recipient who underwent allogeneic stem cell transplantation 20 years earlier.

A literature review does not provide information about the safety of autologous hematopoietic stem cell transplantation (HSCT) in a recipient who has previously received allogeneic HSCT. We treated a 69-year-old woman with diffuse large B cell lymphoma. The patient received autologous stem cell transplantation (ASCT) in the second complete remission of malignant lymphoma. The patient had undergone allogeneic hematopoietic SCT (allo-HSCT) for chronic myeloid leukemia 20 years ago. Chronic myeloid leukemia had been in complete remission for the previous 20 years. Thus, the patient received autologous and allogenic HSCT 20 years apart. ASCT involves the patient receiving "self" hematopoietic cells from an allogeneic donor. In other words, this is immunologically the second allo-HSCT. The allo-HSCT 20 years ago was undergone by a related healthy brother, a human leukocyte antigen (HLA) 8/8 full matched donor. The conditioning regimen was reduced-intensity consisting of fludarabine and busulfan. The patient did not experience acute or chronic graft-versus-host disease (GVHD) after allo-HSCT. The second transplantation, ASCT was performed to the MEAM conditioning regimen. Engraftment was uneventful, and complete donor chimerism had been achieved even after ASCT. She suffered from an acute gastric mucosal lesion 52 days after ASCT. Pathological finding of gastric mucosa was nonspecific acute gastritis with significant neutrophil infiltration. Sex chromosome analysis of gastric mucosa demonstrated that mucosal cells had XX signals, whereas infiltrating neutrophils had XY signals. We speculated the patient onset of an acute gastric GVHD in this recipient after the second transplantation. This case remarked infiltration of neutrophils triggered GVHD reaction by resetting allogeneic immune reaction after the second transplantation. We describe a rare occurrence of GVHD reaction in a recipient of ASCT following allo-HSCT.

Clinical effects of tacrolimus blood concentrations early after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: Tacrolimus (TAC) plus short-term methotrexate (stMTX) is used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TAC blood concentrations are frequently adjusted to enhance the graft-versus-leukemia/lymphoma effect or attenuate severe GVHD. Limited information is available on the clinical impact of these adjustments and the optimal time to perform them in order to achieve good clinical outcomes. METHODS: We retrospectively analyzed 211 patients who underwent allo-HSCT at our institutes. RESULTS: Higher TAC concentrations in week 3 correlated with a significantly higher cumulative incidence of relapse (CIR) (P = 0.03) and lower nonrelapse mortality (P = 0.04). The clinical impact of high TAC concentrations in week 3 on CIR was detected in the refined disease risk index: low/intermediate (P = 0.04) and high (P < 0.01), and conditioning regimens other than cyclophosphamide/total body irradiation and busulfan/cyclophosphamide (P = 0.07). Higher TAC concentrations in week 1 correlated with a lower grade 2-4 acute GVHD rate (P = 0.01). Higher TAC concentrations in weeks 2 and 3 correlated with slightly lower (P = 0.05) and significantly lower (P = 0.02) grade 3-4 acute GVHD rates, respectively. Higher TAC concentrations in weeks 1 and 3 were beneficial for severe acute GVHD in patients with a human leukocyte antigen-matched donor (P = 0.03 and P < 0.01, respectively), not treated with anti-thymocyte globulin (P = 0.02 and P = 0.02, respectively), and receiving three stMTX doses (P = 0.03 and P = 0.02, respectively). CONCLUSIONS: The clinical impact of TAC concentrations varied according to patient characteristics, including disease malignancy, conditioning regimens, donor sources, and GVHD prophylaxis. These results suggest that TAC management needs to be based on patient profiles.

Changes of biomarkers for erythropoiesis, iron metabolism, and FGF23 by supplementation with roxadustat in patients on hemodialysis.

This study aimed to confirm changes in biomarkers of erythropoiesis and iron metabolism and serum fibroblast growth factor 23 (FGF-23) during darbepoetin-α treatment and then switching to the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat. A total of 28 patients on hemodialysis who received weekly doses of darbepoetin-α were switched to roxadustat. Biomarkers for erythropoiesis and iron metabolism and intact and C-terminal FGF-23 were measured in blood samples collected before the HD session on days - 7 (darbepoetin-α injection), - 4, and - 2, and days 0 (switch to roxadustat treatment, three times weekly), 3, 5, 7, 14, 21, and 28. Erythropoietin and erythroferrone levels were elevated on day - 4 by darbepoetin-α injection and decreased to baseline levels at day 0. Levels of erythropoietin were not significantly increased by roxadustat supplementation, but erythroferrone levels were continuously elevated, similar to darbepoetin-α treatment. Hepcidin-25 and total iron binding capacity were significantly decreased or increased in patients treated with roxadustat compared with darbepoetin-α. Changes of intact and C-terminal FGF-23 levels were parallel to changes of phosphate levels during roxadustat treatment. However, the actual and percentage changes of intact FGF-23 and C-terminal FGF-23 in patients with low ferritin levels were greater than those in patients with high ferritin levels. Roxadustat might stimulate erythropoiesis by increasing iron usage through hepcidin-25, which was suppressed by erythroferrone in the physiological erythropoietin condition. Changes of intact FGF-23 and C-terminal FGF-23 levels might be affected by roxadustat in patients on hemodialysis, especially those with a low-iron condition.

Romosozumab successfully regulated progressive osteoporosis in a patient with autosomal dominant polycystic kidney disease undergoing hemodialysis.

Osteoporosis is a crucial complication in patients with chronic kidney disease (CKD), similar to that in the general population. Although romosozumab, a monoclonal antibody targeting sclerostin, has been administered for patients with CKD, its clinical effectiveness in these patients, especially in patients on hemodialysis (HD), remains to be studied. Herein, we report the case of a 42-year-old man on HD who developed severe osteoporosis. Serum calcium levels were extremely high, bone metabolic markers were abnormal, and the patient had pathological fractures. The bone biopsy indicated a bone metabolism disorder and high bone turnover. We administered romosozumab once a month as an intervention for bone alteration. Through the 10-month usage, bone metabolic markers improved, and the decrease in bone mineral density was ameliorated. We hypothesized that romosozumab could be a therapeutic option for osteoporosis in patients undergoing HD, especially in those with bone mineralization disorders.

Distinct Characteristics of Sweet's Syndrome of the Scrotum Caused by All-trans Retinoic Acid in a Patient with Acute Promyelocytic Leukemia.

Induction therapy with all-trans retinoic acid (ATRA) is effective for acute promyelocytic leukemia (APL). ATRA induces neutrophil differentiation and its associated side effects. The differentiation syndrome is the most characterized ATRA-induced adverse effect. Sweet's syndrome, also known as neutrophilic dermatosis, is another form of ATRA-associated disease characterized by neutrophil infiltrating erythema that develops with fever. This is a case of a 34-year-old Japanese man diagnosed with APL. At the onset, the patient did not have skin involvement of APL cells. He was treated with ATRA and induction chemotherapy with idarubicin and cytarabine. Scrotal skin rash occurred at day 14, which developed into scrotal ulceration up to day 28 even after eliminating APL cells in his peripheral blood. Sweet's syndrome is a pathological diagnosis of scrotal skin ulceration representing neutrophil infiltration. The infiltrating neutrophils showed PML-RARα rearrangement. The patient was diagnosed with ATRA-associated Sweet's syndrome with skin ulcer. His cutaneous lesion did not respond to intravenous prednisolone therapy; thereby, ATRA was discontinued. After the cessation of ATRA, the skin lesion improved in the next week. We confirmed he achieved a complete response after induction chemotherapy. In our observation, ATRA-associated Sweet's syndrome is characterized by the following clinical manifestations: preferable occurrence in the scrota, tend to progress into skin ulcer, and pathogenicity associated with PML-RARα-positive matured neutrophils. The etiology, pathogenesis, and risk factors of ATRA-associated scrotal ulceration were discussed in the literature review.

Inpatient Flap Monitoring after Deep Inferior Epigastric Artery Perforator Flap Breast Reconstruction: How Long Is Long Enough?

BACKGROUND: There is a growing trend across health care to perform increasingly complex procedures in less acute settings. This shift has been fueled, in part, by enhanced recovery protocols, which have shortened hospital stays after major surgeries. We set out to determine the timing of microvascular complications after deep inferior epigastric artery perforator (DIEP) free flap breast reconstruction in a high-volume practice using continuous flap monitoring technologies. METHODS: The medical charts of all patients who underwent breast reconstruction with DIEP flaps over 24 consecutive months were reviewed. Postoperatively, all flaps were monitored according to a protocol that included continuous tissue oximetry with near-infrared spectroscopy. The primary end points evaluated included any unplanned return to the operating room, time to takeback, and flap loss rate. RESULTS: A total of 196 patients underwent breast reconstruction with a total of 301 DIEP flaps. Five of the flaps (1.7%) were taken back to the operating room for microvascular issues, and nine (3.0%) were taken back for nonvascular issues. Of patients who were brought back for microvascular issues, all five (100.0%) were initially identified by continuous noninvasive monitoring and taken back to the operating room within the first 14 hours (range: 1.2-13.6 hours). In the series, the flap failure rate was 0.66% (n = 2). CONCLUSION: All of the microvascular issues were detected in the initial 23 hours after surgery, leading to prompt flap salvage. The results of this study bring into question the need for lengthy flap monitoring protocols and suggest that shorter inpatient, or even observation admissions, may be reasonable, particularly when flap monitoring protocols incorporating continuous noninvasive flap monitoring are used.

The current national criteria for carotid artery stenting overestimate its efficacy in patients who are symptomatic and at high risk.

BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) have established guidelines that outline patients who are considered "high risk" for complications after carotid endarterectomy (CEA) for which carotid artery stenting (CAS) may provide benefit. The validity of these high-risk criteria are yet unproven. In this study, we stratified patients who underwent CAS or CEA by CMS high-risk criteria and symptom status and examined their 30-day outcomes. METHODS: A nonrandomized, retrospective cohort study was performed by chart review of all patients undergoing CEA or CAS from January 1, 2005, to December 31, 2010, at our institution. Demographic data and data pertaining to the presence or absence of high-risk factors were collected. Patients were stratified using symptom status and high-risk status as variables, and 30-day adverse events (stroke, death, myocardial infarction [MI]) were compared. RESULTS: A total of 271 patients underwent CAS, with 30-day complication rates of stroke (3.0%), death (1.1%), MI (1.5%), stroke/death (3.7%), and stroke/death/MI (5.2%). A total of 830 patients underwent CEA with 30-day complication rates of stroke (2.0%), death (0.1%), MI (0.6%), stroke/death (1.9%), and stroke/death/MI (2.7%). Among symptomatic patients, physiologic high-risk status was associated with increased stroke/death (6 of 42 [14.3%] vs 2 of 74 [2.7%]; P < .01), and anatomic high-risk status was associated with a trend toward increased stroke/death (5 of 31 [16.1%] vs 0 of 20 [0.0%]; P = .14) in patients who underwent CAS vs CEA. Analysis of asymptomatic patients showed no differences between the two groups overall, except for a trend toward a higher rate of MI after CAS than after CEA (3 of 71 [4.2%] vs 0 of 108 [0.0%]; P = .06) in those who were physiologically at high risk. Among symptomatic patients who underwent CAS, patients with physiologic and anatomic high-risk factors had a higher rate of stroke/death than non-high-risk patients (6 of 42 [14.3%] vs 0 of 24 [0.0%] and 5 of 31 [16.1%] vs 0 of 24 [0.0%], respectively; both P ≤ .05). CONCLUSIONS: Physiologic high-risk status was associated with increased stroke/death, whereas anatomic high-risk status showed a trend toward increased stroke/death in symptomatic patients undergoing CAS compared with non-high-risk patients undergoing CAS or physiologically high-risk patients undergoing CEA. Our results suggest that the current national criteria for CAS overestimate its efficacy in patients who are symptomatic and at high risk.

Accuracy of administrative data versus clinical data to evaluate carotid endarterectomy and carotid stenting.

OBJECTIVE: Administrative data have been used to compare carotid endarterectomy (CEA) and carotid artery stenting (CAS). However, there are limitations in defining symptom status, Centers for Medicare and Medicaid Services high-risk status, as well as complications. Therefore, we did a direct comparison between administrative data and physician chart review as well as between data collected for the National Surgical Quality Improvement Program (NSQIP) and physician chart review for CEA and CAS. METHODS: We performed an outcomes analysis on all CEA and CAS procedures from 2005 to 2011. We obtained International Classification of Diseases, Ninth Revision diagnosis codes from hospital discharge records regarding symptom status, high-risk status, and perioperative stroke. We also obtained data on all CEA patients submitted to NSQIP over the same time period. One of the study authors (R.B.) then performed a chart review of the same patients to determine symptom status, high-risk status, and perioperative strokes and the results were compared. RESULTS: We identified 1342 patients who underwent CEA or CAS between 2005 and 2011 and 392 patients who underwent CEA that were submitted to NSQIP. Administrative data identified fewer symptomatic patients (17.0% vs 34.0%), physiologic high-risk patients (9.3% vs 23.0%), and anatomic high-risk patients (0% vs 15.2%). Although administrative data identified a similar proportion of perioperative strokes (1.9% vs 2.0%), this was due to the fact that these data identified eight false positive and nine false negative perioperative strokes. NSQIP data identified more symptomatic patients compared with chart review (44.1% vs 30.3%), fewer physiologic high-risk patients (13.0% vs 18.6%), fewer anatomic high-risk patients (0% vs 6.6%), and a similar proportion of perioperative strokes (1.5% vs 1.8%, only one false negative stroke and no false positives). CONCLUSIONS: Administrative data are unreliable for determining symptom status, high-risk status, and perioperative stroke and should not be used to analyze CEA and CAS. NSQIP data do not adequately identify high-risk patients, but do accurately identify perioperative strokes and to a lesser degree, symptom status.

Insulin-like growth factor 2 hypomethylation of blood leukocyte DNA is associated with gastric cancer risk.

To determine whether or not the methylation status of blood leukocyte DNA can be used as a surrogate marker of the risk for cancer, we quantitatively determined the methylation levels of insulin-like growth factor 2 (IGF2) and TUSC3 in 299 gastric cancer cases, and 299 age- and gender-matched controls. The IGF2 methylation levels in blood leukocyte DNA of the cases were lower than those of the healthy controls and there was a significant trend of increasing gastric cancer risk with decreasing methylation level of IGF2. Patients with hypermethylated IGF2 in blood leukocyte DNA showed a significantly better survival rate than those with hypomethylated IGF2, indicating that the IGF2 methylation level in blood leukocyte DNA can be a possible marker not only of the risk for but also of the prognosis of gastric cancer. In contrast, the TUSC3 methylation level in blood leukocyte DNA was higher in the cases than in the healthy controls, but the difference was not significant. The past lifestyle and clinicopathological characteristics of the participants were analyzed for any relationship with the methylation level. With aging and smoking, methylation of IGF2 and TUSC3 decreased and increased in blood leukocyte DNA, respectively. These results indicate that the methylation level of IGF2 in blood leukocyte DNA may be used as an important surrogate marker of the risk for gastric cancer.

Anti-invasive activity of α-tocopherol against hepatoma cells in culture via protein kinase C inhibition.

Effects of α-, ß-, γ- and δ-tocopherols on the proliferation and invasion of AH109A hepatoma cells and their modes of action were investigated. Four tocopherols inhibited the invasion as well as the proliferation of AH109A cells. Their inhibitory effects were more prominent on the invasion than on the proliferation. At 1 µM, α-tocopherol showed most potent anti-invasive activity without any influence on the proliferation. We have previously demonstrated that reactive oxygen species increase the invasion of AH109A cells. α-Tocopherol suppressed the reactive oxygen species-induced invasion but failed to suppress the reactive oxygen species-induced rises in intracellular peroxide level. GF 109203X, a protein kinase C inhibitor, decreased the invasive activity of AH109A cells. In contrast, phorbol-12-myristate-13-acetate, a protein kinase C activator, increased the invasive capacity of AH109A cells. α-Tocopherol suppressed the phorbol-12-myristate-13-acetate-induced increase in the invasion, and canceled the phorbol-12-myristate-13-acetate-induced rises in protein kinase C activity and phosphorylation of extracellular signal-regulated kinase. These results suggest that tocopherols, especially α-tocopherol, possess inhibitory effect more strongly on the invasion of AH109A cells than on the proliferation. They also suggest that the anti-invasive activity of α-tocopherol is raised through suppression of PKC/ERK signaling.