Effectiveness of G-CSF in chemotherapy for digestive system tumors: a systematic review of the Clinical Practice Guidelines for the Use of G-CSF 2022 delineated by the Japan Society of Clinical Oncology.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) reportedly reduces the risk of neutropenia and subsequent infections caused by cancer chemotherapy. Although several guidelines recommend using G-CSF in primary prophylaxis according to the incidence rate of chemotherapy-induced febrile neutropenia (FN), the effectiveness of G-CSF in digestive system tumor chemotherapy remains unclear. To address these clinical questions, we conducted a systematic review as part of revising the Clinical Practice Guidelines for the Use of G-CSF 2022 published by the Japan Society of Clinical Oncology. METHODS: This systematic review addressed two main clinical questions (CQ): CQ1: "Is primary prophylaxis with G-CSF effective in chemotherapy?", and CQ2: "Is increasing the intensity of chemotherapy with G-CSF effective?" We reviewed different types of digestive system tumors, including esophageal, gastric, pancreatic, biliary tract, colorectal, and neuroendocrine carcinomas. PubMed, Cochrane Library, and Ichushi-Web databases were searched for information sources. Independent systematic reviewers conducted two rounds of screening and selected relevant records for each CQ. Finally, the working group members synthesized the strength of evidence and recommendations. RESULTS: After two rounds of screening, 5/0/3/0/2/0 records were extracted for CQ1 of esophageal/gastric/pancreatic/biliary tract/colorectal/ and neuroendocrine carcinoma, respectively. Additionally, a total of 2/6/1 records were extracted for CQ2 of esophageal/pancreatic/colorectal cancer, respectively. The strength of evidence and recommendations were evaluated for CQ1 of colorectal cancer; however, we could not synthesize recommendations for other CQs owing to the lack of records. CONCLUSION: The use of G-CSF for primary prophylaxis in chemotherapy for colorectal cancer is inappropriate.

Efficacy, Safety and Quality of Life of Pegcetacoplan in Japanese Patients With Paroxysmal Nocturnal Hemoglobinuria Treated Within the Phase 3 PEGASUS Trial.

INTRODUCTION: Pegcetacoplan, the first approved proximal complement C3 inhibitor, showed superiority to eculizumab in improving hemoglobin levels and clinical outcomes in the phase 3 PEGASUS study in patients with paroxysmal nocturnal hemoglobinuria (PNH) and inadequate response to eculizumab. METHODS: This analysis evaluates the efficacy and safety of pegcetacoplan for Japanese patients in PEGASUS, as they are known for different clinicopathologic features compared to non-Asian patients. Ten Japanese patients were enrolled to receive pegcetacoplan (n=5) or eculizumab (n=5) during the 16-week randomized controlled period. All patients received pegcetacoplan monotherapy during the open-label period until Week 48. RESULTS: Treatment with pegcetacoplan improved hemoglobin with a mean change from baseline of 2.4 g/dL at Week 16, which was sustained through 48 weeks. Pegcetacoplan-treated Japanese patients experienced sustained improvements in key secondary efficacy endpoints, including freedom from transfusion, lactate dehydrogenase level, reticulocyte count, and FACIT-Fatigue score. The safety profile was consistent with previously reported data from pegcetacoplan studies. No events of hemolysis, meningococcal infection, or thrombosis were reported in the Japanese population and all Japanese patients remained on treatment throughout the study. CONCLUSION: These data suggest that Japanese patients with PNH can be effectively and safely managed with pegcetacoplan. CLINICALTRIALS: gov identifier: NCT03500549.

Comparison between a single dose of PEG G-CSF and multiple doses of non-PEG G-CSF: a systematic review and meta-analysis from Clinical Practice Guidelines for the use of G-CSF 2022.

BACKGROUD: Granulocyte colony-stimulating factor (G-CSF) is widely used for the primary prophylaxis of febrile neutropenia (FN). Two types of G-CSF are available in Japan, namely G-CSF chemically bound to polyethylene glycol (PEG G-CSF), which provides long-lasting effects with a single dose, and non-polyethylene glycol-bound G-CSF (non-PEG G-CSF), which must be sequentially administrated for several days. METHODS: This current study investigated the utility of these treatments for the primary prophylaxis of FN through a systematic review of the literature. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis or meta-analysis was conducted to evaluate six outcomes. RESULTS: Through the first and second screenings, 23 and 18 articles were extracted for qualitative synthesis and meta-analysis, respectively. The incidence of FN was significantly lower in the PEG G-CSF group than in the non-PEG G-CSF group with a strong quality/certainty of evidence. The differences in other outcomes, such as overall survival, infection-related mortality, the duration of neutropenia (less than 500/µL), quality of life, and pain, were not apparent. CONCLUSIONS: A single dose of PEG G-CSF is strongly recommended over multiple-dose non-PEG G-CSF therapy for the primary prophylaxis of FN.

Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: Clinical Practice Guidelines for the Use of G-CSF 2022.

Granulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression and thereby relieve symptoms, such as hematuria, infection, bleeding, and pain, as well as to prolong the survival. In this clinical question, we compared treatment with primary prophylactic administration of G-CSF to maintain therapeutic intensity with conventional standard therapy without G-CSF and examined the benefits and risks as major outcomes. A detailed literature search for relevant studies was performed using PubMed, Ichu-shi Web, and Cochrane Library. Data were extracted and evaluated independently by two reviewers. A qualitative analysis of the pooled data was performed, and the risk ratios with corresponding confidence intervals were calculated and summarized in a meta-analysis. Seven studies were included in the qualitative analysis, two of which were reviewed in the meta-analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, and one randomized controlled study showed a reduction in the incidence of FN. Primary prophylactic administration of G-CSF may be beneficial, as shown in a randomized controlled study of dose-dense MVAC therapy. However, there are no studies on other regimens, and we made a "weak recommendation to perform" with an annotation of the relevant regimen (dose-dense MVAC).

Optimal timing of prophylactic pegylated G-CSF after chemotherapy administration for patients with cancer: a systematic review and meta-analysis from Clinical Practice Guidelines for the use of G-CSF 2022.

INTRODUCTION: The timing of prophylactic pegylated granulocyte colony-stimulating factor (G-CSF) administration during cancer chemotherapy varies, with Day 2 and Days 3-5 being the most common schedules. Optimal timing remains uncertain, affecting efficacy and adverse events. This systematic review sought to evaluate the available evidence on the timing of prophylactic pegylated G-CSF administration. METHODS: Based on the Minds Handbook for Clinical Practice Guideline Development, we searched the PubMed, Ichushi-Web, and Cochrane Library databases for literature published from January 1990 to December 2019. The inclusion criteria included studies among the adult population using pegfilgrastim. The search strategy focused on timing-related keywords. Two reviewers independently extracted and assessed the data. RESULTS: Among 300 initial search results, only four articles met the inclusion criteria. A meta-analysis for febrile neutropenia incidence suggested a potential higher incidence when pegylated G-CSF was administered on Days 3-5 than on Day 2 (odds ratio: 1.27, 95% CI 0.66-2.46, p = 0.47), with a moderate certainty of evidence. No significant difference in overall survival or mortality due to infections was observed. The trend of severe adverse events was lower on Days 3-5, without statistical significance (odds ratio: 0.72, 95% CI 0.14-3.67, p = 0.69) and with a moderate certainty of evidence. Data on pain were inconclusive. CONCLUSIONS: Both Day 2 and Days 3-5 were weakly recommended for pegylated G-CSF administration post-chemotherapy in patients with cancer. The limited evidence highlights the need for further research to refine recommendations.

Effectiveness and safety of primary prophylaxis of G-CSF during chemotherapy for prostate cancer, Japanese clinical guideline for appropriate use of G-CSF: clinical practice guidelines for the use of G-CSF 2022.

BACKGROUND: Docetaxel (DTX) is commonly used as a primary chemotherapy, and cabazitaxel (CBZ) has shown efficacy in patients who are DTX resistant. Primary prophylactic granulocyte colony stimulating factor (G-CSF) therapy is currently used with CBZ treatment in routine clinical care in Japan. METHODS: In this study, we performed a systematic review following the Minds guidelines to investigate the effectiveness and safety of primary prophylaxis with G-CSF during chemotherapy for prostate cancer and to construct G-CSF guidelines for primary prophylaxis use during chemotherapy. A comprehensive literature search of various electronic databases (PubMed, Cochrane Library, and Ichushi) was performed on January 10, 2020, to identify studies published between January 1990 and December 31, 2019 that investigate the impact of primary prophylaxis with G-CSF during CBZ administration on clinical outcomes. RESULTS: Ultimately, nine articles were included in the qualitative systematic review. Primary G-CSF prophylaxis during CBZ administration for metastatic castration-resistant prostate cancer was difficult to assess in terms of correlation with overall survival, mortality from infection, and patients' quality of life. These difficulties were owing to the lack of randomized controlled trials comparing patients with and without primary prophylaxis of G-CSF during CBZ administration. However, some retrospective studies have suggested that it may reduce the incidence of febrile neutropenia. CONCLUSION: G-CSF may be beneficial as primary prophylaxis during CBZ administration for metastatic castration resistant prostate cancer, and we made a "weak recommendation to perform" with an annotation of the relevant regimen.

Effectiveness and safety of primary prophylaxis with G-CSF after induction therapy for acute myeloid leukemia: a systematic review and meta-analysis of the clinical practice guidelines for the use of G-CSF 2022 from the Japan society of clinical oncology.

Although granulocyte colony-stimulating factor (G-CSF) reduces the incidence, duration, and severity of neutropenia, its prophylactic use for acute myeloid leukemia (AML) remains controversial due to a theoretically increased risk of relapse. The present study investigated the effects of G-CSF as primary prophylaxis for AML with remission induction therapy. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis of pooled data was conducted, and the risk ratio with corresponding confidence intervals was calculated in the meta-analysis and summarized. Sixteen studies were included in the qualitative analysis, nine of which were examined in the meta-analysis. Although G-CSF significantly shortened the duration of neutropenia, primary prophylaxis with G-CSF did not correlate with infection-related mortality. Moreover, primary prophylaxis with G-CSF did not affect disease progression/recurrence, overall survival, or adverse events, such as musculoskeletal pain. However, evidence to support or discourage the use of G-CSF as primary prophylaxis for adult AML patients with induction therapy remains limited. Therefore, the use of G-CSF as primary prophylaxis can be considered for adult AML patients with remission induction therapy who are at a high risk of infectious complications.

Effectiveness and safety of primary prophylaxis with G-CSF for lung cancer: a systematic review and meta-analysis to develop clinical practice guidelines for the use of G-CSF 2022.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) is commonly administered to cancer patients undergoing myelosuppressive chemotherapy, especially when incidence rate of febrile neutropenia (FN) surpasses 20%. While primary prophylaxis with G-CSF has been proven effective in preventing FN in patients with cancer, there is limited evidence regarding its efficacy in specifically, lung cancer. Our systematic review focused on the efficacy of G-CSF primary prophylaxis in lung cancer. METHODS: We extracted studies on non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) using the PubMed, Ichushi Web, and Cochrane Library databases. Two reviewers assessed the extracted studies for each type of lung cancer and conducted quantitative and meta-analyses of preplanned outcomes, including overall survival, FN incidence, infection-related mortality, quality of life, and musculoskeletal pain. RESULTS: A limited number of studies were extracted: two on NSCLC and six on SCLC. A meta-analysis was not conducted owing to insufficient data on NSCLC. Two case-control studies explored the efficacy of primary prophylaxis with G-CSF in patients with NSCLC (on docetaxel and ramucirumab therapy) and indicated a lower FN frequency with G-CSF. For SCLC, meta-analysis of five studies showed no significant reduction in FN incidence, with an odds ratio of 0.38 (95% confidence interval 0.03-5.56, P = 0.48). Outcomes other than FN incidence could not be evaluated due to low data availability. CONCLUSION: Limited data are available on G-CSF prophylaxis in lung cancer. Primary prophylaxis with G-CSF may be weakly recommended in Japanese patients with NSCLC undergoing docetaxel and ramucirumab combination therapy.

Predictive Model for Occurrence of Febrile Neutropenia after Chemotherapy in Patients with Diffuse Large B-Cell Lymphoma: A Multicenter, Retrospective, Observational Study.

Febrile neutropenia (FN) is a major concern in patients undergoing chemotherapy for diffuse large B-cell lymphoma (DLBCL); however, the overall risk of FN is difficult to assess. This study aimed to develop a model for predicting the occurrence of FN in patients with DLBCL. In this multicenter, retrospective, observational analysis, a multivariate logistic regression model was used to analyze the association between FN incidence and pretreatment clinical factors. We included adult inpatients and outpatients (aged ≥ 18 years) diagnosed with DLBCL who were treated with chemotherapy. The study examined 246 patients. Considering FN occurring during the first cycle of chemotherapy as the primary outcome, a predictive model with a total score of 5 points was constructed as follows: 1 point each for a positive hepatitis panel, extranodal involvement, and a high level of soluble interleukin-2 receptor and 2 points for lymphopenia. The area under the receiver operating characteristic curve of this model was 0.844 (95% confidence interval: 0.777-0.911). Our predictive model can assess the risk of FN before patients with DLBCL start chemotherapy, leading to better outcomes.

Post-infarction Left Ventricular Free Wall Rupture Diagnosed by Contrast-Enhanced Computed Tomography: A Case Report.

A 70-year-old Japanese woman with hypertension, dyslipidemia, and diabetes mellitus complained of abdominal discomfort and vomiting and was brought to our emergency department by ambulance two days later with impaired consciousness. Her vital signs suggested shock with a heart rate of 120 bpm. Electrocardiogram and initial transthoracic echocardiography suggested an inferior wall ST-elevation myocardial infarction, but the altered consciousness was inconsistent. Contrast-enhanced computed tomography was urgently performed to further clarify the cause. It revealed pericardial effusion and apparent extravasation from the left ventricular wall, confirming the early definitive diagnosis of left ventricular free wall rupture. The patient underwent successful emergent surgical repair without sequelae. Differential diagnosis of left ventricular free wall rupture is important in patients with ST-elevation myocardial infarction and impaired consciousness. Contrast-enhanced computed tomography allows early diagnosis and treatment of this life-threatening complication.

Clinicopathological analysis of CD47 and signal regulatory protein alpha expression in myeloid sarcoma patients: CD47 expression is a favourable prognostic factor.

Myeloid sarcoma is a rare extramedullary haematopoietic malignancy. Interaction between CD47 and signal regulatory protein α (SIRPα) inhibits phagocytosis. CD47-positive tumours confer poor prognoses in various malignant tumours, including acute myeloid leukaemia. This study aimed to investigate the clinicopathological effects of CD47 and SIRPα expression in myeloid sarcoma. Immunohistochemistry (IHC) of CD47 and SIRPα was performed in 84 biopsy samples obtained from patients with myeloid sarcoma, some of which were CD47-positive. Patients were categorised into the following two groups based on IHC of SIRPα: those with SIRPα-positive neoplastic cells (nSIRPα) and, SIRPα expression on non-neoplastic stromal cells in tumour microenvironment (miSIRPα). In addition, patients with CD47 positivity had higher lymphocytic infiltration into the tumour microenvironment. Overall, these patients had significantly higher overall survival, however, no significant difference was observed in progression-free survival. No significant prognostic differences were observed between the nSIRPα and miSIRPα groups. This is the first study to demonstrate an association between CD47 expression and improved prognosis in myeloid sarcoma. Nonetheless, it will be necessary to conduct additional research on gene expression and genomic abnormalities to elucidate the corresponding pathogenesis of myeloid sarcoma.

Angioimmunoblastic T-Cell Lymphoma after Treatment of Classic Hodgkin Lymphoma: A Case Report.

We report a case of a 24-year-old man who developed angioimmunoblastic T-cell lymphoma (AITL) after treatment for refractory lymphocyte-rich classic Hodgkin lymphoma (LR-CHL). This patient was treated with the BV+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) protocol for LR-CHL but progressed before completing chemotherapy. The pathological imaging showed the typical findings of LR-CHL at the first onset and first progression. Rescue chemotherapy and high-dose chemotherapy combined with autologous hematopoietic stem cell transplantation (AHSCT) were performed for refractory LR-CHL, and complete remission was achieved. However, the recurrence was suspected 6 months after AHSCT. The pathological findings of the lymph node biopsy at this time were different from those of the previous two lymph node biopsies, demonstrating findings of AITL. The finding of the immunohistochemical staining and polymerase chain reaction results supported the diagnosis. Although it has been reported that the risk for the development of non-Hodgkin lymphoma after treatment for Hodgkin lymphoma is increased, most are B-cell lymphomas, and few cases of AITL have been reported. AITL is a type of peripheral T-cell lymphoma that generally occurs in middle-aged and elderly people and that rarely occurs in young people. Here, we were able to make an accurate diagnosis by performing re-examination even when recurrence of LR-CHL was suspected. As there are no detailed case reports of AITL developing into secondary non-Hodgkin lymphoma, here we report on an identified case.

Clinical Characteristics and Diagnostic Prediction of Severe Fever with Thrombocytopenia Syndrome and Rickettsiosis in the Co-Endemic Wakayama Prefecture, Japan.

Background and Objectives: The Wakayama prefecture is endemic for two types of tick-borne rickettsioses: Japanese spotted fever (JFS) and scrub typhus (ST). Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne hemorrhagic viral disease with a high mortality rate and is often difficult to differentiate from such rickettsioses. SFTS cases have recently increased in Wakayama prefecture. For early diagnosis, this study aimed to evaluate the clinical characterization of such tick-borne infections in the co-endemic area. Materials and Methods: The study included 64 febrile patients diagnosed with tick-borne infection in Wakayama prefecture between January 2013 and May 2022. Medical records of 19 patients with SFTS and 45 with rickettsiosis (JSF, n = 26; ST, n = 19) were retrospectively examined. The receiver operating curve (ROC) and area under the curve (AUC) were calculated to evaluate potential factors for differentiating SFTS from rickettsiosis. Results: Adults aged ≥70 years were most vulnerable to tick-borne infections (median, 75.5 years; interquartile range, 68.5-84 years). SFTS and rickettsiosis occurred mostly between summer and autumn. However, no significant between-group differences were found in age, sex, and comorbidities; 17 (89%) patients with SFTS, but none of those with rickettsiosis, experienced gastrointestinal symptoms such as vomiting, abdominal pain, and diarrhea. Meanwhile, 43 (96%) patients with rickettsiosis, but none of those with SFTS, developed a skin rash. The AUCs of white blood cells (0.97) and C-reactive protein (CRP) levels (0.98) were very high. Furthermore, the differential diagnosis of SFTS was significantly associated with the presence of gastrointestinal symptoms (AUC 0.95), the absence of a skin rash (AUC 0.98), leukopenia <3.7 × 109/L (AUC 0.95), and low CRP levels < 1.66 mg/dL (AUC 0.98) (p < 0.001 for each factor). Conclusions: Clinical characteristics and standard laboratory parameters can verify the early diagnosis of SFTS in areas where tick-borne infections are endemic.

Administration of combined venetoclax and azacitidine in a patient with acute myeloid leukemia and multiple comorbidities undergoing dialysis: A case report.

Patients with acute myeloid leukemia (AML) who have comorbidities have limited treatment options, thereby resulting in poor prognosis. Venetoclax, a specific B-cell lymphoma-2 inhibitor, has recently been approved for AML in combination with hypomethylating agents; however, only one report has described its use in patients undergoing dialysis. Herein, we report the effectiveness of combined venetoclax and azacitidine in a 73-year-old man with AML undergoing dialysis and who was ineligible for standard therapies. The safety of venetoclax and azacitidine in patients undergoing dialysis has been reported, and their combination may be a feasible option for patients with AML undergoing dialysis.

B cell receptor repertoire analysis from autopsy samples of COVID-19 patients.

Neutralizing antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being developed world over. We investigated the possibility of producing artificial antibodies from the formalin fixation and paraffin-embedding (FFPE) lung lobes of a patient who died by coronavirus disease 2019 (COVID-19). The B-cell receptors repertoire in the lung tissue where SARS-CoV-2 was detected were considered to have highly sensitive virus-neutralizing activity, and artificial antibodies were produced by combining the most frequently detected heavy and light chains. Some neutralizing effects against the SARS-CoV-2 were observed, and mixing two different artificial antibodies had a higher tendency to suppress the virus. The neutralizing effects were similar to the immunoglobulin G obtained from healthy donors who had received a COVID-19 mRNA vaccine. Therefore, the use of FFPE lung tissue, which preserves the condition of direct virus sensitization, to generate artificial antibodies may be useful against future unknown infectious diseases.

Effect of SARS-CoV-2 BNT162b2 mRNA vaccine on thyroid autoimmunity: A twelve-month follow-up study.

Objectives: Graves' disease (GD) has been highlighted as a possible adverse effect of the respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine. However, it is unknown if the SARS-CoV-2 vaccine disrupts thyroid autoimmunity. We aimed to present long-term follow-up of thyroid autoimmunity after the SARS-CoV-2 BNT162b2 mRNA vaccine. Methods: Serum samples collected from seventy Japanese healthcare workers at baseline, 32 weeks after the second dose (pre-third dose), and 4 weeks after the third dose of the vaccine were analyzed. The time courses of anti-SARS-CoV-2 spike immunoglobulin G (IgG) antibody, thyroid-stimulating hormone receptor antibody (TRAb), and thyroid function were evaluated. Anti-thyroglobulin antibodies (TgAb) and anti-thyroid peroxidase antibodies (TPOAb) were additionally evaluated in thirty-three participants. Results: The median age was 50 (IQR, 38-54) years and 69% were female. The median anti-spike IgG antibody titer was 17627 (IQR, 10898-24175) U/mL 4 weeks after the third dose. The mean TRAb was significantly increased from 0.81 (SD, 0.05) IU/L at baseline to 0.97 (SD, 0.30) IU/L 4 weeks after the third dose without functional changes. An increase in TRAb was positively associated with female sex (ß = 0.32, P = 0.008) and low basal FT4 (ß = -0.29, P = 0.02) and FT3 (ß = -0.33, P = 0.004). TgAb was increased by the third dose. Increase in TgAb was associated with history of the thyroid diseases (ß = 0.55, P <0.001). Conclusions: SARS-CoV-2 BNT162b2 mRNA vaccine can disrupt thyroid autoimmunity. Clinicians should consider the possibility that the SARS-CoV-2 vaccine may disrupt thyroid autoimmunity.

Lactoferrin and its digestive peptides induce interferon-α production and activate plasmacytoid dendritic cells ex vivo.

Plasmacytoid dendritic cells (pDCs) recognise viral single-stranded RNA (ssRNA) or CpG DNA via Toll-like receptor (TLR)-7 and TLR9, and produce interferon (IFN)-α. Activated pDCs upregulate human leukocyte antigen (HLA)-DR and CD86 expression levels. Ingestion of bovine lactoferrin (LF) activates pDCs, but little is known about its effects. In this study, the effects of LF and its pepsin hydrolysate (LFH) on the production of IFN-α from peripheral blood mononuclear cells (PBMCs) and pDCs were examined. PBMCs were prepared from peripheral blood of healthy adults and incubated with LF, LFH, or lactoferricin (LFcin) in the absence or presence of ssRNA derived from human immunodeficiency virus. The concentration of IFN-α in the supernatant and the expression levels of IFN-α, HLA-DR, and CD86 in pDCs were quantified by enzyme-linked immunosorbent assay and flow cytometry. In the absence of ssRNA, the concentration of IFN-α was negligible and LF had no effect on it. In the presence of ssRNA, IFN-α was detected at a certain level, and LF and LFH significantly increased its concentration. The increase caused by LFH and LFcin were comparable. In addition, LF significantly upregulated the expression levels of IFN-α, HLA-DR, and CD86 in pDCs. LF and its digestive peptides induced IFN-α production and activated pDCs in the presence of ssRNA, suggesting that LF modulates the immune system by promoting pDC activation upon viral recognition.

An evaluation based on relative treatment intensity in older patients treated with reduced-dose R-THP-COP therapy for diffuse large B-cell lymphoma: A multicenter retrospective cohort study.

INTRODUCTION: The number of older patients with diffuse large B-cell lymphoma (DLBCL) is increasing. Although the standard treatment for newly diagnosed younger patients with DLBCL has been established, no consensus has been reached regarding the optimal chemotherapy intensity and regimen for older patients with DLBCL. In addition, no method for evaluating treatment intensity in retrospective studies when different numbers of chemotherapy courses are administered has been elucidated. MATERIALS AND METHODS: A multicenter retrospective analysis was conducted to evaluate the outcomes of a reduced-dose R-THP-COP regimen, which included 30 mg/m2 of pirarubicin, in 54 patients with DLBCL who were aged ≥75. To assess treatment intensity, we defined the relative treatment intensity (RTI) as the number of courses administered multiplied by the relative dose intensity (RDI). RESULTS: The estimated four-year overall survival rates (OS) of the patients aged 75-80 and ≥ 80 were 55.1% and 60.6%, respectively. There was no significant difference in four-year OS between these age groups. In our cohort, there was no significant difference in the estimated four-year OS between the patients who received reduced-dose R-THP-COP at an RDI of ≥61% and those that received it at an RDI of <61% (P = 0.35). On the other hand, the patients who received reduced-dose R-THP-COP at an RTI of ≥2.7 exhibited a significantly higher estimated four-year OS than those treated at an RTI of <2.7 (68.5% vs. 28.7%; P < 0.001). Multivariate analysis revealed that the RTI was a significant independent predictor of OS. The cumulative incidence of treatment-related mortality (TRM) at one year was 4.2% and 3.4% in the 75-80 and ≥ 80 age groups, respectively. The cumulative incidence of TRM was significantly worse among the patients with Charlson Comorbidity Index (CCI) scores of ≥2 than among those with CCI scores of 0 or 1. DISCUSSION: Our study suggests that the reduced-dose R-THP-COP regimen is a suitable treatment option for older patients with DLBCL, especially those with CCI scores of <2. Our study also showed that the RTI may be a valuable tool for assessing treatment intensity in retrospective studies involving older patients.

Allosteric Inhibition of c-Abl to Induce Unfolded Protein Response and Cell Death in Multiple Myeloma.

Endoplasmic reticulum stress activates inositol-requiring enzyme 1α (IRE1α) and protein kinase, R-like endoplasmic reticulum kinase (PERK), the two principal regulators of the unfolded protein response (UPR). In multiple myeloma, adaptive IRE1α signaling is predominantly activated and regulates cell fate along with PERK. Recently, we demonstrated that GNF-2, an allosteric c-Abl inhibitor, rheostatically enhanced IRE1α activity and induced apoptosis through c-Abl conformational changes in pancreatic ß cells. Herein, we analyzed whether the pharmacological modulation of c-Abl conformation resulted in anti-myeloma effects. First, we investigated the effects of GNF-2 on IRE1α activity and cell fate, followed by an investigation of the anti-myeloma effects of asciminib, a new allosteric c-Abl inhibitor. Finally, we performed RNA sequencing to characterize the signaling profiles of asciminib. We observed that both GNF-2 and asciminib decreased cell viability and induced XBP1 mRNA splicing in primary human myeloma cells and myeloma cell lines. RNA sequencing identified the induction of UPR- and apoptosis-related genes by asciminib. Asciminib re-localized c-Abl to the endoplasmic reticulum, and its combination with a specific IRE1α inhibitor, KIRA8, enhanced cell death with the reciprocal induction of CHOP mRNA expression. Together, the allosteric inhibition of c-Abl-activated UPR with anti-myeloma effects; this could be a novel therapeutic target for multiple myeloma.