Case report and review of the literature of primary central nervous system lymphoma of the fourth ventricle.

Background: Primary central nervous system lymphoma of the fourth ventricle is very rare. We present a case of primary central nervous system lymphoma originating from the fourth ventricle and review cases reported in the literature. Case Description: A 54-year-old man with no previous medical history presented with headache and nausea. Magnetic resonance imaging showed a homogeneously enhancing tumor in the fourth ventricle and obstructive hydrocephalus. We performed biopsy of the tumor, which was diagnosed pathologically as diffuse large B-cell lymphoma. Although the tumor disappeared after 5 cycles of R-MPV regimen, the patient required repeated ventricular drainage and finally received a ventriculoperitoneal shunt. Complete response was achieved after 2 cycles of high-dose cytarabine chemotherapy with an autologous peripheral blood stem cell transplant. There was no sign of recurrence at 20 months after biopsy. Conclusion: Morbidity arising due to radical resection/radiotherapy of resistant primary central nervous system lymphoma originating from the fourth ventricle could be prevented by ventriculoperitoneal shunting with chemotherapy and autologous blood stem cell transplantation.

[Severe aplastic anemia exhibiting mild COVID-19 despite high serum IL-6 levels].

COVID-19 is a viral infection characterized by a cytokine storm similar to that in acute respiratory distress syndrome (ARDS). Neutrophils and monocytes are known to play an important role in tissue damage in ARDS. COVID-19 has been reported to be more severe in patients with hematological malignancies; however, there are few reports of COVID-19 in patients with aplastic anemia. Moreover, how aplastic anemia affects COVID-19 remains unclear. Here, we report the case of a COVID-19 patient with aplastic anemia who had high serum IL-6 levels but did not progress to the severe form of COVID-19. We inferred that severe neutropenia and monocytopenia due to aplastic anemia could contribute to a mild form of COVID-19, although a risk of more severe secondary bacterial infections exists.

Clonal Cytopenia of Undetermined Significance in a Patient with Congenital Wilms' Tumor 1 and Acquired DNMT3A Gene Mutations.

Congenital mutations of the Wilms' tumor 1 (WT1) gene can lead to various abnormalities, including renal/gonadal developmental disorders and cardiac malformations. Although there have been many reports of somatic WT1 mutations in patients with acute myeloid leukemia and myelodysplastic syndrome, congenital WT1 mutations have not been reported in hematological disorders. We herein report a patient with early-onset clonal cytopenia of undetermined significance that was associated with a congenital mutation of WT1 and an acquired mutation of DNMT3A [encoding DNA (cytosine-5)-methyltransferase 3A].

Whole-exome sequencing identified mutational profile of a case with T-cell chronic lymphocytic leukemia.

We believe that our report and further case reports on T-cell chronic lymphocytic leukemia with genetic profile will contribute to the molecular classification of this rare but distinct disease.

Unexpected Complication of R-CHOP Chemotherapy: Rapidly Progressive Bronchiolitis Obliterans Syndrome.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is the term used for the progressive obliteration of small airways before the patient has had a confirmatory lung biopsy. It is also recognized as a transplant-related complication. There have been no reports of BOS during initial standard chemotherapy. CASE PRESENTATION: A 50-year-old woman with newly diagnosed follicular lymphoma grade 2, stage 3A, presented with hypoxia and progressive dyspnoea after the fifth cycle of R-CHOP. High-resolution computed tomography showed air trapping enhanced at the end-expiratory phase. Pulmonary function testing revealed severe obstructive and restrictive failure without bronchodilator response. We diagnosed BOS based on current criteria and treated the patient with glucocorticoids and cyclosporin. She was discharged home on oxygen therapy. However, soon after discharge, her respiratory symptoms deteriorated and she was hospitalized in a palliative care unit. She died of respiratory failure within a year of symptom onset. CONCLUSIONS: This is the first case report to describe rapidly progressive BOS in a patient undergoing R-CHOP treatment, which strongly suggests the condition was caused by the chemotherapy. Although a pathological diagnosis was not obtained, the clinical diagnosis of BOS was important so that the patient could receive appropriate treatment and palliative care based on the prognosis of this incurable condition. LEARNING POINTS: R-CHOP chemotherapy may cause rapidly progressive bronchiolitis obliterans syndrome (BOS).When it is difficult to obtain a pathological diagnosis, a clinical diagnosis of BOS is important for early intervention and appropriate palliative care.

Protease-activated receptor-4 (PAR4) variant influences on platelet reactivity induced by PAR4-activating peptide through altered Ca2+ mobilization and ERK phosphorylation in healthy Japanese subjects.

BACKGROUND: Thrombin belongs to the most potent platelet agonists and activates human platelets through GPIbα and two protease activated receptors (PARs), PAR1 and PAR4. However, the details of thrombin receptor system, especially the role of PAR4 on human platelet activation is still not clear. OBJECTIVES: We found a significant difference in PAR4-activating peptide (PAR4-AP)-induced, but not PAR1-AP, platelet aggregation between healthy Japanese subjects. Sequencing analysis revealed a single nucleotide change in PAR4 gene F2RL3 (SNP rs773902) leading to Ala120Thr variant. To elucidate the role of PAR4 in human platelet activation, we examined if platelet activation induced by PAR4-AP may be associated with PAR4 genotype. METHODS: Platelets from 202 healthy Japanese volunteers were genetically analyzed and determined the genotype frequency of rs773902. Agonist induced platelet aggregation, integrin αIIbß3 activation, granule release, Ca2+ mobilization, and activation of ERK and MLC were evaluated. The specificity of effects observed in platelets was confirmed in 293T cells transfected PAR4-Thr120 or Ala120. RESULTS: The frequencies of PAR4 variant Thr/Thr120, Ala/Thr120, and Ala/Ala 120 were 5.9, 37.1, and 57.0%, respectively. Platelets with Thr/Thr120 showed significantly higher reactivity in PAR4-AP-induced platelet aggregation, αIIbß3 activation and granule release compared to platelets with Ala/Ala120. PAR4-AP induced higher Ca2+ mobilization and ERK activation in platelets with Thr/Thr120 than Ala/Ala120. Ca2+ mobilization and ERK activation were also increased in 293T cells transfected with PAR4-Thr120 compared to Ala120. CONCLUSION: Our data suggested that PAR4-AP-induced platelet reactivity between PAR4 rs773902 was associated with altered intensity of Ca2+ mobilization and ERK activation.

Human CalDAG-GEFI deficiency increases bleeding and delays αIIbß3 activation.

Affinity regulation of integrin αIIbß3 for fibrinogen by inside-out signaling plays a critical role in hemostasis. Calcium and diacylglycerol (DAG)-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) was identified as a Rap1-activating molecule, and its role in inside-out αIIbß3 activation was established in CalDAG-GEFI-deficient mice. However, little information regarding CalDAG-GEFI in human platelets is available. Here, we report a 16-year-old girl with CalDAG-GEFI deficiency who has been suffering from severe bleeding tendency. Although talin and kindlin-3 were normally detected, CalDAG-GEFI was undetectable in her platelets by western blotting. Genetic analysis revealed compound heterozygous CalDAG-GEFI mutations, Lys309X and Leu360del, which were responsible for CalDAG-GEFI deficiency. The functional analysis demonstrated impaired αIIbß3 activation by various agonists except for phorbol myristate acetate, normal calcium mobilization, and impaired Rap1 activation, which were consistent with the phenotype of CalDAG-GEFI-deficient mice. Despite substantial αIIbß3 activation at high agonist concentrations, she had severe bleeding tendency. Further functional analysis demonstrated markedly delayed αIIbß3 activation velocity and decreased shear-induced thrombus formation. Contrary to CalDAG-GEFI-deficient mice, which showed integrin-dependent neutrophil functional abnormality, neutrophil ß2 integrin activation was not impaired in the patient. Our results demonstrate the critical role of CalDAG-GEFI in rapid αIIbß3 activation of human platelets.