iPSC-derived hypoimmunogenic tissue resident memory T cells mediate robust anti-tumor activity against cervical cancer.

Functionally rejuvenated human papilloma virus-specific cytotoxic T lymphocytes (HPV-rejTs) generated from induced pluripotent stem cells robustly suppress cervical cancer. However, autologous rejT generation is time consuming, leading to difficulty in treating patients with advanced cancer. Although use of allogeneic HPV-rejTs can obviate this, the major obstacle is rejection by the patient immune system. To overcome this, we develop HLA-A24&-E dual integrated HPV-rejTs after erasing HLA class I antigens. These rejTs effectively suppress recipient immune rejection while maintaining more robust cytotoxicity than original cytotoxic T lymphocytes. Single-cell RNA sequencing performed to gain deeper insights reveal that HPV-rejTs are highly enriched with tissue resident memory T cells, which enhance cytotoxicity against cervical cancer through TGFßR signaling, with increased CD103 expression. Genes associated with the immunological synapse also are upregulated, suggesting that these features promote stronger activation of T cell receptor (TCR) and increased TCR-mediated target cell death. We believe that our work will contribute to feasible "off-the-shelf" T cell therapy with robust anti-cervical cancer effects.

High incidence of disseminated intravascular coagulation and acute cerebral infarction in acute myeloid leukemia with cup-like nuclei.

In this study, we examined a cohort of Japanese patients with acute myeloid leukemia (AML) with cup-like nuclei. In particular, we attempted to provide a detailed definition of the clinical features of AML with cup-like nuclei. The clinical records of patients diagnosed with de novo AML were collected retrospectively. We showed that approximately 23% of all patients with AML diagnosed during the study period had AML with cup-like nuclei. All three cup-like AML cases had FLT3-ITD mutations. In addition, we reported a high incidence of disseminated intravascular coagulation and acute cerebral infarction in patients with AML with cup-like nuclei. Our results show that AML with cup-like nuclei may be more common than expected. Due to these unique characteristics, recognition of this morphology is recommended.

Vitamin B6 Deficiency Anemia Attributed to Levodopa/Carbidopa Intestinal Gel Therapy for Parkinson's Disease: A Diagnostic Pitfall for Myelodysplastic Syndrome with Ring Sideroblasts.

Vitamin B6 (VB6) is essential to heme synthesis, and its deficiency can lead to anemia. VB6 deficiency anemia is typically microcytic, hypochromic, and sideroblastic. VB6 deficiency is a well-recognized complication of levodopa/carbidopa therapy, as metabolism of levodopa to dopamine is VB6-dependent, and carbidopa irreversibly forms bonds and deactivates VB6. We herein report a 75-year-old man with advanced Parkinson's disease who developed severe VB6 deficiency anemia due to levodopa/carbidopa intestinal gel therapy. His anemia was promptly resolved with simple oral supplementation of pyridoxal phosphate hydrate. VB6 deficiency anemia can mimic myelodysplastic syndrome and thus is an important differential diagnosis for patients administered levodopa/carbidopa.

Radiation-Induced Myopathy Developing in a Hodgkin Lymphoma Patient: An Autopsy Case with Systemic Muscle Sampling.

Radiation-induced myopathy (RIM) is a rare complication occurring years after radiotherapy. RIM basically occurs within the irradiation field, but some cases have been reported to be accommodated by myopathy outside the irradiation field, and the actual extent of RIM is obscure. The presented case also showed decreased MMT scores and abnormal needle electromyography results in the muscles outside the irradiated field, and the patient was initially thought to have RIM both within and outside the irradiated field. However, while systemic postmortem muscle sampling revealed prominent myopathy in line with RIM in the irradiated muscles, only mild myogenic changes that could be explained by other causes such as age-related sarcopenia, radiculopathy, and disuse atrophy were observed in the non-irradiated muscles. The number of biopsy sites in live patients is limited due to the invasive nature of the procedure, but we were privileged to systemically evaluate the extent of myopathy through multiple muscle sampling including muscles both inside and outside of the irradiation field because this was an autopsy case. Through the presented case, we conclude that RIM is a phenomenon most probably limited to the muscles within the irradiated field, and myopathy outside the irradiation is due to other causes.

[Multiple myeloma treated with haploidentical hematopoietic stem cell transplantation with the administration of post-transplant cyclophosphamide].

We report the case of a 58-year-old woman with multiple myeloma who relapsed after the first autologous peripheral blood stem cell transplantation. She was refractory to new drugs and underwent a haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT) by administering post-transplantation cyclophosphamide (PTCy) after the second autologous peripheral blood stem cell transplantation. Neutrophil and platelet engraftment were achieved on days 22 and 55, respectively. Grade II cutaneous acute graft-versus-host disease was observed, which was resolved by systemic steroid treatment. Post-transplant bone marrow examination confirmed donor chimerism replacement and immunophenotypic complete response, and the patient is alive and disease-free. Although haplo-HSCT using PTCy for multiple myeloma has not been reported in Japan, it could be performed safely. Here, we report our results with literature review.

Sustainable Tumor-Suppressive Effect of iPSC-Derived Rejuvenated T Cells Targeting Cervical Cancers.

Immunotherapy utilizing induced pluripotent stem cell (iPSC) technology has great potential. Functionally rejuvenated cytotoxic T lymphocytes (CTLs) can survive long-term as young memory T cells in vivo, with continuous tumor eradication. Banking of iPSCs as an unlimited "off-the-shelf" source of therapeutic T cells may be feasible. To generate safer iPSCs, we reprogrammed human papilloma virus type 16 (HPV16) E6-specific CTLs by Sendai virus vector without cotransduction of SV40 large T antigen. The iPSCs efficiently differentiated into HPV16-specific rejuvenated CTLs that demonstrated robust cytotoxicity against cervical cancer. The tumor-suppressive effect of rejuvenated CTLs was stronger and more persistent than that of original peripheral blood CTLs. These rejuvenated HPV16-specific CTLs provide a sustained tumor-suppressive effect even for epithelial cancers and constitute promising immunotherapy for cervical cancer.

[Delivery of a Healthy Newborn by the Partner of a Patient with CML Undergoing Treatment with Nilotinib].

A man in his 40s was diagnosed with CML. He and his partner expressed their desire to have a child. We recommended planning the pregnancy after the achievement of major molecular response and completion of TKI therapy because we could not promise complete safety of the fetus, However, he and his partner insisted on starting the TKI therapy immediately and planned the pregnancy during the therapy. The patient was started on nilotinib 600mg/body. CCyR, MMR, and CMR were achieved in 3, 8, and 12 months, respectively. The patient's partner got pregnant when he had been on TKI therapy for 15 months, and she gave birth to a healthy boy. Since many patients with CMLcan live for a long time after receiving TKI therapy, the quality of life of these patients is more important. Even if the percentage of patients with CML who are under 50 years of age is approximately 30%, the safety information of TKI with respect to pregnancy is unsatisfactory. Doctors struggle to address the problems of the patient's wish of childbearing, priority of TKI therapy, and fetal risks of the treatment. Although only a few cases of pregnancy and delivery of the partners of male patients with CML treated with TKI have been reported, all cases showed healthy childbirth and normal child growth. Our experience also showed that the partner of a male patient with CML treated with TKI became pregnant and delivered a healthy baby.

[Refractory multiple myeloma with impaired consciousness accompanied by hyperammonemia and leukoencephalopathy-like findings].

A 81-year-old female was diagnosed with symptomatic multiple myeloma (MM; IgG κ type, D&S: IIB, ISS: 2) in August 2017. Although treatment with lenalidomide and dexamethasone was started, she developed deep venous thrombosis in the lower extremities as a complication; therefore, the treatment was changed to DBd. In February 2018, she required hospitalization due to general weakness and altered consciousness. Her IgG level and κ/λ ratio were elevated at 4,156 mg/dl and 605.56, respectively, revealing that MM was treatment-resistant. A protein-cell dissociation (cell blood count, 0/µl; protein, 100.6 mg/dl) was detected in the cerebrospinal fluid, whereas the ammonia level in serum was high (172 µg/dl). T2-weighted magnetic resonance imaging showed a broad range of high-density area in deep cerebral white matter suggesting leukoencephalopathy, whereas the cerebrospinal fluid was negative for JC virus. No pathological conditions causing secondary hyperammonemia were found. Although the involvement of drug-induced leukoencephalopathy in altered consciousness could not be ruled out since the chromosome with the normal karyotype at the first visit had a complex chromosomal abnormality, an originally minor clone of MM cells with a chromosomal abnormality might have contributed to the ammonia production resulting in altered consciousness.

Long-term eradication of extranodal natural killer/T-cell lymphoma, nasal type, by induced pluripotent stem cell-derived Epstein-Barr virus-specific rejuvenated T cells in vivo.

Functionally rejuvenated induced pluripotent stem cell (iPSC)-derived antigen-specific cytotoxic T lymphocytes (CTL) are expected to be a potent immunotherapy for tumors. When L-asparaginase-containing standard chemotherapy fails in extranodal natural killer/T-cell lymphoma, nasal type (ENKL), no effective salvage therapy exists. The clinical course then is miserable. We demonstrate prolonged and robust eradication of ENKL in vivo by Epstein-Barr virus-specific iPSC-derived antigen-specific CTL, with iPSC-derived antigen-specific CTL persisting as central memory T cells in the mouse spleen for at least six months. The anti-tumor response is so strong that any concomitant effect of the programmed cell death 1 (PD-1) blockade is unclear. These results suggest that long-term persistent Epstein-Barr virus-specific iPSC-derived antigen-specific CTL contribute to a continuous anti-tumor effect and offer an effective salvage therapy for relapsed and refractory ENKL.

[Recurrent amylase-producing multiple myeloma responding to pomalidomide and carfilzomib-containing therapies].

A 73-year-old woman diagnosed with symptomatic multiple myeloma (MM; IgG-κ type, D&S: IIIA, ISS: 2) was administered bortezomib plus dexamethasone (BD) therapy. Post BD therapy, although autologous hematopoietic stem cell transplantation and thalidomide, lenalidomide, and melphalan/prednisolone/thalidomide (MPT) therapies were also performed, the patient remained unresponsive. However, the disease relapsed, and she eventually developed pantalgia. Therefore, the patient was admitted to our hospital and was administered pomalidomide and dexamethasone (Pd) therapy. The serum amylase (AMY) and urine AMY levels were 6,329 and 6,098 IU/l, respectively, which were salivary gland-type amylase (S-AMY). Notably, the markedly high levels immediately decreased after the first course of the Pd therapy; additionally, the pantalgia also disappeared. The S-AMY level in the supernatant from cultured bone marrow mononuclear cells was higher than that observed in a normal control. In addition, AMY was high when MM previously relapsed, suggesting the presence of AMY-producing MM. Although AMY-producing MM was first reported by Hata et al. in 1988, few cases have been reported in the new-drug era. In conclusion, AMY-producing MM frequently, including in our case (as the patient was refractory to treatment), is difficult to treat. However, our patient positively responded to the novel next-generation drugs such as pomalidomide and carfilzomib.

Double-Expressor Lymphoma Is Associated with Poor Outcomes after Allogeneic Hematopoietic Cell Transplantation.

Double-expressor lymphoma (DEL) is a diffuse large B cell lymphoma that exhibits co-expression of MYC and BCL2 proteins by immunohistochemistry. Patients with double-expressor lymphoma have a poor prognosis after standard chemoimmunotherapy or after high-dose chemotherapy with autologous transplantation, but the prognostic impact of DEL after allogeneic hematopoietic cell transplantation has not been well characterized. We retrospectively analyzed 60 consecutive patients with de novo diffuse large B cell lymphoma or transformed follicular lymphoma who underwent allogeneic transplantation at our center and had available immunohistochemistry data. Thirty-seven patients (62%) had DEL. The 2-year progression-free and overall survival rates were lower in patients with DEL than in those without DEL (20% versus 78%; overall P <.001 and 46% versus 77%; overall P = .016, respectively). The cumulative incidence of disease progression at 2 years was higher in patients with DEL (60% versus 13%; overall P = .005). The cumulative incidence of nonrelapse mortality did not differ statistically in the 2 groups. Even in patients with DEL and chemosensitive disease at transplantation, the 2-year progression-free survival rate was only 27% due to early disease progression. Multivariate analysis showed associations between DEL and increased risks of progression-free survival events (hazard ratio [HR], 4.58; 95% confidence interval [CI], 2.07-10.2; P <.001), overall mortality (HR, 2.29; 95% CI, 1.03-5.09; P = .042) and disease progression (HR, 3.60; 95% CI, 1.38-9.44; P = .009). Patients with DEL had poor outcomes after allogeneic transplantation. Innovative strategies are needed to improve outcomes in this population.

[A methotrexate-associated lympholiferative disorder patient with gastrointestinal perforation].

A 70-year-old woman was diagnosed with chronic rheumatoid arthritis and treated with methotrexate and prednisolone. She visited our hospital to determine the cause of her continuous fatigue and fever for the past three weeks. She consumed no food orally and was provided antibiotics because free air was found on computed tomography (CT). Intraperitoneal small lymphadenopathy and swelling of both adrenal glands was also found on CT, and MTX-associated lymphoproliferative disorder (MTX-LPD) was suspected. Am adrenal gland biopsy showed diffuse large B-cell lymphoma (DLBCL) associated with MTX-LPD. The causes of gastrointestinal perforation with collagen diseases have been reported to be functional gastrointestinal disorders with collagen diseases like amyloidosis, gastrointestinal infections in immunocompromised patients, and side effects of medication, such as steroids or NSAIDs and MTX. MTX-LPD is an uncommon side effect of methotrexate. To ensure its appropriate diagnosis and treatment, it is important to improve the degree of recognition of MTX-LPD, and a prompt response is needed.