Phase II Trial of Romidepsin as Consolidation Therapy after Gemcitabine, Dexamethasone, and Cisplatin in Elderly Transplant-Ineligible Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma.

Romidepsin is an important therapeutic option for patients with peripheral T-cell lymphoma (PTCL). However, the timing of romidepsin administration remains controversial. The objective of this study was to characterize the safety and efficacy of romidepsin as consolidation therapy after gemcitabine, dexamethasone, and cisplatin (GDP) therapy (GDPR). This study of patients treated between March 2019 and March 2021 was registered with the Japan Registry of Clinical Trials (registration number: jRCT0000000519). If complete response, partial response, or stable disease was confirmed after 2-4 GDP cycles, romidepsin was administered every 4 weeks for 1 year. Seven patients with relapsed/refractory (R/R) PTCL (T-follicular helper phenotype [n = 1] and angioimmunoblastic T-cell lymphoma [n = 6]) were included in this prospective study (PTCL-GDPR). After a median follow-up of 34 months of patients in PTCL-GDPR, the 2-year overall survival rate was 71%, and the overall response rate after treatment was 57%. Common adverse events in patients with PTCL-GDPR included hematological toxicities such as neutropenia, which improved with supportive treatment. There were no treatment-related mortalities. GDPR might be safe and effective in elderly transplant-ineligible patients with R/R PTCL; however, further investigation is required.

Efficacy of daratumumab in newly diagnosed multiple myeloma patients with 1q21 gain.

BACKGROUND: Gain and amplification of 1q21 (1q21+) are adverse chromosomal aberrations of multiple myeloma (MM) that lead to refractoriness to a variety of therapies. While it is known that daratumumab, an anti-cancer monoclonal antibody, cannot overcome the disadvantage of 1q21+in relapsed/refractory MM patients, its benefit in newly diagnosed MM (NDMM) patients with 1q21+has not been clarified. PATIENTS: We retrospectively evaluated 11 (55%) 1q21+patients (3 copies: 6, > 4 copies: 5) among 20 NDMM patients (median age, 74 years) who received daratumumab-containing regimens at Shibukawa Medical Center from October 2019 to October 2022. RESULTS: The overall response rate was 82% for patients with 1q21+and 78% for patients without 1q21+. Median progression-free survival (PFS) and median overall survival (OS) were not reached in either group. Neither 1q21 copy number nor co-existence of other high-risk cytogenetic abnormalities significantly affected PFS or OS. CONCLUSION: Our preliminary data suggests that outcomes of daratumumab treatment in NDMM 1q21+patients might be non-inferior to those in non-1q21+patients.

Primary analysis of a prospective cohort study of Japanese patients with plasma cell neoplasms in the novel drug era (2016-2021).

The emergence of novel drugs has significantly improved outcomes of patients with plasma cell neoplasms (PCN). The Japanese Society of Hematology conducted a prospective observational study in newly diagnosed PCN patients between 2016 and 2021. The analysis focused on 1385 patients diagnosed with symptomatic PCN between 2016 and 2018. The primary endpoint was the 3-year overall survival (OS) rate among patients requiring treatment (n = 1284), which was 70.0% (95%CI 67.4-72.6%). Approximately 94% of these patients received novel drugs as frontline therapy. The 3-year OS rate was 90.3% (95%CI 86.6-93.1%) in the 25% of patients who received upfront autologous stem cell transplantation (ASCT), versus just 61.4% (95%CI 58.0-64.6%) in those who did not receive upfront ASCT. The only unfavorable prognostic factor that affected OS in ASCT recipients was an age of 65 or higher. For patients who did not receive ASCT, independent unfavorable prognostic factors included frontline treatment with conventional chemotherapies, international staging system score of 2/3, extramedullary tumors, and Freiberg comorbidity index of 2/3. This study unequivocally demonstrates that use of novel drugs improved OS in Japanese myeloma patients, and underscores the continued importance of upfront ASCT as the standard of care in the era of novel drugs.

Pseudocyclic Arylbenziodoxaboroles as Water-Triggered Aryne Precursors in Reactions with Organic Sulfides.

Pseudocyclic arylbenziodoxaboroles are unique aryne precursors under neutral aqueous conditions that selectively react with organic sulfides, forming the corresponding sulfonium salts. This reaction is compatible with various substituents (alkyl, halogen, CN, NO2, CHO, and cyclopropyl) in the aromatic ring or alkyl group of the sulfide. Similar reactions of sulfoxides afford o-hydroxy-substituted sulfonium salts. The structures of key products were confirmed by X-ray analysis.

Improving gastrointestinal quality of life: romidepsin to tucidinostat in a case of angioimmunoblastic T cell lymphoma.

Relapsed/refractory (R/R) peripheral T cell lymphoma (PTCL) has a poor prognosis, with limited treatment options and generally no durable response. However, long-term remission with the histone deacetylase (HDAC) inhibitor romidepsin has been reported, especially in angioimmunoblastic T cell lymphoma (AITL). Recently, tucidinostat, a novel oral HDAC inhibitor that selectively inhibits class I and class IIb HDACs, was approved for R/R PTCL in China and Japan. We present the case of a patient with AITL whose gastrointestinal symptoms and health-related quality of life improved after switching from romidepsin to tucidinostat as maintenance therapy. Romidepsin and tucidinostat appear to have different safety profiles; non-haematological toxicities such as nausea, vomiting, constipation, anorexia and fatigue may be reported less frequently with tucidinostat than with romidepsin. This case suggests that switching to tucidinostat therapy may be a viable option for patients with PTCL suffering from severe gastrointestinal adverse events with romidepsin.

Preparation and X-ray Structural Study of Dibenzobromolium and Dibenzochlorolium Derivatives.

Various five-membered cyclic dibenzobromolium salts (dibenzo[b,d]bromol-5-ium chloride, nitrate, hydrogen sulfate, dihydrogen phosphate, trifluoroacetate, and tetrafluoroborate) were prepared by diazotization-cyclization of 2'-bromo-[1,1'-biphenyl]-2-amine in solution of appropriate acids. The chlorolium analogues (iodide, trifluoroacetate, and tetrafluoroborate) were obtained by a similar procedure. Additional dibenzohalolium derivatives (dibenzo[b,d]bromol-5-ium and dibenzo[b,d]chlorol-5-ium azides, bis(trifluoromethanesulfonyl)imidates, thiocyanates, and trifluoromethanesulfonates) were prepared by anion exchange. Structures of ten of these dibenzohalolium derivatives were established by X-ray analysis. Bond distances and angles for the halogen atoms in different dibenzohalolium derivatives were summarized and discussed.

Peptide coupling using recyclable bicyclic benziodazolone.

We report a greener peptide coupling using bicyclic benziodazolone and triarylphosphine as coupling reagents. Bicyclic benziodazolone also works as a base and can be recovered as the corresponding iodine(I) compound after use, which can be converted to the original iodine(III) reagent by electrolytic oxidation.

Isolated ACTH deficiency: an uncommon cause of hyperferritinaemia.

Isolated adrenocorticotropic hormone deficiency (IAD) is a rare disorder but not a known cause of hyperferritinaemia. We here report a man with IAD who presented with mild anaemia and unexpected hyperferritinaemia (serum ferritin, 1796 µg/L). He had high serum hepcidin and relatively low erythropoietin levels for his anaemia, with hepcidin and ferritin levels reducing with hydrocortisone supplementation. We speculate that low glucocorticoid levels might suppress erythropoiesis and anti-inflammatory activity, resulting in a higher hepcidin level and hyperferritinaemia. The possibility of adrenal insufficiency including IAD should be considered as a differential diagnosis in patients with unexplained hyperferritinaemia.

Prevalence and clinical outcomes of vitamin D deficiency among Japanese multiple myeloma patients: a single-center observational study.

PURPOSE: Vitamin D plays a crucial role in skeletal metabolism and holds significant importance in the pathophysiology of multiple myeloma (MM). This study aimed to determine the prevalence of vitamin D deficiency among Japanese MM patients and its correlation with clinical outcomes. METHODS: Serum 25-hydroxyvitamin D (25(OH)D) levels were assessed in 68 MM patients at a single institution in Japan, analyzing their association with clinical status, laboratory parameters including procollagen type 1 N-propeptide (P1NP) and tartrate-resistant acid phosphatase 5b (TRACP-5b), health-related quality of life (HR-QOL) scores, and overall survival. Additionally, patients with suboptimal 25(OH)D levels received cholecalciferol supplementation (1000 IU/day), and changes in laboratory parameters were monitored. RESULTS: The median 25(OH)D level was 22 ng/ml, with 32% and 51% of patients exhibiting vitamin D deficiency (< 20 ng/ml) and insufficiency (20-29 ng/ml), respectively. The 25(OH)D levels were unrelated to sex, age, MM stage, or bone lesions, but the vitamin D-deficient group showed a tendency towards lower HR-QOL scores. Among patients achieving complete remission, vitamin D supplementation increased P1NP, while TRACP-5b remained unchanged. Overall survivals from vitamin D measurement and from MM diagnosis were significantly worse in the vitamin D-deficient group compared to the vitamin D-insufficient/-sufficient group. CONCLUSION: The study identified a considerable number of Japanese MM patients with insufficient serum vitamin D levels, with one-third being deficient. Additionally, vitamin D deficiency predicted poor overall survival in Japanese MM patients. Further investigation is required to determine whether vitamin D supplementation can improve the frailty and survival of vitamin D-deficient MM patients.

Coexistence of IgG4-Related Disease and Reactive Granuloma to Paraffin Plombage.

We present a patient with IgG4-related disease (IgG4-RD) that developed after receiving extra-periosteal paraffin-embedded therapy for the treatment of pulmonary tuberculosis. The patient showed clinicopathological features consistent with IgG4-RD, including the enlargement of affected organs (salivary glands, lymph nodes, and retroperitoneal soft tissue mass), elevation of serum IgG4 levels, and infiltration of IgG4-positive plasma cells. The presence of reactive granulomas with foreign body giant cells (FBGCs) surrounding the paraffin-filled site suggested a type 2 helper T (Th2)-dominant immune response induced by the implanted biomaterial. Furthermore, paraffin, known to act as an adjuvant, may have played a role in activating the immune response and inducing IgG4-RD-like symptoms. This case highlights the potential relationship between foreign substances and the development of autoimmune diseases such as IgG4-RD.

A Nosocomial Outbreak Caused by Human Rhinovirus Species A Type 61 in a Welfare Facility in Gunma Prefecture, Japan.

Human rhinovirus (HRV) infections are generally referred to as the common cold, and are the main cause of mild symptoms. HRV is less frequently implicated in the development of severe respiratory infections. This study reports a nosocomial outbreak of bronchitis and pneumonia caused by HRV in a hospital during the COVID-19 epidemic in September 2022 in Gunma Prefecture, Japan. The patient continued to be symptomatic for nine days. During this outbreak, all 15 residents displayed respiratory symptoms. HRV-A was detected in 12 of the 12 samples, and phylogenetic analysis classified the strain as HRV-A type 61. HRV, COVID-19, and other respiratory infections cannot be differentiated based solely on clinical symptoms. A surveillance system to monitor them is thus needed.

Real-world efficacy of DA-EPOCH-R/HD-MTX regimen in CD5-positive diffuse large B cell lymphoma: a single-institute analysis.

CD5-positive diffuse large B cell lymphoma (CD5+ DLBCL) is a high-risk lymphoma type. Recently, the PEARL5 (a Phase II trial of DA-EPOCH and Rituximab with HD-MTX therapy for newly diagnosed DLBCL with CD5 expression) study demonstrated the efficacy of the DA-EPOCH-R (cyclophosphamide, etoposide, doxorubicin, vincristine, prednisone, and rituximab)/HD-MTX (high-dose methotrexate) regimen for CD5+ DLBCL. In this report, we revealed the impact of the DA-EPOCH-R/HD-MTX regimen on the clinical course of CD5+ DLBCL in the real-world. We retrospectively compared CD5+ and CD5- DLBCL patients diagnosed from January 2017 to December 2020 and analyzed their clinicopathological characteristics, treatment, and prognosis. There was no difference in age, sex, clinical stage, and cell of origin; however, the CD5-positive group had higher lactate dehydrogenase levels and a worse performance status than the CD5-negative group (p=0.00121 and p=0.0378, respectively). International prognostic index (IPI) was worse in the CD5-positive group than in the CD5-negative group (p=0.0498), but NCCN-IPI (National Comprehensive Cancer Network-IPI) was no different between the two groups. The CD5-positive group was more frequently treated with the DA-EPOCH-R/HD-MTX regimen than the CD5-negative group (p =0.001857). Complete remission rate and 1-year overall survival did not differ between the CD5-positive and -negative groups (90.0% vs 81.4%, p=0.853; 81.8% vs 76.9%, p=0.433). We conclude that the DA-EPOCH-R/HD-MTX regimen is effective for CD5+ DLBCL in this single institute analysis.

The Assessment of the Efficacy and Safety of Favipiravir for Patients with SARS-CoV-2 Infection: A Multicenter Non-randomized, Uncontrolled Single-arm Prospective Study.

Objective Among treatment options for coronavirus infectious disease 2019 (COVID-19), well-studied oral medications are limited. We conducted a multicenter non-randomized, uncontrolled single-arm prospective study to assess the efficacy and safety of favipiravir for patients with COVID-19. Methods One hundred participants were sequentially recruited to 2 cohorts: cohort 1 (Day 1: 1,600 mg/day, Day 2 to 14: 600 mg/day, n=50) and cohort 2 (Day 1: 1,800 mg/day, Day 2 to 14: 800 mg/day, n=50). The efficacy endpoint was the negative conversion rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the odds ratio (OR) of cohort 2 to cohort 1 for negative conversion on Day 10 was calculated. Characteristics of all participants and profiles of adverse events (AEs) were collected and analyzed. Results The mean age of participants was 62.8±17.6 years old. Thirty-four patients (34.0%) experienced worsening pneumonia, 7 (7.0%) were intubated, and 4 (4.0%) died during the observation period. Cohort 2 showed a higher negative conversion rate than cohort 1 [adjusted OR 3.32 (95% confidence interval (CI), 1.17 to 9.38), p=0.024], and this association was maintained after adjusting for the age, sex, body mass index, and baseline C-reactive protein level. Regarding adverse events, hyperuricemia was most frequently observed followed by an elevation of the liver enzyme levels (all-grade: 49.0%, Grade ≥3: 12.0%), and cohort 2 tended to have a higher incidence than cohort 1. However, no remarkable association of adverse events was observed between patients <65 and ≥65 years old. Conclusion The antiviral efficacy of favipiravir was difficult to interpret due to the limitation of the study design. However, no remarkable issues with safety or tolerability associated with favipiravir were observed, even in elderly patients with COVID-19.

In Situ Generation of N-Triflylimino-λ3-iodanes: Application to Imidation of Phosphines and Catalytic α-Amidation of 1,3-Dicarbonyl Compounds.

We describe the imidation of phosphines and α-amidation of 1,3-dicarbonyl compounds using N-triflylimino-λ3-iodane, which is generated in situ from iodosylarene and triflylamide without any other additives. Furthermore, the imino-λ3-iodane catalytically generated from an iodoarene precatalyst with oxone and triflylamide promotes α-amidation of 1,3-dicarbonyl compounds, representing the first method catalyzed by imino-λ3-iodane.

Efficient Catalytic Synthesis of Condensed Isoxazole Derivatives via Intramolecular Oxidative Cycloaddition of Aldoximes.

The intramolecular oxidative cycloaddition reaction of alkyne- or alkene-tethered aldoximes was catalyzed efficiently by hypervalent iodine(III) species to afford the corresponding polycyclic isoxazole derivatives in up to a 94% yield. The structure of the prepared products was confirmed by various methods, including X-ray crystallography. Mechanistic study demonstrated the crucial role of hydroxy(aryl)iodonium tosylate as a precatalyst, which is generated from 2-iodobenzoic acid and m-chloroperoxybenzoic acid in the presence of a catalytic amount of p-toluenesulfonic acid.

Convenient Synthesis of Benziodazolone: New Reagents for Direct Esterification of Alcohols and Amidation of Amines.

Hypervalent iodine heterocycles represent one of the important classes of hypervalent iodine reagents with many applications in organic synthesis. This paper reports a simple and convenient synthesis of benziodazolones by the reaction of readily available iodobenzamides with m-chloroperoxybenzoic acid in acetonitrile at room temperature. The structure of one of these new iodine heterocycles was confirmed by X-ray analysis. In combination with PPh3 and pyridine, these benziodazolones can smoothly react with alcohols or amines to produce the corresponding esters or amides of 3-chlorobenzoic acid, respectively. It was found that the novel benziodazolone reagent reacts more efficiently than the analogous benziodoxolone reagent in this esterification.

Synthesis of α-(aminoethyl)-α,ß-enones via alkyne aza-Prins cyclization and their synthetic application to pyrrolidines.

We developed a synthetic method for α-(aminoethyl)-α,ß-enones from aryl-substituted homopropargyl sulfonamides and aldehydes, representing the first synthesis of conjugated enones via alkyne aza-Prins cyclization. These products could be converted into pyrrolidines by a formal 5-endo-trig cyclization.

Pembrolizumab-induced Pure Red Cell Aplasia Successfully Treated with Intravenous Immunoglobulin.

We herein report a 64-year-old man who was treated with pembrolizumab for relapsed Hodgkin lymphoma. After the third administration of pembrolizumab, he showed acute anemia with a positive direct anti-globulin test. Because of the markedly erythroid hypoplasia, he was diagnosed with pure red cell aplasia (PRCA) caused by pembrolizumab. He was initially treated with prednisolone, but the reticulocytes decreased after tapering prednisolone. He then received high-dose intravenous immunoglobulin (IVIG) with prednisolone, and PRCA was successfully treated. Although the pathogenesis of PRCA caused by immune checkpoint inhibitors (CPIs) remains unclear, IVIG treatment may be effective for some steroid-refractory CPI-induced PRCA cases.

BF3-Catalyzed Skeletal Rearrangement of 7-En-2-ynones to endo-Type Cyclic Dienes.

Transition-metal-catalyzed cycloisomerization reactions with skeletal rearrangement of 1,n-enynes to afford cyclic dienes (particularly exo-cyclization products) have been well studied. However, there are few reports on the nonmetal-catalyzed skeletal rearrangement of enynes and skeletal rearrangement of electron-deficient enynes such as n-en-2-ynones. Here, we describe BF3·MeCN-catalyzed synthesis of 3-alkylidenecyclohexenes from 7-en-2-ynones, representing the first nonmetal-catalyzed skeletal rearrangement of 1,6-enynes to endo-type cyclic dienes.