Good's Syndrome With Pure Red Cell Aplasia and Subclinical Myasthenia Gravis: A Case Report and Review of Literature.

Good's syndrome is a pathologic condition characterized by thymoma and immunoglobulin disorder. Here, we report a rare case of a patient with Good's syndrome with simultaneous pure red cell aplasia (PRCA) and subclinical myasthenia gravis with detectable serum anti-acetylcholine receptor antibody (AChR Ab). While thymectomy did not result in the improvement of any paraneoplastic syndromes, cyclosporine A (CsA) treatment successfully improved PRCA; however, hypoglobulinemia was not recovered, and anti-AchR Ab did not disappear by CsA treatment in our case. A review of the literature on simultaneous Good's syndrome with PRCA also suggested the efficacy of CsA on PRCA but not hypoglobulinemia, suggesting the distinct underlying mechanisms between these two paraneoplastic symptoms with thymoma. Future research is needed to understand the mechanism underlying this rare pathologic condition and to generate appropriate treatment.

Prognostic model for relapsed/refractory transplant-ineligible diffuse large B-cell lymphoma utilizing the lymphocyte-to-monocyte ratio.

We conducted a multi-institutional retrospective study in 100 transplant-ineligible (TI) patients with diffuse large B-cell lymphoma (DLBCL) that relapsed or progressed after first-line R-CHOP (or -like) therapy to develop a robust predictive model for TI relapsed/refractory (r/r) DLBCL, which has a heterogeneous but poor prognosis by currently available treatment modalities other than chimeric antigen receptor T-cell (CAR-T) therapy or bispecific antibodies. The median age at relapse or progression was 76 years. The median progression-free survival (PFS) and overall survival (OS) from the first progression were 11.5 months and 21.9 months, respectively. Multivariate analysis identified low lymphocyte-to-monocyte ratio (LMR), elevated high lactate dehydrogenase, and elevated C-reactive protein at progression as independent predictors of OS. A predictive model based on these three factors, here designated as the Kyoto Prognostic Index for r/r DLBCL (KPI-R), successfully stratified their OS and PFS with statistical significance. In addition, event-free survival less than 24 months for R-CHOP and low LMR were identified as significant predictive factors for non-response in any sequence of salvage therapy. We concluded that LMR is a bonafide predictor of treatment response and prognosis in patients with TI r/r DLBCL, and may be helpful in treatment decision-making.

Skeletal muscle index impacts the treatment outcome of elderly patients with diffuse large B cell lymphoma.

Sarcopenia is a crucial factor in the physical fitness of elderly individuals. This study investigated the prognostic values of multiple parameters of sarcopenia in association with established prognostic factors in elderly Japanese patients with diffuse large B cell lymphoma (DLBCL). As candidate indicators for sarcopenia, the skeletal muscle index (SMI) (cm2 /m2 ), the psoas muscle index, the erector spinae muscle index, the visceral fat index, the subcutaneous fat index, and the visceral to subcutaneous fat area ratio at the third lumbar level were assessed by computed tomography at their initial diagnosis in 102 patients with DLBCL over 75 years old those were diagnosed and treated in our institute from 2007 to 2020. The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). The median age of patients analyzed was 80 years at diagnosis. The sex-specific cut-offs for the indices adopted two approaches: (i) the historical cut-off values established in the previous study for healthy Japanese individuals (Hamaguchi Y. J Cachexia Sarcopenia Muscle. 2018), and (ii) each sex-specific lowest quartile in our cohort. As the results, SMI evaluated by the historical cut-off and sex-specific lowest quartile was identified as the most influential independent prognostic factor for both OS and PFS among various parameters for sarcopenia. Furthermore, we developed an elderly sarcopenia prognostic index (ESPI). ESPI, which combines SMI evaluated by the historical cut-off and LDH > ULN, demonstrated statistically significant prognostic impacts on OS and PFS. Moreover, compared to the R-IPI, ESPI showed the ability to identify intermediate-risk groups and indicated a trend toward improved predictive accuracy. Our study revealed that SMI is the most appropriate assessment method for evaluating sarcopenia and the critical prognostic factor in OS and PFS of elderly patients with DLBCL.

Clinical impacts of severe thrombocytopenia in the first cycle of azacitidine monotherapy and cytogenetics in patients with myelodysplastic syndrome: The Kyoto Conditional Survival Scoring System.

Azacitidine (AZA) has been one of the standard treatments for transplantation-ineligible patients with myelodysplastic syndrome (MDS); however, hematological toxicities frequently cause treatment interruption in the early phase of the therapy. The present study conducted a multicenter retrospective study to investigate the prognostic impacts of various factors, including factors included in the Revised International Prognostic Scoring System (IPSS-R) and severe cytopenia in the early phase of AZA monotherapy in 212 patients with MDS. Severe cytopenia was evaluated after the initiation of therapy by absolute neutrophil counts on the 29th day after AZA (ANC29) initiation, and red cell concentrates (RCC) and platelet concentrate (PC) transfusion units required within 28 days from the start of AZA, designated in the present study as RCC28 and PC28, respectively. The survival period was determined from the 29th day of AZA treatment to death from any cause as the conditional survival period after the first cycle of AZA (CS-AZA1). Multivariate analysis demonstrated that severe thrombocytopenia defined by >30 units of PC28 and very poor risk cytogenetics according to IPSS-R were independent prognostic factors for CS-AZA1. The Kyoto Conditional Survival Scoring System was subsequently developed by incorporating severe thrombocytopenia defined by PC28 and very poor risk cytogenetics, which successfully stratified the risks of the patients in CS-AZA1. In conclusion, extreme PC transfusion dependency during the first cycle of AZA and very poor risk cytogenetics are important prognostic factors in AZA monotherapy for MDS.

Negative impact of immunoparesis in response to anti-SARS-CoV-2 mRNA vaccination of patients with multiple myeloma.

Multiple myeloma reduces cellular and humoral immunity. Optimal prediction of antibody response to anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in patients with MM and related disorders is essential to prevent coronavirus disease 2019 (COVID-19) during the SARS-CoV-2 pandemic. This study analyzed the humoral response to the anti-SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine and its associated factor in 83 patients from June to November 2021 at seven member institutions of the Kyoto Clinical Hematology Study Group. SARS-CoV-2 neutralizing antibody (nAb) was measured from 12 to 210 days. The result revealed that 40 (48.2%) patients with MM and 59 (100%) healthy controls became seropositive after vaccination. Receiver operating characteristic curve analysis identified serum immunoglobulin (Ig) M of > 18 mg/dL at vaccination as the optimal threshold level associated with seropositivity in the whole cohort. Moreover, the multivariate analysis identified serum IgM of > 18 mg/dL as the independent predictor for a favorable response. Serum IgA level was positively associated with vaccine response in a sub-cohort. Our findings indicate a significant association between immunoparesis and impaired humoral response against mRNA vaccination, including that against SARS-CoV-2, and that serum non-M-protein Ig levels can serve as surrogate biomarkers of nAb production ability.

Real-world practice-based prognostic model for higher-risk myelodysplastic syndromes treated with azacitidine monotherapy: The Kyoto prognostic scoring system.

The prognostic impact of patient-related factors, including age, nutritional parameters, and inflammation status, in higher-risk myelodysplastic syndromes (HR-MDS) has been largely unexplored. This multicenter retrospective study aimed to establish a real-world practice-based prognostic model for HR-MDS by considering both disease- and patient-related parameters in 233 patients treated with AZA monotherapy at seven institutions. We found that anemia, presence of circulating blasts in peripheral blood, low absolute lymphocyte count, low total cholesterol (T-cho) and albumin serum levels, complex karyotype, and del(7q) or - 7 were poor prognostic factors. Therefore, we developed a new prognostic model called the Kyoto Prognostic Scoring System (KPSS) by incorporating the two variables with the highest C-indexes (complex karyotype and serum T-cho level). The KPSS classified patients into the following three groups: good (0 risk factors), intermediate (1), and poor (2). Median overall survival for these groups was 24.4, 11.3, and 6.9, respectively (p < 0.001). The discriminatory power of the KPSS was higher than that of the traditional International Prognostic Scoring System. In conclusion, we identified several nutritional parameters with prognostic relevance in patients with HR-MDS and generated a prognostic model consisting of complex karyotype and serum T-cho level that enabled excellent risk stratification.

Impact of Treatment with Anti-CD20 Monoclonal Antibody on the Production of Neutralizing Antibody Against Anti-SARS-CoV-2 Vaccination in Mature B-Cell Neoplasms.

Background and Purpose: Anti-CD20 monoclonal antibodies (MoAbs), rituximab (RIT), and obinutuzumab (OBZ) are the central components of immunochemotherapy for B-cell lymphoma (BCL). However, these agents potentially cause B-cell depletion, resulting in the impairment of antibody (Ab) production. During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the optimal prediction of Ab response against anti-SARS-CoV-2 vaccination is critically important in patients with BCL treated by B-cell depletion therapeutics to prevent coronavirus disease 2019 (COVID-19). Patients and Methods:  We investigated the effect of using RIT and/or OBZ on the Ab response in 131 patients with various types of BCL who received the second SARS-CoV-2 mRNA vaccine either after, during, or before immunochemotherapy containing B-cell-depleting moiety between June and November 2021 at seven institutes belonging to the Kyoto Clinical Hematology Study Group. The SARS-Cov-2 neutralizing Ab (nAb) was measured from 14 to 207 days after the second vaccination dose using the iFlash3000 automatic analyzer and the iFlash-2019-nCoV Nab kit. Results: Among 86 patients who received the vaccine within 12 months after B-cell depletion therapy, 8 (9.3%) were seropositive. In 30 patients who received the vaccine after 12 months from B-cell depletion therapy, 22 (73%) were seropositive. In 15 patients who were subjected to B-cell depletion therapy after vaccination, 2 (13%) were seropositive. The multivariate analysis indicated that an interval of 12 months between B-cell depletion therapy and the subsequent vaccination was significantly associated with effective Ab production. Receiver operating characteristic curve analysis identified the optimal threshold period after anti-CD20 MoAb treatment, which determines the seropositivity against SARS-CoV-2, to be 342 days. Conclusion: The use of anti-CD20 MoAb within 12 months before vaccination is a critical risk for poor Ab response against anti-SARS-CoV-2 vaccination in patients with BCL.

Durable Remission of Chemotherapy-Refractory Myeloid Sarcoma by Azacitidine.

Myeloid sarcoma is a rare disease entity of extramedullary myeloid neoplasm that can occur both as an initial isolated myeloid sarcoma without leukemic cell invasion in the peripheral blood and bone marrow, and as the secondary lesion of acute and chronic myeloid leukemias, myelodysplastic syndrome and chronic myeloproliferative neoplasms. Due to its rarity and its frequent emergence as the recurrent lesion after intensive systemic therapy, including allogeneic hematopoietic stem cell transplantation, the standard treatment has not been established for myeloid sarcoma. In this report, we presented an 84-year-old female patient with isolated myeloid sarcoma which progressed to myelodysplastic syndrome and systemic myeloid sarcoma despite various types of conventional anti-leukemic chemotherapies. However, the patient got a durable partial response by the monotherapy of azacitidine, a hypomethylating agent. She received thirteen courses of azacitidine therapy without progression. We discuss the possibility that hypomethylating agents are the novel effective and feasible therapeutic options for myeloid sarcoma, even in cases refractory to or relapsed after intensive systemic treatment. We also discuss the possible future development of hypomethylating agent-containing combinatory therapeutic strategy for myeloid sarcoma, given its direct anti-leukemic effect and immunomodulatory effect.

Primary dendrites of mitral cells synapse unto neighboring glomeruli independent of their odorant receptor identity.

In the mouse olfactory bulb, neural map topography is largely established by axon-axon interactions of olfactory sensory neurons (OSNs). However, to make the map functional, the OSNs must make proper connections to second-order neurons, the mitral cells. How do the mitral-cell dendrites find their partner glomeruli for synapse formation with OSN axons? Here, we analyze dendrite connections of mitral cells in various mutant mice in which glomerular formation is perturbed. Our present results support the proximity model, whereby mitral cells tend to connect primary dendrites to the nearest neighboring glomeruli regardless of their odorant receptor identities. The physical location of glomeruli rather than the odorant-receptor specificity appears to play a key role in matching mitral cells with their partner OSN axons.

A major allogenic leukocyte antigen in the agnathan hagfish.

All vertebrates, from jawless fish to mammals, possess adaptive immune systems that can detect and inactivate non-self-antigens through a vast repertoire of antigen receptors. Unlike jawed vertebrates, the hagfish utilizes variable lymphocyte receptors (VLRs) that are unrelated to immunoglobulin molecules but are diversified by copy-choice gene conversion mechanism. Here, we report that hagfish VLRs react with allogenic leukocyte antigens but not with self-antigens. We found that a highly polymorphic membrane protein, NICIR3, is recognized by VLRs as an allogenic leukocyte antigen (ALA). In a serological cross-reactivity test, a close correlation was observed between the amino acid differences in the protein sequences and the VLR cross-reactivities. This leukocyte antigen was predominantly expressed in phagocytic leukocytes, where it was associated with phagocytosed protein antigens. These findings suggest that a polymorphic leukocyte antigen, NICIR3/ALA, plays a pivotal role in jawless vertebrate adaptive immunity.