Sequential cellular and humoral responses after repetitive COVID-19 vaccination in patients treated with anti-CD20 antibodies.

Patients treated with anti-CD20 antibodies for haematological disorders have insufficient immune responses to mRNA COVID-19 vaccines; however, relevant sequential data are lacking. We sequentially evaluated the humoral and cellular immune responses in 22 patients who had received anti-CD20 antibodies within 12 months before the first vaccination, before and after the third and fourth vaccinations. Humoral responses improved gradually, along with the resolution of B-cell depletion. A steady increase was noted in cellular responses, regardless of the B-cell status. Our findings suggest the potential benefit of repeated vaccinations in these patients until B-cell recovery is confirmed while enhancing cellular responses.

Trajectories of the SARS-CoV-2 RNA load in patients with hematological malignancy.

OBJECTIVES: The higher risk of prolonged viral shedding in coronavirus disease (COVID-19) patients with hematological malignancies (HM) necessitates test-based de-isolation strategies. However, evidence to establish their appropriate isolation period is insufficient. This study investigated the factors affecting prolonged viral shedding and the requisite isolation period in these patients. METHODS: We retrospectively reviewed 14 COVID-19 patients with HM between January and April 2022, who were subjected to our test-based de-isolation strategy, followed by analysis of the viral load trajectory. The viral loads of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were evaluated using the cycle threshold (Ct ) of the reverse-transcription quantitative polymerase chain reaction. The trajectories were classified according to the time-interval from COVID-19 onset to the attainment of Ct values >30. RESULTS: The median interval between onset and attainment of a Ct value >30 was 22 days. Five patients with mild or moderate COVID-19 without intense treatment histories achieved Ct values >30 within 20 days. The other nine patients needed more than 20 days, including three patients who did not meet this criterion during the observation period. CONCLUSIONS: The SARS-CoV-2 viral load trajectories in patients with HM can be stratified by treatment history for the underlying HM and severity of COVID-19.

Humoral response and safety of the BNT162b2 and mRNA-1273 COVID-19 vaccines in allogeneic hematopoietic stem cell transplant recipients: An observational study.

BACKGROUND: The effectiveness of mRNA COVID-19 vaccines and the optimal timing of vaccine administration in allogeneic hematopoietic stem cell transplantation (Allo-HSCT) recipients remains inadequately investigated. We examine the effectiveness and safety of mRNA COVID-19 vaccines in allo-HSCT recipients. METHOD: This prospective observational study included 44 allo-HSCT recipients and 38 healthy volunteers. The proportion of subjects acquiring anti-S1 IgG antibodies were considered as the primary endpoint. The occurrence of adverse events after vaccination and objective deterioration of chronic graft-versus-host disease (GVHD) were defined as secondary endpoints. In addition, we compared the geometric mean titers (GMT) of anti-S1 antibody titers in subgroups based on time interval between transplantation and vaccination. RESULTS: A humoral response to the vaccine was evident in 40 (91%) patients and all 38 healthy controls. The GMT of anti-S1 titers in patients and healthy controls were 277 (95% confidence interval [CI]: 120-643) BAU/mL and 532 (95% CI 400-708) BAU/mL, respectively. (p = 0.603). A short time interval between transplantation and vaccination (≤6 months) was associated with low anti-S1 IgG antibody titers. No serious adverse events and deterioration of chronic GVHD were observed. Only one case of new development of mild chronic GVHD was recorded. CONCLUSION: Messenger RNA COVID-19 vaccines induce humoral responses in allo-HSCT recipients and can be administered safely.

CD38 expression is an important prognostic marker in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of diseases with variable outcomes. Although several prognostic markers have been developed, specific biomarkers for stratifying treatment strategies have not been fully investigated. This study aimed to analyze the clinical impact of the expression of cluster of differentiation (CD) 38, which is associated with cellular proliferation and disease progression, in patients with de-novo DLBCL. Using flow cytometry analysis, 137 cases with DLBCL were investigated for surface expression of CD38. Based on the cut-off value by the survival classification and regression tree analysis, the patients were categorized into a CD38HIGH group (n = 37) and CD38LOW group (n = 100). The 4-years progression-free survival (PFS) was 31.6% in the CD38HIGH group and 60.7% in the CD38LOW group (p < 0.001). Multivariate analysis showed the CD38HIGH group to be associated with significantly worse PFS (adjusted hazard ratio [aHR], 2.15, 95% CI: 1.26-3.68, p = 0.005) and poor overall survival (OS) (aHR, 2.54, 95% CI: 1.25-5.19, p = 0.010) than the CD38LOW group. In conclusion, we demonstrated that high CD38 expression is an independent adverse prognostic factor associated with poor clinical outcomes compared to low CD38 expression. CD38 expression in DLBCL cells might be useful for predicting outcomes and designing risk-adapted therapies for patients with de-novo DLBCL.

Sequential breast implant infections due to Campylobacter fetus subsp. fetus.

Campylobacter jejuni and Campylobacter coli are the leading causes of bacterial intestinal infections worldwide, while Campylobacter fetus subsp. fetus (C. fetus) has been reported to cause extraintestinal infections, including medical device implant infections. However, breast implant infections have rarely been reported. We describe the case of a 64-year-old woman with breast implant infection and vertebral osteomyelitis due to C. fetus. The patient recovered by surgical removal of the infected left implant and was treated with antibiotics for 6 weeks. However, two weeks after the completion of antibiotics, she experienced an infection in the right implant due to C. fetus, which had developed quinolone resistance with a G91T mutation during the treatment course. This case showed that C. fetus can cause breast implant infections, and although the infection may appear to be unilateral initially, the possibility of sequential contralateral infection should be considered.

Stochastic model based on preharvest peripheral CD34-positive cell count and collection efficiency predicting processed blood volume in peripheral hematopoietic stem cell apheresis.

BACKGROUND: Processed blood volume (PBV) required to obtain a predefined number of stem cells can be estimated from peripheral blood CD34+ cell concentration, body weight, and collection efficiency (CE). Because CE is indefinite, this study was designed to formulate and validate a new model of PBV based on stochastic CE distribution. STUDY DESIGN AND METHODS: Data were retrospectively collected on 146 peripheral blood stem cell harvests from 114 patients and donors in a single institution from April 2014 to February 2018. The training set consisted of all procedures performed from April 2014 to June 2016 and the validation set of all procedures performed from July 2016 to February 2018. A new algorithm, based on CE2 distribution of the training set, was affirmed using the validation set. The positive predictive value of the model was estimated from the expected percentage of procedures that reached the target CD34-positive dose, with predicted PBV processed as the gold standard. RESULTS: The 10th and 50th percentiles of CE2 were 33.4% and 52.5%, respectively. When PBV was assorted into three categories, defined as greater than 90%, 50% to 90%, and less than 50% of procedures reaching the targeted CD34-positive dose, the positive predictive values of the new model were 100%, 70%, and 100%, respectively. CONCLUSION: The new model was validated with a high positive predictive value and can reliably estimate the required PBV and the success rate corresponding to the PBV. The model can be utilized easily with a Web-based tool.

Impact of folate therapy on combined immunodeficiency secondary to hereditary folate malabsorption.

Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder. Severe folate deficiency in HFM can result in immunodeficiency. We describe a female infant with HFM who acquired severe Pneumocystis pneumonia. The objective of the present study was to elucidate her immunological phenotype and to examine the time course of immune recovery following parenteral folate therapy. The patient demonstrated a combined immunodeficiency with an impaired T cell proliferation response, pan-hypogammaglobulinemia, and an imbalanced pro-inflammatory cytokine profile. She had normal white blood cell count, normal lymphocyte subsets, and normal complement levels. Two novel mutations were identified within the SLC46A1 gene to produce a compound heterozygote. We confirmed full recovery of her immunological and neurophysiological status with parenteral folate replacement. The time course of recovery of her immunological profile varied widely, however. HFM should be recognized as a unique form of immunodeficiency.

IP-10/CXCL10 and MIG/CXCL9 as novel markers for the diagnosis of lymphoma-associated hemophagocytic syndrome.

Lymphoma-associated hemophagocytic syndrome (LAHS) is a serious disorder, and its early diagnosis and treatment with appropriate chemotherapy are very important. However, reliable markers for early diagnosis of LAHS have not been identified. We screened serum cytokines using a newly introduced assay system, cytometric bead array (CBA), and identified interferon-inducible protein 10 (IP-10)/CXCL10 and monokine induced by interferon gamma (MIG)/CXCL9 as useful markers. Serum concentrations of IP-10 and MIG at the time of LAHS diagnosis were greater than 500 and 5,000 pg/ml, respectively. The sensitivity and specificity for LAHS diagnosis were 100 and 95 %, respectively, when we set the above values as the cut-off levels. Serum levels of these two chemokines were already elevated at the time of admission and significantly decreased after successful treatment, indicating their usefulness for both the diagnosis and therapeutic outcomes for LAHS. IP-10 and MIG were also useful in distinguishing severe from moderate/mild LAHS, and B-cell-type LAHS from T-cell/natural killer cell-type LAHS. Furthermore, IP-10 and MIG were of use to distinguish LAHS from sepsis in patients with hematologic malignancies. Rapid measurement of IP-10 and MIG by CBA appeared to be important for early diagnosis and treatment of LAHS.

Complete detection of FR1 to FR3 primer-based PCR patterns of immunoglobulin heavy chain rearrangement in the BIOMED-2 protocol is associated with poor prognosis in patients with diffuse large B-cell lymphoma.

Somatic hypermutations (SHMs) in the variable region (VH) of the immunoglobulin heavy chain (IgH) gene are common in diffuse large B-cell lymphoma (DLBCL). Recently, IgH VH SHMs have become known as immunogenic neoantigens, but few studies have evaluated the prognostic impact of the frequency of VH SHMs in DLBCL. The BIOMED-2 protocol is the gold standard polymerase chain reaction (PCR) for clonality analysis in lymphoid malignancies, but can produce false negatives due to the presence of IgH VH SHMs. To overcome this problem, three primer sets were designed for the three framework regions (FR1, FR2, and FR3). We evaluated the predictive value of this PCR pattern in patients with DLBCL. To evaluate the prognostic impact of complete detection of the clonal amplifications (VHFR1-JH, VHFR2-JH, and VHFR3-JH) in the BIOMED-2 protocol, we retrospectively analyzed 301 DLBCL patients who were initially treated with anthracycline-based immunochemotherapy. Complete detection of the FR1 to FR3 primer-based IgH VH PCR patterns in the BIOMED-2 protocol was associated with low frequency of VH SHMs (p < 0.001). Patients who were positive for all these three PCRs (n = 79) were significantly associated with shorter 5-year overall survival (OS; 54.2% vs. 73.2%; p = 0.002) and progression-free survival (PFS; 34.3% vs. 59.3%; p < 0.001) compared to patients with other PCR patterns (n = 202). Specifically, the successful FR3-JH detection was associated with significantly worse OS (p < 0.001) and PFS (p < 0.001). PCR patterns of complete IgH rearrangement using the BIOMED-2 protocol are clinically meaningful indicators for prognostic stratification of DLBCL patients.

Haploidentical Stem Cell Transplantation Using Post-Transplant Cyclophosphamide for T-Cell Prolymphocytic Leukemia after Alemtuzumab Induction Therapy: A Case Report.

T-cell prolymphocytic leukemia (T-PLL) is a rare aggressive disease with a poor prognosis. Allogeneic stem cell transplantation (allo-SCT) followed by alemtuzumab administration is the most promising treatment for T-PLL but is associated with a high risk of infections as alemtuzumab strongly suppresses cellular immunity, leading to high transplant-related mortality and unsatisfactory survival rates. In addition, for patients without human leukocyte antigen-matched donors, haploidentical stem cell transplantation (haplo-SCT) using post-transplant cyclophosphamide (PTCy) has been used because of the ready availability of donors and achievement of results comparable to those of transplantation with human leukocyte antigen-matched donors. However, there are no reports on the efficacy and safety, including infectious complications, of haplo-SCT with PTCy after alemtuzumab therapy in patients with. Here, we describe a 66-year-old Japanese male patient with T-PLL treated successfully with haplo-SCT after induction therapy of alemtuzumab for T-PLL. Approximately 3 months after the achievement of complete remission with alemtuzumab for T-PLL, haplo-SCT with reduced-intensity conditioning and PTCy was performed. Infectious complications were improved by early therapeutic interventions, and peripheral T cell counts gradually recovered. The patient was alive for more than 16 months after allo-SCT with no signs of relapse. Thus, haplo-SCT using PTCy should be considered as an option after alemtuzumab treatment for T-PLL.

A multicenter study to investigate the positive rate of SARS-CoV-2 in middle ear and mastoid specimens from otologic surgery patients.

OBJECTIVE: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel coronavirus, causes coronavirus disease 2019 (COVID-19). Otologic surgeries with drilling by powered instruments induce significant aerosols, which may induce SARS-CoV-2 transmission to medical staff if SARS-CoV-2 exists in the middle ear and mastoid cavity. During a COVID-19 pandemic, therefore, confirming a negative COVID-19 test prior to otologic surgery is recommended. However, previous coronavirus studies demonstrated that coronavirus was detected in the middle ear in some patients even though the polymerase chain reaction (PCR) test using their nasopharyngeal swab was negative. This study aimed to elucidate the probability of a positive SARS-CoV-2 PCR test in the middle ear or mastoid specimens from otologic surgery patients in whom SARS-CoV-2 was not detected by preoperative PCR test using a nasopharyngeal swab. METHODS: We conducted a prospective, multicenter clinical study. Between April 2020 and December 2021, during the COVID-19 pandemic, 251 ears of the 228 participants who underwent otologic surgery were included in this study. All participants had no symptoms suggesting COVID-19 or close contact with a confirmed COVID-19 patient two weeks prior to the surgery. They were also negative in the SARS-CoV-2 PCR tests using a nasopharyngeal swab before surgery. We collected mucosa, granulation, bone dust with mucosa or fluid from the middle ear or mastoid for the SARS-CoV-2 PCR tests during each otologic surgery. RESULTS: The median age of the participants at surgery was 31.5 years old. Mastoidectomy using a powered instrument was conducted in 180 of 251 otologic surgeries (71.8%). According to intraoperative findings, active inflammation in the middle ear or mastoid cavities was evident in 20 otologic surgeries (8.0%), while minor inflammation was observed in 77 (30.7%). All SARS-CoV-2 PCR tests of otologic specimens showed a negative result. No patient suffered from COVID-19 within two months after otologic surgery. Furthermore, no hospital-acquired infections associated with otologic surgery occurred in our institutions CONCLUSIONS: Our results showed that PCR testing did not detect SARS-CoV-2 in middle ear and mastoid specimens, suggesting that the risk of transmission of SARS-CoV-2 is not high in otologic surgeries even using powered instruments when both clinical and laboratory tests are confirmed to be negative for COVID-19.

Successful treatment of γ-heavy-chain disease with rituximab and fludarabine.

An 84-year-old Japanese man was admitted because of pancytopenia. The bone marrow was hypoplastic with a predominance of abnormal small lymphocytes and grape cells, which were positive for CD19 and CD20, and partially for the surface ĸ-light chain. Systemic CT scanning showed neither lymph node swelling nor hepatosplenomegaly. Serum immunoelectrophoresis and rocket immunoselection assays showed the presence of monoclonal IgG protein without a corresponding light chain and faint IgMĸ monoclonal protein. Histologic analysis of the clot preparation of the bone marrow aspirate facilitated a diagnosis of lymphoplasmacytic lymphoma (LPL). PCR analysis of the marrow cells demonstrated a clonal rearrangement of the immunoglobulin heavy-chain gene. From these results, we made a final diagnosis of γ-heavy-chain disease (γ-HCD) with underlying LPL localized in the bone marrow. We performed only a single course of immunochemotherapy (rituximab and fludarabine) in view of severely impaired hematopoiesis, which resulted in marked reduction of lymphoma cells and improvement of hematopoiesis. This report suggests the efficacy of rituximab plus fludarabine therapy for LPL-associated γ-HCD.

Blastic plasmacytoid dendritic cell neoplasm expressing the CD13 myeloid antigen.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN), currently considered to originate from immature plasmacytoid dendritic cells (DC), is a rare and aggressive CD4+CD56+ neoplasm that frequently involves the skin and bone marrow. We present a case of an 80-year-old man with a CD4+CD56+ BPDCN that affected the orbital cavity and bone marrow. Although BPDCN has not been reported to express any lineage-specific markers, the neoplastic cells strongly expressed the CD13 antigen. Therefore, in addition to pathological examination, we attempted to induce in vitro morphological and surface marker changes with IL-3 and CD40 ligand. After treatment with these cytokines, the tumor cells enlarged markedly, acquired many fine dendrites, similar to mature DC, and showed enhanced expression of antigens specific to DC or antigen-presenting cells, such as CD40, CD80, CD83 and CD86. To the best of our knowledge, this is the first report of BPDCN expressing a myeloid antigen, CD13, although CD33 expression has been described in some cases. The present patient received 2 courses of combination chemotherapy consisting of cytarabine and etoposide, which resulted in complete remission. Given that the cellular origin of plasmacytoid DC is still controversial, myeloid antigen expression involving CD13 may not exclude a diagnosis of BPDCN.

[Exacerbation of autoimmune neutropenia to agranulocytosis in association with severe autoimmune thrombocytopenia and hemolytic anemia in a patient with Sjögren's syndrome].

A 73-year-old woman with Sjögren's syndrome and autoimmune neutropenia (AIN) associated with large granular lymphocytosis of the polyclonal T cell type, demonstrated autoimmune thrombocytopenia (AIT) at diagnosis of sigmoid colon cancer. Ten months later, both AIN and AIT had exacerbated to agranulocytosis and severe thrombocytopenia below 10×10(9)/L, respectively. There were no dysplastic features of bone marrow hematopoietic cells. Furthermore, an in vitro assay of hematopoietic progenitors showed normal granuloid and erythroid colony formation. Although we serially treated her with prednisolone (oral), filgrastim, intravenous high-dose immunoglobulin infusion, cyclophosphamide (oral), danazol, cyclosporine A (oral), and rituximab, number of neutrophils and platelets elevated only temporarily. During the course of agranulocytosis and severe thrombocytopenia, the patient also developed autoimmune hemolytic anemia (AIHA). She died of pneumonia 5 months after the onset of agranulocytosis. This case is very unique and novel in terms of autoimmune phenomena simultaneously directed to granulocytes, platelets, and red blood cells under the background of Sjögren's syndrome.

[Angioimmunoblastic T-cell lymphoma complicated by recurrent drug-induced agranulocytosis].

A 73-year-old man was hospitalized with fever, erythema, generalized superficial lymphadenopathy and marked neutropenia in July 2007. Hematologic examination demonstrated a white blood cell count of 1,400/microl with 0% neutrophils, and 18% abnormal lymphocytes. A bone marrow aspirate showed marked myeloid hypoplasia. A diagnosis of drug-induced agranulocytosis was made. Although neutrophil counts immediately returned to normal levels in response to filgrastim, fever, skin rash and systemic lymphadenopathy were all persistent. He also developed autoimmune hemolytic anemia and a second episode of agranulocytosis. The causative agent of the both episodes of agranulocytosis appeared to be acetaminophen. The histologic picture of a biopsied lymph node showed diffuse infiltration of polymorphous lymphoid cells with clear cytoplasm and proliferation of arborizing capillary vessels. Based on the histologic findings, PCR, and immunohistologic analyses, he was diagnosed with angioimmunoblastic T cell lymphoma (AILT) in leukemic state. The response of the lymphoma to conventional chemotherapy (CHOP and ESHAP) was poor. We next performed an immunomodulatory therapy using cyclosporine A to suppress cytokine production by neoplastic T cells. The treatment resulted in a partial remission of AILT including disappearance of circulating lymphoma cells. To our knowledge, this is the first published report of AILT complicated by drug-induced agranulocytosis.

Safety and effectiveness of FOLFOXIRI plus molecular target drug therapy for metastatic colorectal cancer: A multicenter retrospective study.

INTRODUCTION: FOLFOXIRI plus bevacizumab has a promising efficacy as first-line systemic chemotherapy for metastatic colorectal cancer (mCRC). This study aimed to evaluate the safety and effectiveness of FOLFOXIRI plus antibodies. RESULTS: Fifty-five patients were enrolled (median age: 60 years, males: 25, females: 30). Twenty-six subjects had RAS mutations and 29 had RAS wild-type. Anti-VEGF and anti-EGFR antibodies were administered to 38 and 17 patients, respectively. The most common severe adverse event was neutropenia (51%). The overall response rate (ORR) was 69% (55% with anti-VEGF antibodies and 100% with anti-EGFR antibodies; P = 0.190), and the disease control rate was 98% (stable disease: 16 patients). With a median follow-up period of 18.4 months, the median progression-free survival (mPFS) was 11.0 months and the median overall survival (mOS) was 41.9 months. The mPFS and mOS did not significantly differ between patients treated with anti-EGFR antibodies and those with anti-VEGF antibodies. METHODS: We retrospectively collected data from mCRC patients treated with FOLFOXIRI plus antibodies between March 2014 and December 2017. CONCLUSIONS: FOLFOXIRI plus antibody therapy was effective in patients with mCRC. The response rate was higher in patients treated with anti-EGFR antibodies than in those treated with anti-VEGF antibodies.

T-cell large granular lymphocytic (LGL) leukemia consists of CD4+/CD8dim and CD4-/CD8+ LGL populations in association with immune thrombocytopenia, autoimmune neutropenia, and monoclonal B-cell lymphocytosis.

CD3+/CD57+ T-cell large granular lymphocyte leukemia (T-LGLL) is an indolent neoplasm, exhibiting mostly CD8+, less frequently CD4+ phenotypes, and T-LGLL consisting of 2 populations with CD8+ and CD4+ phenotypes is markedly rare. An 87-year-old female was admitted under a diagnosis of immune thrombocytopenia (ITP) with a platelet count of 5.0×109/L and increased number of LGL with unknown etiology. Her neutrophil count also decreased to 0.27×109/L and she was positive for antineutrophil antibody. The WBC count was 2.7×109/L with 34.7% LGL and flow cytometry (FCM) analysis revealed 16% CD3+/CD4+/CD8dim/CD57+ and 20.9% CD3+/CD8+/CD57+ populations. These populations also expressed granzyme B and perforin. Circulating mononuclear cells were found to be clonal by PCR analysis of T-cell receptor ß-chain gene. Serum immunofixation and bone marrow FCM analyses demonstrated 2 clonal B-cells producing IgG-λ and IgA-λ. Deep amplicon sequencing of STAT3 and STAT5B genes revealed a STAT3 R302G mutation with an allele burden of 2.6%. The thrombocytopenia and neutropenia were successfully treated by prednisolone and romiplostim with negative conversion of antineutrophil antibody. This is the first reported case of T-LGLL with dual components of CD4+/CD8dim and CD4-/CD8+ populations in terms of multiple comorbidities related to the respective CD8+ and CD4+ T-LGLLs.

Expression of multiple leukemic stem cell markers is associated with poor prognosis in de novo acute myeloid leukemia.

Leukemic stem cells (LSCs) play a crucial role in chemotherapy resistance in acute myeloid leukemia (AML). Although the association between the expression of individual LSC markers and poor prognosis has been reported, few studies have evaluated the prognostic effect of multiple LSC markers in patients with AML. Herein, we examined three LSC markers (CD25, CD96, and CD123) and the combined effect of their expression on clinical outcome. We retrospectively analyzed 80 adult patients with de novo AML who received intensive chemotherapy. Multiple LSC marker expression was significantly associated with shorter three-year overall survival (OS), compared with single or no LSC marker expression (18.2 vs. 65.0%, p < .001). Multivariate analysis showed that the expression of multiple LSC markers remained significant in terms of three-year OS (hazard ratio: 3.80, p = .001). Therefore, the combined evaluation of several LSC markers can predict the clinical outcome in patients with AML.