[Successful treatment with tucidinostat in a patient with relapsed adult T-cell leukemia/lymphoma following allogeneic hematopoietic stem cell transplantation].

Aggressive types of adult T-cell leukemia-lymphoma (ATL), namely, the acute type, lymphoma type, and chronic type with poor prognostic factors, have a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (HSCT) may improve prognosis, relapse is common. In June 2021, tucidinostat was approved for relapsed or refractory ATL in Japan. We report a case of a 62-year-old man with relapsed ATL after allogeneic HSCT. In March 2017, he was diagnosed with ATL (acute type) and received two courses of mLSG-15 therapy. ATL cells reappeared in his peripheral blood, so he underwent allogeneic bone marrow transplantation in September 2017. In June 2021, his soluble interleukin-2 receptor (sIL-2R) level increased, and he began experiencing sensory abnormalities in his face and legs. In September, he developed respiratory failure and was diagnosed with relapse of ATL. He was again treated with mLSG-15. His sIL-2R normalized and the sensory abnormalities decreased, but sIL-2R rose again in February 2022. After tucidinostat treatment was initiated, sIL-2R normalized and the patient's general condition improved. Tucidinostat shows promise as an effective treatment for ATL that has relapsed after allogeneic HSCT.

Transmission electron microscopic study of the surface layer of surgical resected disc specimens in human temporomandibular joint.

In this study, we investigated specific and characteristic findings of the surface layer of surgical resected disc specimens in human temporomandibular joint osteoarthritis cases by transmission electron microscopy (TEM).Specimens were surgically removed from the TMJ of 5 cases (4 female patients: 5 cases) clinically osteoarthritis. Following findings were observed by TEM. Images were photographed on a JEM1400-Flash Electron microscope (JEOL, Japan) equipped with an EM-14661FLASH high-sensitivity digital complementary metal-oxide-semiconductor camera.Following findings were observed by TEM. 1) The surface is covered with plump fibroblastic and histiocytoid cells. 2) Collagen fiber bundles and collagenous matrix are exposed onto the eroded disc surface. 3) Fibrinous dense material is observed on the eroded disc surface. 4) Bundles of collagen fibers are densely observed. 5) Collagen bundles are rich around capillary vessels. 6) Synovial surface cells reveal features of activated macrophages with vacuole formation. Especially, plump fibroblastic and histiocytoid cells, and activated macrophages with vacuole, which were significant findings of the surface layer. These findings might have a significant effect on the regulation of synovial fluid.

COVID­19 antibody production by vaccination in chemotherapy with CD20 antibody for B­cell lymphoma.

Most hematologic diseases are immunosuppressed, either by the disease itself or by treatment. As such, the implementation of vaccination is largely at the discretion of the attending physician. In this context, an objective measure is needed, therefore the index of vaccination against coronavirus disease 2019 (COVID-19) in B-cell lymphomas treated with antibody therapy against CD20 (including after the completion of therapy) was examined. A total of 40 patients with B-cell lymphoma during or after antibody therapy against CD20 were vaccinated twice with the BNT162b2 messenger RNA (mRNA) COVID-19 vaccine (Pfizer, Inc. and BioNTech SE.) at 3-week intervals and then again six months later with the same vaccine or mRNA-1273 (Moderna, Inc.). Antibody testing was conducted ~1 month after the third vaccination. Analysis was performed using the antibody titers to the anti-spike immunoglobulin assay, with a titer of 0.8 U/ml or higher (considered positive) and a titer of 264 U/ml or higher (considered the value at which the efficacy of the vaccine can be fully expected). Significant factors of antibody acquisition were identified when i) antibody titers were 0.8 U/ml or higher (CD4 ≥400/µl), ii) no anti-CD20 antibody maintenance therapy was undertaken (CD19 ≥100/µl), iii) patients were not on treatment (CD4 ≥400/µl), or 4) at least six months had passed since treatment ended (CD19 ≥100/µl). When antibody titers were 264 U/ml or higher, the treatment method, the stage of the primary disease and other factors related to the condition treatment method of the patient were relevant. When these were analyzed by multivariate analysis, the significant factor when antibody titers were set to 0.8 U/ml was CD19 ≥100/µl. In contrast, when setting them to 264 U/ml or higher, CD4 ≥400/µl was not significant, but there was a tendency for it to be related. The findings of the present study on vaccine-induced antibody acquisition in patients with B-cell lymphoma indicated that it is desirable to have a CD19 titer of at least 100/µl and a CD4 titer of at least 400/µl (both conditions should be met), and that no maintenance therapy with anti-CD20 antibody should be administered for at least six months after the last treatment or completion of the treatment. Interestingly, when the criteria for antibody titers were compared between 0.8 U/ml, where antibody titer is detected, and 264 U/ml, where vaccine efficacy is expected, several key factors were different. It is possible that these key factors may change depending on the antibody titer used as a criterion.

Dominant-negative type of IKZF1 deletion showed a favorable prognosis in adult B-cell acute lymphoblastic leukemia.

IKZF1 deletion is a recurrent genomic alteration in B-cell acute lymphoblastic leukemia (B-ALL) and is divided into dominant-negative (DN) and loss of function (LOF) deletions. The prognostic impact of each deletion has not been fully elucidated. We retrospectively analyzed 117 patients with adult B-ALL including 60 patients with BCR::ABL1-positive B-ALL and 57 patients with BCR::ABL1-negative B-ALL by the fluorescence in situ hybridization (FISH) method for IKZF1 deletion and multiplex PCR for the 4 most common IKZF1 deletions (∆4-7, ∆2-7, ∆2-8, and ∆4-8). Samples, in which IKZF1 deletion was detected by FISH but a specific type of deletion was not identified by the PCR, were categorized as "other." Patients were classified into a DN group that had at least 1 allele of ∆4-7 (n = 23), LOF and other group (n = 40), and wildtype group (n = 54). DN type IKZF1 deletions were found in 33.3% of BCR::ABL1-positive cases and 5.2% of BCR::ABL1-negative cases. LOF and other type IKZF1 deletions were found in 43.4% of BCR::ABL1-positive cases and 24.6% of BCR::ABL1-negative cases. Patients with the DN group showed significantly higher overall survival (OS) than that of the LOF and other and WT groups (P = 0.011). Multivariate analysis including age, WBC counts, complex karyotype, and DN type IKZF1 deletion showed that the DN type of IKZF1 deletion (HR = 0.22, P = 0.013) had a positive impact and age ≥ 65 (HR = 1.92, P = 0.029) had a negative impact on OS. The prognostic impact of IKZF1 deletion depends on the type of deletion and DN type of IKZF1 deletion showed better prognosis in adult B-ALL patients.Clinical trial registration This study was part of a prospective observational study (Hokkaido Leukemia Net, UMIN000048611). It was conducted in compliance with ethical principles based on the Helsinki Declaration and was approved by the institutional review board of Hokkaido University Hospital (#015-0344).

Hepatitis C Virus (HCV)-Ribonucleic Acid (RNA) As a Biomarker for Lymphoid Malignancy with HCV Infection.

The hepatitis C virus (HCV) is potentially associated with liver cancer, and advances in various drugs have led to progress in the treatment of hepatitis C and attempts to prevent its transition to liver cancer. Furthermore, reactivation of HCV has been observed in the treatment of lymphoma, during which the immortalization and proliferation of lymphocytes occur, which leads to the possibility of further stimulating cytokines and the like and possibly to the development of lymphoid malignancy. There are also cases in which the disappearance of lymphoid malignancy has been observed by treating HCV and suppressing HCV-Ribonucleic acid (RNA), as well as cases of recurrence with an increase in HCV-RNA. While HCV-associated lymphoma has a poor prognosis, improving the prognosis with Direct Acting Antivirals (DAA) has recently been reported. The reduction and eradication of HCV-RNA by means of DAA is thus important for the treatment of lymphoid malignancy associated with HCV infection, and HCV-RNA can presumably play a role as a biomarker. This review provides an overview of what is currently known about HCV-associated lymphoma, its epidemiology, the mechanisms underlying the progression to lymphoma, its treatment, the potential and limits of HCV-RNA as a therapeutic biomarker, and biomarkers that are expected now that DAA therapy has been developed.

A case of chronic gastric anisakiasis coexisting with early gastric cancer.

Background: Anisakiasis is a parasitic disease caused by the consumption of raw or undercooked fish that is infected with Anisakis third-stage larvae. In countries, such as Japan, Italy, and Spain, where people have a custom of eating raw or marinated fish, anisakiasis is a common infection. Although anisakiasis has been reported in the gastrointestinal tract in several countries, reports of anisakiasis accompanied by cancer are rare. Case presentation: We present the rare case of a 40-year-old male patient with anisakiasis coexisting with mucosal gastric cancer. Submucosal gastric cancer was suspected on gastric endoscopy and endoscopic ultrasonography. After laparoscopic distal gastrectomy, granulomatous inflammation with Anisakis larvae in the submucosa was pathologically revealed beneath mucosal tubular adenocarcinoma. Histological and immunohistochemical investigation showed cancer cells as intestinal absorptive-type cells that did not produce mucin. Conclusion: Anisakis larvae could have invaded the cancer cells selectively because of the lack of mucin in the cancerous epithelium. Anisakiasis coexisting with cancer is considered reasonable rather than coincidental. In cancer with anisakiasis, preoperative diagnosis may be difficult because anisakiasis leads to morphological changes in the cancer.

Subclinical minute FLT3-ITD clone can be detected in clinically FLT3-ITD-negative acute myeloid leukaemia at diagnosis.

Recent advances in next-generation sequencing (NGS) have enabled the detection of subclinical minute FLT3-ITD. We selected 74 newly diagnosed, cytogenetically normal acute myeloid leukaemia (AML) samples in which FLT3-ITD was not detected by gel electrophoresis. We sequenced them using NGS and found minute FLT3-ITDs in 19 cases. We compared cases with clinically relevant FLT3-ITD (n = 37), cases with minute FLT3-ITD (n = 19) and cases without detectable FLT3-ITD (n = 55). Molecular characteristics (location and length) of minute FLT3-ITD were similar to those of clinically relevant FLT3-ITD. Survival of cases with minute FLT3-ITD was similar to that of cases without detectable FLT3-ITD, whereas the relapse rate within 1 year after onset was significantly higher in cases with minute FLT3-ITD. We followed 18 relapsed samples of cases with clinically FLT3-ITD-negative at diagnosis. Two of 3 cases with minute FLT3-ITD relapsed with progression to clinically relevant FLT3-ITD. Two of 15 cases in which FLT3-ITD was not detected by NGS relapsed with the emergence of minute FLT3-ITD, and one of them showed progression to clinically relevant FLT3-ITD at the second relapse. We revealed the clonal dynamics of subclinical minute FLT3-ITD in clinically FLT3-ITD-negative AML. Minute FLT3-ITD at the initial AML can expand to become a dominant clone at relapse.

Radiation-induced fibrosarcoma after breast-conserving therapy for breast cancer: a case report and literature review.

BACKGROUND: Radiation-induced sarcoma (RIS) has a 10-year incidence of 0.2-0.27% and a poor prognosis, although the radiation should need for breast-conserving surgery. In particular, radiation-induced fibrosarcoma has been rarer, and its incidence is 2.6-3.7% of RIS. CASE PRESENTATION: A 43-year-old woman with pT1N1M0 breast cancer underwent breast-conserving surgery, chemotherapy, radiation therapy 8 years ago, and continued hormonal therapy. She complained of a hard unprotruded mass palpated in her right upper outer quadrant of breast. Although we suspected local recurrence, core needle biopsy revealed atypical spindled tumor cells without mammary or epithelial markers. A diagnosis of fibrosarcoma was made via tumorectomy. She underwent additional enlarged surgery. CONCLUSIONS: We report a rare case of fibrosarcoma in breast after breast-conserving surgery and radiation therapy. Fibrosarcoma after radiation therapy for breast cancer has been reported in 30 cases, including the present case. The dead and alive cases were not significantly different in terms of age, primary breast cancer, radiation dose, and following months. Patients with breast masses after radiation therapy should be suspected local recurrence and RIS.

Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain mutation in cytogenetically normal acute myeloid leukemia: a Hokkaido Leukemia Net study.

Mutation status of FLT3, NPM1, and CEBPA is used to classify the prognosis of acute myeloid leukemia, but its significance in patients with cytogenetically normal (CN) AML is unclear. We prospectively analyzed these genes in 295 patients with CN-AML and identified 76 (25.8%) FLT3-ITD, 113 (38.3%) NPM1 mutations, and 30 (10.2%) CEBPA biallelic mutations. We found that patients with FLT3-ITD had a poor prognosis at any age, while patients with CEBPA biallelic mutation were younger and had a better prognosis. FLT3-ITD and NPM1 mutations were correlated, and the favorable prognostic impact of being FLT3-ITD negative and NPM1 mutation positive was evident only in patients aged 65 years or more. For CEBPA, 86.7% of the patients with biallelic mutation and 9.1% of patients with the single allele mutation had in-frame mutations in the bZIP domain, which were strongly associated with a favorable prognosis. Multivariate analysis showed that age < 65 years, FLT3-ITD and CEBPA bZIP in-frame mutation were independent prognostic factors. The results suggest that analyzing these gene mutations at diagnosis can inform selection of the optimal intensity of therapy for patients with CN-AML.

Clinical features of complex karyotype in newly diagnosed acute myeloid leukemia.

Complex karyotype acute myeloid leukemia (CK-AML) has been classified as an adverse-risk subtype. Although a few reports have further classified CK-AML as typical (including monosomy of chromosomes 5, 7 and 17 or deletion of 5q, 7q and/or 17p) or atypical, the clinical features of these subtypes in Japanese patients remain unclear. We retrospectively analyzed a total of 115 patients with CK-AML, including 77 with typical CK-AML and 38 with atypical CK-AML. Median overall survival (OS) was significantly shorter in patients with typical CK-AML than atypical CK-AML (143 days vs. 369 days, P = 0.009). Among patients with typical CK-AML, those with monosomy 17 or deletion of 17p had significantly shorter OS than patients without such abnormalities (105 days vs. 165 days, P = 0.033). TP53 mutations were more predominant in patients with typical CK-AML than in patients with atypical CK-AML (69.7% vs. 32.4%, P < 0.001). Patients with typical CK-AML had a poor prognosis regardless of TP53 mutation status. Among patients with atypical CK-AML, however, prognosis was worse for those with the TP53 mutation than those without the mutation. In conclusion, prognosis is extremely poor for both typical CK-AML and atypical CK-AML with TP53 mutation.

Enzyme-labeled Antigen Method: Factors Influencing the Deterioration of Antigen-binding Activity of Specific Antibodies during Formalin Fixation and Paraffin Embedding.

The enzyme-labeled antigen method is an immunohistochemical technique detecting plasma cells producing specific antibodies in tissue sections. The probe is an antigen labeled with an enzyme or biotin. This immunohistochemical technique is appliable to frozen sections of paraformaldehyde (PFA)-fixed tissues, but it has been difficult to apply it to formalin-fixed, paraffin-embedded (FFPE) sections. In the current study, factors inactivating the antibody reactivity during the process of preparing FFPE sections were investigated. Lymph nodes of rats immunized with horseradish peroxidase (HRP) or a mixture of keyhole limpet hemocyanin/ovalbumin/bovine serum albumin were employed as experimental models. Plasma cells producing specific antibodies, visualized with HRP (as an antigen with enzymatic activity) or biotinylated proteins in 4% PFA-fixed frozen sections, significantly decreased in unbuffered 10% formalin-fixed frozen sections. The positive cells were further decreased by paraffin embedding following formalin fixation. In paraffin-embedded sections fixed in precipitating fixatives such as ethanol and acetone and those prepared with the AMeX method, the antigen-binding reactivity of antibodies was preserved. Fixation in periodate-lysine-paraformaldehyde and Zamboni solution also kept the antigen-binding reactivity in paraffin to some extent. In conclusion, formalin fixation and paraffin embedding were major causes inactivating antibodies. Precipitating fixatives could retain the antigen-binding reactivity of antibodies in paraffin-embedded sections.

A Rare Case of BCL2-Positive Multiple Myeloma Complicated with Follicular Lymphoma.

A 68-year-old woman presented with follicular lymphoma complicated by IgG kappa-positive multiple myeloma. In this case, both follicular lymphoma and plasma cells were positive for BCL2 by immunostaining. T-cell association in the FL and MM was also analyzed in this case. Some CD3-positive T-cells were found around the plasma cells. These cells were mainly CD8-positive T-cells and not CD4-positive T-cells. These results suggest that CD4-positive T-cells were not associated with the proliferation of the plasma cells in this case. Although the FL that developed was initially positive for BCL2 protein, this does not indicate that plasma cells were derived from FL cells because of the eventual complication that occurred in this case. Furthermore, in this case, rituximab and bendamustine were effective for FL. They were not effective for MM, however, demonstrating that additional treatment options are necessary for the simultaneous treatment of BCL2-positive MM with FL.

Periprosthetic joint infection due to Mycoplasma hominis in a multiple sclerosis patient treated with fingolimod.

Mycoplasma hominis is a commensal pathogen normally found in urogenital tract of humans and has been associated with a wide variety of extra-genitourinary infections, such as mediastinitis, bacteremia, and septic arthritis, particularly in immunocompromised patients. Here, we present a case of a 48-year-old male, who had been treated with fingolimod for relapsing multiple sclerosis and presented with fever and right-sided hip pain following total hip arthroplasty. CT scan revealed localized fluid collection in the right quadriceps femoris muscle adjacent to the joint cavity of right hip. The percutaneously aspirated fluid grew M. hominis, which was also isolated from blood culture. With diagnosis of periprosthetic joint infection, the patient underwent surgical debridement with retained prosthesis and was treated with antimicrobial agents. Infected granulation tissues excised from the hip was observed under an electron microscope, which revealed electron-dense rounded structures contained in neutrophils, consistent with Mycoplasma particles. Fingolimod, an immunomodulatory drug that acts on the sphingosine-1-phosphate receptor and prevents the egress of lymphocytes from lymph nodes, might increase host susceptibility to a systemic M. hominis infection.

Synchronous Jejunal Sarcomatoid Carcinoma and Incidentally Associated Localized Peritoneal Malignant Mesothelioma.

Sarcomatoid carcinoma (SCA) of the small bowel is a rare aggressive variant of small intestinal cancer accompanying a poor prognosis. The tumor primarily affects middle-aged and elderly patients. We report herein a 67-year-old Japanese male who manifested anemia. He had a history of asbestos exposure 30 years earlier. An abdominal computed tomography (CT) scan showed a 6.5-cm aneurysmal, dilated mass of the small intestine. Capsule endoscopy revealed a large circumferential hemorrhagic ulcerative lesion in the jejunum. Biopsy indicated sarcomatoid carcinoma, and partial resection of the small bowel and adjacent transverse colon and omentum was performed. In addition to the T3N0M0 jejunal giant sarcomatoid carcinoma (SCA), a 3-mm small localized peritoneal (omental) malignant mesothelioma (LMM) was also incidentally included. Synchronous presentation of small intestinal and mesothelial malignancies is extremely rare, and the avoidance of incorrect clinical staging is critically important. Surgical resection is still considered the best first-line therapy, because of a poor response to chemotherapy and radiotherapy. Dual-color fluorescent in situ hybridization (FISH) for p16/CDKN2A and chromosome 9 indicated homologous deletion of p16/CDKN2A in SCA and a normal pattern in LMM. Methylthioadenosine phosphorylase (MTAP) was negative in SCA but positive in LMM. Both tumors consistently expressed BRCA1-associated protein 1 (BAP1). Tumor necrosis factor receptor-associated factor 7 (TRAF7) was suppressed, and neural cell adhesion molecule L1 precursor (NCAML1/L1CAM) was agitated in both tumors. Diffuse and strong expression of programmed death-ligand 1 (PD-L1) and the association of tumor-infiltrating lymphocytes in SCA may indicate a potential for PD-L1-targeted immunotherapy for treating this type of aggressive cancer. PD-L1 was focally expressed in LMM. The postoperative course was uneventful for two years.

Epstein-Barr virus-positive mucocutaneous ulcer, plasmablastic type, associated with nodal CD4+ angioimmunoblastic T-cell lymphoma and generalised pruritus: a self-limiting lymphoproliferative disorder resembling cutaneous plasmablastic lymphoma.

A woman in her 80s reported of generalised pruritus, which was treated with phototherapy and steroid administration. Two months after onset, lymph node biopsy revealed CD4+ angioimmunoblastic T-cell lymphoma with systemic superficial nodal involvement. Intractable prurigo was judged as T-cell lymphoma related. After effective chemotherapy (7 months later), skin nodules appeared multifocally, including on the lip, thumb and lower leg. The biopsied infiltrative lesion on the right lower leg microscopically revealed subcutaneous growth of atypical plasmablasts with nearly 100% Ki-67 labelling and Epstein-Barr virus (EBV)-encoded small nuclear RNA positivity. Plasmablastic lymphoma (CD45/CD19/CD38/CD138/MUM1+, CD20/CD79a/PAX5-) was suspected. Immunoglobulin light-chain restriction and nuclear expression of c-myc protein were undetectable, and the ulcers were spontaneously epithelialised by the cessation of steroid administration. After 10 months, non-progressive prurigos persisted on the extremities, but without regrowth of nodal T-cell lymphoma and cutaneous lymphoproliferative lesion. Reactive nature of the EBV-induced mucocutaneous plasmablastic growth (EBV-positive mucocutaneous ulcer, plasmablastic type) is discussed.

High CRP-albumin ratio predicts poor prognosis in transplant ineligible elderly patients with newly diagnosed acute myeloid leukemia.

Acute myeloid leukemia (AML) patients older than 65 years have a poor prognosis. Recently, CAR (C-reactive-protein/albumin ratio) has been actively reported as a prognostic index reflecting the nutritional and inflammatory status of elderly patients with solid tumors, but the usefulness of this index as a prognostic indicator in transplant-ineligible elderly AML patients has not been investigated. We studied genetic alterations and CARs in 188 newly diagnosed AML patients aged 65 years or older who were treated in a multicenter setting and had treated without HSCT. Both NCCN 2017 risk group, reflecting the genetic component of the tumor, and CAR, reflecting the inflammatory and nutritional status of the patient, successfully stratified the overall survival (OS) of the patients (2-year OS; CAR low vs high, 42.3% vs 17.8%, P < 0.001). Furthermore, in multivariate analysis, NCCN 2017 poor group and high CAR were extracted as independent poor prognostic factors predicting 2-year OS in the current study. We found, for the first time, that CAR at diagnosis predicted the prognosis of elderly patients with newly diagnosed AML treated without HSCT.

The safety and efficacy of hematopoietic stem cell mobilization using biosimilar filgrastim in related donors.

In April 2014, the Japan Society for Hematopoietic Cell Transplantation started a prospective observational study entitled "A short-term follow-up investigation of related hematopoietic stem cell donors receiving biosimilar G-CSF to mobilize peripheral blood stem cells." A total of 106 donors were registered from 25 transplant facilities through the end of March 2017. The study cohort consisted of 47 men and 58 women, and their median age was 38.5 years (range 15-65 years). The mean total count of collected CD34-positive cells/recipient body weight for all 106 donors was 4.40 ± 2.38 × 10 6/kg. The yield of CD34-positive cells was weakly correlated with donor age was observed. However, gender, WBC count on day 4, G-CSF dose reduction, type of apheresis device, collection speed, and treated blood volume had no significant impact on the collection efficacy of CD34-positive cells. The safety profile of biosimilar G-CSF was also acceptable: 126 adverse events in 73 donors were reported, but none was serious. The most common adverse events were low back pain, headache, and bone pain. This prospective study confirmed that biosimilar G-CSF had comparable efficacy and safety to reference G-CSF for CD34-positive cell mobilization in healthy related donors.