Nomogram for predicting survival of patients with diffuse large B-cell lymphoma.

The international prognostic index (IPI) system has been widely used to predict prognosis in diffuse large B-cell lymphoma (DLBCL). However, this system categorizes DLBCL patients into four risk groups, and cannot optimize individualized prognosis. In addition, other clinicopathological factors, such as molecular aberrations, are not incorporated into the system. To partly overcome these weak points, we developed nomograms to predict individual patient survival. We also incorporated MYD88L265P and CD79BY196 mutations into the nomograms since these mutations are associated with a worse prognosis and their signaling pathways have been highlighted as a therapeutic target. We analyzed 302 DLBCL cases for which multivariate analysis by Cox proportional hazard regression was performed. Nomograms for progression-free survival (PFS) and overall survival (OS) were constructed and assessed by a concordance index (C-index). The nomograms were also evaluated using an open external dataset (n = 187). The MYD88L265P and/or CD79BY196 (MYD88/CD79B) mutation was detected in 62/302 patients. The nomograms incorporating IPI factors exhibited a C-index of 0.738 for PFS and a C-index of 0.765 for OS. The nomograms incorporating IPI factors and the MYD88/CD79B mutation showed a C-index of 0.745 for PFS and a C-index of 0.769 for OS. The nomograms we created were evaluated using an external dataset and were well validated. The present nomograms incorporating IPI factors and the MYD88/CD79B mutation have sufficient discrimination ability, and may effectively predict prognosis in DLBCL patients. The prognostic models we have presented here may help clinicians personalize prognostic assessments and clinical decisions.

Real-world clinical characteristics of post-essential thrombocythemia and post-polycythemia vera myelofibrosis.

There are few prospective studies on patients with post-essential thrombocythemia myelofibrosis (PET-MF) and post-polycythemia vera myelofibrosis (PPV-MF). Therefore, we conducted a nationwide longitudinal prospective survey to clarify the clinical characteristics of these diseases. A total of 197 PET-MF and 117 PPV-MF patients diagnosed between 2012 and 2021 were analyzed. The median age at diagnosis was 70.0 years for both diseases. The time from diagnosis of ET or PV to that of MF was 9.6 and 10.4 years, respectively, with no significant difference. Patients with PPV-MF had higher hemoglobin levels and white blood cell counts than those with PET-MF, whereas those with PET-MF had higher platelet counts than those with PPV-MF. Although splenomegaly was more frequent in patients with PPV-MF at diagnosis, there was no difference in the frequency of constitutional symptoms. Ruxolitinib was the most common treatment administered to 74.6% and 83.8% of patients with PET-MF and PPV-MF, respectively. Patients with PET-MF and PPV-MF had similar prognoses, with 3-year overall survival (OS) of 0.742 in PET-MF and 0.768 in PPV-MF patients. In both diseases, leukemic transformation was the leading cause of death, followed by infection. The 3-year OS for patients with PET/PPV-MF and primary MF diagnosed during the same period was 0.754 and 0.626, respectively, with no significant difference. This survey provides real-world clinical features and prognostic data on secondary myelofibrosis in the ruxolitinib era.

Humoral and cellular immune response to second and third severe acute respiratory syndrome coronavirus 2 mRNA vaccine in patients with plasma cell dyscrasia.

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.

＜Editors' Choice＞ Myelodysplastic syndrome with trisomy 8 presenting periodic fever and multiple MEFV gene variants outside exon 10: a case report.

Myelodysplastic syndrome is associated with the development of autoinflammatory conditions, such as recurrent fever, polymyalgia, arthralgia, and erythema. Trisomy 8 is a common chromosomal abnormality in patients with myelodysplastic syndrome. Myelodysplastic syndrome with trisomy 8 involves autoinflammatory conditions, especially Behçet's disease-like symptoms with intestinal mucosal damage. MEFV variants, particularly those in exon 10, are pathogenic in familial Mediterranean fever, the most common autoinflammatory disease, presenting typical symptoms such as periodic fever and pleuritis/pericarditis/peritonitis. MEFV variants outside exon 10 are common in Japanese patients with familial Mediterranean fever and are associated with atypical symptoms, including myalgia and erythema. MEFV variants in myelodysplastic syndrome with trisomy 8 have rarely been investigated, although myelodysplastic syndrome with trisomy 8 might develop autoinflammatory conditions similar to those in familial Mediterranean fever. We encountered a 67-year-old man who had myelodysplastic syndrome with trisomy 8 and multiple MEFV variants outside exon 10. He presented with periodic fever, as well as chest/abdominal pain, myalgia, and erythema, although the symptoms did not fulfill the diagnostic criteria of familial Mediterranean fever. We discussed the possibility that these symptoms are modified by MEFV variants outside exon 10 in myelodysplastic syndrome with trisomy 8.

A comprehensive evaluation of humoral immune response to second and third SARS-CoV-2 mRNA vaccination in patients with malignant lymphoma.

More information is needed regarding the efficacy of SARS-CoV-2 mRNA vaccines in immunocompromised populations, including patients with malignant lymphoma. This study aimed to evaluate humoral responses to the second and third mRNA vaccine doses in 165 lymphoma patients by retrospective analysis of serum SARS-CoV-2 spike protein antibody (S-IgG) titers. Patients with S-IgG titers ≥ 300, 10-300, and ≤ 10 binding antibody units (BAU)/mL were defined as adequate responders, low responders, and non-responders, respectively. S-IgG titers > 10 BAU/mL were considered to indicate seroconversion. After the second dose, 56%, 16%, and 28% of patients were adequate responders, low responders and non-responders, respectively. Multivariate analysis revealed that being an adequate responder after the second dose was associated with receiving the vaccine > 12 months after last chemotherapy, total peripheral lymphocyte count of ≥ 1000/µL, estimated glomerular filtration rate of ≥ 50 mL/min/1.73 m2, and vaccine type (mRNA-1273). After the third dose, patients had significantly higher S-IgG titers and a greater proportion achieved seroconversion. With this third dose, 26% of second-dose non-responders achieved seroconversion and 68% of second-dose low responders became adequate responders. Subsequent SARS-CoV-2 mRNA vaccinations may elicit an immune response in immunocompromised patients who do not initially respond to vaccination.

Symptoms and health-related quality of life in patients with newly diagnosed multiple myeloma: a multicenter prospective cohort study.

OBJECTIVE: Existing cross-sectional observational studies indicate that patients with multiple myeloma experience negative physical and psychological symptoms and low health-related quality of life. The study aim was to determine symptom prevalence, health-related quality of life and symptoms associated with health-related quality of life in patients with newly diagnosed multiple myeloma. METHODS: This multicenter longitudinal cohort study was conducted in four hospitals in Japan. Patients with newly diagnosed multiple myeloma were asked to report their symptom intensity and health-related quality of life using validated questionnaires at three points: at diagnosis (T1), 1 month (T2) and 12 months after diagnosis (T3). Symptoms associated with health-related quality of life were explored using a mixed-effects model. RESULTS: A total of 106 patients completed the assessment at T1. The symptoms more than 30% of patients reported were pain, disturbed sleep and distress at T1, pain, dry mouth, disturbed sleep and fatigue at T2, fatigue, numbness of tingling and pain and numbness or tingling at T3. Pain and depression were significantly associated with health-related quality of life negatively. CONCLUSIONS: The finding suggests that more than 30% of multiple myeloma patients suffered from pain and various symptoms and they received suboptimal palliative care within a year after starting initial chemotherapy. Pain and depression should be the main targets of interventions to improve health-related quality of life in this population.

Newly diagnosed follicular lymphoma during pembrolizumab treatment for lung cancer.

Malignant lymphoma developing during anti-PD-1 antibody treatment is extremely rare. A 74-year-old female was admitted with left hypochondrial pain. She was diagnosed with squamous cell carcinoma of the right upper lobe of the lung, and had undergone surgery and postoperative chemotherapy three years prior. Needle biopsy of a mediastinal lymph node revealed recurrent lung cancer (LC). Pembrolizumab (PEM) monotherapy was started as salvage treatment. Although her lymphadenopathy improved, thrombocytopenia and splenomegaly developed during treatment with nine doses of PEM. Laboratory findings included anemia, increased lactate dehydrogenase, and soluble interleukin-2 receptor levels of 6379 U/mL. Flow cytometry of peripheral blood and bone marrow showed CD20+, κ ≪ λ cell populations. IGH-BCL2 fusion was detected by fluorescence in situ hybridization in bone marrow. Positron emission tomography showed abnormal uptake in tonsils, both cervical lymph nodes, mediastinum (different location from the recurrent LC), spleen, and abdominal cavity. Follicular lymphoma (FL) grade 1/2 was histologically diagnosed by tonsillar biopsy. She achieved a complete metabolic response (CMR) after rituximab monotherapy on PEM discontinuation. Relapsed FL was diagnosed by submandibular gland biopsy four months after restarting PEM and she achieved a second CMR after rituximab-containing chemotherapy. We describe the first case of newly diagnosed FL during PEM treatment.

The Epidemiology of Admission-Requiring Pediatric Respiratory Infections in a Japanese Community Hospital Using Multiplex PCR.

Respiratory tract infections (RTIs) are the most common diseases globally among children. This study aimed to assess the epidemiology of admission-requiring pediatric RTI cases and evaluate the effect of the pathogen type on the length of hospital stay (LOS) using the FilmArray® respiratory panel, a multiplex PCR test. The age-specific distribution and seasonality of viruses were investigated between March 26, 2018 and April 12, 2019. Multivariable linear regression analyses were performed to evaluate the effect of pathogen type and coinfection on LOS. Among 153 hospitalized RTI patients, respiratory syncytial virus was the leading cause of hospitalization in infants < 12 months of age (27.7%). Human metapneumovirus and parainfluenza virus were also major causes of hospitalization in patients aged 2-3 years (22.6% and 22.6%, respectively). In the multivariable linear regression model excluding rhinovirus/enterovirus, there was a significant association between viral coinfection and longer LOS (p = 0.012), while single viral infection of any type was not positively correlated with LOS. This study revealed the epidemiology of admission-requiring pediatric RTIs.

Genomic analysis of multiple myeloma using targeted capture sequencing in the Japanese cohort.

Previous genomic studies have revealed the genomic landscape of myeloma cells. Although some of the genomic abnormalities shown are believed to be correlated to the molecular pathogenesis of multiple myeloma and/or clinical outcome, these correlations are not fully understood. The aim of this study is to elucidate the correlation between genomic abnormalities and clinical characteristics by targeted capture sequencing in the Japanese multiple myeloma cohort. We analysed 154 patients with newly diagnosed multiple myeloma. The analysis revealed that the study cohort consisted of a less frequent hyperdiploid subtype (37·0%) with relatively high frequencies of KRAS mutation (36·4%) and IGH-CCND1 translocation (26·6%) compared with previous reports. Moreover, our targeted capture sequencing strategy was able to detect rare IGH-associated chromosomal translocations, such as IGH-CCND2 and IGH-MAFA. Interestingly, all 10 patients harboured MAX mutations accompanied by 14q23 deletion. The patients with del(17p) exhibited an unfavourable clinical outcome, and the presence of KRAS mutation was associated with shorter survival in patients with multiple myeloma, harbouring IGH-CCND1. Thus, our study provides a detailed landscape of genomic abnormalities, which may have potential clinical application for patients with multiple myeloma.

Plasma cell myeloma positive for t(14;20) with relapse in the central nervous system.

t(14;20)(q32;q11)/IGH-MAFB is a rare chromosomal abnormality in plasma cell myeloma (PCM), accounting for 1-2% of PCM cases. Patients with this translocation may have a poor prognosis. However, the clinicopathological features and response to novel agents have not been well clarified. We present a 63-year-old Japanese female with PCM positive for t(14;20). The tumor responded well to a proteasome inhibitor, bortezomib, and the patient achieved complete remission. Six months after remission, tumor relapse was noted in the left cerebellum and the right frontal lobe of the cerebrum. After whole brain radiation therapy, the tumor masses decreased in size. The patient was followed up with best-care support, but died of the disease 29 months after the initial PCM diagnosis. t(14;20)-positive PCM responded well to bortezomib at the time of the initial treatment. The CNS tumor involvement, which is rare in PCM, may be associated with the clinical aggressiveness of the t(14;20)-positive form of this myeloma.

[Prognostic significance of tryptophan catabolism in adult T-cell leukemia/lymphoma].

PURPOSE: Indoleamine 2,3-dioxygenase 1 (IDO1: IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway, and is an important micro-environmental factor suppressing antitumor immune responses. We investigated the prognostic significance of Trp catabolism in adult T-cell leukemia/lymphoma (ATL). EXPERIMENTAL DESIGN: We quantified serum Trp and Kyn in 96 ATL patients, 38 human T-cell lymphotropic virus type-1 asymptomatic carriers (HTLV-1 ACs), and 40 healthy adult volunteers. The relationships between various clinical parameters were analyzed. IDO expression was evaluated in the affected lymph nodes of ATL patients. RESULTS: Serum Kyn concentrations and Kyn/Trp ratios were significantly higher in HTLV-1 ACs than in healthy controls. Both increased significantly with progression from HTLV-1 AC to ATL. There were no significant differences in serum Trp concentrations between ATL patients, HTLV-1 ACs and controls. IDO was possibly produced by ATL and/or cells in the microenvironment. Multivariate analyses demonstrated a high serum Kyn/Trp ratio and high Kyn level, but not a high Trp level, to be significant independent detrimental prognostic factors in ATL and aggressive variant ATL. CONCLUSIONS: Quantification of serum Kyn and Trp is prognostically useful for individual ATL patients. Furthermore, ATL is an appropriate disease for testing novel cancer immunotherapies targeting IDO.

[Successful treatment of high-dose methotrexate-induced oliguric acute renal failure by using a combination of hemodialysis filtration and direct hemoperfusion].

A 64-year-old man with central nervous system metastases from systemic non-Hodgkin lymphoma was treated with high- dose intravenous methotrexate(MTX 3.5 g/m2). The patient subsequently developed oliguric acute renal failure 12 hours after MTX initiation, and his serum MTX level was 163 mM at 26 hours. Hemodialysis filtration(HDF)combined with direct hemoperfusion(DHP)was initiated at 45hours. Seven sessions of combined HDF and DHP and 2 courses of HDF alone were performed, and the mean MTX extraction rates were 68.2% and 74.3%, respectively. The patient experienced severe respiratory failure, febrile neutropenia, myelosuppression, and oral mucositis. However, his urine output began to improve on day 7 after MTX initiation, and his renal function gradually recovered. His serum MTX level declined to 0.04 mM on day 23 after MTX initiation. In the present case, we immediately initiated HDF and DHP and successfully treated the patient for MTX-induced renal failure.

Prognostic Significance of Tryptophan Catabolism in Adult T-cell Leukemia/Lymphoma.

PURPOSE: Indoleamine 2,3-dioxygenase 1 (IDO1: IDO), an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway, is increasingly being recognized as an important microenvironmental factor suppressing antitumor immune responses. The purpose of the present study was to determine the prognostic significance of Trp catabolism in adult T-cell leukemia/lymphoma (ATL). EXPERIMENTAL DESIGN: We quantified serum Trp and Kyn in 96 ATL patients, 38 human T-cell lymphotropic virus type-1 asymptomatic carriers (HTLV-1 ACs), and 40 healthy adult volunteer controls. The relationships between various clinical parameters including overall survival were analyzed. IDO expression was evaluated in the affected lymph nodes of ATL patients. RESULTS: Serum Kyn concentrations and Kyn/Trp ratios were significantly higher in HTLV-1 ACs than healthy controls. Both increased significantly with progression from HTLV-1 AC to ATL. However, there were no significant differences in the serum Trp concentrations between ATL patients, HTLV-1 ACs, and controls. IDO was possibly produced by ATL and/or cells of the microenvironment. Multivariate analyses demonstrated that a high serum Kyn/Trp ratio and high Kyn level, but not a high Trp level, were significantly independent detrimental prognostic factors in ATL, as well as in that subset of patients with aggressive variant ATL. CONCLUSIONS: Quantification of serum Kyn and Trp is useful for predicting prognosis of an individual ATL patient. Furthermore, ATL, especially in patients with a high serum Kyn/Trp ratio, is an appropriate disease for testing novel cancer immunotherapies targeting IDO.

Highly frequent and enhanced injection site reaction induced by peripheral venous injection of fosaprepitant in anthracycline-treated patients.

BACKGROUND: Fosaprepitant-associated injection site reaction (ISR) has been reported in patients treated with cisplatin, an irritant drug. We conducted this retrospective study to clarify the incidence and symptoms of fosaprepitant-associated ISR in patients treated with anthracycline. PATIENTS AND METHODS: Fifty six patients receiving 159 injections administering doxorubicin/cyclophosphamide (AC), fluorouracil/epirubicin/cyclophosphamide (FEC), or rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R-)CHOP regimen through a peripheral vein at ambulatory treatment centers reviewed for this study from patients' medical records. Incidence of ISR was compared between 24 patients with fosaprepitant injection (fosaprepitant group) and 32 patients without fosaprepitant (control group). Frequency and symptoms of ISR per injection were also compared between 61 injections with fosaprepitant and 98 injections without fosaprepitant. RESULTS: Both the ISR incidence rate per patient and per injection were significantly higher in the fosaprepitant group than in the control group (67% vs. 16%; P=0.0002, 34% vs. 8.2%; P<0.0001, respectively). By multivariate analysis, fosaprepitant injection was found to be a significant independent variable correlated with ISR risk. Symptoms observed in 61 injections of fosaprepitant were pain (n=14, 23%), erythema (n=10, 16%), swelling (n=6, 10%), and delayed drip infusion (n=6, 10%). After the observation period, no ISR occurred when the administration route was changed to central venous injection or oral aprepitant was administered despite the continuation of chemotherapy. CONCLUSION: ISR occurred more frequently and severely when fosaprepitant was injected through the peripheral vein in patients treated with anthracyclines compared to those without fosaprepitant.

[A case of acute myeloid leukemia in an obese patient--determining the therapeutic dose of anticancer drugs].

Currently, there is no consensus to determine whether the therapeutic doses of anticancer drugs should be based on the actual or the ideal body weight of obese cancer patients. We performed induction and consolidation chemotherapy at doses calculated by using the actual body weight of an obese patient with acute myeloid leukemia (AML). A 47-year-old Japanese man presented with pancytopenia at our hospital, and he was diagnosed with AML (FAB classification M0). At the initial diagnosis, the patient was 170 cm tall and weighed 132 kg; therefore, his body surface area was 2.37 m(2). His performance status and organ functions were quite good. The calculations for determining doses of anticancer drugs required were based on his actual body weight. He received induction chemotherapy and achieved complete remission. Subsequently, he was treated with 4 courses of consolidation chemotherapy. Febrile neutropenia was a complication during each course, and it was relieved via myeloid recovery. Chemotherapy was administered every 4-5 weeks, except for the second course where platelet recovery was prolonged, and the prescribed treatment was completed. The guidelines of the American Society of Clinical Oncology (ASCO) recommend that physicians routinely use an obese patient's actual body weight to calculate the appropriate doses of almost all chemotherapy drugs. Therefore, the ease and compromised usage of under-dosing because of heaviness owing to obesity should be avoided.

Global real-time quantitative reverse transcription-polymerase chain reaction detecting proto-oncogenes associated with 14q32 chromosomal translocation as a valuable marker for predicting survival in multiple myeloma.

CCND1, FGFR3 and c-MAF mRNA expression of tumor samples from 123 multiple myeloma patients were analyzed by global RQ/RT-PCR. CCND1, FGFR3 and c-MAF were positive in 44 (36%), 28 (23%) and 16 (13%) of patients, respectively. In 7 patients, both FGFR3 and c-MAF were positive. The expression of c-MAF was independent unfavorable prognostic factors for overall survival (OS). Autologous stem cell transplantation improved progression-free survival of CCND1-positive patients. Bortezomib, thalidomide or lenalidomide extended OS of FGFR3 and/or c-MAF-positive patients. Thus, CCND1, FGFR3 and c-MAF mRNA expression can predict survival and is useful for planning stratified treatment strategies for myeloma patients.

Primary large cell neuroendocrine carcinoma of the ureter.

Large cell neuroendocrine carcinoma (LCNEC) is the rarest type of urinary tract malignancy. Herein, we report a case of LCNEC that arose in the ureter of a 78-year-old Japanese man with a history of ascending colon cancer that had been excised by a right hemicolectomy. Left-sided hydronephrosis associated with the ureteral tumor was discovered during follow-up. A left nephroureterectomy combined with a partial resection of the urinary bladder was performed because atypical cells were detected using voided urine cytology. A histopathological examination revealed that the ureteral tumor contained large atypical epithelial cells of neuroendocrine morphology without a urothelial carcinomatous component. The neoplastic cells were immunohistochemically positive for synaptophysin, chromogranin A, CD56, and cytokeratins, but they were negative for uroplakin III and thyroid transcription factor-1. The Ki-67 labeling index of the neoplastic cells was 50%. Transmission electron microscopy demonstrated the presence of numerous dense granules in the cytoplasm of the neoplastic cells. The ureteral lesion was finally classified as stage III, pT3 cN0 cM0. The patient's postoperative course was uneventful without chemoradiotherapy, and LCNEC did not recur in the subsequent nine months. This case demonstrates that LCNEC can occur in the ureter, which normally does not contain neuroendocrine cells in the urothelium.

Stimulation of bone formation in cortical bone of mice treated with a receptor activator of nuclear factor-κB ligand (RANKL)-binding peptide that possesses osteoclastogenesis inhibitory activity.

To date, parathyroid hormone is the only clinically available bone anabolic drug. The major difficulty in the development of such drugs is the lack of clarification of the mechanisms regulating osteoblast differentiation and bone formation. Here, we report a peptide (W9) known to abrogate osteoclast differentiation in vivo via blocking receptor activator of nuclear factor-κB ligand (RANKL)-RANK signaling that we surprisingly found exhibits a bone anabolic effect in vivo. Subcutaneous administration of W9 three times/day for 5 days significantly augmented bone mineral density in mouse cortical bone. Histomorphometric analysis showed a decrease in osteoclastogenesis in the distal femoral metaphysis and a significant increase in bone formation in the femoral diaphysis. Our findings suggest that W9 exerts bone anabolic activity. To clarify the mechanisms involved in this activity, we investigated the effects of W9 on osteoblast differentiation/mineralization in MC3T3-E1 (E1) cells. W9 markedly increased alkaline phosphatase (a marker enzyme of osteoblasts) activity and mineralization as shown by alizarin red staining. Gene expression of several osteogenesis-related factors was increased in W9-treated E1 cells. Addition of W9 activated p38 MAPK and Smad1/5/8 in E1 cells, and W9 showed osteogenesis stimulatory activity synergistically with BMP-2 in vitro and ectopic bone formation. Knockdown of RANKL expression in E1 cells reduced the effect of W9. Furthermore, W9 showed a weak effect on RANKL-deficient osteoblasts in alkaline phosphatase assay. Taken together, our findings suggest that this peptide may be useful for the treatment of bone diseases, and W9 achieves its bone anabolic activity through RANKL on osteoblasts accompanied by production of several autocrine factors.