Monitoring of blood levels in patients administered CYP3A4 inhibitor during the maintenance phase of venetoclax administration
.

OBJECTIVE: Venetoclax, an oral B-cell lymphoma-2 inhibitor, necessitates dose adjustment when combined with a CYP3A4 inhibitor; however, the dosing regimen remains unclear on adding a CYP3A4 inhibitor after venetoclax administration. CASE SUMMARY: We present a case report of a patient who was simultaneously treated with a CYP3A4 inhibitor and a steady daily dose of venetoclax. A 30-year-old male diagnosed with acute myeloid leukemia received a combination of venetoclax and azacitidine as remission induction therapy. He was prescribed 400 mg/day venetoclax at a steady daily dose, with fosfluconazole initiated on day 18. Given that fosfluconazole can induce moderate CYP3A4 inhibitory effects, the venetoclax dosage was reduced to 200 mg/day on the same day. Despite dose reduction, plasma trough levels of venetoclax continued rising gradually. Nearly 10 days were required to decrease blood levels to a steady state. CONCLUSION: The risk of elevated venetoclax blood levels needs to be considered when initiating CYP3A4 inhibitors and reducing venetoclax dosage on the same day.

Relationship between the Rod complex and peptidoglycan structure in Escherichia coli.

Peptidoglycan for elongation in Escherichia coli is synthesized by the Rod complex, which includes RodZ. Although various mutant strains of the Rod complex have been isolated, the relationship between the activity of the Rod complex and the overall physical and chemical structures of the peptidoglycan have not been reported. We constructed a RodZ mutant, termed RMR, and analyzed the growth rate, morphology, and other characteristics of cells producing the Rod complexes containing RMR. The growth and morphology of RMR cells were abnormal, and we isolated suppressor mutants from RMR cells. Most of the suppressor mutations were found in components of the Rod complex, suggesting that these suppressor mutations increase the integrity and/or the activity of the Rod complex. We purified peptidoglycan from wild-type, RMR, and suppressor mutant cells and observed their structures in detail. We found that the peptidoglycan purified from RMR cells had many large holes and different compositions of muropeptides from those of WT cells. The Rod complex may be a determinant not only for the whole shape of peptidoglycan but also for its highly dense structure to support the mechanical strength of the cell wall.

Pleural lymphoma combined with pleural sarcoidosis.

A patient with sarcoidosis was found to have a massive left pleural effusion. Her chest computed tomography showed small nodules in the lung parenchyma and swelling of the hilar lymph nodes, with normal visceral and parietal pleura. Thoracoscopy showed white nodules on the visceral pleura and normal parietal pleura, which were resected. Epithelioid granulomas were seen in the visceral pleura and lung parenchyma. Surprisingly, in the parietal pleura, abnormal cells that were positive for the leukocyte common antigen, CD20, and CD79a were found, leading to the diagnosis of malignant B-cell lymphoma.

HTLV-1 cell-free DNA in plasma as a potential biomarker in HTLV-1 carriers and adult T-cell leukemia-lymphoma.

Viral cell-free DNA (cfDNA) in plasma has been widely evaluated for detecting cancer and monitoring disease in virus-associated tumors. We investigated whether the amount of cfDNA of human T-cell leukemia virus type 1 (HTLV-1) correlates with disease state in adult T-cell leukemia-lymphoma (ATL). HTLV-1 cfDNA in aggressive ATL was significantly higher than that in indolent ATL and asymptomatic carriers. Notably, patients with lymphoma type represented higher HTLV-1 cfDNA amount than chronic and smoldering subtypes, though they had no abnormal lymphocytes in the peripheral blood. HTLV-1 cfDNA can be a universal biomarker that reflects the expansion of ATL clones.

Type II Cryoglobulinemic Membranoproliferative Glomerulonephritis Caused by Mucosa-associated Lymphoid Tissue Lymphoma.

A 67-year-old man complained of lower limb edema with a purpuric skin rash. Laboratory tests revealed proteinuria, elevated serum creatinine levels, and low serum albumin levels. The patient was also positive for cryoglobulin in serum, immunoglobulin (Ig) M gammopathy, hypocomplementemia, and rheumatoid factor. He was negative for anti-hepatitis C virus antibodies. A pathological analysis of the renal tissue revealed membranoproliferative glomerulonephritis, common histological features of cryoglobulinemic vasculitis (CV), and mucosa-associated lymphoid tissue lymphoma invasion. Although hematologic malignancy is a rare cause of type II CV, these clinical findings suggest that mucosa-associated lymphoid tissue lymphoma (MALT) lymphoma may have been the cause in the present case.

Intracranial Myeloid Sarcoma Mimicking Hypertensive Intracerebral Hemorrhage.

We herein report a case of intracranial myeloid sarcoma mimicking hypertensive intracerebral hemorrhage. A 71-year-old man with a history of acute myeloid leukemia was admitted with acute-onset dysarthria. A hematoma-like lesion was found on computed tomography in the left putamen. Magnetic resonance imaging (MRI) and cerebrospinal fluid cytology confirmed the diagnosis of intracranial myeloid sarcoma. The patient showed a favorable response to chemotherapy, and follow-up MRI revealed shrinkage of the tumor. Since the computed tomography findings resemble those of intracerebral hemorrhage, it is important to suspect intracranial neoplasm, particularly in cases with a history of hematologic diseases.

Effect of Temporal Sampling Rate on Estimates of the Perfusion Parameters for Patients with Moyamoya Disease Assessed with Simultaneous Multislice Dynamic Susceptibility Contrast-enhanced MR Imaging.

PURPOSE: The effect of temporal sampling rate (TSR) on perfusion parameters has not been fully investigated in Moyamoya disease (MMD); therefore, this study evaluated the influence of different TSRs on perfusion parameters quantitatively and qualitatively by applying simultaneous multi-slice (SMS) dynamic susceptibility contrast-enhanced MR imaging (DSC-MRI). METHODS: DSC-MRI datasets were acquired from 28 patients with MMD with a TSR of 0.5 s. Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), and time to maximum tissue residue function (Tmax) were calculated for eight TSRs ranging from 0.5 to 4.0 s in 0.5-s increments that were subsampled from a TSR of 0.5 s datasets. Perfusion measurements and volume for chronic ischemic (Tmax ≥ 2 s) and non-ischemic (Tmax < 2 s) areas for each TSR were compared to measurements with a TSR of 0.5 s, as was visual perfusion map analysis. RESULTS: CBF, CBV, and Tmax values tended to be underestimated, whereas MTT and TTP values were less influenced, with a longer TSR. Although Tmax values were overestimated in the TSR of 1.0 s in non-ischemic areas, differences in perfusion measurements between the TSRs of 0.5 and 1.0 s were generally minimal. The volumes of the chronic ischemic areas with a TSR ≥ 3.0 s were significantly underestimated. In CBF and CBV maps, no significant deterioration was noted in image quality up to 3.0 and 2.5 s, respectively. The image quality of MTT, TTP, and Tmax maps for the TSR of 1.0 s was similar to that for the TSR of 0.5 s but was significantly deteriorated for the TSRs of ≥ 1.5 s. CONCLUSION: In the assessment of MMD by SMS DSC-MRI, application of TSRs of ≥ 1.5 s may lead to deterioration of the perfusion measurements; however, that was less influenced in TSRs of ≤ 1.0 s.

Diffuse Large B-cell Lymphoma Involving an Abundant Infiltration of T Follicular Helper Cells.

A 76-year-old man presented with skin plaque and splenic nodules, and diffuse large B-cell lymphoma (DLBCL) with infiltration of T-cells was suspected based on the skin lesions. The disease showed indolent clinical behavior for three months, when systemic lymphadenopathy rapidly evolved. An inguinal lymph node biopsy revealed DLBCL with abundant infiltration of T follicular helper (TFH) cells. A polymerase chain reaction-based analysis of immunoglobulin variable heavy chain showed that the skin, splenic nodules, and inguinal lymph node shared the same clone. This case indicates that the dysregulated infiltration of TFH cells in the tumor microenvironment accelerates the lymphomagenesis and progression of DLBCL.

Higher neutrophil counts are associated with successful tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia.

OBJECTIVE: Treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation at the first attempt is a therapeutic goal for patients with chronic phase chronic myeloid leukemia (CML-CP). However, it remains unclear whether discontinuation of TKIs at a second or subsequent attempt can be performed safely. PATIENTS AND METHOD: Here, we report a 72-year-old man diagnosed with CML-CP. He achieved TFR successfully after TKI discontinuation at the third attempt. Before discontinuation, the patient received imatinib, nilotinib, and finally nilotinib. His neutrophil count at the third attempt was higher than after the second attempt. We also performed a retrospective investigation of 53 patients who discontinued TKIs on the first or subsequent attempts. RESULTS: Overall, 64 TKI discontinuations were documented (first, 53; second, ten; third, one). We found that a higher neutrophil count at the time of TKI discontinuation (>2439/µL; hazard ratio, 0.325; 95% confidence interval, 0.137-0.772; p = 0.011) was associated independently with lower rates of molecular relapse. CONCLUSION: We report a case of a patient who successfully achieved third attempt TKI discontinuation and, an increased neutrophil percentage may reflect stronger antitumor immune responses in patients with CML-CP.

Paradoxical symptomatic cerebral blood flow decreases after combined revascularization surgery for patients with pediatric moyamoya disease: illustrative case.

BACKGROUND: Transient neurological deficits (TNDs) develop after cerebral revascularization in patients with moyamoya disease (MMD). The authors report a rare pediatric MMD case with extensive decreased cerebral blood flow (CBF) and prolonged TNDs after combined revascularization. OBSERVATIONS: A 9-year-old boy presented with transient left upper limb weakness, and MMD was diagnosed. A right-sided combined surgery was performed. Two years after the surgery, frequent but transient facial (right-sided) and upper limb weakness appeared. The left internal carotid artery terminal stenosis had progressed. Therefore, a left combined revascularization was performed. The patient's motor aphasia and right upper limb weakness persisted for approximately 10 days after surgery. Magnetic resonance angiography showed that the direct bypass was patent, but extensive decreases in left CBF were observed using single photon emission tomography. With adequate fluid therapy and blood pressure control, the neurological symptoms eventually disappeared, and CBF improved. LESSONS: The environment of cerebral hemodynamics is heterogeneous after cerebral revascularization for MMD, and the exact mechanism of CBF decreases was not identified. TNDs are significantly associated with the onset of stroke during the early postoperative period. Therefore, appropriate treatment is desired after determining complex cerebral hemodynamics using CBF studies.

The usefulness and safety of dexmedetomidine for postoperative sedation in pediatric patients with moyamoya disease.

OBJECTIVE: After revascularization surgery in pediatric patients with moyamoya disease (MMD), resting and avoiding crying is important. However, this inaction is often difficult because of pain or anxiety. Dexmedetomidine (DEX), which has sedative and analgesic properties, may be useful in reducing those uncomfortable conditions; however, its common side effects include bradycardia and hypotension, which have a risk of decreasing the cerebral blood flow. The aim of this study was to investigate the efficacy and safety of using DEX for pediatric patients with MMD in the acute period after revascularization surgery. METHODS: This retrospective study included pediatric patients with MMD who underwent revascularization surgery. Based on whether DEX was used for light sedation during postoperative days (PODs) 0-1 after extubation, the patients were divided into DEX or control groups. For neurological outcomes, the incidence of symptomatic cerebral infarction and transient neurological events (TNEs) during PODs 0-1 and the entire hospitalization were investigated. In addition, the Richmond Agitation-Sedation Scale (RASS) was used to assess the effect of DEX, and bradycardia and hypotension were evaluated as side effects. RESULTS: A total of 84 surgical procedures were included in this study (27 in the DEX group and 57 in the control group). During PODs 0-1, symptomatic infarction was not observed in either group. The incidence of TNEs was almost the same in both groups: 2 (7.4%) of the 27 procedures in the DEX group and 4 (7.0%) of the 57 procedures in the control group (p > 0.99). Moreover, the incidences of symptomatic infarction and TNEs during the entire hospitalization did not differ significantly (symptomatic infarction, p > 0.99; TNEs, p = 0.20). Regarding the DEX effect, the median RASS scores during PODs 0-1 were -1.0 (drowsy) in the DEX group and +1.0 (restless) in the control group, showing a significant difference (p < 0.01). Regarding side effects, bradycardia was observed only in 3 (11.1%) of the 27 procedures in the DEX group (p = 0.03), and hypotension was not observed in any of the cases. CONCLUSIONS: In pediatric patients with MMD who are extubated after revascularization surgery, DEX produced appropriate light sedation and analgesia. The risk for symptomatic infarction is almost the same in cases in which DEX is used and those in which it is not; however, neurosurgeons should be cautious of bradycardia and TNEs as potential side effects.

[HLA-haploidentical peripheral blood stem cell transplantation with post-transplantation cyclophosphamide for adult T-cell leukemia].

Recently, allogeneic peripheral blood stem cell transplantation from human leukocyte antigen (HLA)-haploidentical donors using post-transplantation cyclophosphamide (PTCY-haploPBSCT) has become available in clinical practice. However, the efficacy of PTCY in adult T-cell leukemia (ATL) is not fully established yet. In this study, we retrospectively examined data of seven patients who underwent PTCY-haploPBSCT. The overall survival rate at 100 days after transplantation was 85.7%, and the 1-year overall survival rate was 68.6%. The cumulative incidence of relapse at 1 year was 31.4%, whereas the 1-year nonrelapse mortality was 17.1%. The cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) on day 100 was 14.3%, and the incidence of chronic GVHD at 1 year was 33.3%. These results suggest that PTCY-haploPBSCT can be a viable option even in patients with ATL. Further accumulation of knowledge and improvement of transplantation outcomes are warranted in the future.

Blood flow stagnation after treatment of a giant internal carotid artery aneurysm: a computed fluid dynamics analysis.

Balloon test occlusion (BTO) is an angiographic test to evaluate ischemic tolerance after permanent occlusion of an internal carotid artery (ICA). BTO can simulate ischemia caused by parent artery occlusion and can be used to select a suitable bypass surgery using specific criteria. On the other hand, a postoperative thrombus can form despite proper case selection, optimal radiological evaluation, and an appropriate surgical strategy. Postoperative ischemic complications related to perforating branches are clinically significant. This simulation study aimed to analyze postoperative flow characteristics and elucidate the cause of ischemic complications related to the perforating branch using computational fluid dynamics (CFD). An unexpected postoperative thrombus formation related to the perforating branch occurred after treating a giant aneurysm in the cavernous portion of the ICA in a patient. Three-dimensional digital subtraction angiography was used to acquire flow data and set up the CFD simulation. The flow simulations were performed at various bypass flow rates. The CFD analysis indicated flow stagnation in the ICA only when surgical treatment using a low-flow bypass graft was performed. Thrombus formation may lead to ischemic complications related to the perforating branch, such as the anterior choroidal artery. BTO did not reflect the influence of bypass blood flow. Therefore, recognizing that blood flow stagnation may occur and comprehensively deciding on the surgical strategy by CFD analysis can be helpful to prevent ischemic complications in patients with giant aneurysms.

Changes in cerebral blood flow in the postoperative chronic phase after combined cerebral revascularization for moyamoya disease with ischaemic onset.

The purpose of this study was to examine the effects of combined revascularization for ischaemic-onset moyamoya disease (MMD) on cerebral haemodynamics by comparing cerebral blood flow (CBF) during the postoperative chronic phase with preoperative CBF. A retrospective cohort of 24 MMD patients (representing 31 surgeries) who received single photon emission computed tomography (SPECT) before and more than 6 months after surgery was investigated. The CBF value of each vascular territory was extracted from SPECT data, and the value relative to the ipsilateral cerebellar value (relative CBF, or RCBF) was calculated. The correlation between the revascularization effect and the proportional change in RCBF before and after surgery (calculated as post-RCBF/pre-RCBF ("post/pre-RCBF")) was analysed. Furthermore, the relationships between changes in neurological symptoms and post/pre-RCBF were investigated. Preoperative and postoperative mean RCBF values were 0.92 ± 0.15 and 0.96 ± 0.13 (p = 0.619) in the anterior cerebral artery territory, 0.99 ± 0.17 and 1.01 ± 0.17 (p = 0.598) in the middle cerebral artery territory and 1.15 ± 0.22 and 1.14 ± 0.19 (p = 0.062) in the posterior cerebral artery territory, respectively. No significant correlation was found between the revascularization score and post/pre-RCBF. The revascularization score and post/pre-RCBF were not significant predictors of worsening neurological symptoms postoperatively. No significant change in RCBF was observed in any vascular territory in the chronic phase after revascularization. Combined revascularization may assist in the redirection of blood flow from the internal to the external carotid system and contribute to CBF maintenance.

Risk Factors for Cerebral Infarction Early After Revascularization in Children Younger than 5 Years with Moyamoya Disease.

OBJECTIVE: Cerebral revascularization is necessary for pediatric patients younger than 5 years with moyamoya disease (MMD). However, they have a high risk of developing cerebral infarction early after surgery. This study aimed to analyze the risk factors for developing cerebral infarction among these patients. METHODS: The charts of 21 consecutive patients with MMD (39 surgeries) younger than 5 years who had undergone revascularization at our hospital were retrospectively analyzed. Because cerebral infarction occurring within 1 month after surgery was the primary end point, other clinical information was evaluated, including each surgical procedure. Multivariate analysis of the risk factors for postoperative cerebral infarction was performed. RESULTS: Cerebral infarction occurred after 7 of 39 surgeries (17.9%). Of the 39 surgeries, 23 (59%) included direct and indirect combined revascularization. The incidence of cerebral infarction did not differ significantly between the combined (21.7%) and indirect (12.5%) groups (P = 0.46). Logistic regression showed no association between the revascularization procedure and the occurrence of cerebral infarction after surgery (P = 0.3). However, younger age at surgery was correlated with a higher risk of developing cerebral infarction in the early postoperative period (P = 0.05). CONCLUSIONS: No differences were found in the risk of developing cerebral infarction early after surgery as a result of surgical procedures. However, younger patients had higher postoperative risk. Further multicenter research should examine this issue for young pediatric patients with moyamoya at high risk of developing cerebral infarction.

Challenging direct bypass surgery for very young children with moyamoya disease: technical notes.

Cerebral revascularization for moyamoya disease (MMD) is an effective treatment for improving cerebral ischaemia and preventing rebleeding. Although direct bypass surgery is commonly performed on older children and adults, it is challenging in very young children due to the high difficulty level of the procedure. The subjects were MMD patients under 3 years of age on whom surgery was performed by a single surgeon (Y.A.). Preoperative clinical findings, information related to direct bypass surgery, bypass patency, and the incidence of postoperative stroke were investigated. Combined revascularization, including direct bypass surgery, was performed on 3 MMD patients (3 sides) under 3 years of age. The average diameter of the grafts used in direct bypass was 0.8 mm. The average recipient diameter was 0.8 ± 0.17 (range 0.6-1) mm. In all cases, the anastomotic procedure was completed using 11-0 monofilament nylon thread, and patency was confirmed. Direct bypass for MMD patients under 3 years old is technically challenging. However, despite the anatomical differences between very young children and elderly individuals, direct bypass surgery could certainly be completed. In addition, a rapid recovery from cerebral blood flow insufficiency could yield a promising neurological outcome.

＜Editors' Choice＞ Indocyanine green emission timing of the recipient artery in revascularization surgery for moyamoya disease.

In superficial temporal artery to middle cerebral artery anastomosis with indirect revascularization for patients with moyamoya disease, the optimal method for selecting the most appropriate cortical artery for the recipient in anastomosis has not been established. We investigated the relationship between the fluorescence emission timing of the recipient artery in the preanastomosis indocyanine green videoangiography and operative outcomes. This retrospective study included 51 surgical revascularization procedures for 39 moyamoya disease patients. The enrolled surgical procedures were classified into three groups based on the fluorescence emission timing of the recipient artery in preanastomosis indocyanine green videoangiography: the EARLIEST, the INTERMEDIATE, and the LATEST. Clinical characteristics and operative outcomes were also collected. The occurrence of white thrombus at the anastomosis site and symptomatic hyperperfusion showed significant differences between the groups classified by the fluorescence emission timing of the recipient artery in preanastomosis indocyanine green videoangiography (white thrombus, p = 0.001; symptomatic hyperperfusion, p = 0.026). The development of white thrombi was significantly higher in the LATEST group, and all symptomatic hyperperfusion was observed in the EARLIEST group. These results indicated that the LATEST group had a significantly higher risk for developing white thrombus, and the EARLIEST group was prone to occur symptomatic hyperperfusion. Selecting the recipient artery based on evaluating the fluorescence emission timing in preanastomosis indocyanine green videoangiography may be useful in reducing perioperative complications.

Transcriptome-wide analysis of intracranial artery in patients with moyamoya disease showing upregulation of immune response, and downregulation of oxidative phosphorylation and DNA repair.

OBJECTIVE: Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive occlusion of the internal carotid artery and the secondary formation of collateral vessels. Patients with MMD have ischemic attacks or intracranial bleeding, but the disease pathophysiology remains unknown. In this study, the authors aimed to identify a gene expression profile specific to the intracranial artery in MMD. METHODS: This was a single-center, prospectively sampled, retrospective cohort study. Microsamples of the middle cerebral artery (MCA) were collected from patients with MMD (n = 11) and from control patients (n = 9). Using microarray techniques, transcriptome-wide analysis was performed. RESULTS: Comparison of MCA gene expression between patients with MMD and control patients detected 62 and 26 genes whose expression was significantly (p < 0.001 and fold change > 2) up- or downregulated, respectively, in the MCA of MMD. Gene set enrichment analysis of genes expressed in the MCA of patients with MMD revealed positive correlations with genes involved in antigen processing and presentation, the dendritic cell pathway, cytokine pathway, and interleukin-12 pathway, and negative correlations with genes involved in oxidative phosphorylation and DNA repair. Microarray analysis was validated by quantitative polymerase chain reaction. CONCLUSIONS: Transcriptome-wide analysis showed upregulation of genes for immune responses and downregulation of genes for DNA repair and oxidative phosphorylation within the intracranial artery of patients with MMD. These findings may represent clues to the pathophysiology of MMD.

Changes in Vessel Wall Enhancement Related to the Recent Neurological Symptoms in Patients with Moyamoya Disease.

Moyamoya disease (MMD) causes intracranial arterial stenosis progression. The progression of intracranial arterial stenosis will increase the risk of ischemic cerebrovascular events. This study aims to investigate the relationship between intracranial arterial stenosis progression, vessel wall enhancement (VWE), and the recent neurological symptoms. A total of 39 MMD patients (12 male; 37.6 ± 18.0 years old) were registered in this study analysis between April 2016 and July 2018. All patients received MRI at registration and 6, 12, and 24 months post-registration. The incidence of ischemic cerebrovascular events (transit ischemic attacks or cerebral infarction) was checked until December 2018. We evaluated the relationship between the intensity of VWE, intracranial arterial stenosis, and the recent neurological symptoms. During the mean follow-up period of 13.8 ± 5.5 months, the changes in VWE were observed in 33 hemispheres (42.3%), stenosis progression was observed in 21 hemispheres (26.9%), and recent neurological symptoms occurred in 10 hemispheres (12.8%). Stenosis progression was observed in 11 hemispheres (33.3%) in the VWE(+) group and ten hemispheres (22.2%) in the VWE(-) group (p = 0.310). The recent neurological symptoms were observed in eight hemispheres (21.2%) in the VWE(+) group and two hemispheres (4.44%) in the VWE(-) group (odds ratio 6.88, 95% confidence interval 1.35-34.98, p = 0.015). The intensity of VWE sometimes changes. The changes in VWE were significantly associated with the recent neurological symptoms but not with stenosis progression.