Elevated plasma and bile levels of corisin, a microbiota-derived proapoptotic peptide, in patients with severe acute cholangitis.

BACKGROUND: Acute cholangitis is a severe, life-threatening infection of the biliary system that requires early diagnosis and treatment. The Tokyo Guidelines recommend a combination of clinical, laboratory, and imaging findings for diagnosis and severity assessment, but there are still challenges in identifying severe cases that need immediate intervention. The microbiota and its derived products have been implicated in the pathogenesis of acute cholangitis. Corisin is a microbiome-derived peptide that induces cell apoptosis, acute tissue injury, and inflammation. This study aimed to evaluate the potential of plasma and bile corisin as a biomarker of acute cholangitis. METHODS: Forty patients with acute cholangitis associated with choledocholithiasis or malignant disease were enrolled. Nine patients without acute cholangitis were used as controls. Corisin was measured by enzyme immunoassays in plasma and bile samples. Patients were classified into severe and non-severe groups. The associations of plasma and bile corisin with the clinical grade of acute cholangitis and other parameters were analyzed by univariate and multivariate regression analysis. RESULTS: Plasma and bile corisin levels were significantly higher in patients with acute cholangitis than in controls. Patients with severe acute cholangitis had significantly higher plasma and bile corisin levels than those with non-severe form of the disease. Bile corisin level was significantly correlated with markers of inflammation, coagulation, fibrinolysis, and renal function. Univariate analysis revealed a significant association of bile corisin but a weak association of plasma corisin with the clinical grade of acute cholangitis. In contrast, multivariate analysis showed a significant relationship between plasma corisin level and the disease clinical grade. The receiver operating characteristic curve analysis showed low sensitivity but high specificity for plasma and bile corisin to detect the severity of acute cholangitis. The plasma and bile corisin sensitivity was increased when serum C-reactive protein level was included in the receiver operating characteristic curve analysis. CONCLUSIONS: Overall, these findings suggest that plasma and bile corisin levels may be useful biomarkers for diagnosing and monitoring acute cholangitis and that corisin may play a role in the pathophysiology of the disease by modulating inflammatory, coagulation and renal pathways.

Successful treatment of systemic AL amyloidosis with autologous hematopoietic stem cell transplantation combined with cell-free and concentrated ascites reinfusion therapy.

Key Clinical Message: AL patients develop the unique toxicities of fluid retention and non-cardiogenic pulmonary edema during the course of stem cell mobilization. We propose mobilization with CART as effective and safe treatment for AL patients with refractory anasarca. Abstract: We describe a 63-year-old male with systemic immunoglobulin light chain (AL) amyloidosis with cardiac, renal, and liver involvement. After four courses of CyBorD, mobilization with G-CSF at 10 µg/kg was initiated and CART was simultaneously performed for fluid retention. No adverse events were observed during collection or reinfusion. Anasarca gradually disappeared and he underwent autologous hematopoietic stem cell transplantation. The complete remission of AL amyloidosis has been maintained, and the condition of the patient has remained stable for 7 years. We propose mobilization with CART as an effective and safe treatment option for AL patients with refractory anasarca.

Antimicrobial Effects of Lactoferrin against Helicobacter pylori Infection.

Helicobacter (H.) pylori is the primary causative agent of various gastroduodenal diseases. H. pylori is an adapted microorganism that has evolved to survive in the acidic conditions of the human stomach, possessing a natural strategy for colonizing harsh environments. Despite the implementation of various eradication regimens worldwide, the eradication rate of H. pylori has decreased to less than 80% in recent years due to the emergence of antibiotic-resistant strains. This has posed a significant challenge in treating H. pylori infection, as antibiotic resistance and side effects have become increasingly problematic. Lactoferrin, a member of the transferrin family, is an iron-binding protein with antioxidant, antibacterial, antiviral, and anti-inflammatory properties that promote human health. The concentrations of lactoferrin in the gastric juice and mucosa significantly increase during H. pylori infection and are strongly correlated with the severity of gastric mucosal inflammation. Numerous researchers have studied the antimicrobial properties of lactoferrin both in vitro and in vivo. In addition, recent studies have investigated the addition of oral lactoferrin supplementation to H. pylori eradication therapy, even though monotherapy with lactoferrin does not eradicate the microorganism. In this article, we reviewed the survival strategy of H. pylori to evade the antimicrobial activity of human lactoferrin and explore the potential of lactoferrin in H. pylori eradication therapy.

Helicobacter pylori infection: is there circulating vacuolating cytotoxin A or cytotoxin-associated gene A protein?

BACKGROUND: Helicobacter pylori infection is a well-recognized cause of gastric diseases, including chronic gastritis, peptic ulcer, and gastric cancer. Vacuolating cytotoxin-A (VacA) and cytotoxin-associated gene A protein (CagA) play a role in the pathogenesis of H. pylori-related gastric diseases. Also, extragastric disorders are frequent morbid complications in patients with H. pylori infection. However, the direct pathologic implication of these virulence factors in extragastric manifestations remains unclear. Our hypothesis in the present study is that VacA and CagA released by H. pylori in the gastric mucosa leak into the systemic circulation, and therefore they can be measured in serum. RESULTS: Sixty-two subjects were enrolled. They were allocated into the H. pylori-positive and H. pylori-negative groups. VacA and CagA were measured by immunoassays. The serum levels of VacA and CagA above an upper limit cut-off (mean plus two standard deviations of the mean in patients without H. pylori infection) were considered positive for antigen circulating level. Five out of 25 H. pylori-positive patients were positive for both serum VacA and serum CagA. The serum levels of VacA and CagA were significantly correlated with the serum levels of anti- H. pylori antibody and interleukin-12p70 among all H. pylori-positive and H. pylori-negative patients. CONCLUSIONS: This study suggests that spill-over of VacA and CagA antigens in the systemic circulation may occur in some patients with H. pylori infection.

Acute Calculous Cholecystitis Caused by Streptococcus gallolyticus subspecies pasteurianus: A Case Report.

Acute cholecystitis is an infectious disease of the gallbladder caused mainly by Escherichia coli, Klebsiella, and Enterococcus species. Streptococcus gallolyticus subsp. pasteurianus, previously known as Streptococcus bovis biotype II/2, rarely causes endocarditis, meningitis, and septicemia, mainly in children. Biliary tract infections by Streptococcus gallolyticus subsp. pasteurianus are extremely rare. There have been no reports of cases in Japan. Here, we describe the first case in Japan of acute calculous cholecystitis caused by Streptococcus gallolyticus subsp. pasteurianus infection. A 63-year-old man was admitted to our hospital with epigastric pain and vomiting. He had moderate tenderness and a full sensation in the epigastrium. Abdominal imaging revealed multiple stones in the gallbladder. After admission, he had a high fever that did not improve with antibiotics. Percutaneous transhepatic gallbladder drainage was performed. The patient underwent open cholecystectomy. During surgery, several small stones in the gallbladder and an abscess were observed at the gallbladder base. Streptococcus gallolyticus subsp. pasteurianus was detected by bacterial culture of the bile juice. The gallstones were bilirubin calcium stones. The endoscopic study showed three adenomas in the colon, but the histopathological examination demonstrated no malignant cells. Although infection by this bacterium may not be rare, this is the first reported case in Japan of acute calculous cholecystitis caused by Streptococcus gallolyticus subsp. pasteurianus infection.

Successful ixazomib treatment for relapsed and refractory acute myeloid leukemia transformed from myelodysplastic syndrome.

Elevated NF-kB levels have been identified in primitive bone marrow cells from patients with MDS/AML, suggesting NF-kB as a therapeutic target in MDS/AML. We herein describe an MDS patient ineligible for SCT who, following treatment with azacitidine and bortezomib, transformed to leukemia, but maintained complete remission after monotherapy with ixazomib.

Successful Treatment of Incidental Histiocytic Sarcoma Concomitant with Laryngeal Carcinoma.

Histiocytic sarcoma (HS) is an extremely rare non-Langerhans cell disorder with an aggressive course and limited treatment options. HS most often presents at an advanced clinical stage, with a limited response to chemotherapy and high mortality. No standard treatment has been established for HS. We herein describe the first case of HS concomitant with laryngeal carcinoma that was promptly diagnosed and successfully treated; the condition of the patient has remained stable for 4 years with no recurrence.

The association of lymphocyte phenotypes and outcomes after discontinuing eltrombopag in immune thrombocytopenia.

AIM: Eltrombopag is a highly effective treatment for immune thrombocytopenia (ITP). Cases of durable remission after the discontinuation of eltrombopag in adult ITP have recently been reported; however, the frequency and mechanisms responsible for this phenomenon remain unknown. In the present study, we examined the phenotypes of lymphocytes in ITP to clarify whether they predict outcomes after the discontinuation of eltrombopag. METHODS: We analysed 56 adult ITP patients treated with eltrombopag at our hospital between January 2008 and January 2020. Patients' characteristics at the initiation and discontinuation of eltrombopag, the prognostic significance of lymphocytes and other factors were evaluated. RESULTS: A total of 38 patients showed complete response (CR). Eltrombopag was discontinued in 28 of 38 patients who achieved CR. Among the 28 patients, 12 (42.8%) had an immediate relapse after discontinuing eltrombopag and 16 (57.2%) showed sustained response without additional ITP therapy, despite discontinuing eltrombopag, with a median follow-up of 42 months. No significant differences were observed in platelets, the median duration of eltrombopag, the absolute number of T, B and NK cells at the initiation of eltrombopag between patients who sustained response and those who relapsed after discontinuing eltrombopag. However, the number of B and NK cells at the discontinuation of eltrombopag was higher in patients who sustained response than in those who relapsed (P = .022 and P = .012 respectively). CONCLUSIONS: The present results indicate that the absolute number of B (≥0.20 × 109 /L) and NK (≥0.30 × 109 /L) cells at the discontinuation of eltrombopag contributes to the prediction of outcomes.

Impact of the CD4:CD8 ratio in bone marrow on stem cell mobilization and engraftment in autologous stem cell transplant patients.

Bone marrow (BM) damage after previous chemotherapy, such as that involving alkylating agents, and radiation therapy alone cannot explain poor hematopoietic progenitor cell mobilization. We examined the T lymphocytes of BM in 67 autologous peripheral blood stem cell transplant (auto-PBSCT) patients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM) to establish whether the cellular phenotype predicts mobilization and engraftment between January 2000 and January 2020 at the Japanese Red Cross Society Wakayama Medical Center. The total number of mobilized CD34+ cells was <2 × 106 /kg in 30 patients (group A) and ≥2 × 106 /kg in 37 (group B). The median absolute number of CD3+CD4+ cells was lower in group A than in group B (P = .013), and the median absolute number of CD3+CD8+ cells was higher in group A than in group B (P = .016). A low CD4:CD8 ratio was observed in all patients in group A, whereas all patients in group B showed a normal CD4:CD8 ratio (P < .001). A strong correlation was found between the CD4:CD8 ratio and median total CD34+ cells yield (r = .723, P < .001). The present results showed that a lower CD4:CD8 ratio correlated with later neutrophil and platelet engraftment (r = .662, P = .007 and r = .571, P = .008, respectively). The present results indicate that the CD4:CD8 ratio in BM contributes to the prediction of mobilization and engraftment in auto-PBSCT patients.

The acquisition of trisomy 8 associated with Behçet's-like disease in myelodysplastic syndrome.

A relationship has been reported between myelodysplastic syndrome (MDS) and autoimmune disease. Behçet's disease is a multisystem inflammatory disorder with mucocutaneous, articular, gastrointestinal, neurological, and vascular manifestations. The co-occurrence of MDS with trisomy 8 and Behçet's-like disease was recently demonstrated. We herein describe a case that shows the relationship between the acquisition of trisomy 8 and occurrence of Behçet's-like disease. Immune dysregulation and altered T-cell hemostasis play an important role in the pathogenesis of Behçet's-like disease and MDS with trisomy 8.

Prediction of response to first-line therapy with ITP by flow cytometric analysis of bone marrow lymphocyte phenotypes.

In the present study, we analyzed phenotypes of cells in the lymphocyte region of bone marrow in 68 patients with primary immune thrombocytopenia (ITP) to determine whether cellular phenotype predicts response to first-line therapy (corticosteroids or corticosteroids plus intravenous immunoglobulin). In 52 newly diagnosed ITP patients, an abnormal CD4:CD8 ratio (CD4/CD8 ratio < 0.4 and 2.3 < CD4/CD8 ratio) was noted in 22 patients in the responder group, whereas all non-responder and control individuals showed normal CD4:CD8 ratio (p < 0.001). The absolute number of CD19+ cells in patients with 0.4 ≤ CD4/CD8 ratio ≤ 2.3 or 2.3 < CD4/CD8 ratio was higher than that in other groups. (p = 0.016). In 16 chronic ITP patients, the absolute number of NK cells in the responder group was lower than those in the non-responder and control groups (p = 0.032). An abnormal CD4:CD8 ratio was noted in all patients in the responder group, whereas all patients in non-responder and control groups showed normal CD4:CD8 ratio (p < 0.001). The present results indicate that CD4:CD8 ratio, B cells, and NK cells contribute to the prediction of therapeutic outcomes of ITP patients.

Effects of charged lipids on the physicochemical and biological properties of lipid-styrene maleic acid copolymer discoidal particles.

Styrene maleic acid copolymers (SMA) form discoidal lipid nanoparticles (lipid nanodisks) that mimic plasma high-density lipoproteins. We have previously prepared and characterized lipid nanodisks composed of SMA and the neutral phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). In the present study, we tested whether the surface charges can alter the physicochemical and biological properties of lipid-SMA discoidal particles. Unlike the case of DMPC alone, addition of saline to the buffer was necessary to induce the formation of lipid-SMA complexes containing either 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) or 1,2-dimyristoyl-3-trimethylammonium-propane (DMTAP), with formation efficiency being dependent on the concentration of charged lipids. After purification, DMPG- or DMTAP-containing discoidal particles with an approximate size of 10 nm were obtained in a manner similar to DMPC alone. Although DMPG and DMTAP appeared to be similarly incorporated into the lipid nanodisks, the zeta potentials of both particles were comparable. That is, no significant differences were observed in the physicochemical properties between the lipid-SMA nanodisks. Compared to DMPC-SMA nanodisks, the uptake of DMPG or DMTAP-containing discoidal particles by RAW264 cells was increased for both particle types, whereas in MDA-MB-231 cells, only DMTAP-containing discoidal particle uptake was increased. In addition, fluorescence microscopy revealed that lipid-SMA nanodisks are localized adjacent to the plasma membrane of RAW264 cells but in MDA-MB-231 cells they accumulated in the center of the cell. Furthermore, these particles caused cytotoxicity in a cell-type dependent manner, with high toxicity in MDA-MB-231. These results raised the possibility that compositional alterations in lipid-SMA discoidal particles may modulate biological reactions in vivo.

Effective upfront treatment with low-dose ibrutinib for a patient with B cell prolymphocytic leukemia.

B cell prolymphocytic leukemia (B-PLL) is a rare and aggressive disease that is associated with poor survival. Although initially asymptomatic patients do not require therapy, most patients will progress and inevitably require treatment. More than 50% of patients with B-PLL carry abnormalities in the TP53 tumor suppressor gene and/or complex karyotype and show resistance to conventional chemotherapy. The efficacy of ibrutinib, a B cell receptor inhibitor, for B-PLL with the TP53 abnormality as second-line therapy was recently demonstrated. We herein report that low-dose ibrutinib as upfront therapy induced a complete response in a B-PLL patient with the TP53 abnormality, whose condition has since remained stable with no recurrence for 12 months. Effective treatments for B-PLL are lacking and given its rarity, prospective comparative therapies are not yet available. This case suggests that upfront therapy with ibrutinib improves the outcome of B-PLL.

Successful treatment with brentuximab vedotin for relapsed and refractory adult T cell leukemia.

Although treatments for adult T-cell leukemia/lymphoma in the past two decades have advanced, the current standard treatment for aggressive adult T-cell leukemia/lymphoma, particularly in patients who are not eligible for stem cell transplantation, remains inadequate; therefore, treatments to prolong the duration of remission and provide relevant benefits in terms of survival and quality of life are needed. Adult T-cell leukemia/lymphoma tumor cells express CD30 in some cases and the increased expression of CD30 is considered to be one of the causes of constitutive NF-κB activation in adult T-cell leukemia/lymphoma cells. Brentuximab vedotin represents a major breakthrough in the treatment of CD30-positive lymphomas. Elderly patients treated with chemotherapy generally have higher rates of grade 3 or 4 adverse events; however a retrospective analysis demonstrated the safety and efficacy of brentuximab vedotin in adults ≥60 years with relapsed and refractory CD30-positive lymphomas. We herein report the clinical effects of brentuximab vedotin and the significance of CD30 expression in an elderly refractory/relapse adult T-cell leukemia/lymphoma patient. CD30 expression is associated with disease progression in adult T-cell leukemia/lymphoma patients and brentuximab vedotin may be a new and promising treatment option for these patients. Further investigations on the use of brentuximab vedotin for adult T-cell leukemia/lymphoma are needed.

Clinical effects of CD45 on the prognosis of extramedullary myeloma relapse.

WHAT IS KNOWN AND OBJECTIVES: The incidence of extramedullary relapse (EMR) arising during the clinical course of multiple myeloma (MM) has increased in recent years. Therefore, we herein investigated the effects of immunophenotyping on the prognosis of MM patients with EMR. METHODS: We conducted a retrospective review on data collected from MM patients with EMR between January 2007 and December 2018 at the Japanese Red Cross Society Wakayama Medical Center. Patient characteristics at the diagnosis of EMR, the prognostic significance of immunophenotyping and other factors were evaluated. RESULTS AND DISCUSSION: Extramedullary relapse was detected in 55 of 231 patients (23.8%). At the diagnosis of EMR, CD45, the leucocyte common antigen, was detected in 54.5% of cases. CD45 negativity in bone marrow correlated with thrombocytopenia and higher serum LDH levels. Moreover, high-risk cytogenetics was more frequently observed in CD45- than in CD45+ patients. A univariate analysis showed that overall survival (OS) was significantly shorter in CD45- than in CD45+ patients. Thrombocytopenia, higher serum LDH levels and high-risk cytogenesis were also associated with shorter OS. A multivariate analysis confirmed that CD45 negativity, higher serum LDH levels and high-risk cytogenesis were independent adverse prognostic factors for OS. A Kaplan-Meier analysis revealed the potential of CD45- as a prognostic factor in patients with EMR and that it correlated with shorter survival. WHAT IS NEW AND CONCLUSION: The present results showed that the expression of CD45 in the neoplastic plasma cells of MM patients with EMR was associated with patient prognosis independent of other prognostic factors. The establishment of a treatment strategy for EMR patients with CD45- MM cells is needed to improve poor outcomes.