Efficacy of Venetoclax and Azacitidine in Acute Myeloid Leukemia Compared to Azacitidine Monotherapy: Real-World Experience.

BACKGROUND/AIM: The combination of venetoclax (VEN) and azacitidine (AZA) (VEN+AZA) leads to higher complete remission rates and longer overall survival (OS) in patients with untreated acute myeloid leukemia (AML) who are ineligible for intensive combination chemotherapy. In practice, the doses of VEN and AZA are reduced at the attending physician's discretion to avoid adverse events; however, the impact of dose and duration reductions has not been fully clarified. We analyzed whether the efficacy was maintained with reduced VEN+AZA compared to AZA monotherapy in the real world. PATIENTS AND METHODS: A total of 33 patients were included; 17 (10 newly diagnosed, 7 primary refractory or relapsed) received VEN+AZA, and 16 (7 newly diagnosed, 9 primary refractory or relapsed) received AZA. We analyzed complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates, OS, and the incidence of adverse events. RESULTS: CR/CRi were achieved in 7/17 (41.2%) and 11/17 (64.7%) patients in the VEN+AZA group and 0/15 (0%) and 2/15 (6.7%) patients in the AZA group, respectively. The CR/CRi rate was higher in the VEN+AZA group than in the AZA group (p=0.001). OS was longer in the VEN+AZA group than in the AZA group (p=0.03), with a median of 506 days [95% confidence interval (CI)=234-585 days] and 208 days (95% CI=52-343 days), respectively. CONCLUSION: The doses of the VEN+AZA combination were reduced at the attending physician's discretion, resulting in a higher CR/CRi rate and longer OS than AZA monotherapy and is considered useful for AML in the real world.

Influence of conversion factors on the radioactivity evaluation of clearance objects consisting of several materials.

Control panel waste generated from nuclear power plants is a new candidate for clearance under Japan's amended regulations. In the radioactivity evaluation, a simplified conversion factor for density and source location conditions has been used, assuming that it applies to unmixed materials such as metals. To investigate its applicability to control panels consisting of metal and organic materials, we examined the application of the conventional conversion factor by simulations of radiation measurements for a point source in a control panel.

Chronic neutrophilic leukemia preceded by myelodysplastic syndromes.

Chronic neutrophilic leukemia (CNL) is primarily diagnosed by excluding myelodysplastic syndromes (MDS). We report the case of a patient who developed secondary CNL 3 years after hypoplastic MDS. We used droplet digital polymerase chain reaction mutation detection assay to analyze genomic alterations during the progression from MDS to CNL. At the time of MDS diagnosis, U2AF1 Q157P and SETBP1 D868N were dominant and additional mutation of ASXL1 1934_insG was observed. CSF3R T618I and SETBP1 D868N were increasing at the time of CNL diagnosis. We revealed the accumulation of multiple gene mutations during CNL development from MDS. This suggests that CNL was clonally developed from the founding clone of MDS and CSF3R mutation contributes to the development of CNL in the present case. These findings provide insights into the pathology of CNL.

The effect of introducing a nurse-practitioner-led peripherally inserted central venous catheter placement program on the utilization of central venous access device: A retrospective study in Japan.

BACKGROUND: Nurse-led peripherally inserted central venous catheter (PICC) placement teams are common in western hospitals, but they are still in their infancy in Japan. Although implementing a dedicated program may improve ongoing vascular-access management, the direct hospital-level effects of launching a nurse-led PICC team on specific outcomes have not been formally investigated. OBJECTIVES: To evaluate the effect of introducing a nurse practitioner (NP)-led PICC-placement program on subsequent utilization of centrally inserted central catheters (CICCs) and to contrast the quality of PICC placements conducted by physicians and NPs. MATERIALS AND METHODS: Patients who underwent central venous access devices (CVADs) between 2014 and 2020 at a university hospital in Japan were evaluated retrospectively using an interrupted time-series analysis on the trend for monthly CVAD utilization and logistic regression and propensity score-based analyses for PICC-related complications. RESULTS: Among 6007 CVAD placements, 2230 PICCs were inserted into 1658 patients (725 by physicians and 1505 by NPs). The monthly number of CICC utilization fell from 58 in April 2014 to 38 in March 2020, while PICC placements by the NP PICC team increased from 0 to 104. The implementation of the NP PICC program reduced the immediate rate (by 35.5; 95% confidence interval [CI]: 24.1-46.9; p < 0.001) and post-intervention trend (by 2.3; 95% CI: 1.1-3.5; p < 0.001) of monthly CICC utilization. Overall immediate complication rates were lower in the NP group than the physician group (1.5% vs 5.1%; adjusted odds ratio = 0.31; 95% CI: 0.17-0.59; p < 0.001). The cumulative incidences of central line-associated bloodstream infections were comparable between the NP and physician groups (5.9% vs 7.2%; adjusted hazard ratio = 0.96; 95% CI: 0.53-1.75; p = .90). CONCLUSIONS: This NP-led PICC program reduced CICC utilization without affecting the quality of PICC placement or complication rate.

External validation of the Michigan PICC catheter-associated bloodstream infections score (MPC score) for predicting the risk of peripherally inserted central catheter-associated bloodstream infections: A single-center study in Japan.

The Michigan peripherally inserted central catheter-associated bloodstream infection score (MPC score) had been developed for hospitalized medical patients but had not been externally validated. A retrospective analysis of a clinically heterogeneous case-mix in a university hospital cohort in Japan failed to validate its originally reported good performance.

Successful Treatment of an Aggressive Adult T-cell Leukemia/Lymphoma with Strong CD30 Expression Using Brentuximab Vedotin as Combination and Maintenance Therapy.

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive malignant tumor associated with a poor prognosis. We herein report a 63-year-old man who was newly diagnosed with aggressive ATL. He was treated with brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (A+CHP therapy), along with intrathecal chemotherapy using methotrexate and cytarabine. After achieving remission, he was placed on maintenance therapy with BV in the outpatient setting every 21 days for 17 months, without relapse. We suggest that initial treatment with A+CHP therapy and BV maintenance therapy may be beneficial against strongly CD30-expressing ATL.

Quantitative evaluation of treatment response to lenalidomide by applying fluorescence in situ hybridization for peripheral blood granulocytes in a patient with 5q- syndrome.

The introduction of lenalidomide has significantly improved clinical outcomes in myelodysplastic syndrome (MDS) with isolated interstitial deletion of the long arm of chromosome 5 (del(5q)) (5q- syndrome). These days, MDS with isolated del(5q) includes cases with one additional chromosome abnormality other than monosomy 7 or del(7q), and so we need a better way to monitor tumor cells in each patient than the clinical parameters used to date. An 82-year-old woman with MDS with isolated del(5q) was treated with lenalidomide daily for 21 days in a 4-week cycle. Fluorescence in situ hybridization with CSF1R located at 5q was applied to the peripheral blood samples. Because mature lymphocytes are not involved in the MDS clone, based on the nuclear morphology, polymorphonuclear cells (PMNs) and round-shaped nuclear cells (RSNs) were separately evaluated during treatment. After a single course of treatment, the number of PMNs with del(5q) decreased; by the end of the second course of treatment, both PMNs and RSNs with del(5q) had disappeared. The dynamics of 5q- PMNs is a simple but rapid and reliable indicator to confirm the effect of lenalidomide in MDS with del(5q).

Evaluation of the probability distribution of radioactivity estimated by inverse problem solution using Monte Carlo Method.

In this study, we derived the posterior probability distribution of the total activity estimated by inverse problem solution. The posterior probability distribution was derived by applying the Monte Carlo approach of the GUM Supplement 1 to the model of evaluation. The decision threshold, the detection limit, and the limits of the coverage interval for the results, all of which are defined in ISO 11929-2 as characteristic limits, were also derived.

Successful Treatment of Immune Thrombocytopenic Purpura with Intracranial Hemorrhaging and Duodenal Bleeding Following SARS-CoV-2 Vaccination.

Several vaccines have been developed for coronavirus disease 2019 - caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - in record time. A few cases of immune thrombocytopenic purpura (ITP) following SARS-CoV-2 vaccination have been reported. We herein report a 90-year-old man who received the Pfizer-BioNTech SARS-CoV-2 vaccine (BNT162b2) and developed severe thrombocytopenia with intracranial hemorrhaging and duodenal bleeding, consistent with vaccine-related ITP. He was successfully treated with intravenous immunoglobulin, prednisolone, and eltrombopag and discharged without cytopenia. Vaccine-related ITP should be suspected in patients presenting with abnormal bleeding or purpura after vaccination.

Increased MYC expression without MYC gene translocation in patients with the diffuse large B-cell-lymphoma subtype of iatrogenic immunodeficiency-associated lymphoproliferative disorders.

Post-transplant lymphoproliferative disorder (PTLD) and other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) are iatrogenic lymphoproliferative disorders (LPD) that develop in association with immunosuppressive treatment in the setting of organ transplantation and autoimmune disease, respectively. Each has a spectrum of pathologies ranging from lymphoid hyperplasia to lymphoma. To clarify the characteristics of the diffuse large B-cell lymphoma (DLBCL) subtype in a cohort of 25 patients with PTLD or OIIA-LPD from our institute, we selected 13 with a histological subtype of DLBCL, including 2 cases of PTLD and 11 of OIIA-LPD. The median patient age at diagnosis was 70 years, with a female predominance. Both PTLD cases developed after kidney transplant. Of the patients with OIIA-LPD, 10 had rheumatoid arthritis, 1 had mixed connective tissue disease, and 8 were treated using methotrexate. Both of the PTLD patients and 6 of the OIIA-LPD patients had extranodal manifestations. All patients except for one were classified as having the non-germinal center B-cell (non-GCB) subtype according to the Hans algorithm. Tissue samples from 8 patients were positive for CD30 and 8 were positive for Epstein-Barr virus (EBV)-encoded small RNA. Seven patients had MYC-positive tissue samples, but none had MYC translocation. Our study suggests that extranodal manifestations and the non-GCB subtype are common, that EBV is associated with the DLBCL subtype of PTLD and OIIA-LPD, and that anti-CD30 therapy is applicable. In addition, our patients with the DLBCL subtype of PTLD and OIIA-LPD exhibited MYC overexpression without MYC translocation, suggesting an alternative mechanism of MYC upregulation.

Derivation of uncertainty propagation for clearance measurement.

Clearance measurements are performed to calculate the sum of the ratios of the measured activity concentration to the limit for all nuclides to be considered. In the derivation of the uncertainty, the modeling of the measurement is essential. By using formula for the modeling, the uncertainty and upper limits of the coverage interval can be calculated by uncertainty propagation. The treatment of the ratio of the activity concentration of difficult-to-measure-nuclides to that of the key nuclide is also described.

Evaluation of the detection limit of net count in peak for the energy spectrum of CZT detector.

Pulse shape processing techniques have been used to improve the energy spectrum of the cadmium zinc telluride (CZT) detector, however, quantitative evaluation of the improvement, to determine whether it is acceptable to the related stakeholders, is required. In this study, the detection limit of net count in the full-energy absorption peak according to ISO 11929-1:2019 was selected to quantitatively evaluate the improvement of the characteristics of net count in the peak in the energy spectrum.

[Leukemic cell kinetics of APL with a novel complex variant t (12;17;15)(p13;q21;q22)].

A 69-year-old woman with leukocytopenia and thrombocytopenia was referred to our hospital. Her bone marrow comprised 70.5% abnormal promyelocytes that were positive for myeloperoxidase/CD33/CD117 and CD13 (dim) and negative for CD2/CD34/CD56 and HLA-DR. Chromosome analysis of the bone marrow showed t (12;17;15) (p13;q21;q22), and fluorescence in situ hybridization revealed the PML-RARA fusion signal only on the derivative chromosome 15. The patient was diagnosed with acute promyelocytic leukemia (APL) with PML-RARA and was treated using all-trans retinoic acid (ATRA). In peripheral blood (PB), PML-RARA-positive polymorphonuclear cells (PMNs) appeared on the second week and became negative on the sixth week after treatment, whereas PML-RARA-negative PMNs started to increase in number on the sixth week. Molecular remission was confirmed on the 10th week. Quantitative evaluation of the differentiated leukemic cells of APL and recovered cells from normal hematopoiesis in PB can provide useful information for a safer induction therapy. No significant difference was noted in the kinetics of the leukemic cells under ATRA treatment as well as in the clinical features between our patient without RARA-PML and those with t (15;17), which is a cytogenetic evidence for the critical role of PML-RARA in the pathogenesis of APL.

Light-chain plasma cell myeloma caused by 14q32/IGH translocation and loss of the other allele.

Light-chain plasma cell myeloma (LC-PCM) is a PCM subtype in which only immunoglobulin light-chain is secreted. However, the absence of immunoglobulin heavy-chain (IGH) production in this condition has not been fully elucidated. To address this issue, we retrospectively analyzed patients at our center with LC-PCM and found a group who had only split signals of IGH gene derived from 14q32/IGH translocations by fluorescence in situ hybridization (FISH). Six patients were identified with only split signals of the IGH gene derived from 14q32/IGH translocations. Five of these patients were newly diagnosed, while one had IgG-λ PCM at presentation, which transformed to λ LC-PCM after treatment. The translocation partners were identified in four patients: two cases of (11;14)(q13;q32) and two cases of (4;14)(p16;q32). The development of LC-PCM appears to be explained by the application of allelic exclusion in these patients, such that 14q32/IGH translocation in one allele contributes to the pathogenesis of PCM and the subsequent loss of the other allele is responsible for the loss of IGH production. These findings suggest that a FISH pattern of IGH with "split and loss" may constitute a unique subgroup of LC-PCM.

Correction to: Cell dynamics during differentiation therapy with all-trans retinoic acid in acute promyelocytic leukemia.

In the original publication of the article, Table 2 was published incorrectly. The column names were swapped under the column heading "Prom (%)". The correct column names are PB and BM.

Cell dynamics during differentiation therapy with all-trans retinoic acid in acute promyelocytic leukemia.

The introduction of all-trans retinoic acid (ATRA) has made acute promyelocytic leukemia (APL) a curable disease; however, early death prior to the completion of treatment remains a problem. In quantitative evaluation of response to ATRA treatment, lymphocytes must be excluded as they do not originally have t(15;17). We categorized peripheral blood leukocytes by nuclear morphology into polymorphonuclear cells (PMNs) comprising segmented granulocytes, and non-polymorphonuclear cells (NPMs) which includes lymphocytes, monocytes, band cells, and immature myeloid cells. We consecutively evaluated the ratio of t(15;17)-positive cells using fluorescence in situ hybridization in eight newly diagnosed patients with APL. We confirmed the differentiation of APL cells until cytogenetic complete remission; the association of a decrease of t(15;17)-positive NPMs and an increase of t(15;17)-positive PMNs was followed by a decrease of t(15;17)-positive PMNs. The kinetic pattern of t(15;17)-positive NPMs and PMNs was consistent in most patients, irrespective of leukocyte counts at diagnosis, additional chromosomal changes, and ATRA with or without chemotherapies. Kinetic analysis enables us to evaluate treatment response and the recovery of normal hematopoiesis in individuals.

[MALT lymphoma with t (X;14) (p11.2;q32) developing during the course of cutaneous leukocytoclastic angitis].

A 73-year-old man with left parotid gland swelling over 2 months was referred to our hospital in March 201X. Purpura on the lower legs had been recurrent for >20 years. Biopsy of the parotid gland demonstrated diffuse infiltration of abnormal lymphocytes that were negative for CD10 and positive for CD19, CD20, and κ-chain. The Ki-67 positivity was <10%; lymphoepithelial lesions were observed. The patient was diagnosed with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Chromosome analysis revealed t (X;14) (p11.2;q32), and fluorescence in situ hybridization (FISH) of metaphase spreads showed three signals of the immunoglobulin heavy chain (IGH) gene on the derivative chromosomes X and 14, besides the normal chromosome 14. CT findings of parotid glands were suggestive of Sjogren syndrome, and biopsy of the purpura on the leg demonstrated leukocytoclastic vasculitis. In the literature, only seven patients with lymphoma and t (X;14) translocation have been reported. Of these, five patients had MALT lymphoma, one had nodal marginal zone lymphoma, and one had diffuse large B-cell lymphoma. In all patients, lymphoma evolved from previous autoimmune diseases. It is suggested that MALT lymphoma with the t (X;14) translocation forms a new entity of lymphoma.

Expression of activating natural killer-cell receptors is a hallmark of the innate-like T-cell neoplasm in peripheral T-cell lymphomas.

Peripheral T- or natural killer (NK)-cell lymphomas are rare and difficult-to-recognize diseases. It remains arduous to distinguish between NK cell- and cytotoxic T-lymphocyte-derived lymphomas through routine histological evaluation. To clarify the cells of origin, we focused on NK-cell receptors and examined the expression using immunohistochemistry in 22 cases with T- and NK-cell neoplasms comprising angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase (ALK)-positive and -negative anaplastic large-cell lymphomas, extranodal NK/T-cell lymphoma, nasal type, monomorphic epitheliotropic intestinal T-cell lymphoma, aggressive NK-cell leukemia, and other peripheral T-cell lymphomas. Inhibitory receptor leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) was detected in 14 (64%) cases, whereas activating receptors DNAM1, NKp46, and NKG2D were expressed in 7 (32%), 9 (41%), and 5 (23%) cases, respectively. Although LILRB1 was detected regardless of the disease entity, the activating NK-cell receptors were expressed predominantly in TIA-1-positive neoplasms (DNAM1, 49%; NKp46, 69%; and NKG2D, 38%). In addition, NKp46 and NKG2D were detected only in NK-cell neoplasms and cytotoxic T-lymphocyte-derived lymphomas including monomorphic epitheliotropic intestinal T-cell lymphoma. One Epstein-Barr virus-harboring cytotoxic T-lymphocyte-derived lymphoma mimicking extranodal NK/T-cell lymphoma, nasal type lacked these NK-cell receptors, indicating different cell origin from NK and innate-like T cells. Furthermore, NKG2D expression showed a negative impact on survival among the 22 examined cases, which mainly received the standard chemotherapy regimen (log-rank test, P = .024). We propose that the presence of activating NK-cell receptors may provide new insights into understanding peripheral T-cell lymphomas and characterizing them as innate-like T-cell neoplasm.

De novo acute lymphoblastic leukemia-like disease of high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements: a case report and literature review.

BACKGROUND: B-cell lymphomas harboring the 8q24/MYC plus 18q21/BCL2 translocations are now referred to as high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-MBR). Although HGBL-MBR is frequently found in cases with diffuse large B-cell lymphoma or Burkitt lymphoma-like B-cell lymphoma, acute lymphoblastic leukemia (ALL)-like disease of HGBL-MBR (AL-HGBL-MBR) has been reported incidentally. CASE PRESENTATION: A 69-year-old Japanese woman developed remittent fever and increasing systemic bone pain. The bone marrow examination revealed that more than 90% of nuclear cells were blastoid cells, which were positive for CD10, CD19, CD20, and surface IgMκ and negative for terminal deoxynucleotidyl transferase (TdT). Cytogenetic studies confirmed that the patient had de novo AL-HGBL-MBR with the extra copies of MYC and loss of chromosome 17p. She showed resistance to chemoimmunotherapy and died seven months after the diagnosis. The literature review identified further 47 de novo AL-HGBL-MBR cases within the last 32 years. The median age was 61 years (range, 27 - 86); the male/female ratio was 2.0. Thirty-eight cases (79%) presented a clinical picture of ALL at diagnosis; 14 (36%) of 39 available cases showed central nervous system involvement. Loss of 17p and translocations at 2p12-13, 3q27, 9p13 were frequently observed as additional cytogenetic abnormalities. Although the median survival of 46 available cases was only five months (range, 0.1-18), rituximab use significantly improved the survival of AL-HGBL-MBR (log-rank test, P = 0.0294). CONCLUSION: Our patient and most reported de novo AL-HGBL-MBR cases showed resistance to conventional chemoimmunotherapy and disastrous consequences. AL-HGBL-MBL is a rare, but should be considered a distinct clinical condition in HGBL-MBR. Other therapeutic strategies, such as using inhibitors of MYC and BCL2, are needed to overcome the chemoresistance of AL-HGBL-MBR.