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Afuresertib (AFU), a novel inhibitor of the serine/threonine kinase AKT, has clinical efficacy as a monotherapy against hematological malignancies and is expected to be used in combination with standard therapies for multiple myeloma (MM). To develop a more effective and less toxic combination of immunomodulatory drugs (IMiDs) for therapy, the antitumor effect of sub‑optimal doses of AFU, pomalidomide plus dexamethasone (PD), and the AFU‑PD combination on MM cells were examined in the present study. Two MM cell lines, XG‑7 and U266, with low sensitivity to both PD and AFU monotherapies, were subjected to these combinations and analyzed. Although the cell lines showed a slight reduction in viability with the sub‑optimal doses of each monotherapy, the combination of the treatments resulted in a reduction in cell viability and the progression of apoptosis. Co‑treatment with sub‑optimal doses of PD and AFU enhanced caspase activation and highly suppressed the expression of IKZF1 and IKZF3. In addition, this combination promoted the dephosphorylation and stabilization of 4EBP1, an inhibitor of eIF4E activation, which led to the impairment of eIF4E‑mediated translational activity. Furthermore, AFU showed a sufficient inhibitory effect on the phosphorylation of FOXO1, a tumor suppressor, in monotherapy or in combination with PD, which may be attributable to the activation of FOXO1, the subsequent inhibition of tumor growth, and the induction of cell death. In conclusion, the combination therapy with sub‑optimal doses of PD and AFU exhibited potent antitumor activity in MM cells and may provide a novel strategy for the treatment of patients who experienced intolerable toxicity or insufficient response during IMiD therapy. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an incurable B‐cell malignancy often accompanied by profound immunodeficiency. Lenalidomide (Len) is an immunomodulatory drug that exerts promising therapeutic effects on MM through the immune system. However, predictive markers related to the effects of Len treatment are not fully understood. This study aimed to identify candidate biomarkers for predicting the clinical efficacy of Len and dexamethasone (Ld) therapy through a comprehensive analysis of serum cytokines. The levels of 48 cytokines in the serum of patients with MM just before Ld therapy (n = 77), at the time of best response (n = 56), and at disease progression (n = 49) were measured and evaluated. Patients with high IL‐18 and M‐CSF levels showed significantly shorter progression‐free survival and overall survival (OS). In contrast, patients with high PDGF‐BB levels had longer survival. Moreover, low levels of G‐CSF, IL‐7, IL‐8, and SDF‐1α were associated with shorter OS after Ld therapy. During Ld therapy, pro‐inflammatory cytokines such as IL‐2Rα, IL‐18, and TNF‐α were decreased, while IFN‐γ was increased. IL‐4 and IL‐6 levels increased during disease progression. In conclusion, this study provides a better understanding of the association between cytokines and the efficacy of Ld therapy as well as the unique changes in cytokines related to inflammatory and immune responses during Ld therapy. [ABSTRACT FROM AUTHOR]

Background: Invasive fungal infections (IFIs) represent a potentially fatal complication in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) if the initiation of therapy is delayed. Some guidelines recommend antifungal prophylaxis or preemptive therapy for these patients depending on the risk of IFIs following allogeneic HSCT. This retrospective study aimed to identify the group of patients who safely undergo allogeneic HSCT with low‐dose fluconazole (FLCZ) prophylaxis (100 mg/day). Methods: We retrospectively reviewed 107 patients who underwent their first allogeneic HSCT at Nagoya City University Hospital from January 1, 2010, to December 31, 2019. We analyzed the efficacy of low‐dose FLCZ prophylaxis and investigated the relationship between major risk factors and antifungal prophylaxis failure (APF) within 100 days post‐transplant. Results: Of the 107 patients, 70 received low‐dose FLCZ prophylaxis, showing a cumulative incidence of APF of 37.1% and a proven/probable IFI rate of 4.3%. There were no fungal infection‐related deaths, including Aspergillus infections, in the FLCZ prophylaxis group. In a multivariable analysis, cord blood transplantation (CBT) (subdistribution hazard ratio (SHR), 3.55; 95% confidence interval (CI), 1.44–8.77; p = 0.006) and abnormal findings on lung CT before transplantation (SHR, 2.24; 95% CI, 1.02–4.92; p = 0.044) were independent risk factors for APF in the FLCZ prophylaxis group. Conclusion: Low‐dose FLCZ prophylaxis is a useful and safe option for patients receiving allogeneic HSCT, except in those undergoing CBT or having any fungal risk features including history of fungal infections, positive fungal markers, and abnormal findings on lung CT before transplantation. [ABSTRACT FROM AUTHOR]

Bortezomib (Btz) is an active agent used to treat multiple myeloma (MM). Not all patients who receive Btz-containing therapy show a favorable response. Interaction of cellular adhesion molecules with MM and bone marrow stromal cells is crucial for the survival of MM cells. However, little is known about the role of these molecules in the sensitivity of MM to Btz-containing therapy. Thus, we evaluated the correlation between the level of cellular adhesion molecules in MM cells and the efficacy of Btz plus dexamethasone (Bd) therapy. The expression of the neural cell adhesion molecule gene (NCAM, also known as CD56), ITGA4, CXCR4, and other genes were analyzed in 74 samples of primary MM cells collected from patients before they received Bd therapy. Of the eight genes tested, expression of NCAM was lower among patients who responded poorly to Bd therapy. In vitro expression of NCAM induced by transfection of MM cells enhanced their sensitivity to Btz treatment by causing accumulation of polyubiquitinated proteins. Our results indicate that expression of NCAM is associated with better response to Btz treatment and is a promising candidate biomarker for predicting response to therapies involving Btz. [ABSTRACT FROM AUTHOR]

Background: The recently developed severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) mRNA vaccine has a short history of use and further information is needed regarding its efficacy, especially in immunocompromised conditions, such as plasma cell dyscrasia (PCD). Methods: We retrospectively measured serum SARS‐CoV‐2 antibodies against the spike protein (S‐IgG) after the second and third mRNA vaccine doses (doses 2 and 3, respectively) in 109 patients with PCD. We evaluated the proportion of patients with an adequate humoral response (defined as S‐IgG titers ≥300 antibody units/mL). Results: Although active anti‐myeloma treatments prior to vaccination had a significantly negative impact on adequate humoral response, specific drug subclasses including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies were not negatively associated, except for B‐cell maturation antigen‐targeted therapy. Dose 3 (booster vaccination) led to significantly higher S‐IgG titers and more patients acquired an adequate humoral response. Furthermore, evaluation of vaccine‐induced cellular immune response in patients using T‐spot Discovery SARS‐CoV‐2 kit, revealed an enhanced cellular immune response after Dose 3. Conclusions: This study highlighted the significance of booster SARS‐CoV‐2 mRNA vaccination in patients with PCD with respect to humoral and cellular immunity. Moreover, this study highlighted the potential impact of certain drug subclasses on vaccine‐induced humoral immune response. [ABSTRACT FROM AUTHOR]

Extranodal NK/T cell lymphoma (NKTCL), nasal type (ENKL) that shows no apparent nasal involvement, is termed extranasal NKTCL or non-nasal NKTCL. In this study, we aimed to explore therapeutic approaches and outcomes in patients with extranasal NKTCL in current clinical practice. A data set of patients with newly diagnosed NKTCL who were diagnosed at 31 institutes in Japan between 2000 and 2013 was used for analysis. The patients' fitness for steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy was assessed using the major inclusion criteria of the SMILE phase 2 study. Of 358 patients, 47 (13%) had extranasal NKTCL. The most frequent extranodal sites of involvement in extranasal NKTCL were skin/subcutaneous tissue (n = 18). Six (13%) of the patients with extranasal NKTCL had localized disease and were diagnosed before 2010. With a median follow-up of 5.8 years, the 2-year overall survival (OS) in patients with nasal and extranasal NKTCL was 70% (95% confidence interval [CI], 65-75%) and 34% (95% CI, 21-47%), respectively. OS in patients with nasal NKTCL had a trend toward better according to treatment era (P = 0.063). In contrast, no obvious improvement of OS was observed in extranasal NKTCL (P = 0.43). The major inclusion criteria of the SMILE-P2 were met in 21% (10/47) of patients with extranasal NKTCL and 60% (188/311) of those with nasal NKTCL (P < 0.001). Despite the advent of new treatments for ENKL, OS remains unfavorable in extranasal NKTCL. A more effective therapy is needed for extranasal NKTCL. [ABSTRACT FROM AUTHOR]

Our goal was to evaluate the usefulness of labial salivary gland (LSG) biopsy for diagnosing immunoglobulin light chain (AL) amyloidosis, by comparing bone marrow and skin biopsies in the same patient population. This retrospective study included 34 consecutive patients who showed evidence of monoclonal proteins and symptoms considered to be due to amyloidosis, and who underwent a tissue biopsy from LSG between January 2005 and December 2012 at Nagoya City University Hospital. All samples of superficial tissues, including LSG, bone marrow, and skin, were independently evaluated as having amyloid deposits by a central review, which was blind to clinical information. An AL amyloidosis diagnosis was based on evidence of amyloid deposition in any biopsied tissue. Eighteen patients were diagnosed with AL amyloidosis. The sensitivity for detecting amyloid deposition was highest in biopsies of LSG at 89 %, followed by 77 % for bone marrow, and 72 % for skin. Amyloid deposition was detected in at least one superficial tissue of all the 18 patients. An LSG biopsy may be appropriate as a first-choice procedure to diagnose AL amyloidosis. Multiple biopsies of superficial tissues, including LSG, bone marrow, and skin, are recommended to increase the sensitivity for diagnosing AL amyloidosis. [ABSTRACT FROM AUTHOR]

There is limited evidence regarding the impact of updated Charlson comorbidity index (CCI) on survival in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen. We retrospectively reviewed 125 patients with newly diagnosed DLBCL receiving R-CHOP as a first-line immunochemotherapy who were admitted to Nagoya City West Medical Center between May 2011 and December 2018. We evaluated the association between their survival and the 5 following baseline indexes: CCI, age-adjusted CCI, updated CCI, Barthel index and mini-nutritional assessment (MNA-SF). Baseline characteristics of the 125 patients with newly diagnosed DLBCL were as follows: median age was 75 years; 84% was >60 years; 70% had high LDH (> upper limit of normal); 33% had ECOG-PS ≥2; Ann Arbor stage of I, II, III, IV was 14%, 21%, 18% and 48%, respectively; 39% had extranodal site ≥2; 11% had high BNP levels (BNP≥100 pg/mL). None of CCI, age-adjusted CCI and updated CCI was associated with the survival, although both a lower Barthel index and malnutrition were significantly associated with shorter overall survival. The patients with high BNP levels had worse prognosis compared to those with low levels. Multivariate analysis revealed that age >60 years, extranodal site ≥2 and malnutrition (MNA-SF ≤7) were independent risk factors for survival (adjusted hazard ratios, 2.9, 2.2 and 2.0, respectively; p < 0.05). In our cohort, none of CCI, age-adjusted CCI and updated CCI had impact on survival in patient with DLBCL receiving R-CHOP treatment, whereas malnutrition (MNA-SF ≤7) had negative impact on survival in those patients. Well-designed clinical trials are warranted to identify not only lymphoma-related factors but also host factors for survival. [ABSTRACT FROM AUTHOR]

Introduction There is limited evidence regarding the impact of updated Charlson comorbidity index (CCI) on survival in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen. Methods We retrospectively reviewed 125 patients with newly diagnosed DLBCL receiving R-CHOP as a first-line immunochemotherapy who were admitted to Nagoya City West Medical Center between May 2011 and December 2018. We evaluated the association between their survival and the 5 following baseline indexes: CCI, age-adjusted CCI, updated CCI, Barthel index and mini-nutritional assessment (MNA-SF). Result Baseline characteristics of the 125 patients with newly diagnosed DLBCL were as follows: median age was 75 years; 84% was >60 years; 70% had high LDH (> upper limit of normal); 33% had ECOG-PS ≥2; Ann Arbor stage of I, II, III, IV was 14%, 21%, 18% and 48%, respectively; 39% had extranodal site ≥2; 11% had high BNP levels (BNP≥100 pg/mL). None of CCI, age-adjusted CCI and updated CCI was associated with the survival, although both a lower Barthel index and malnutrition were significantly associated with shorter overall survival. The patients with high BNP levels had worse prognosis compared to those with low levels. Multivariate analysis revealed that age >60 years, extranodal site ≥2 and malnutrition (MNA-SF ≤7) were independent risk factors for survival (adjusted hazard ratios, 2.9, 2.2 and 2.0, respectively; p < 0.05). Conclusion In our cohort, none of CCI, age-adjusted CCI and updated CCI had impact on survival in patient with DLBCL receiving R-CHOP treatment, whereas malnutrition (MNA-SF ≤7) had negative impact on survival in those patients. Well-designed clinical trials are warranted to identify not only lymphoma-related factors but also host factors for survival. [ABSTRACT FROM AUTHOR]