3D CNN-based Deep Learning Model-based Explanatory Prognostication in Patients with Multiple Myeloma using Whole-body MRI.

Although magnetic resonance imaging (MRI) data of patients with multiple myeloma (MM) are used to predict prognosis, few reports have applied artificial intelligence (AI) techniques for this purpose. We aimed to analyze whole-body diffusion-weighted MRI data using three-dimensional (3D) convolutional neural networks (CNNs) and Gradient-weighted Class Activation Mapping (Grad-CAM), an explainable AI, to predict prognosis and explore the factors involved in prediction. We retrospectively analyzed the MRI data of a total of 142 patients with MM obtained from two medical centers. We defined the occurrence of progressive disease after MRI evaluation within 12 months as a poor prognosis and constructed a 3D CNN-based deep learning model to predict prognosis. Images from 111 cases were used as the training and internal validation data; images from 31 cases were used as the external validation data. Internal validation of the AI model with stratified 5-fold cross-validation resulted in a significant difference in progression-free survival (PFS) between good and poor prognostic cases (2-year PFS, 91.2% versus [vs.] 61.1%, P = 0.0002). The AI model clearly stratified good and poor prognostic cases in the external validation cohort (2-year PFS, 92.9% vs. 55.6%, P = 0.004), with an area under the receiver operating characteristic curve of 0.804. According to Grad-CAM, the MRI signals of the spleen and bones of the vertebrae and pelvis contributed to prognosis prediction. This study is the first to show that image analysis of whole-body MRI using a 3D CNN without any other clinical data is effective in predicting the prognosis of patients with MM.

[Relapsed primary central nervous system lymphoma treated with CD19 chimeric antigen receptor T-cell therapy and allogeneic hematopoietic stem cell transplantation].

Relapsed and/or refractory (R/R) primary central nervous system lymphoma (PCNSL) has a poor prognosis. A 57-year-old man diagnosed with PCNSL achieved a complete response by high-dose methotrexate-based chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT). The disease was not cured, so he was treated with the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel after the third relapse. However, the disease relapsed again 28 days after CAR T-cell therapy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was attempted as curative therapy after bridging with second ASCT and tirabrutinib monotherapy. Although a temporary response was achieved, the disease relapsed 98 days after allo-HSCT. While receiving tirabrutinib for relapse after allo-HSCT, the patient developed acute respiratory failure due to transplant-related toxicity and post-transplant thrombotic microangiopathy. He died 175 days after allo-HSCT. Although various treatments for PCNSL have been investigated in recent years, the treatment strategy for R/R PCNSL has not been established. Further studies are warranted to improve the outcomes of patients with R/R PCNSL.

Antibody status following booster vaccination against SARS-CoV-2 virus in patients with haematologic malignancies.

Antibody titres in 462 patients with haematological malignancies after the second (D2) and third (D3) SARS-CoV-2 vaccine were compared with those of healthy controls (HCs). Significant decay of antibody titre was observed pre D3, but titre surged post D3. The number of seronegative patients decreased from 79 (17.1%) to 44 (9.5%) from post D2 to post D3, and patients with adequate antibody titre increased from 204 (44.2%) to 358 (77.5%). Of the patients who received B-cell-targeted therapy, 80% were seronegative and 71% remained seronegative after D3. CD19+, CD4+, CD8+ cell counts, and immunoglobulin G (IgG) levels were identified as independent predictors for adequate serologic response.

A Highly Conductive n-Type Coordination Complex with Thieno[3,2-b]thiophene Units: Facile Synthesis, Orientation, and Thermoelectric Properties.

An organometallic nickel complex containing thieno[3,2-b]thiophene units was designed and synthesized. Composite films of the resulting nickel complex and polyvinylidene difluoride, which can be fabricated via a simple solution process under atmospheric conditions, exhibit remarkably high n-type conductivity (>200 S cm-1). Moreover, the thermoelectric power factor of the n-type composite film was proven to be air stable. A grazing-incidence wide-angle X-ray diffraction analysis indicated a significant impact of introducing the thieno[3,2-b]thiophene core into the backbone of the nickel complex on the orientation within the composite films.

Depletion of CD38-positive regulatory T cells by anti-CD38 monoclonal antibodies induces a durable response to SARS-CoV-2 vaccination in patients with plasma cell dyscrasia.

This study reports the relationship between CD38+ regulatory T cells (Tregs) and messenger RNA coronavirus disease 2019 (mRNA-COVID-19) vaccination in 60 patients with plasma cell dyscrasia. Patients treated with anti-CD38 monoclonal antibodies (mAbs) had significantly lower CD38+ Tregs than those not treated (0.9 vs. 13.2/µl). Late-responders, whose antibody titres increased from weeks 4-12 after the second vaccination, had significantly lower CD38+ Treg counts than non-late-responders (2.5 vs. 10.3/µl). Antibody titres in patients with lower CD38+ Treg levels were maintained from weeks 4-12 but decreased in those with higher CD38+ Treg levels. Therefore, depletion of CD38+ Tregs by anti-CD38 mAbs may induce a durable response to mRNA-COVID-19 vaccination.

Multiple myeloma with t(11;14)-associated immature phenotype has lower CD38 expression and higher BCL2 dependence.

CD38 expression on myeloma cells is a critical factor affecting the early response to the anti-CD38 antibody daratumumab. However, factors affecting CD38 expression in untreated multiple myeloma are not fully elucidated. In this study, we found that CD38 expression was significantly lower in myeloma patients with the translocation t(11;14)-associated immature plasma cell phenotype, and particularly in those expressing B-cell-associated genes such as PAX5 and CD79A. CD138, a representative marker of plasmacytic differentiation, was also significantly lower in these patients, suggesting that CD38 expression may be associated with the differentiation and maturation stages of myeloma cells. Furthermore, the BCL2/BCL2L1 ratio, a response marker of the BCL2 inhibitor venetoclax, was significantly higher in patients with the immature phenotype expressing B-cell-associated genes. The BCL2/BCL2L1 ratio and CD38 expression were significantly negatively correlated. We also confirmed that patients with translocation t(11;14) expressing B-cell-associated genes were indeed less sensitive to daratumumab-mediated direct cytotoxicity but highly sensitive to venetoclax treatment in ex vivo assays. Moreover, all-trans-retinoic acid, which enhances CD38 expression and induces cell differentiation in myeloma cells, reduced B-cell marker expression and the BCL2/BCL2L1 ratio in myeloma cell lines, leading to reduced efficacy of venetoclax. Venetoclax specifically induces cell death in myeloma with t(11;14), although why patients with translocation t(11;14) show BCL2 dependence is unclear. These results suggest that BCL2 dependence, as well as CD38 expression, are deeply associated with the differentiation and maturation stages of myeloma cells. This study highlights the importance of examining t(11;14) and considering cell maturity in myeloma treatment strategies.

Total diffusion volume in MRI vs. total lesion glycolysis in PET/CT for tumor volume evaluation of multiple myeloma.

OBJECTIVE: This study compared the tumor burden and prognostic impact of total diffusion volume (tDV) and total lesion glycolysis (TLG) in the same patients with newly diagnosed multiple myeloma (NDMM) simultaneously. We also examined the relationship between these imaging tumor volumes (TVs) and plasma cell (PC) TV in bone marrow (BM) specimens. METHODS: We retrospectively reviewed the data of 63 patients with newly diagnosed multiple myeloma (NDMM) from April 2016 to March 2018. tDV was calculated from whole-body diffusion-weighted imaging and TLG was calculated from the average standard uptake value and the metabolic tumor volume, respectively. Cellularity of BM hematopoietic tissue and the percentage of BM PCs were used as a reference of PC volume in the BM. RESULTS: The Spearman correlation coefficient between tDV and TLG was moderate (ɤs = 0.588, p < 0.001) when PET false-negative patients were excluded. There were positive correlations between the BM plasma cell volume (BMPCV) and the imaging TVs (ɤs = 0.505, vs. tDV; and 0.464, vs. TLG). Patients with high tDV and high TLG, as determined by the receiver operating characteristic curve, had worse survival; moreover, patients with both high tDV and high TLG showed the worst prognosis (median progression-free and overall survival: 13.2 and 28.9 months, respectively). CONCLUSIONS: Although tDV and TLG each reflected the total TV, in several cases, tDV and TLG were discrepant due to the biological features of each MM. It is important to use both modalities for complementary assessment of total tumor burden and biological characteristics in MM. KEY POINTS: • Total diffusion volume (tDV) and total lesion glycolysis (TLG) reflect the total tumor volume and have prognostic value in patients with multiple myeloma (MM). • tDV and TLG could assess MM from different biological perspectives and should be considered for each patient individually.

Light chain deposition disease involving kidney and liver in a patient with IgD myeloma.

BACKGROUND: IgD multiple myeloma (MM) is a rare subtype of MM and light chain deposition disease (LCDD) outside the kidney is also a rare and has scarcely been reported. We report herein the details of the first reported case of LCDD involving the kidney and liver co-occurring with IgD myeloma. CASE PRESENTATION: A 66-year-old female with IgD MM presented with rapidly progressive acute renal failure, ascites and pleural effusion. Immunofluorescent study of revealed the characteristic linear deposition of Igκ light chain along the glomerular and tubular basement membrane in kidney. Electron microscopy showed the powdery electron-dense deposits along the tubular and glomerular basement membrane consistent with the diagnosis of LCDD. Laser microdissection followed by mass spectrometry identified only Igκ light chain with more than 95% probability confirm the diagnosis of κ-LCDD but not heavy/light chain deposition disease. Liver biopsy with immunofluorescence study revealed the linear deposition of Igκ chain along the perisinusoidal space indicating the hepatic involvement of κ-LCDD. The patient was successfully treated with combination therapy with bortezomib, cyclophosphamide, dexamethasone, and daratumumab. CONCLUSIONS: This report emphasizes that prompt biopsy of affected organs and initiation of clone directed therapy led to the correct diagnosis and favorable outcome in patient with LCDD who has extrarenal involvement.

Pre-treatment metabolic tumour volume and total lesion glycolysis are superior to conventional positron-emission tomography/computed tomography variables for outcome prediction in patients with newly diagnosed multiple myeloma in clinical practice.

Metabolic tumour volume (MTV) and total lesion glycolysis (TLG) are positron-emission tomography/computed tomography (PET/CT) variables for predicting multiple myeloma's (MM) outcome. We retrospectively investigated and compared the predictive value of MTV, TLG and high-risk PET/CT variables in clinical practice in 185 patients with newly diagnosed symptomatic MM. High-risk PET/CT findings were defined as the presence of at least one of the following: more than three focal lesions, maximum standardised uptake value (SUVmax ) >4·2 and extramedullary disease. MTV was defined as the volume of myeloma lesions visualised on PET/CT with SUV ≥ 2·5. TLG was calculated as the sum of the product of the average SUV and MTV of all lesions. The mortality prediction optimal cut-off values for MTV and TLG were 56·4 cm3 and 166·4 g, respectively. High-burden MTV (≥56·4 cm3 ), TLG (≥166·4 g) and high-risk PET/CT findings differed significantly in progression-free survival (PFS) and overall survival (OS). High-burden MTV and TLG findings also predicted survival outcomes in young patients (age <75 years) and patients with high-risk chromosomal abnormalities. High-burden MTV and TLG independently predicted both worse PFS and OS. Pre-treatment MTV and TLG independently predicted survival outcomes in clinical practice and may be more useful than high-risk PET/CT variables.

[Hairy cell leukemia complicated by bone marrow necrosis following cladribine administration].

Classic hairy cell leukemia (classic HCL) is a rare disease associated with indolent mature B-cell lymphoma. A 50-year-old man presented with pancytopenia for 3 years and was diagnosed with classic HCL because his lymphoid cells showed a hairy morphology with oval nuclei and indistinct nucleoli both in the peripheral blood and bone marrow (BM) smears. Flow cytometric analysis revealed that these cells expressed CD11c, CD25, and CD103, and the Sanger sequence method detected BRAF V600E mutation. Cladribine (0.09 mg/kg/day) was initiated for 7 days via continuous intravenous injection. On day 13, the patient died from bloodstream infection caused by methicillin-resistant Staphylococcus epidermidis. Autopsy findings revealed BM necrosis without residual leukemia cells caused by classic HCL, severe infection, and agents, such as cladribine and granulocyte-colony stimulating factor; however, its cause remained undetermined. Both early diagnosis and immediate clinical intervention are required to improve the clinical outcomes in classic HCL. The cause of hematopoiesis disturbance should also be identified using BM biopsy or magnetic resonance imaging before initiating treatment in classic HCL with severe pancytopenia.

[Hyper-IL-6 syndrome mimicking IgG4-related disease].

Distinguishing between IgG4-related disease (IgG4-RD) and hyper-interleukin (IL) -6 syndrome, such as immune mediated conditions, autoimmune diseases, and idiopathic multicentric Castleman disease (iMCD) is challenging. Here, we report the case of a 69-year-old man with cervical lymphadenopathy who was admitted to our hospital and histologically diagnosed with hyper-IL-6 syndrome mimicking IgG4-RD phenotypically. Laboratory data detected polyclonal hypergammaglobulinemia comprising IgG, including IgG4 (2,350 mg/dl). Computed tomography revealed presence of systemic lymphadenopathy, enlarged bilateral submandibular glands, and infiltrative shadow in the right lower lung. Magnetic resonance imaging revealed diffusely enlarged pancreas the size of a sausage and hypointense rim on T2, suggesting autoimmune pancreatitis as part of IgG4-RD. Biopsy of the cervical lymph node revealed proliferation of IL-6-positive mature plasma cells in the expanded interfollicular area with an elevated IgG4+/IgG+ cell ratio (approximately 70%). These histological findings were consistent with hyper-IL-6 syndrome rather than IgG4-RD; however, the serum IL-6 level was slightly elevated. Bone marrow aspiration detected both IgG4- and IL-6-positive mature plasma cells. Although this case cannot be diagnosed as IgG4-RD because it failed to meet its diagnostic criteria, administration of oral prednisolone (0.5 mg/kg) resulted in rapidly improved lymphadenopathy, enlarged pancreas, and serological findings. This report can be helpful for the diagnostic assessment of polyclonal hypergammaglobulinemia conditions.

Combination of reduced post-transplant cyclophosphamide and early tacrolimus initiation increases the incidence of chronic graft-versus-host disease in human leukocyte antigen-haploidentical peripheral blood stem-cell transplantation.

We evaluated the clinical impacts of the concurrent modification of post-transplant cyclophosphamide (PTCy) dose and tacrolimus (Tac)-initiation timing in 61 patients with human leukocyte antigen-haploidentical transplantation. Reduced-dose PTCy (80 mg/kg) was associated with a higher incidence of moderate-to-severe chronic graft-versus-host disease (GVHD) than standard-dose PTCy (100 mg/kg) (35.0% vs. 26.6%, p = 0.053). Notably, early-initiation Tac (day -1) increased moderate-to-severe chronic GVHD than standard-initiation Tac (day 5) in the reduced-dose PTCy group (p = 0.032), whereas Tac-initiation timing did not impact chronic GVHD in the standard-dose PTCy group. These data indicate that the combination of reduced-dose PTCy and early-initiation Tac can amplify chronic GVHD.

Analysis of baseline circulating tumor cells integrated with PET/CT findings in transplant-ineligible multiple myeloma.

ABSTRACT: We aimed to improve prognostic predictors in patients with transplant-ineligible multiple myeloma (TIE-MM) by combining baseline circulating clonal tumor cells (CTCs) and positron emission tomography/computed tomography (PET/CT) findings. The factors associated with prognosis were retrospectively investigated in 126 patients with TIE-MM who underwent CTC quantification by multiparameter flow cytometry and PET/CT at the initial presentation. The total lesion glycolysis (TLG) level was calculated using the Metavol software. The median percentage of CTC was 0.06% (range, 0%-4.82%), and 54 patients (42.9%) demonstrated high CTC levels. High CTC levels were associated with significantly poorer progression-free survival (PFS, 2-year 43.4% vs 68.1%; P < .001) and overall survival (OS, 5-year 39.0% vs 68.3%; P < .001). Similarly, high TLG levels significantly worsened the PFS (2-year, 41.2% vs 67.6%; P = .038) and OS (5-year, 37.7% vs 63.1%; P = .019). The multivariate analyses showed that Revised International Staging System (R-ISS) III, high CTC and TLG levels, and complete response were significant prognostic factors for PFS and OS. A novel predictive model was constructed using CTCs, TLG, and R-ISS III. The patients were stratified into 3 groups according to the number of risk factors, revealing an extremely high-risk group with a 2-year PFS of 0% and a 5-year OS of 20%. Patients without any high-risk features had better prognosis, with a 2-year PFS of 78.6% and a 5-year OS of 79.5%. The combination of CTCs and volumetric assessment of PET/CT at diagnosis augments the existing stratification systems and may pave the way for a risk-adapted treatment approach.

Remission of hypersensitivity pneumonitis after allogeneic hematopoietic stem cell transplantation.

A 50-year-old man was diagnosed with hypersensitivity pneumonitis caused by the environment of his bar owing to worsening symptoms, laboratory test results, and computed tomography images after an environmental inhalation challenge test. His hypersensitivity pneumonitis exacerbated despite receiving prednisolone 20 mg/day. The patient underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-matched unrelated donor for myelodysplastic syndrome. No exacerbation of hypersensitivity pneumonitis was observed after HSCT. An environmental inhalation challenge test involving exposure to his bar confirmed the remission of hypersensitivity pneumonitis after HSCT. This case demonstrates that hypersensitivity pneumonitis can be remitted by HSCT.

Chimeric antigen receptor T-cell therapy after COVID-19 in refractory high-grade B-cell lymphoma.

Although chimeric antigen receptor T-cell (CAR-T) therapies have dramatically improved the outcomes of relapsed/refractory B-cell malignancies, recipients suffer from severe humoral immunodeficiencies. Furthermore, patients with coronavirus disease 2019 (COVID-19) have a poor prognosis, as noted in several case reports of recipients who had COVID-19 before the infusion. We report the case of a 70-year-old woman who developed COVID-19 immediately before CAR-T therapy for high-grade B-cell lymphoma. She received Tixagevimab-Cilgavimab chemotherapy and radiation therapy but never achieved remission. She was transferred to our hospital for CAR-T therapy, but developed COVID-19. Her symptoms were mild and she was treated with long-term molnupiravir. On day 28 post-infection, lymphodepleting chemotherapy was restarted after a negative polymerase chain reaction (PCR) test was confirmed. The patient did not experience recurrence of COVID-19 symptoms or severe cytokine release syndrome. Based on the analysis and comparison of the previous reports with this case, we believe that CAR-T therapy should be postponed until a negative PCR test is confirmed. In addition, Tixagevimab-Cilgavimab and long term direct-acting antiviral agent treatment can be effective prophylaxis for severe COVID-19 and shortening the duration of infection.