Pathogenesis of Gastrointestinal Follicular Lymphomas: Consideration Based on Histopathology and Endoscopic Findings.

Gastrointestinal (GI) follicular lymphoma (FL) is the most frequently diagnosed extranodal FL; however, its pathogenesis is debatable. We investigated the distribution, endoscopic, and histopathologic findings of 366 GI FL samples obtained from 298 patients. FLs were most frequently observed in the small intestine (71%), including the duodenum (52%), but were also commonly found in the stomach (15%) and colon (12%). The proportion of granular lesions in the duodenum, terminal ileum, colon, and stomach was 74%, 39%, 24%, and 0%, respectively. Submucosal or ulcerated tumors were frequently observed in the stomach (48%) and colon (52%). Most GI FL showed grade 1 to 2 histology (89%) as well as CD10 + (93%) and BCL2 + (98%) positivity. There were no significant differences in the endoscopic or histologic findings between primary and secondary GI FLs. As known, the mucosa of the small intestine is thin and villous, while the mucosa of the stomach and colon is thicker and has a smooth surface. Granular lesions corresponding to very small FL were detected in the former but rarely in the latter. Nine (7%) patients with primary GI FL developed histologic transformation to diffuse large B-cell lymphoma (n=8) or high-grade B-cell lymphoma (n=1) 10 months to 14 years after the diagnosis of FL. Two patients died of lymphoma. In conclusion, the incidence and endoscopic findings differed, but the histopathology was similar in FLs in each site. These differences might be attributed to variations in each GI site's mucosal structure and the neoplastic follicles' size. Due to its characteristic structure, very small classic FLs might be detectable mainly in the small intestine.

Diagnostic clues of BCL2-negative, faint, or controversial follicular lymphomas: a study of 103 cases.

BCL2 positivity by immunohistochemistry is helpful for the diagnosis of follicular lymphoma (FL); however, a minority of FL cases are BCL2-negative, and the diagnosis is thus challenging. We retrospectively analyzed the incidence, morphology, immunophenotype, and genetic status of BCL21+ (weakly/focally positive by clone 124), BCL20 (negative), and BCL2controversial FLs compared with BCL22+ (strongly positive) FLs to clarify diagnostic clues. In 1068 FL cases, 103 (10%) with BCL21+ (37 cases, 4%), BCL20 (61 cases, 6%), or BCL2controversial (5 cases, 0.5%) were included in the final analysis. BCL21+ and BCL20 FLs tended to have limited stage disease, nodal disease, and grades 3A/3B histology and showed a higher complete response rate than BCL22+ FLs. Among 103 BCL20, BCL21+, or BCL2controversial FL cases, 34 (33%) had a diffuse area composed of CD20-positive small-to medium-sized lymphoid cells, a feature of low-grade B-cell lymphoma. Interfollicular dense CD20-positive cells and interfollicular clusters of CD10-positive cells were observed in 59% and 37% of cases, respectively. In remaining 13/40 cases (33%), BCL2 was converted to BCL22+ by other clones E17/SP66. CD23 and MUM1 were positive in 10/40 (25%) and 1/40 (3%) cases, respectively. IGH/BCL2 fusion and clonality were detected in 6/37 (16%) and 31/34 (91%) cases, respectively. In conclusion, morphological examination of the distribution of CD20-and/or CD10-positive cells and the presence of diffuse area could be used to diagnose FL in most cases. The majority of the remaining FL cases could be diagnosed using other BCL2 clones and clonality analyses.

CD3-and CD20-negative extramedullary non-Hodgkin leukemia/lymphoma: a histopathological study of 118 cases.

Histopathological diagnoses are challenging for rare CD3-and CD20-negative extramedullary leukemias/lymphomas. We report 118 cases of CD3- CD20-extramedullary leukemias/lymphomas (2.4% of 4977 cases). CD45 was positive in 68% of cases. Forty-nine (41%) cases were anaplastic large cell lymphomas. Thirty-five (30%) cases were large B-cell lymphomas/plasmablastic lymphomas positive for at least one of the following markers: CD79a, PAX5, CD19, CD138, and MUM1. Nine (8%) cases were peripheral T/NK-cell lymphomas, where at least CD43, CD45RO, or cytotoxic molecules were positive; 4, 3, and 2 cases were extranodal NK/T-cell lymphoma, nasal type, peripheral T-cell lymphoma-not otherwise specified, and adult T-cell leukemia/lymphoma, respectively. The remaining 25 (21%) cases included 11, 8, and 6 cases of myeloid sarcoma, blastic plasmacytoid dendritic cell neoplasm, and B- or NK-cell lymphoblastic leukemia/lymphoma, respectively. For large B-cell lymphoma/plasmablastic lymphoma diagnosis, MUM1 (92%) was the most sensitive marker, followed by CD79a (63%), PAX5 (52%), CD138 (42%), and CD19 (36%). EBER 1 and HHV8 were positive in 32% and 0% of the cases. For peripheral T/NK-cell lymphomas other than ALCL, CD45RO and CD43 were positive in nine cases; however, cytotoxic molecules (TIA1, 86%; granzyme B, 71%) were the most sensitive markers. In conclusion, most cases of the 118 (2.4%) CD3- CD20- extramedullary leukemia/lymphoma were represented by anaplastic large cell lymphomas (41%). The second most frequent group of neoplasia, large B-cell lymphoma/plasmablastic lymphoma (30%), characterized a special diagnostic challenge when B-cell markers were not expressed, requiring immunohistochemistry for multiple B-cell markers and molecular analysis in some cases.

Clinical significance of the lymphocyte-to-monocyte ratio in multiple myeloma patients with negative minimal residual disease: a single-center retrospective analysis.

Minimal residual disease (MRD) is a surrogate marker for survival in multiple myeloma (MM), while the lymphocyte-to-monocyte ratio (LMR) is a prognostic factor associated with the patients' immunological status. We retrospectively evaluated the clinical impact of MRD negativity and LMR. MRD was analyzed by multicolor flowcytometry (threshold, 1 × 10-5). Fifty-eight patients (median age 70 years) who achieved complete response were included in this study. Twenty-two patients received autologous stem cell transplantation, 14 received daratumumab-based chemotherapy, and 22 received another treatment. Forty-one (70.7%) patients achieved MRD negativity. Over the median follow-up time of 15.1 months, PFS in MRD-negative patients was significantly longer than in MRD-positive patients (P = 0.020). In addition, a high LMR at MRD assessment was associated with MRD negativity (P = 0.019) and long PFS (P = 0.009). Finally, neither MRD negativity nor high LMR at MRD assessment was associated with significantly shorter PFS compared with MRD positivity or low LMR (P = 0.002). In conclusion, high LMR was associated with MRD negativity and can be used as a predictor of long PFS. Change of treatment strategy might be essential for patients with MRD positivity and high LMR at MRD assessment due to their short PFS.

Acute Compartment Syndrome of the Upper Extremity in Acquired Hemophilia A: A Case Report and Literature Review.

CASE: Acute compartment syndrome (ACS) with acquired hemophilia A (AHA) is rare and has no established treatment strategy. A 64-year-old woman presented with a giant hematoma in the rectus abdominis. Laboratory findings included decreased hemoglobin and increased activated partial thromboplastin time. Arterial embolization was performed for hemostasis. After catheter removal, she developed severe arm pain and numbness with blistering. Fasciotomy was performed to decrease intracompartmental pressure. Laboratory investigations revealed decreased factor VIII (FVIII) activity and increased FVIII inhibitor. AHA was diagnosed and treated with immunosuppressive and FVIII inhibitor-bypassing agents. CONCLUSIONS: Fasciotomy should be performed promptly if ACS with AHA is suspected.

[Utility of core-needle biopsy as a primary diagnostic method for detecting aggressive B-cell lymphoma in the intensive care unit].

A 68-year-old male presented with appetite loss and abdominal distention. The whole-body computed tomography scan revealed an ileocecal mass with a large amount of ascites, which was consistent with malignant lymphoma. Due to the worsening of his general condition following admission, he was intubated and admitted to the intensive care unit (ICU). In the ICU, we performed a core-needle biopsy (CNB) on the left peritoneal mass, the findings of which showed a pathological diffuse infiltration of CD20+ middle-sized lymphoid cells. After chemotherapy was initiated, the patient showed complete response, suggesting that CNB can be performed immediately and safely even on a critically ill patient.

Successful bridge therapy of gilteritinib to cord blood transplantation in relapsed acute myeloid leukemia after bone marrow transplantation.

The FMS-related tyrosine kinase 3 (FLT3) internal tandem duplication mutations (FLT3-ITD) positive acute myeloid leukemia (AML) is a disease with a dismal outcome. Gilteritinib is a second-generation FLT3 inhibitor with activity against ITD and high affinity toward the FLT3 receptor, thereby showing therapeutic potential for relapsed/refractory FLT3-mutated AML. Bone marrow transplantation (BMT) from a human leukocyte antigen (HLA) identical sibling donor was performed in a 38-year-old Japanese male with FLT3-ITD positive AML. Neutrophil engraftment (>0.5 × 109/L) was achieved on day 16, and bone marrow remission was revealed on day 32. The patient's AML relapsed hematologically four months after BMT and was resistant to salvage chemotherapy. Gilteritinib was administered and the patient achieved non-remission but 'stable disease' status according to the response criteria. During administration, liver damage was observed but controllable. The patient received cord blood transplantation (CBT) as the second hematopoietic stem cell transplantation (HSCT) three months after relapse and achieved second remission. There was no evidence of recurrence of AML four months after CBT. This case demonstrates that gilteritinib can control FLT3-ITD positive AML that relapsed early after initial HSCT and can bridge to second HSCT.

[All-trans retinoic acid/arsenic trioxide combination therapy for a patient with acute promyelocytic leukemia on dialysis].

We report a 55-year-old man who began undergoing hemodialysis for polycystic kidney disease 17 years ago. Because pancytopenia and susceptibility to infection were identified, a bone marrow biopsy was performed, resulting in a diagnosis of acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA) treatment was initiated, but promyelocytic leukemia/retinoic acid receptor alpha gene fusion without remission was identified by fluorescence in situ hybridization. We administered ATRA/arsenic trioxide (ATO) combination therapy for therapy-resistant APL and confirmed molecular genetic remission. The ATRA/ATO combination therapy was continued, obtaining complete remission 2 years after commencement of treatment. Cystic infections continued during ATRA/ATO combination therapy, similar to infections before APL morbidity, and there were no adverse events leading to treatment discontinuation. ATRA/ATO combination therapy is considered a safe and effective treatment for therapy-resistant APL patients on hemodialysis.

[Successful treatment with preceding low-intensity chemotherapy in a primary mediastinal large B cell lymphoma patient diagnosed at 11 weeks of pregnancy].

At 11 weeks of pregnancy, a 31-year-old woman presented with an anterior chest tumor and dyspnea. A computed tomography (CT) scan revealed a bulky tumor in the mediastinum that compressed the trachea. She underwent a CT-guided needle biopsy and was diagnosed with primary mediastinal large B cell lymphoma. She was initially treated with steroid pulse therapy, followed by vincristine-cyclophosphamide-prednisolone (VCP) therapy, which relieved her dyspnea. She was then treated with 8 cycles of rituximab-cyclophosphamide-doxorubicin-vincristine-prednisolone (R-CHOP) therapy at 13 weeks of pregnancy. The patient delivered her baby at 35 weeks and 6 days of pregnancy. Despite the preterm delivery and other than the low-birth weight, her baby was healthy. A positron emission tomography-CT scan showed that a complete metabolic response was achieved. Our case report suggests that steroid pulse and VCP therapy followed by R-CHOP therapy is safe and effective for patients with malignant lymphoma in their first trimester of pregnancy.

Imaging individual proton-conducting spots on sulfonated multiblock-copolymer membrane under controlled hydrogen atmosphere by current-sensing atomic force microscopy.

The proton-conductive spots on the membrane surface of sulfonated poly(arylene ether) multiblock copolymer were successfully imaged by current-sensing atomic force microscopy under hydrogen atmosphere at various temperatures and humidities. These spots should be connected to the proton-conductive paths inside the membrane. The average diameter of the spots was approximately 12 nm, consistent with the size of hydrophilic domains observed by transmission electron microscopy. The size of the proton-conducting spots was almost unchanged regardless of the temperature and humidity, whereas the number of the spots increased at higher humidity; the total area of the proton-conducting spots increased accordingly on the membrane surface. This increase in the conducting area at high humidity should be related to the bulk ionic conductivity measured by impedance spectroscopy.

Structural basis for the bifunctionality of fructose-1,6-bisphosphate aldolase/phosphatase.

Enzymes catalyse specific reactions and are essential for maintaining life. Although some are referred to as being bifunctional, they consist of either two distinct catalytic domains or a single domain that displays promiscuous substrate specificity. Thus, one enzyme active site is generally responsible for one biochemical reaction. In contrast to this conventional concept, archaeal fructose-1,6-bisphosphate (FBP) aldolase/phosphatase (FBPA/P) consists of a single catalytic domain, but catalyses two chemically distinct reactions of gluconeogenesis: (1) the reversible aldol condensation of dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GA3P) to FBP; (2) the dephosphorylation of FBP to fructose-6-phosphate (F6P). Thus, FBPA/P is fundamentally different from ordinary enzymes whose active sites are responsible for a specific reaction. However, the molecular mechanism by which FBPA/P achieves its unusual bifunctionality remains unknown. Here we report the crystal structure of FBPA/P at 1.5-Å resolution in the aldolase form, where a critical lysine residue forms a Schiff base with DHAP. A structural comparison of the aldolase form with a previously determined phosphatase form revealed a dramatic conformational change in the active site, demonstrating that FBPA/P metamorphoses its active-site architecture to exhibit dual activities. Thus, our findings expand the conventional concept that one enzyme catalyses one biochemical reaction.