[Successful polatuzumab vedotin and rituximab therapy for post-CAR-T relapse of diffuse large B-cell lymphoma].

Relapse or progressive disease after chimeric antigen receptor T-cell (CAR-T) treatment remains a major issue for poor-risk aggressive large B-cell lymphoma. However, limited data are available on post-CAR-T use of polatuzumab vedotin. Here we describe the case of a patient with diffuse large B-cell lymphoma (DLBCL) who experienced relapse three months after CD19-directed CAR-T therapy with tisagenlecleucel. However, the relapsed lesions rapidly disappeared following treatment with polatuzumab vedotin and rituximab. Notably, long-term remission was achieved without severe cytopenia, infections or peripheral neuropathy, showing the therapeutic benefit of polatuzumab vedotin for CAR-T failure.

Autobullectomy with COVID-19 in a patient with chronic obstructive pulmonary disease.

A 72-year-old man with chronic obstructive pulmonary disease (COPD) was admitted for coronavirus disease 2019 (COVID-19). He was discharged on day 30; however, he was readmitted 6 days later due to a left lung organizing pneumonia secondary to COVID-19. After methylprednisolone treatment, the patient was discharged on day 15. One year later, computed tomography showed shrinkage of emphysematous lesions, and both total lung capacity measured using computed tomography and fraction of low attenuation volume decreased in the left lung compared to that before COVID-19. Here, we report a rare case of autobullectomy with COVID-19 in a patient with COPD.

Mogamulizumab for post-transplant relapse of adult T-cell leukemia/lymphoma: a case study.

Mogamulizumab (MOG), a humanized monoclonal anti-CCR4 antibody, exerts strong antibody-dependent cellular cytotoxic effects on CCR4-positive adult T-cell leukemia/lymphoma (ATLL) cells. As CCR4 is highly expressed on regulatory T cells as well as ATLL cells, pre-transplant MOG induces severe graft-versus-host disease (GvHD). However, limited data are available on post-transplant use of MOG for relapsed ATLL. Here we describe the case of a patient with ATLL who experienced post-transplant relapse with involvement of peripheral blood, skin, lungs, and lymph nodes. Neither tacrolimus dose reduction nor cytotoxic chemotherapy was effective, but a single dose of MOG (1 mg/kg) induced complete remission. After treatment with MOG, leukemic cells in the peripheral blood rapidly disappeared, and the skin, lymph node, and lung lesions gradually regressed. Most notably, the long-term remission was accompanied by recurrence of moderate acute GvHD (grade II, skin stage 2, gut stage 1, liver stage 0). Our findings indicate that MOG can augment allogeneic immune-mediated anti-tumor reactions through graft-versus-ATLL (GvATLL) even during post-transplant relapse involving the lymph nodes and lungs, along with inducing GvHD.

Pentacyclic triterpenoid ursolic acid induces apoptosis with mitochondrial dysfunction in adult T-cell leukemia MT-4 cells to promote surrounding cell growth.

We investigated the antitumor effects of oleanolic acid (OA) and ursolic acid (UA) on adult T-cell leukemia cells. OA and UA dose-dependently inhibited the proliferation of adult T-cell leukemia cells. UA-treated cells showed caspase 3/7 and caspase 9 activation. PARP cleavage was detected in UA-treated MT-4 cells. Activation of mTOR and PDK-1 was inhibited by UA. Autophagosomes were detected in MT-4 cells after UA treatment using electron microscopy. Consistently, mitophagy was observed in OA- and UA-treated MT-4 cells by confocal microscopy. The mitochondrial membrane potential in MT-4 cells considerably decreased, and mitochondrial respiration and aerobic glycolysis were significantly reduced following UA treatment. Furthermore, MT-1 and MT-4 cells were sorted into two regions based on their mitochondrial membrane potential. UA-treated MT-4 cells from both regions showed high activation of caspase 3/7, which were inhibited by Z-vad. Interestingly, MT-4 cells cocultured with sorted UA-treated cells showed enhanced proliferation. Finally, UA induced cell death and ex vivo PARP cleavage in peripheral blood mononuclear cells from patients with adult T-cell leukemia. Therefore, UA-treated MT-4 cells show caspase activation following mitochondrial dysfunction and may produce survival signals to the surrounding cells.

Post-transplant food anaphylaxis in an adult cord blood transplant recipient (Ms. No. IJHM-D-20-01037R1).

Transplant acquired food allergy (TAFA) is a well-known complication following pediatric liver transplantation, but post-cord blood transplantation (post-CBT) TAFA has rarely been reported. Here, we describe a case of new-onset food anaphylaxis after CBT in an adult patient that demonstrates that post-CBT allergen-challenge is not a risk for long-term allergic sensitization even in adult recipients. The patient was a 39-year-old Japanese man with aggressive NK cell leukemia. He had no previous history of allergies. After receiving CBT, the patient had an unbalanced diet with high preference for bread, bananas, miso-soup, cow's milk, cheese, egg, sesame and buckwheat soba noodles, and experienced repeated diarrhea. Six months later, he developed symptoms such as vomiting, epigastric pain, diarrhea, high fever and hypotension. The condition was initially diagnosed as enterocolitis, but symptoms recurred after consumption of buckwheat. Anaphylaxis induced by buckwheat was confirmed with serum radioallergosorbent tests (RAST), showing allergen-specific IgE for buckwheat (greater than 100 U/mL, Class 6) and egg ovomucoid (Class 4). Nineteen months after a buckwheat and egg-free diet, serum RAST for buckwheat and egg significantly improved. As a result, the patient acquired a tolerance and was able to consume buckwheat and egg without allergic symptoms.

Rational Design of Domain-Swapping-Based c-Type Cytochrome Heterodimers by Using Chimeric Proteins.

The design of protein oligomers with multiple active sites has been gaining interest, owing to their potential use for biomaterials, which has encouraged researchers to develop a new design method. Three-dimensional domain swapping is the unique phenomenon in which protein molecules exchange the same structural region between each other. Herein, to construct oligomeric heme proteins with different active sites by utilizing domain swapping, two c-type cytochrome-based chimeric proteins have been constructed and the domains swapped. According to X-ray crystallographic analysis, the two chimeric proteins formed a domain-swapped dimer with two His/Met coordinated hemes. By mutating the heme coordination structure of one of the two chimeric proteins, a domainswapped heterodimer with His/Met and His/H2 O coordinated hemes was formed. Binding of an oxygen molecule to the His/H2 O site of the heterodimer was confirmed by resonance Raman spectroscopy, in which the Fe-O2 stretching band was observed at 580 cm-1 for the reduced/oxygenated heterodimer (at 554 cm-1 under an 18 O2 atmosphere). These results show that domain swapping is a useful method to design multiheme proteins.

Relationship between triterpenoid anticancer drug resistance, autophagy, and caspase-1 in adult T-cell leukemia.

We previously reported that the inflammasome inhibitor cucurbitacin D (CuD) induces apoptosis in human leukemia cell lines. Here, we investigated the effects of CuD and a B-cell lymphoma extra-large (Bcl-xL) inhibitor on autophagy in peripheral blood lymphocytes (PBL) isolated from adult T-cell leukemia (ATL) patients. CuD induced PBL cell death in patients but not in healthy donors. This effect was not significantly inhibited by treatment with rapamycin or 3-methyladenine (3-MA). The Bcl-xL inhibitor Z36 induced death in primary cells from ATL patients including that induced by CuD treatment, effects that were partly inhibited by 3-MA. Similarly, cell death induced by the steroid prednisolone was enhanced in the presence of Z36. A western blot analysis revealed that Z36 also promoted CuD-induced poly(ADP ribose) polymerase cleavage. Interestingly, the effects of CuD and Z36 were attenuated in primary ATL patient cells obtained upon recurrence after umbilical cord blood transplantation, as compared to those obtained before chemotherapy. Furthermore, cells from this patient expressed a high level of caspase-1, and treatment with caspase-1 inhibitor-enhanced CuD-induced cell death. Taken together, these results suggest that rescue from resistance to steroid drugs can enhance chemotherapy, and that caspase-1 is a good marker for drug resistance in ATL patients.

Autophagy is associated with cucurbitacin D-induced apoptosis in human T cell leukemia cells.

We previously reported that the inflammasome inhibitor cucurbitacin D (CuD) induces apoptosis in human leukemia cell lines. In the present study, we investigated the effects of co-treatment with an additional Bcl-xL inhibitor, Z36. Treatment with Z36 induced cell death in leukemia cell lines, with MT-4 cells exhibiting the lowest sensitivity to Z36. Co-treatment of cells with Z36 and CuD resulted in a greater degree of cell death for Hut78 and Jurkat cells than treatment with CuD alone. In contrast, co-treatment of MT-4 cells with Z36 and CuD had a suppressive effect on cell death. The autophagy inhibitor 3-methyladenine (3-MA) suppressed the growth of leukemia cell lines HuT78, Jurkat, MT-1, and MT-4. CuD-induced cell death was enhanced by 3-MA in Jurkat cells, but inhibited in MT-4 cells. Western blotting results revealed cleavage of poly(ADP ribose) polymerase (PARP), supporting CuD-induced cell death; 3-MA enhanced CuD-Z36-induced PARP cleavage. Taken together, our results indicate that autophagy negatively regulates chemical-induced cell death of leukemia cells, and that controlling autophagy could be beneficial in the development of more effective chemotherapies against leukemia.

Asian sand dust causes subacute peripheral immune modification with NF-κB activation.

Asian sand dust (ASD), a type of particulate matter found in Asia, migrates to East Asia. The increased airborne spread of ASD has led to concerns regarding possible adverse health effects. Our group previously reported that ASD induces lung inflammation in mice, but it is still unclear whether ASD affects lymphoid organs. In this study, we investigated the effect of ASD on splenocytes in a mouse model of ASD exposure. ICR mice were intratracheally administered a single dose of normal saline (control) or ASD and were subsequently sacrificed 1 or 3 days later. TNF-α production in bronchoalveolar lavage fluids was higher at day 1, but not at day 3, after ASD administration. The enzyme-linked immunosorbent assay results showed that ASD administration increased mitogen-induced IL-2, TNF-α, and IL-6 production in splenocytes. Additionally, cell viability assay showed enhanced splenocyte proliferation at day 3, but not at day 1, after ASD administration. The electrophoretic mobility shift assay results demonstrated that nuclear factor κB (NF-κB) was activated in splenocytes on day 3, but not on day 1. In particular, NF-κB activation was detected in CD4(+) and CD11b(+) cells on day 3. These results suggest that ASD induces subacute inflammatory responses with NF-κB activation in the spleen, in contrast to acute inflammation in the lungs.

Case of adult T-cell leukemia/lymphoma with rapid progression of pulmonary areas of ground-glass attenuation and multiple nodules.

We report a case of adult T-cell leukemia/lymphoma (ATL) with rapidly progressive pulmonary areas of ground-glass attenuation (GGA) and nodules resulting from acute transformation of chronic ATL. A 48-year-old Japanese man was admitted for progressive dyspnea. Chest computed tomography showed rapidly progressive bilateral pulmonary areas of GGA and nodules. Flow cytometry of bronchoalveolar lavage fluid and immunohistochemical examination of lung biopsy specimens revealed invasion of ATL cells. Systemic chemotherapy improved the pulmonary findings. Rapidly expanding areas of GGA and nodules are a rare manifestation of pulmonary invasion of ATL that clinicians should nevertheless keep in mind.

[Early onset of anti- erythropoietin antibody-mediated pure red cell aplasia after commencement of subcutaneous administration of epoetin-ß].

We report a 73-year-old Japanese man with early onset pure red cell aplasia (PRCA) caused by subcutaneous administration of recombinant epoetin-ß. Two months after the start of epoetin therapy, he developed PRCA. Anti-erythropoietin (EPO) antibody, detected in the patient's serum by enzyme immunoassay and radioimmunoprecipitation method, inhibited EPO-dependent growth of AS-E2 cells in vitro. Treatment with prednisone (1 mg/kg) significantly reduced antibody levels 3 months later. It is important to have an awareness of antibody-mediated PRCA. Our case shows that subcutaneous epoetin administration produces this complication in the early period of therapy.