Long-term remission after upfront autologous hematopoietic stem cell transplant for CD5+ diffuse large-B cell lymphoma.

CD5+ diffuse large B-cell lymphoma (DLBCL) is a rare subtype characterized by an inferior outcome. While dose-dense therapy shows promising activity, the optimal management remains to be determined. To evaluate the benefit of consolidative autologous hematopoietic stem cell transplantation (ASCT), we retrospectively reviewed the medical records of 47 consecutive patients with newly diagnosed de novo CD5+ DLBCL. Of 19 patients ≤ 70 of age with age-adjusted International Prognostic Index 2-3, eight underwent upfront ASCT, and nine did not, despite preserved organ function and response after induction therapy. The remaining two, ineligible for ASCT due to early progression or comorbidities, had a dismal clinical course. Among younger 17 high-risk patients eligible for ASCT, ASCT was associated with better overall (p = 0.0327) and progression-free survival (p = 0.0184). Younger patients without ASCT demonstrated similar outcomes to older patients with similar risk profiles. ASCT could be considered for high-risk CD5+ DLBCL with a response after induction therapy.

Isolated massive pleural effusion as a manifestation of chronic graft versus host disease successfully treated with corticosteroid.

Isolated pleural effusion is a rare manifestation of chronic graft versus host disease (cGVHD) after hematopoietic stem cell transplantation (HSCT). We herein report a 58-year-old woman presenting with massive pleural effusion approximately 1 year after allogeneic HSCT, who was successfully treated with corticosteroid. She had discontinued tacrolimus approximately 1 month before she presented with pleural effusion, which was attributed to cGVHD after a thorough exclusion process. This case illustrates a unique manifestation of atypical cGVHD and highlights the need for prompt therapy initiation.

Usefulness of the preoperative thoracic inlet angle in comparison to the T1 slope for predicting cervical kyphosis after laminoplasty.

PURPOSE: Thoracic inlet angle (TIA) is a sagittal radiographic parameter with a constant value regardless of posture and is significantly correlated with the sagittal balance of the cervical spine. However, the practical use of TIA has not been studied. This study aimed to investigate the usefulness of the preoperative TIA for predicting the development of kyphotic deformity after cervical laminoplasty in comparison to the preoperative T1 slope (T1S). METHODS: A total of 98 patients who underwent cervical laminoplasty without preoperative kyphotic alignment were included (mean age, 73.7 years; 41.8% female). Radiography was evaluated before surgery and at the 2-year follow-up examination. The cervical sagittal parameters were measured on standing radiographs, and the TIA was measured on T2-weighted MRI in a supine position. Cervical alignment with a C2-C7 angle of ≥ 0° was defined as lordosis, and that with an angle of < 0° was defined as kyphosis. RESULTS: Postoperative kyphosis occurred in 11 patients (11.2%). Preoperatively, the kyphosis group showed significantly lower values in the T1S (23.5° vs. 30.3°, p = 0.034) and TIA (76.1° vs. 81.8°, p = 0.042). We performed ROC curve analysis to clarify the impact of the preoperative TIA and T1S on kyphotic deformity after laminoplasty. The optimal cutoff angles for TIA and T1S were 68° and 19°, respectively, with similar diagnostic accuracy. CONCLUSION: This study demonstrated the clinical utility of the preoperative TIA for predicting the risk of postoperative kyphotic deformity after cervical laminoplasty. These findings suggest the importance of the preoperative assessment of thoracic inlet alignment in cervical spine surgery.

Proteinuria screening and risk of bone fracture: a retrospective cohort study using a nationwide population-based database.

Background and hypothesis: Proteinuria is associated with an increased risk of kidney function deterioration, cardiovascular disease, or cancer. Previous reports suggesting an association between kidney dysfunction and bone fracture may be confounded by concomitant proteinuria and were inconsistent regarding the association between proteinuria and bone fracture. Therefore, we aimed to evaluate the association using a large administrative claims database in Japan. Methods: Using the DeSC database, we retrospectively identified individuals with laboratory data including urine dipstick test between August 2014 and February 2021. We evaluated the association between proteinuria and vertebral or hip fracture using multivariable Cox regression analyses adjusted for various background factors including kidney function. We also performed subgroup analyses stratified by sex and kidney function and sensitivity analyses with Fine & Gray models considering death as a competing risk. Results: We identified 603 766 individuals and observed 21 195 fractures. With reference to the negative proteinuria group, the hazard ratio for hip or vertebral fracture was 1.10 [95% confidence interval (CI), 1.05-1.14] and 1.16 (95%CI, 1.11-1.22) in the trace and positive proteinuria group, respectively, in the Cox regression analysis. The subgroup analyses showed similar trends. The Fine & Gray model showed a subdistribution hazard ratio of 1.09 (95%CI, 1.05-1.14) in the trace proteinuria group and 1.15 (95% CI, 1.10-1.20) in the positive proteinuria group. Conclusions: Proteinuria was associated with an increased risk of developing hip or vertebral fractures after adjustment for kidney function. Our results highlight the clinical importance of checking proteinuria for predicting bone fractures.

Induction of CYP3A activity by dexamethasone may not be strong, even at high doses: insights from a case of tacrolimus co-administration.

BACKGROUND: Dexamethasone (DEX) induces CYP3A activity in a concentration-dependent manner. However, no study has examined changes in the blood concentration of CYP3A substrate drugs when DEX is administered at high doses. Herein, we present a case in which tacrolimus (TAC), a typical CYP3A substrate drug, was co-administered with a chemotherapy regimen that included high-dose DEX. CASE PRESENTATION: A 71-year-old woman underwent liver transplantation for hepatocellular carcinoma 18 years prior to her inclusion in this case study. She was receiving TAC orally at 2 mg/day and had a stable trough blood concentration of approximately 4 ng/mL and a trough blood concentration/dose (C/D) ratio of approximately 2. The patient was diagnosed with post-transplant lymphoproliferative disease (histological type: Burkitt's lymphoma) after admission. Thereafter, the patient received cyclophosphamide-prednisolone (CP), followed by two courses of R-HyperCVAD (rituximab, cyclophosphamide, doxorubicin, vincristine, and DEX) and R-MA (rituximab, methotrexate, and cytarabine) replacement therapy. DEX (33 mg/day) was administered intravenously on days 1-4 and days 11-14 of R-HyperCVAD treatment, and aprepitant (APR) was administered on days 1-5 in both courses. The TAC C/D ratio decreased to approximately 1 on day 11 during both courses, and then increased. Furthermore, a decreasing trend in the TAC C/D ratio was observed after R-MA therapy. The decrease in the TAC C/D ratio was attributed to APR administration rather than to DEX. CONCLUSION: The induction of CYP3A activity by a high dose of DEX may not be strong. The pharmacokinetic information on DEX and in vitro enzyme activity induction studies also suggested that CYP3A activity induction is not prominent under high-dose DEX treatment.

Risk factors for early mortality in elderly patients with unstable isolated C2 odontoid fracture treated with halo-vest or surgery.

The aim of this study was to compare in-hospital mortality of three procedures -halo-vest immobilization, anterior spinal fixation (ASF), and posterior spinal fixation (PSF)- in the treatment of elderly patients with isolated C2 odontoid fracture. We extracted data for elderly patients who were admitted with C2 odontoid fracture and treated with at least one of the three procedures (halo-vest immobilization, ASF, or PSF) during hospitalization. We conducted a generalized propensity score-based matching weight analysis to compare in-hospital mortality among the three procedures. We further investigated independent risk factors for in-hospital death. The study involved 891 patients (halo-vest, n = 463; ASF, n = 74; and PSF, n = 354) with a mean age of 78 years. In-hospital death occurred in 45 (5.1%) patients. Treatment type was not significantly associated with in-hospital mortality. Male sex (odds ratio 2.98; 95% confidence interval 1.32-6.73; p = 0.009) and a Charlson comorbidity index of ≥ 3 (odds ratio 9.18; 95% confidence interval 3.25-25.92; p < 0.001) were independent risk factors for in-hospital mortality. In conclusion, treatment type was not significantly associated with in-hospital mortality in elderly patients with isolated C2 odontoid fracture. Halo-vest immobilization can help to avoid adverse events in patients with C2 odontoid fracture who are considered less suitable for surgical treatment.

Radiographic Predictors of Subaxial Subluxation After Atlantoaxial Fusion.

STUDY DESIGN: A retrospective study. OBJECTIVE: The aim of this study was to clarify preoperative radiographic predictors associated with the development of subaxial subluxation (SAS) after surgery. BACKGROUND: The incidence of atlantoaxial fusion for atlantoaxial instability has been increasing. SAS can develop after surgery despite atlantoaxial fusion with the optimal C1-C2 angle. We hypothesized that preoperative discordant angular contribution in the upper and subaxial cervical spine is associated with the occurrence of postoperative SAS. MATERIALS AND METHODS: Patients who underwent surgery for atlantoaxial instability with a minimum 5-year follow-up and control participants were included. The O-C2 angle, C2 slope (C2S), C2-C7 cervical lordosis (CL), and T1 slope (T1S) were measured. We focused on the angular contribution ratio in the upper cervical spine to the whole CL, and the preoperative C2/T1S ratio was defined as the ratio of C2S to T1S. RESULTS: Twenty-seven patients (SAS=11, no-SAS=16; mean age, 60.7 y old; 77.8% female; mean follow-up duration, 6.8 y) and 23 demographically matched control participants were enrolled. The SAS onset was at 4.7 postoperative years. Preoperatively, the O-C2 angle, C2-C7 CL, and T1S were comparable between the SAS, no-SAS, and control groups. The preoperative C2S and C2/T1S ratio were smaller in the SAS group than in the no-SAS or control group (C2S, 11.0 vs. 18.4 vs. 18.7 degrees; C2/T1S ratio, 0.49 vs. 0.77 vs. 0.78, P <0.05). The receiver operating characteristic curve analysis demonstrated that the C2/T1S ratio had higher specificity and similar sensitivity as a predictor of postoperative SAS than C2S (specificity: 0.90 vs. 0.87; sensitivity: 0.73 vs. 0.73). The estimated cutoff values of the C2S and C2/T1S ratio were 14 degrees and 0.58, respectively. CONCLUSIONS: The preoperative C2/T1S ratio was closely associated with postoperative SAS. Patients with a C2/T1S ratio <0.58 were at a high risk of SAS after atlantoaxial fusion. LEVEL OF EVIDENCE: Level 4.

Acalabrutinib and steroid for autoimmune thrombocytopenia due to relapsed chronic lymphocytic leukemia with severe bone marrow infiltration.

Thrombocytopenia is a frequent complication in chronic lymphocytic leukemia (CLL). Differentiating autoimmune thrombocytopenia from thrombocytopenia due to bone marrow infiltration is necessary for appropriate treatment, but sometimes difficult. Here we report a 60-year-old male patient with CLL who had achieved complete response after treatment with fludarabine, cyclophosphamide, and rituximab two years prior to presentation. He was admitted with severe thrombocytopenia that was unresponsive to intravenous immunoglobulin. Imaging studies revealed systemic enlarged lymph nodes and bone marrow aspiration was hypercellular with > 95% lymphocytes and scant megakaryocytes. Acalabrutinib 200 mg/day was administered for the treatment of CLL exacerbation. A gradual decrease in CLL cells and recovery of megakaryocytes in bone marrow were observed, but platelet counts remained low. Systemic administration of prednisolone 0.5 mg/kg, in addition to acalabrutinib, was started, considering the contribution of autoimmune thrombocytopenia; platelet recovery was rapid and sustained for more than a year. Even if bone marrow examination suggested thrombocytopenia due to direct leukemic infiltration, it is difficult to exclude the possibility of concomitant immunogenic thrombocytopenia. We conclude that for CLL patients with severe thrombocytopenia, repeating bone marrow examination and concurrent immunosuppressive therapies and treatment of the underlying CLL may be beneficial.

Upregulation of Taurine Biosynthesis and Bile Acid Conjugation with Taurine through FXR in a Mouse Model with Human-like Bile Acid Composition.

Taurine, the end product in the sulfur-containing amino acid pathway, is conjugated with bile acids (BAs) in the liver. The rate-limiting enzymes in both taurine synthesis and BA conjugation may be regulated by a nucleus receptor, FXR, that promotes BA homeostasis. However, it is controversial because BAs act as natural FXR agonists or antagonists in humans and mice, respectively, due to the species differences in BA synthesis. The present study evaluated the influences of different BA compositions on both pathways in the liver by comparing Cyp2a12-/-/Cyp2c70-/- mice with a human-like BA composition (DKO) and wild-type (WT) mice. The DKO liver contains abundant natural FXR agonistic BAs, and the taurine-conjugated BA proportion and the taurine concentration were significantly increased, while the total BA concentration was significantly decreased compared to those in the WT liver with natural FXR antagonistic BAs. The mRNA expression levels of the enzymes Bacs and Baat in BA aminations and Cdo and Fmo1 in the taurine synthesis, as well as Fxr and its target gene, Shp, were significantly higher in the DKO liver than in the WT liver. The present study, using a model with a human-like BA composition in the liver, confirmed, for the first time in mice, that both the taurine synthesis and BA amidation pathways are upregulated by FXR activation.

Recurrent bilateral adrenal infarction with myelodysplastic/myeloproliferative neoplasm-unclassifiable (MDS/MPN-U): a case report.

BACKGROUND: Bilateral adrenal infarction is rare and only a small number of cases have been reported so far. Adrenal infarction is usually caused by thrombophilia or a hypercoagulable state, such as antiphospholipid antibody syndrome, pregnancy, and coronavirus disease 2019. However, adrenal infarction with myelodysplastic/myeloproliferative neoplasm (MDS/MPN) has not been reported. CASE PRESENTATION: An 81-year-old man with a sudden severe bilateral backache presented to our hospital. Contrast-enhanced computed tomography (CT) led to the diagnosis of bilateral adrenal infarction. Previously reported causes of adrenal infarction were all excluded and a diagnosis of MDS/MPN-unclassifiable (MDS/MPN-U) was reached, which was considered to be attributed to adrenal infarction. He developed a relapse of bilateral adrenal infarction, and aspirin administration was initiated. Partial primary adrenal insufficiency was suspected as the serum adrenocorticotropic hormone level was persistently high after the second bilateral adrenal infarction. CONCLUSION: This is the first case of bilateral adrenal infarction with MDS/MPN-U encountered. MDS/MPN has the clinical characteristics of MPN. It is reasonable to assume that MDS/MPN-U may have influenced bilateral adrenal infarction development, considering the absence of thrombosis history and a current comorbid hypercoagulable disease. This is also the first case of recurrent bilateral adrenal infarction. It is important to carefully investigate the underlying cause of adrenal infarction once adrenal infarction is diagnosed, as well as to assess adrenocortical function.

Favorable outcome of hematopoietic stem cell transplantation in late-onset Krabbe disease.

BACKGROUND: Late-onset Krabbe disease is a disorder with autosomal recessive inheritance caused by a deficiency in galactocerebrosidase (GALC) activity. Its late-onset form usually shows slow disease progression with atypical symptoms including spastic paresis. The efficacy of hematopoietic stem cell transplantation (HSCT) in late-onset Krabbe disease has not been fully established. CASE REPORT: We describe the case of a patient with late-onset Krabbe disease showing progressive spastic paraparesis. At the age of 18, one and a half years after the development of symptoms, the patient underwent HSCT. After HSCT, the patient's GALC activity returned to a normal level and the lesions in the brain and spinal cord became faint on images. Over two and a half years after the HSCT, the patient's gait remained spastic, however, an improvement in gait speed and modified Rankin Scale score was observed. No severe adverse events occurred during this period. CONCLUSION: Our experience reported herein provides additional evidence for a favorable course in HSCT conducted in the early course of late-onset Krabbe disease.

The Effects of SGLT2 Inhibitors on Liver Cirrhosis Patients with Refractory Ascites: A Literature Review.

Decompensated liver cirrhosis is often complicated by refractory ascites, and intractable ascites are a predictor of poor prognosis in patients with liver cirrhosis. The treatment of ascites in patients with cirrhosis is based on the use of aldosterone blockers and loop diuretics, and occasionally vasopressin receptor antagonists are also used. Recent reports suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors may be a new treatment for refractory ascites with a different mechanism with respect to conventional agents. The main mechanisms of ascites reduction with SGLT2 inhibitors appear to be natriuresis and osmotic diuresis. However, other mechanisms, including improvements in glucose metabolism and nutritional status, hepatoprotection by ketone bodies and adiponectin, amelioration of the sympathetic nervous system, and inhibition of the renin-angiotensin-aldosterone system, may also contribute to the reduction of ascites. This literature review describes previously reported cases in which SGLT2 inhibitors were used to effectively treat ascites caused by liver cirrhosis. The discussion of the mechanisms involved is expected to contribute to establishing SGLT2 therapy for ascites in the future.

Breach of tolerance versus burden of bile acids: Resolving the conundrum in the immunopathogenesis and natural history of primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a classic autoimmune disease due to the loss of tolerance to self-antigens. Bile acids (BA) reportedly play a major role in biliary inflammation and/or in the modulation of dysregulated immune responses in PBC. Several murine models have indicated that molecular mimicry plays a role in autoimmune cholangitis; however, they have all been limited by the relative failure to develop hepatic fibrosis. We hypothesized that species-specific differences in the BA composition between mice and humans were the primary reason for this limited pathology. Here, we aimed to study the impact of human-like hydrophobic BA composition on the development of autoimmune cholangitis and hepatic fibrosis. We took advantage of a unique construct, Cyp2c70/Cyp2a12 double knockout (DKO) mice, which have human-like BA composition, and immunized them with a well-defined mimic of the major mitochondrial autoantigen of PBC, namely 2-octynoic acid (2OA). 2OA-treated DKO mice were significantly exacerbated portal inflammation and bile duct damage with increased Th1 cytokines/chemokines at 8 weeks post-initial immunization. Most importantly, there was clear progression of hepatic fibrosis and increased expression of hepatic fibrosis-related genes. Interestingly, these mice demonstrated increased serum BA concentrations and decreased biliary BA concentrations; hepatic BA levels did not increase because of the upregulation of transporters responsible for the basolateral efflux of BA. Furthermore, cholangitis and hepatic fibrosis were more advanced at 24 weeks post-initial immunization. These results indicate that both the loss of tolerance and the effect of hydrophobic BA are essential for the progression of PBC.

Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis.

The fate of resolution of liver fibrosis after withdrawal of liver injury is still incompletely elucidated. Toll-like receptor 4 (TLR4) in tissue fibroblasts is pro-fibrogenic. After withdrawal of liver injury, we unexpectedly observed a significant delay of fibrosis resolution as TLR4 signaling was pharmacologically inhibited in vivo in two murine models. Single-cell transcriptome analysis of hepatic CD11b+ cells, main producers of matrix metalloproteinases (MMPs), revealed a prominent cluster of restorative Tlr4-expressing Ly6c2-low myeloid cells. Delayed resolution after gut sterilization suggested its microbiome-dependent nature. Enrichment of a metabolic pathway linking to a significant increase of bile salt hydrolase-possessing family Erysipelotrichaceae during resolution. Farnesoid X receptor-stimulating secondary bile acids including 7-oxo-lithocholic acids upregulated MMP12 and TLR4 in myeloid cells in vitro. Fecal material transplant in germ-free mice confirmed phenotypical correlations in vivo. These findings highlight a pro-fibrolytic role of myeloid TLR4 signaling after injury withdrawal and may provide targets for anti-fibrotic therapy.

A case of intravascular lymphoma presenting with a lesion in the splenium of the corpus callosum.

Intravascular lymphoma (IVL) is difficult to diagnose because its clinical presentation and laboratory and imaging findings are nonspecific. Herein, we report a case of IVL presenting as a lesion in the splenium of the corpus callosum. A 52-year-old man attended the emergency department with a 2-week history of progressively worsening abnormal behavior and gait disturbance. Magnetic resonance imaging on admission revealed an oval lesion in the splenium of the corpus callosum. The follow-up magnetic resonance imaging performed 2 months after disease onset revealed multiple high-signal areas in the bilateral cerebral white matter on T2-weighted images and diffusion-weighted images. The blood test results showed an elevated level of lactate dehydrogenase and serum-soluble interleukin-2 receptor. These findings were compatible with the diagnosis of IVL. IVL is often difficult to diagnose due to a wide variety of clinical presentations and imaging findings.

Exercise-acclimated microbiota improves skeletal muscle metabolism via circulating bile acid deconjugation.

Habitual exercise alters the intestinal microbiota composition, which may mediate its systemic benefits. We examined whether transplanting fecal microbiota from trained mice improved skeletal muscle metabolism in high-fat diet (HFD)-fed mice. Fecal samples from sedentary and exercise-trained mice were gavage-fed to germ-free mice. After receiving fecal samples from trained donor mice for 1 week, recipient mice had elevated levels of AMP-activated protein kinase (AMPK) and insulin growth factor-1 in skeletal muscle. In plasma, bile acid (BA) deconjugation was found to be promoted in recipients transplanted with feces from trained donor mice; free-form BAs also induced more AMPK signaling and glucose uptake than tauro-conjugated BAs. The transplantation of exercise-acclimated fecal microbiota improved glucose tolerance after 8 weeks of HFD administration. Intestinal microbiota may mediate exercise-induced metabolic improvements in mice by modifying circulating BAs. Our findings provide insights into the prevention and treatment of metabolic diseases.