Unveiling the Nature of Chemical Bonds in Real Space.

Recent advent of diverse chemical entities necessitates a re-evaluation of chemical bond concepts, underscoring the importance of experimental evidence. Our prior study introduced a general methodology, termed Core Differential Fourier Synthesis (CDFS), for mapping the distribution of valence electron density (VED) in crystalline substances within real space. In this study, we directly compare the VED distributions obtained through CDFS with those derived from high-accuracy theoretical calculation using long-range corrected density functional theory, which quantitatively reproduces accurate orbital energies. This comparison serves to demonstrate the precision of the CDFS in replicating complex details. The VED patterns observed experimentally exhibited detailed structures and phases of wave functions indicative of sp3 hybrid orbitals, closely aligning with theoretical predictions. This alignment underscores the utility of our approach in gathering quantum chemical data experimentally, a crucial step for discussing the chemical properties, such as reaction mechanisms.

Giant impurity effect on anomalous Hall effect of Mn3Sn.

Mn3Sn is an anomalous Hall effect (AHE) antiferromagnet that exhibits the hysteretic AHE in antiferromagnetic (AFM) phase at room temperature. We report that whisker Mn3Sn crystals grown by the flux method exhibit a non-hysteretic AHE at mid-to-low temperatures when the whisker Mn3Sn is surrounded by a thin layer of ferromagnetic Mn2-xSn. These crystals exhibit a hysteretic AHE above 275 K due to the spin alignment of the inverse triangular lattice, which is similar to other crystals. However, upon cooling the crystal, it exhibits a non-hysteretic AHE with a spiral AFM spin structure at 100-200 K. We concluded that the non-hysteretic AHE is induced at the interface of Mn2-xSn/Mn3Sn. We believe that the scalar-spin chirality in the spiral AFM phase of Mn3Sn, modulated by Mn2-xSn through the magnetic proximity effect, produces the AHE. This discovery opens a new avenue for tailoring the AHE by magnetic layers.

Impaction bone grafting for femoral revision hip arthroplasty with Exeter stem in Japan: An extended 10- to 15-year stem survival analysis of the previously reported series.

BACKGROUND: Femoral impaction bone grafting (IBG) was introduced in the late 1990s in Japan and has gradually become recognized as a useful option for femoral revision. The aim of the present study was to retrospectively analyze 10 to 15 years of clinical results of femoral revision arthroplasties of IBG using Exeter stem performed by experienced Japanese surgeons. METHODS: We investigated radiographic and clinical records more than 2 years after surgery in 99 hips of 93 patients. The average age was 66.3 years (36-84 years) and the average follow-up period was 11 years (2-23 years and 8 months). Merle d'Aubigné and Postel hip score was used for clinical assessment, and re-operations for any reason were recorded. The survival curve was estimated using Kaplan-Meier method. RESULTS: The mean Merle d'Aubigné and Postel hip score improved from 9.0 points to 14.5 points at the final follow-up. Re-operations were undertaken in 15 hips of 14 patients for aseptic acetabular component loosening (n = 1 hip), recurrent dislocation (n = 2 hips), infection (n = 4 hips), and periprosthetic femoral fracture (n = 8 hips). The survival rates at 10 and 15 years after operation were 87.1% and 81.1% with any type of re-operation as the endpoint, 92.2% and 92.2% with stem removal or exchange as the endpoint, 94.9% and 88.1% with re-operation for periprosthetic femoral fracture as the endpoint, and 99.0% and 99.0% with re-operation for aseptic stem loosening as the endpoint, respectively. CONCLUSIONS: The present study showed encouraging results of femoral IBG over 10 years by experienced surgeons in Japan. Although femoral IBG is recognized as a technically complex procedure, survivorship of the stem is excellent, with a 15-year stem survival rate of 99.0% at the end point of aseptic loosening.

Four stem fractures in a 12-year follow-up study of 9,135 patients with Exeter hip stems at seven teaching facilities in Japan.

BACKGROUND: Although excellent long-term results have been reported for the Exeter stem, stem fracture is recognized as a rare complication. However, there have been no reports on the incidence and risk factors for stem fractures based on detailed population information. This study aimed to clarify the incidence of Exeter hip stem fracture based on detailed population information from seven Exeter stem teaching centers in Japan and to examine the risk factors for stem fracture. METHODS: A total of 8,499 primary total hip arthroplasties (THA) and 636 revision hip arthroplasties (revisions) performed at seven Exeter teaching hospitals between 1999 and 2021 were included and retrospectively investigated based on medical records. RESULTS: Stem fractures were identified in two primary THA (fracture rate: 0.02%) and two revision THA (fracture rate: 0.21%) cases. The stem length was ≤125 mm in three out of these four cases. Revision and 30 stem were the risk factors for stem fractures. Weight and body mass index (BMI) were not significantly associated with the occurrence of stem fractures. CONCLUSIONS: In Western countries, the incidence of Exeter stem fractures is reportedly 0.017-0.15% for primary THA and 0.99-1.21% for revision THA. In this study, the incidence of primary THA was 0.02%, which is similar to the lowest reported rate, whereas the incidence of revision THA was 0.21%, which is lower than that reported in previous studies. Revision surgery had the same risk factors as those reported in the West-namely, stem length ≤125 mm (except for the 30 stem) and BMI, which were not risk factors in Japanese patients.

Multi-center study of use of the Exeter stem in Japan: a 10-year follow-up report.

PURPOSE: Since the introduction of the Exeter stem for clinical use in Japan in 1996, the number of stems used has continued to rise owing to its favorable results. We investigated the outcomes of patients who had previously undergone total hip arthroplasty with the Exeter stem in Japan with a 10-year + follow-up period. METHODS: This retrospective cohort study used clinical and radiographic data of 682 cases of primary total hip arthroplasty performed using the Exeter stem. RESULTS: The mean postoperative follow-up period was 13.3 years. Femoral-side revision was required in 14 hips, with no cases of aseptic stem loosening-associated revision observed. Kaplan-Meier survival analysis predicted 97.3% 15-year survival when revision for any reason was used as the endpoint. CONCLUSION: The obtained findings suggested the excellent long-term stability of the Exeter stem for primary total hip arthroplasty in Japan.

Overestimation of fibrinogen concentration in cryoprecipitate by repeated freeze-thawing with long thawing period as used in the Clauss method.

BACKGROUND: Cryoprecipitate (CRY) is widely used for treating acquired hypofibrinogenemia. During our study to determine an optimal preparation method, we noticed that the measurement of fibrinogen concentration in CRY had a risk of overestimation. We analyzed this condition and mechanism. STUDY DESIGN AND METHODS: CRY was prepared from fresh frozen plasma (FFP) under four conditions: A, 30 h thawing time, 2 cycles; B, 24 h thawing time, 2 cycles; C, 30 h thawing time, 1 cycle; and D, 24 h thawing time, 1 cycle. Then, fibrinogen concentrations in CRY and cryosupernatant (CS) were measured by the Clauss method. RESULTS: Purification (CRY/CRY+CS) and recovery (CRY/FFP) rates in CRY prepared under 2-cycle conditions were higher than those under 1 cycle. However, recovery rates often exceeded 100%, particularly in the case of CRY prepared under A condition, and fibrinogen concentrations calculated by direct measurement were higher than those indirectly calculated from FFP and CS, suggesting an overestimation of fibrinogen values. The level of soluble fibrin monomer complex was considerably higher in CRY prepared under A than under D condition, indicating that CRY adopted a hypercoagulated state. We further found that repeated thawing/freezing increased fibrinogen values as measured by the Clauss method while mechanical vortexing did not. DISCUSSION: Our findings suggest that direct assessment of fibrinogen contents in CRY prepared by repeated freeze-thawing with a longer thawing period presents a higher risk of overestimation. For the purpose of quality control, we propose an alternative method to indirectly estimate fibrinogen concentrations in CRY from those of CS and FFP.

Superconductivity in High-Entropy Antimonide M1-xPtxSb (M = Equimolar Ru, Rh, Pd, and Ir).

The high-entropy concept was applied to the synthesis of transition-metal antimonides, M1-xPtxSb (M = equimolar Ru, Rh, Pd, and Ir). High-entropy antimonide samples crystallized in a pseudo-hexagonal NiAs-type crystal structure with a P63/mmc space group were successfully synthesized through a conventional solid-state reaction and subsequent quenching. A detailed investigation of the composition and equilibration conditions confirmed the reversible phase transition between a multiphase state at low temperature and an entropy-driven single-phase solid solution at high temperatures. Electrical resistivity, magnetization, and heat capacity measurements of single-phase M1-xPtxSb (x = 0.2) samples revealed a bulk superconducting transition at 2.15(2) K. This study demonstrates that the high-entropy concept provides numerous opportunities for the discovery of new functional materials such as superconductors.

Mean 14-year Outcomes of Hybrid Total Hip Arthroplasty Using Bulk Femoral Head Autografts for Acetabular Reconstruction.

BACKGROUND: We aimed to evaluate the mean 14-year outcomes of hybrid total hip arthroplasty (THA) with cementless acetabular cups using bulk femoral head autografts in acetabular reconstruction and specify the radiological characteristics of cementless acetabular cups using this technique. METHODS: This retrospective study included 98 patients (123 hips) who underwent hybrid THA with a cementless acetabular cup using bulk femoral head autografts for bone deficiency in acetabular dysplasia and who were followed-up for a mean of 14 years (range, 10 to 19.6). The percentage of bone coverage index (BCI) and cup center-edge (CE) angles were evaluation radiologically of acetabular host bone coverage. The survival rate of the cementless acetabular cup and autograft bone ingrowth were assessed. RESULTS: The survival rate with all revisions of cementless acetabular cups was 97.1% (95% confidence interval: 91.2 to 99.1). The autograft bone was remodeled or reoriented in all cases except in 2 hips where the bulk femoral head autograft collapsed. Radiological evaluation revealed a mean cup CE angle of -17.8° (range, -52 to -7°) and a BCI of 44.4% (range, 10 to 75.4%). CONCLUSION: Cementless acetabular cups using bulk femoral head autografts for bone deficiency of the acetabular roof remained stable even if the average BCI was 44.4% and the average cup CE angle was -17.8°. Cementless acetabular cups using these techniques showed good 10-year to 19.6-year outcomes and viabilities of graft bones.

Total hip arthroplasty with femoral shortening osteotomy using polished cemented stem vs. modular cementless stem in patients with Crowe type IV developmental dysplasia of the hip.

INTRODUCTION: There is still little information regarding the advantages of a using a polished tapered stem for Crowe Type IV developmental dysplasia of the hip (DDH). This study aimed to investigate the mid-term clinical and radiological outcomes of primary total hip arthroplasty (THA) with femoral shortening osteotomy using modular and polished tapered stems and to compare the results between the modular and polished tapered stems. MATERIALS AND METHODS: This retrospective review included 32 patients (37 hips) with Crowe type IV DDH who underwent primary THA with femoral shortening osteotomy using a modular stem (cementless group, 14 hips) or a polished tapered stem (cement group, 23 hips) between 1996 and 2018. Clinical data and radiographic assessments were reviewed to analyze the differences between the two groups. RESULTS: The mean duration of patient follow-up of the cementless group (134.4 months) was longer than that of the cement group (75.5 months). There were no differences in clinical results, time of bone union, and survival rate between the two groups. However, the cementless group exhibited a higher ratio of intraoperative fracture and thinning of cortical bone including stress shielding, medullary changes, stem alignment changes, and osteolysis, compared to the cement group. CONCLUSIONS: The findings of this study suggest that THA with femoral shortening osteotomy using both cemented and modular stems can provide satisfactory results. However, considering the occurrence of intraoperative fracture and radiographic analysis in the current study, the cement stem may have an advantage for patients with bone fragility and deterioration in bone quality.

Linear Trimer Molecule Formation by Three-Center-Four-Electron Bonding in a Crystalline Solid RuP.

Some inorganic solids undergo phase transitions that result in the formation of "molecules" in their crystalline frameworks, which are frequently accompanied by dramatic changes in physical properties; the metal-insulator transition (MIT) in vanadium dioxide, for instance, is accompanied by the formation of dimer molecules with conventional two-center-two-electron bonding. We have discovered the creation of a linear ruthenium trimer with atypical three-center-four-electron bonding in ruthenium monophosphide at its MIT. Our detailed structural investigation and electronic structure calculations reveal that charge transfer from polymerized phosphorous to ruthenium automatically tunes the electron density to precisely four per trimer at the MIT, with all conduction electrons present at high temperatures being trapped by the trimer's molecular orbitals at low temperatures. Our results demonstrate that molecules are essential even in solid crystals, as they impact their electronic properties.

Long-term outcomes and central nervous system relapse in extranodal natural killer/T-cell lymphoma.

To elucidate the long-term outcomes of non-anthracycline-containing therapies and central nervous system (CNS) events in patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL), the clinical data of 313 patients with ENKTL diagnosed between 2000 and 2013 in a nationwide retrospective study in Japan were updated and analyzed. At a median follow-up of 8.4 years, the 5-year overall survival (OS) and progression-free survival (PFS) were 71% and 64%, respectively, in 140 localized ENKTL patients who received radiotherapy-dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) in clinical practice. Nine (6.4%) patients experienced second malignancies. In 155 localized ENKTL patients treated with RT-DeVIC, 10 (6.5%) experienced CNS relapse (median, 12.8 months after diagnosis). In five of them, the events were confined to the CNS. Nine of the 10 patients who experienced CNS relapse died within 1 year after CNS relapse. Multivariate analysis identified gingival (hazard ratio [HR], 54.35; 95% confidence interval [CI], 8.60-343.35) and paranasal involvement (HR, 7.42; 95% CI, 1.78-30.89) as independent risk factors for CNS relapse. In 80 advanced ENKTL patients, 18 received steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy as first-line treatment. Patients who received SMILE as their first-line treatment tended to have better OS than those who did not (p = 0.071). Six (7.5%) advanced ENKTL patients experienced isolated CNS relapse (median, 2.6 months after diagnosis) and died within 4 months of relapse. No second malignancies were documented in advanced ENKTL patients. In the entire cohort, the median OS after first relapse or progression was 4.6 months. 12 patients who survived 5 years after PFS events were disease-free at the last follow-up. Of those, 11 (92%) underwent hematopoietic stem cell transplantation. Our 8-year follow-up revealed the long-term efficacy and safety of RT-DeVIC and SMILE. The risk of CNS relapse is an important consideration in advanced ENKTL.

Clinical utility of oral management in allogeneic hematopoietic stem cell transplantation recipients: microbiological evidence based on molecular analysis of oral bacteria.

PURPOSE: This study aimed to clarify the clinical utility of oral management to prevent bloodstream infections by oral bacteria microbiologically in patients undergoing allogeneic hematopoietic stem cell transplantation (ASCT). METHODS: Ten consecutive patients with hematological malignancies undergoing ASCT were enrolled in this study. We implemented dental treatments before transplantation, if required, and carried out oral hygiene instructions and oral management every other day after transplantation. Molecular analysis of bacterial DNA for seven oral species using a polymerase chain reaction (PCR) assay was performed for oral samples and peripheral blood once a week for 3 weeks after transplantation. RESULTS: Periodontitis was found in all 10 patients (mild grade in 3 and middle grade in 7) for whom basic periodontal therapy was conducted. Necessary dental procedures, including tooth extraction were performed in 5 patients. After transplantation, oral mucositis occurred in 10 patients (grade 1 in 3, grade 2 in 2, and grade 3 in 5) for whom oral hygiene instruction and oral care were continued every other day. PCR-identified three to six bacterial species in oral samples from nine patients, but none in peripheral blood from any patient during the observation period. CONCLUSIONS: Our study suggests that oral management could prevent bloodstream infections by oral bacteria in ASCT recipients despite the existence of periodontitis or oral mucositis. Its utility was confirmed by microbiological evidence based on molecular data.

Multi-centre study of cement-in-cement and in-cement femoral revision total hip arthroplasty using polished, stainless steel stems.

BACKGROUND: Exposure of the acetabular component during revision total hip arthroplasty is often difficult and stems are often difficult to remove. Polished and tapered cemented stems are easily removed and can be easily reconstructed by either cement-in-cement or in-cement technique. This study was a retrospective review of the medium-term outcomes of revision total hip arthroplasty conducted with the Exeter stem fixed by cement-in-cement or in-cement method in four institutions. METHODS: This study included hips (n = 103) reconstructed by cement-in-cement or in-cement technique on the femoral side during revision total hip arthroplasty in four institutions between 2003 and 2015. The mean age at surgery was 71.1 years (range, 43-86 years), and the mean follow-up period was 5.6 years (range, 0-13 years). RESULTS: Revision arthroplasty was required for acetabular component complications in 69 hips, for dislocation in 25, for infection in eight, and for stem fracture in one hip. Re-revision was required in 10 hips for: infection (n = 6), acetabular component complications (n = 3), and dislocation (n = 1). No radiographic loosening, cement fractures, or osteolysis of the femoral components were observed. Ten-year survival rate was 99% with the endpoint of femoral revision surgery, and 100% with the endpoint of femoral aseptic loosening. CONCLUSIONS: The medium-term outcomes of revision total hip arthroplasty on the femoral side conducted using the cement-in-cement or in-cement technique were favourable, with no cases of aseptic loosening. As long as the bone-cement interface remains robust, there is no need to remove all the cement, and the cement-in-cement or in-cement technique should be used for reconstruction.

Artificial intelligence diagnostic system predicts multiple Lugol-voiding lesions in the esophagus and patients at high risk for esophageal squamous cell carcinoma.

BACKGROUND: It is known that an esophagus with multiple Lugol-voiding lesions (LVLs) after iodine staining is high risk for esophageal cancer; however, it is preferable to identify high-risk cases without staining because iodine causes discomfort and prolongs examination times. This study assessed the capability of an artificial intelligence (AI) system to predict multiple LVLs from images that had not been stained with iodine as well as patients at high risk for esophageal cancer. METHODS: We constructed the AI system by preparing a training set of 6634 images from white-light and narrow-band imaging in 595 patients before they underwent endoscopic examination with iodine staining. Diagnostic performance was evaluated on an independent validation dataset (667 images from 72 patients) and compared with that of 10 experienced endoscopists. RESULTS: The sensitivity, specificity, and accuracy of the AI system to predict multiple LVLs were 84.4 %, 70.0 %, and 76.4 %, respectively, compared with 46.9 %, 77.5 %, and 63.9 %, respectively, for the endoscopists. The AI system had significantly higher sensitivity than 9/10 experienced endoscopists. We also identified six endoscopic findings that were significantly more frequent in patients with multiple LVLs; however, the AI system had greater sensitivity than these findings for the prediction of multiple LVLs. Moreover, patients with AI-predicted multiple LVLs had significantly more cancers in the esophagus and head and neck than patients without predicted multiple LVLs. CONCLUSION: The AI system could predict multiple LVLs with high sensitivity from images without iodine staining. The system could enable endoscopists to apply iodine staining more judiciously.

Detecting early gastric cancer: Comparison between the diagnostic ability of convolutional neural networks and endoscopists.

OBJECTIVES: Detecting early gastric cancer is difficult, and it may even be overlooked by experienced endoscopists. Recently, artificial intelligence based on deep learning through convolutional neural networks (CNNs) has enabled significant advancements in the field of gastroenterology. However, it remains unclear whether a CNN can outperform endoscopists. In this study, we evaluated whether the performance of a CNN in detecting early gastric cancer is better than that of endoscopists. METHODS: The CNN was constructed using 13,584 endoscopic images from 2639 lesions of gastric cancer. Subsequently, its diagnostic ability was compared to that of 67 endoscopists using an independent test dataset (2940 images from 140 cases). RESULTS: The average diagnostic time for analyzing 2940 test endoscopic images by the CNN and endoscopists were 45.5 ± 1.8 s and 173.0 ± 66.0 min, respectively. The sensitivity, specificity, and positive and negative predictive values for the CNN were 58.4%, 87.3%, 26.0%, and 96.5%, respectively. These values for the 67 endoscopists were 31.9%, 97.2%, 46.2%, and 94.9%, respectively. The CNN had a significantly higher sensitivity than the endoscopists (by 26.5%; 95% confidence interval, 14.9-32.5%). CONCLUSION: The CNN detected more early gastric cancer cases in a shorter time than the endoscopists. The CNN needs further training to achieve higher diagnostic accuracy. However, a diagnostic support tool for gastric cancer using a CNN will be realized in the near future.

A novel CDK-independent function of p27Kip1 in preciliary vesicle trafficking during ciliogenesis.

p27Kip1, a member of the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors, is now known as a multifunctional protein that plays crucial roles in cell architecture and migration by regulating rearrangements of the actin cytoskeleton and microtubules. The intracellular level of p27Kip1 is increased by anti-proliferative stimuli, such as mitogen deprivation and contact inhibition, which also induce formation of primary cilia, microtubule-based membranous organelles that protrude from the cell surface. However, it remains unknown whether p27Kip1 is associated with ciliogenesis. Here, we have generated p27Kip1-knockout hTERT-immortalized human retinal pigment epithelial cells, and found that ciliogenesis is almost completely disrupted in p27Kip1-knockout cells. The defect of ciliogenesis is rescued by the exogenous expression of wild-type p27Kip1 and, surprisingly, its 86-140 amino acid region, which is neither responsible for CDK inhibition nor remodeling of the actin cytoskeleton and microtubules. Moreover, transmission electron microscopy and immunofluorescence analyses reveal that p27Kip1 abrogation impairs one of the earliest events of ciliogenesis, docking of the Ehd1-associated preciliary vesicles to the distal appendages of the basal body. Our findings identify a novel CDK-independent function of p27Kip1 in primary cilia formation.

First-in-human phase I clinical trial of the NY-ESO-1 protein cancer vaccine with NOD2 and TLR9 stimulants in patients with NY-ESO-1-expressing refractory solid tumors.

Cholesteryl pullulan (CHP) is a novel antigen delivery system. CHP and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) antigen complexes (CHP-NY-ESO-1) present multiple epitope peptides to the MHC class I and II pathways. Adjuvants are essential for cancer vaccines. MIS416 is a non-toxic microparticle that activates immunity via the nucleotide-binding oligomerization domain 2 (NOD2) and TLR9 pathways. However, no reports have explored MIS416 as a cancer vaccine adjuvant. We conducted a first-in-human clinical trial of CHP-NY-ESO-1 with MIS416 in patients with NY-ESO-1-expressing refractory solid tumors. CHP-NY-ESO-1/MIS416 (µg/µg) was administered at 100/200, 200/200, 200/400 or 200/600 (cohorts 1, 2, 3 and 4, respectively) every 2 weeks for a total of 6 doses (treatment phase) followed by one vaccination every 4 weeks until disease progression or unacceptable toxicity (maintenance phase). The primary endpoints were safety and tolerability, and the secondary endpoint was the immune response. In total, 26 patients were enrolled. Seven patients (38%) continued vaccination in the maintenance phase. Grade 3 drug-related adverse events (AEs) were observed in six patients (23%): anorexia and hypertension were observed in one and five patients, respectively. No grade 4-5 drug-related AEs were observed. Eight patients (31%) had stable disease (SD). Neither augmentation of the NY-ESO-1-specific IFN-γ-secreting CD8+ T cell response nor an increase in the level of anti-NY-ESO-1 IgG1 was observed as the dose of MIS416 was increased. In a preclinical study, adding anti-PD-1 monoclonal antibody to CHP-NY-ESO-1 and MIS416 induced significant tumor suppression. This combination therapy is a promising next step.

DA-EPOCH-R combined with high-dose methotrexate in patients with newly diagnosed stage II-IV CD5-positive diffuse large B-cell lymphoma: a single-arm, open-label, phase II study.

CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase II study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 World Health Organization classification were eligible. Four cycles of DA-EPOCH-R followed by two cycles of HD-MTX and four additional cycles of DAEPOCH- R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary end point was 2-year progression-free survival (PFS). Between September 25, 2012, and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow up of 3.1 years (range, 2.0-4.9 years), the 2- year PFS was 79% [95% confidence interval (CI): 64-88]. The 2-year overall survival was 89% (95%CI: 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation. (Trial registered at: UMIN-CTR: UMIN000008507.).

[Therapy-related acute promyelocytic leukemia with complex karyotype accompanied by cryptic PML/RARA on chromosome 15 by metaphase FISH].

A 53-year-old male presented with pancytopenia for 13 months. He had a past history of follicular lymphoma and hypopharyngeal cancer, which was treated via chemotherapy and radiotherapy. Bone marrow aspiration biopsy of the patient revealed a hypocellular marrow with 32% of hypergranular blasts without Auer bodies. There were also erythroid and megakaryocytic dysplasia in the bone marrow. Although the PML/RARA transcript was detected by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR), the G-banding karyotype analysis showed a complex karyotype without t (15;17). The PML/RARA fusion signal was identified on chromosome 15 by metaphase FISH. The patient was diagnosed of therapy-related acute promyelocytic leukemia (t-APL) with cryptic PML/RARA. He successfully attained molecular complete remission with all-trans retinoic acid (ATRA) and two courses of arsenic trioxide (ATO). He was subsequently administered nivolumab without ATRA maintenance therapy because of a progressing metastasis of a hypopharyngeal cancer to the lung. The patient had a relapse of t-APL following nine courses of nivolumab, 8 months after ending consolidation therapy with ATO. Reinduction therapy with ATRA was not effective for the relapsed t-APL that was accompanied by del (5q) and monosomy 7. Little has been previously reported on t-APL with cryptic PML/RARA. Therefore, the clinical course of this patient may provide useful insights about the characteristics of t-APL with cryptic PML/RARA.

[Successful treatment with a combination of elotuzumab, lenalidomide and dexamethasone of extramedullary disease in a patient with refractory multiple myeloma].

A 56-year-old man diagnosed with multiple myeloma was treated with CBD (cyclophosphamide, bortezomib, and dexamethasone; DEX), which was discontinued because of bortezomib-associated adverse events. Thereafter, he was treated with Ld (lenalidomide; LEN+DEX) followed by high-dose chemotherapy with autologous stem cell rescue, resulting in a complete response. Ld as maintenance therapy was discontinued because of immune thrombocytopenia, resulting in disease progression. Although treatment was switched to Pd (pomalidomide+DEX), DLd (daratumumab+LEN+DEX), and IRd (ixazomib+LEN+DEX); the patient's M protein level continued to increase and the extramedullary disease expanded despite radiotherapy. He was treated with E-Ld (elotuzumab+LEN+DEX) after 3 cycles of short VAD (vincristine, doxorubicin, and DEX). The extramedullary disease disappeared after 8 cycles of E-Ld. To the best of our knowledge, this is the first report showing the effectiveness of E-Ld treatment for extramedullary disease of a heavily treated patient for multiple myeloma. We believe that the clinical course of this patient provides useful insights about the antimyeloma mechanism of elotuzumab.