A Case of Relapsed/Refractory CD56-Positive Acute Promyelocytic Leukemia, in Which Complete Molecular Remission Was Achieved Following Combination Therapy with Venetoclax and Azacitidine.

An 84-year-old woman was diagnosed as having acute promyelocytic leukemia(APL)in July Year X-3. The test for promyelocytic leukemia- retinoic acid receptor alpha(PML-RARA)mRNA was positive, while that for CD56 was negative. Since her white blood cell( WBC) count was <3,000/µL, with a count of APL cells of <1,000/µL, she was started on monotherapy with all-trans retinoic acid(ATRA). In September Year X-3, complete hematological remission(CHR)was confirmed. she refused to provide consent for receiving consolidation therapy. In February Year X-2, hematological relapse occurred. She was started on re-induction therapy with arsenite(ATO), and in June Year X-2, complete molecular remission(CMR)was achieved. She was started on post-remission therapy with ATO. In August Year X-1, she developed molecular relapse and was started on tamibarotene(Am80). In October Year X-1, hematological relapse was detected, and the test for CD56 was positive. She was started on combined venetoclax(VEN)+azacitidine(AZA)(VEN+AZA). After completion of 1 course of treatment, CMR was achieved, but she developed hematological relapse after 5 courses of treatment. She died of gastrointestinal hemorrhage. This is considered a valuable case for accumulating information on the treatment of CD56-positive APL resistant to ATRA and ATO.

A Case of Immune Thrombocytopenia Occurring after Radiotherapy plus Atezolizumab Treatment for Bladder Cancer.

An 84-year-old female developed gross hematuria. She was diagnosed as urinary bladder carcinoma. She was initiated on concurrent atezolizumab plus radiation(a phase Ⅱ clinical trial)(jRCT2031180060). After 8 cycles of atezolizumab, complete response was confirmed. Maintenance atezolizumab treatment was started. Platelet(Plt)count decreased, there was no rechallenge with atezolizumab. Bone marrow examination revealed normal. Plt count recovered. Plt count decreased again. The serum levels of interleukin-6(IL-6)were elevated. She was diagnosed as having immune thrombocytopenia. She was started on treatment with prednisolone(PSL)at dose of 20 mg/day. Plt count was increased.

Bi-glandular and persistent enterovirus infection and distinct changes of the pancreas in slowly progressive type 1 diabetes mellitus.

In slowly progressive type 1 diabetes mellitus (SPIDDM), the pancreas shows sustained islet inflammation, pancreatitis, pancreatic acinar cell metaplasia/dysplasia (ADM), and intraepithelial neoplasia (PanIN), a precancerous lesion. The mechanisms underlying these changes remain unclear. The presence of enterovirus (EV) encoded-capsid protein 1 (VP1) and -2A protease (2Apro) and the innate immune responses of the pancreas were studied using immunohistochemistry and in situ hybridization in 12 SPIDDM and 19 non-diabetic control pancreases. VP1, 2Apro, and EV-RNA were detected in islets and the exocrine pancreas in all SPIDDM pancreases. Innate immune receptor, melanoma differentiation-associated gene 5 (MDA5), and interferon (IFN)-beta1 were intensified in the islets of SPIDDM patients with short disease duration. However, expressions of MDA5 and IFN-beta1were suppressed in those with longer disease duration. CD3+ T cell infiltration was observed in the VP1- and insulin-positive islets (insulitis) and exocrine acinar cells. CD11c+ dendritic cells (DCs) in islets were scarce in long-term SPIDDM. This study showed the consistent presence of EV, suggesting an association with inflammatory changes in the endocrine and exocrine pancreas in SPIDDM. Suppressed expressions of MDA5 and IFN-beta1, as well as decreased numbers of DCs in the host cells, may contribute to persistent EV infection and induction of ADM/PanIN lesions, which may potentially provide a scaffold for pancreatic neoplasms.

A Case of Diffuse Large B-Cell Lymphoma Complicated by Helicobacter Pylori-Negative Russell Body Gastritis.

A 76-year-old woman with a past history of diabetes mellitus and Hashimoto's disease, in regard to her personal history, she did not smoke or drink alcohol. In March, year X-1, she became aware of cervical lymphadenopathy. Based on the findings of lymph node biopsy, she was diagnosed as having diffuse large B-cell lymphoma(DLBCL). An upper gastrointestinal endoscopy(U-GIE)revealed white granular prominences in the gastric fornix, and biopsy of these lesions revealed the diagnosis of Russell body gastritis(RBG). Neither lymphoma infiltration nor other malignant findings were found. Diagnostic tests for Helicobacter pylori were negative. The clinical stage of the DLBCL was determined as stage ⅢA, and the International Prognostic Index was"high intermediate". She received 6 cycles of R-CHOP therapy, with concomitant use of a proton pump inhibitor. Complete remission was confirmed in November, year X-1. An U-GIE performed again no longer showed the white granular prominences in the gastric fornix. The present report is the first of DLBCL complicated by RBG; our findings suggested that the two diseases were associated with each other.

Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma Associated with Nephrotic Syndrome during Hemodialysis, Treated Successfully with Tirabrutinib.

A 74-year-old woman was diagnosed with Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) in X-18. Fludarabine plus rituximab (FR) was started, and she showed remission. In July X-7, the serum creatinine (Cr) level increased to 1.67 mg/dL, and bendamustine plus rituximab (BR) was started. By November X-7, the Cr level had increased to 8.41 mg/dL, so she was started on hemodialysis (HD). In September X-1, she developed nephrotic syndrome. She was started on tirabrutinib at 480 mg. In July X, her nephrotic syndrome had improved, and a complete response (CR) was achieved. This is the first case of the administration of tirabrutinib in a patient undergoing HD.

Kasumi leukemia cell lines: characterization of tumor genomes with ethnic origin and scales of genomic alterations.

Kasumi-1 has played an important role in an experimental model with t(8;21) translocation, which is a representative example of leukemia cell lines. However, previous studies using Kasumi-1 show discrepancies in the genome profile. The wide use of leukemia cell lines is limited to lines that are well-characterized. The use of additional cell lines extends research to various types of leukemia, and to further explore leukemia pathogenesis, which can be achieved by uncovering the fundamental features of each cell line with accurate data. In this study, ten Kasumi cell lines established in Japan, including five that were previously unknown, have been characterized by SNP microarray and targeted sequencing. SNP genotyping suggested that the genetic ancestry in four of the ten Kasumi cell lines was not classified as Japanese but covered several different east-Asian ethnicities, suggesting that patients in Japan are genetically diverse. TP53 mutations were detected in two cell lines with complex array profiles, indicating chromosomal instability (CIN). A quantitative assessment of tumor genomes at the chromosomal level was newly introduced to reveal total DNA sizes and Scales of Genomic Alterations (SGA) for each cell line. Kasumi-1 and 6 derived from relapsed phases demonstrated high levels of SGA, implying that the level of SGA would reflect on the tumor progression and could serve as an index of CIN. Our results extend the leukemia cellular resources with an additional five cell lines and provide reference genome data with ethnic identities for the ten Kasumi cell lines.

Selectively high efficacy of eribulin against high-grade invasive recurrent and/or metastatic squamous cell carcinoma of the head and neck.

Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) have a poor prognosis. Over the past decade, a major development in the first-line treatment of R/M SCCHN was the introduction of cetuximab in combination with platinum plus 5-fluorouracil chemotherapy. Currently, a promising novel treatment option in R/M SCCHN has emerged, termed immune checkpoint inhibitors. However, only a few patients presenting with R/M SCCHN have exhibited meaningful tumor regression with these agents. Therefore, novel agents are required to order improve the overall survival of patients with R/M SCCHN. Recently, we demonstrated that R/M SCCHN cells are highly sensitive to eribulin. In the present study, the effects of eribulin, paclitaxel and vinblastine were investigated in R/M SCCHN (OLC-01 and OSC-19) and locally advanced SCCHN (OSC-20) cells. Tumour-inhibitory activities of eribulin against R/M SCCHN were evaluated in orthotopic xenograft models. The data revealed that eribulin has sub-nM growth inhibitory activities in vitro against OLC-01 cells, and that it is more potent than paclitaxel and vinblastine. The reduced expression of Tubulin Beta 3 Class III (TUBB3) following treatment was correlated with a high sensitivity to eribulin. Histological analysis of OLC-01 cells in NOD-SCID mice demonstrated that they had a higher invasiveness in the tissue around the alveolar cancer when compared with the histology of OSC-19 cells, which has been reported in our previous study. Treatment with eribulin revealed marked inhibitory activities in vivo at 0.125 mg/kg against OLC-01 cells orthotopic xenografts. In conclusion, the results highlight the existence of invasive-type heterogeneity in R/M SCCHN with respect to eribulin sensitivity. Eribulin is already an approved clinical agent; therefore, the continued investigation of its preclinical antitumor attributes may contribute significantly to the future process of identifying novel uses of eribulin against R/M SCCHN.

Isolated pancreatic metastasis from malignant melanoma: a case report and literature review.

Isolated pancreatic metastasis from malignant melanoma is rare. Pancreatic metastasis is difficult to diagnose in patients with unknown primary malignant melanoma. Endoscopic ultrasound-guided fine-needle aspiration plays an important role in confirming the diagnosis. A 67-year-old woman was referred to our institution because of a mass in her pancreas. Computed tomography and magnetic resonance imaging revealed a 35-mm mass localized on the pancreatic tail, with low attenuation, surrounded by a high-attenuation rim. Endoscopic ultrasonography revealed a hypoechoic mass with central anechoic areas. Endoscopic ultrasound-guided fine-needle aspiration of the mass was performed, and the pathological diagnosis was malignant melanoma. Intense fluorodeoxyglucose uptake was observed in the pancreatic tail on positron emission tomography-computed tomography. No other malignant melanoma was found. Distal pancreatectomy was performed. Six months postoperatively, positron emission tomography-computed tomography revealed high uptake in the left nasal cavity, and biopsy revealed the mass to be a malignant melanoma, indicating that the primary site of the malignant melanoma was the left nasal cavity and that the pancreatic mass and peritoneal lesion were metastases. The patient had survived > 2 years after the distal pancreatectomy. Pancreatic resection of isolated pancreatic metastasis can possibly prolong survival; however, metastatic melanoma usually has poor prognosis.

Increase of apoplastic ascorbate induced by ozone is insufficient to remove the negative effects in tobacco, soybean and poplar.

Apoplastic ascorbate (ASCapo) is an important contributor to the detoxification of ozone (O3). The objective of the study is to explore whether ASCapo is stimulated by elevated O3 concentrations. The detoxification of O3 by ASCapo was quantified in tobacco (Nicotiana L), soybean (Glycine max (L.) Merr.) and poplar (Populus L), which were exposed to charcoal-filtered air (CF) and elevated O3 treatments (E-O3). ASCapo in the three species were significantly increased by E-O3 compared with the values in the filtered treatment. For all three species, E-O3 significantly increased the malondialdehyde (MDA) content and decreased light-saturated rate of photosynthesis (Asat), suggesting that high O3 has induced injury/damage to plants. E-O3 significantly increased redox state in the apoplast (redox stateapo) for all species, whereas no effect on the apoplastic dehydroascorbate (DHAapo) was observed. In leaf tissues, E-O3 significantly enhanced reduced-ascorbate (ASC) and total ascorbate (ASC+DHA) in soybean and poplar, but significantly reduced these in tobacco, indicating different antioxidative capacity to the high O3 levels among the three species. Total antioxidant capacity in the apoplast (TACapo) was significantly increased by E-O3 in tobacco and poplar, but leaf tissue TAC was significantly enhanced only in tobacco. Leaf tissue superoxide anion (O2•-) in poplar and hydrogen peroxide (H2O2) in tobacco and soybean were significantly increased by E-O3. The diurnal variation of ASCapo, with maximum values occurring in the late morning and lower values experienced in the afternoon, appeared to play an important role in the harmful effects of O3 on tobacco, soybean and poplar.

Long-Term Outcomes of 107 Cases of Primary Thyroid Mucosa-Associated Lymphoid Tissue Lymphoma at a Single Medical Institution in Japan.

Context: Thyroid mucosa-associated lymphoid tissue (MALT) lymphoma is a type of extranodal lymphoma with a favorable prognosis. Objective: To provide information on long-term outcomes that would facilitate establishment of the optimal management strategy for thyroid lymphoma. Design, Setting, and Participants: Medical records of 107 patients (median age 67 years, 20 males, 87 females) who were diagnosed with localized thyroid MALT lymphoma stage IE or IIE at Ito Hospital were retrospectively reviewed. Main Outcome Measure: Overall and event-free survival (EFS). Results: Initial treatments included radiation therapy (RT) alone (n = 58), combined modality therapy (CMT) (n = 48), or chemotherapy alone (n = 1). All 107 patients responded to the treatment, six of whom experienced relapse. Only one patient died of lymphoma. The 5-year overall survival (OS) and EFS rates were 94% [95% confidence interval (CI), 87% to 97%] and 92% (95% CI, 85% to 95%), respectively, and the 10-year OS and EFS rates were 91% (95% CI, 83% to 95%) and 84% (95% CI, 74% to 90%), respectively. Of the 106 patients with information available on adverse events, 71 patients (67%) developed hypothyroidism after primary thyroid lymphoma treatment. The CMT group showed additional chemotherapy-induced adverse reactions in the form of neutropenia, neuropathy, constipation, and pneumonia. The 5-year OS rates of patients treated with CMT and RT were 93% (95% CI, 81% to 98%) and 94% (95% CI, 84% to 98%), respectively. Conclusions: Long-term outcomes of localized thyroid MALT lymphoma are favorable with all initial treatment modalities.

Evaluation of an e-learning system for diagnosis of gastric lesions using magnifying narrow-band imaging: a multicenter randomized controlled study.

Background and study aim Magnifying narrow-band imaging (M-NBI) is useful for the accurate diagnosis of early gastric cancer (EGC). However, acquiring skill at M-NBI diagnosis takes substantial effort. An Internet-based e-learning system to teach endoscopic diagnosis of EGC using M-NBI has been developed. This study evaluated its effectiveness. Participants and methods This study was designed as a multicenter randomized controlled trial. We recruited endoscopists as participants from all over Japan. After completing Test 1, which consisted of M-NBI images of 40 gastric lesions, participants were randomly assigned to the e-learning or non-e-learning groups. Only the e-learning group was allowed to access the e-learning system. After the e-learning period, both groups received Test 2. The analysis set was participants who scored < 80 % accuracy on Test 1. The primary end point was the difference in accuracy between Test 1 and Test 2 for the two groups. Results A total of 395 participants from 77 institutions completed Test 1 (198 in the e-learning group and 197 in the non-e-learning group). After the e-learning period, all 395 completed Test 2. The analysis sets were e-learning group: n = 184; and non-e-learning group: n = 184. The mean Test 1 score was 59.9 % for the e-learning group and 61.7 % for the non-e-learning group. The change in accuracy in Test 2 was significantly higher in the e-learning group than in the non-e-learning group (7.4 points vs. 0.14 points, respectively; P < 0.001). Conclusion This study clearly demonstrated the efficacy of the e-learning system in improving practitioners' capabilities to diagnose EGC using M-NBI.Trial registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN000008569).

Impact of the automatic rounding-off function of the computerized physician order entry system on the ordering time and dose dispersion of chemotherapeutic drugs in regimens for hematologic malignancies.

INTRODUCTION: EGMAIN-GX is the computerized physician order entry system used in Japan. The automatic rounding-off of the calculated dose of chemotherapeutic drugs is an update in version 4, compared to version 2. We conducted a comparative study between EGMAIN-GX versions 2 and 4 to estimate the effect of the automatic rounding-off function on ordering time and dose dispersion. METHODS: Twelve hematologists ordered 5 predefined chemotherapeutic regimens most commonly used in treating hematologic malignancies, twice for each regimen. RESULTS: EGMAIN-GX version 4 significantly reduced ordering times compared to version 2 (635s vs. 259s, p<0.01). EGMAIN-GX version 4 also yielded a significantly higher ratio of actual to ideal doses of chemotherapeutic drugs than did version 2 (1.0097 and 0.9997, respectively; p<0.01) and a lower standard deviation (0.0275 and 0.0290, respectively). CONCLUSIONS: The automatic rounding-off function could decrease the ordering time and dose dispersion of chemotherapeutic drugs.

Diagnostic Accuracy on Magnetic Resonance Imaging for the Diagnosis of Osteoarthritis of the Temporomandibular Joint.

OBJECTIVES: Osteoarthritis, which is also called degenerative arthritis or degenerative joint disease, is primarily a disease that results from the breakdown and loss of cartilage in joints. The purpose of this study was to investigate the diagnostic accuracy of magnetic resonance images for the diagnosis of osteoarthritis of the temporomandibular joint. MATERIALS AND METHODS: Fifty patients (50 joints) with closed locking of the temporomandibular joint were examined with magnetic resonance imaging and then underwent arthroscopic surgery. The agreement of osteoarthritis between magnetic resonance images and arthroscopic findings was studied using the κ coefficient. RESULTS: The incidence of osteoarthritis on magnetic resonance images (38%) was significantly lower than that in arthroscopic findings (78%). There was no significant agreement between these two findings (p=.108). The κ coefficient was 0.154. CONCLUSION: The diagnostic accuracy of magnetic resonance images for osteoarthritis of the temporomandibular joint was low; early osteoarthritis could not be diagnosed from magnetic resonance images. Clinicians should understand that the diagnostic accuracy of osteoarthritis without arthroscopy is not always high.

Rituximab-including combined modality treatment for primary thyroid lymphoma: an effective regimen for elderly patients.

BACKGROUND: Primary thyroid lymphoma (PTL) develops mostly in middle-aged and older females. However, the optimal treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL), which accounts for most PTL cases, is unclear. Rituximab is a promising drug that, in combination with traditional combination therapy, has demonstrated an increased antitumor effect without a substantial increase in toxicity. In this study, treatment outcomes of elderly patients with thyroid DLBCL who underwent rituximab-including combination therapy were analyzed. METHOD: Between January 2005 and December 2011, 43 patients 60 years of age or older (median 71 years, range 60-80 years) were diagnosed as having stage IE (n=12) or stage IIE (n=31) DLBCL, and three courses of R-CHOP therapy (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, adriamycin 40 mg/m2, vincristine 1.4 mg/m2, and prednisolone 100 mg/body) and involved field irradiation were planned. Treatment outcomes of these patients were retrospectively reviewed. RESULTS: Two patients terminated the treatment because of interstitial pneumonia during R-CHOP therapy. Only one patient showed treatment resistance and the regimen was changed; 42 patients (98%) responded to the treatment. Five-year overall survival and event-free survival were 87% (95% confidence interval [95% CI], 64-96%) and 74% (95% CI, 50-89%), respectively. CONCLUSION: The results of the present study indicate that rituximab-including combination therapy was effective for elderly patients with thyroid DLBCL. A multicenter, long-term observational study is needed to confirm this, and additional refinement of the treatment protocol is required to optimize the antitumor effect.

[A case of alpha-fetoprotein-producing fetal gut-like small intestinal cancer].

A 72-year-old Japanese woman was admitted because of vomiting and abdominal pain. An enhanced computed tomography scan showed a small intestinal obstruction due to ileal wall thickening and multiple liver metastases. Her serum alpha-fetoprotein (AFP) level was high at 1671.9ng/ml. An ileocecal resection was performed. The histological diagnosis was AFP-producing small intestinal cancer resembling the primitive gut epithelium of a fetus. The present case suggested that even intestinal cancer could produce AFP.

Changes in metabolic profiles after the Great East Japan Earthquake: a retrospective observational study.

BACKGROUND: A magnitude 9.0 earthquake struck off eastern Japan in March 2011. Many survivors have been living in temporary houses provided by the local government since they lost their houses as a result of the great tsunami (tsunami group) or the expected high-dose radiation resulting from the nuclear accident at the Fukushima Daiichi Nuclear Power Plant (radiation group). The tsunami was more than 9 m high in Soma, Fukushima, which is located 30 km north of the Fukushima Daiichi Nuclear Power Plant and adjacent to the mandatory evacuation area. A health screening program was held for the evacuees in Soma in September 2011. The aim of this study was to compare the metabolic profiles of the evacuees before and after the disaster. We hypothesized that the evacuees would experience deteriorated metabolic status based on previous reports of natural disasters. METHODS: Data on 200 subjects who attended a health screening program in September or October of 2010 (pre-quake) and 2011 (post-quake) were retrospectively reviewed and included in this study. Pre-quake and post-quake results of physical examinations and laboratory tests were compared in the tsunami and radiation groups. A multivariate regression model was used to determine pre-quake predictive factors for elevation of hemoglobin A1c (HbA1c) in the tsunami group. RESULTS: Significantly higher values of body weight, body mass index, waist circumference, and HbA1c and lower high-density lipoprotein cholesterol levels were found at the post-quake screening when compared with the pre-quake levels (p = 0.004, p = 0.03, p = 0.008, p < 0.001, and p = 0.03, respectively). A significantly higher proportion of subjects in the tsunami group with high HbA1c, defined as ≥ 5.7%, was observed after the quake (34.3%) than before the quake (14.8%) (p < 0.001). Regional factors, periodic clinic visits, and waist circumference before the quake were identified as predictive factors on multivariate analysis for the deterioration of HbA1c. CONCLUSIONS: Post-quake metabolic variables were impaired compared with pre-quake baseline levels in survivors who were living in temporary houses. A natural disaster could affect metabolic profiles, and careful follow-up for survivors should be planned.