Background
There are few data on the clinical implications of immunosuppressive protein expression in tumors and immune cell infiltration within the tumor microenvironment in patients with gastric ...cancer (GC).
Methods
In this study, 243 patients with curatively resected GC were included. The levels of immunosuppressive protein expression programmed cell death 1 ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO) in tumors and the densities of immune cells CD3(+), CD4(+), CD8(+), or PD-1(+) cells within the tumor microenvironment were measured using immunohistochemical analysis.
Results
Positive PD-L1, CTLA-4, and IDO expression was observed in 43.6, 65.8, and 47.7 % of the patients, respectively. Expression of PD-L1, CTLA-4, and IDO was related to less advanced stage, intestinal type, and well/moderately differentiated adenocarcinoma (
P
< 0.05). PD-L1 expression was related to better disease-free survival (DFS) and overall survival (OS) in GC PD-L1(+) vs. PD-L1(−) tumors: 5-year DFS rate, 82.6 vs. 66.9 %; 5-year OS rate, 83.0 vs. 69.1 % (
P
values <0.05). Survival outcomes were also better in patients with a higher density of CD3(+) cells within the tumor microenvironment than in those with a lower density of CD3(+) cells 5-year DFS rate, 80.9 vs. 67.0 %; 5-year OS rate, 82.5 vs. 68.0 % (
P
values <0.05). In multivariate analysis, these two immune markers had a prognostic impact on survival, independent of other clinical variables.
Conclusions
GC patients with immunosuppressive protein expression (PD-L1, CTLA-4, or IDO) had distinct clinicopathological characteristics. PD-L1(+) expression and a high-CD3 tumor microenvironment are favorable prognostic markers in GC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Extramedullary multiple myeloma (EMD) is an aggressive subentity of multiple myeloma (MM) with poor prognosis. As more innovative therapeutic approaches are needed for the treatment of MM with EMD, ...we conducted this multicenter, non-randomized phase II trial of daratumumab in combination with dexamethasone, cyclophosphamide, etoposide and cisplatin (DARA-DCEP). A total of 32 patients (median age 59, range 35-73) were treated with DARA-DCEP. Based on the best response during the study, the complete remission (CR) rate was 35.5% and overall response rate (ORR) 67.7%. During the median follow-up of 11 months, the median progression-free survival (PFS) was 5 months and median overall survival (OS) 10 months. There were 7 long-term responders whose median PFS was not reached. The most common grade greater than or equal to 3 hematologic AE was thrombocytopenia. The most common non-hematologic AE was nausea (22.6%), followed by dyspepsia, diarrhea and stomatitis (all 12.9%). Grade greater than or equal to 3 daratumumab infusion-related reaction was noted in 9.7% of the patients. Except for the planned 30% dose adjustment in cycle 1, only 2 patients required DCEP dose reduction. This is one of the very few prospective trials focusing on EMD and we successfully laid grounds for implementing immunochemotherapy in MM treatment. Keywords: Multiple myeloma, Relapse/refractory, Extramedullary multiple myeloma, Daratumumab, DCEP
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
POEMS syndrome is a rare form of plasma cell dyscrasia characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal proteins, and skin changes. Owing to its low incidence, there are few ...reports regarding this syndrome. This multicenter study included 84 patients diagnosed with POEMS syndrome in South Korea.
We retrospectively evaluated 84 patients diagnosed with POEMS syndrome at 8 hospitals in South Korea between January 2000 and October 2022. The clinical characteristics and treatment outcomes were analyzed.
The median patient age was 53 years (range, 26-77 years), and 63.1% of the patients were male. All patients had peripheral neuropathy, and 81 (96.4%) had monoclonal plasma cell proliferation. Plasma vascular endothelial growth factor levels were available for 32 patients with a median of 821 pg/mL (range, 26-12,900 pg/mL). Other common features included skin changes (54.2%), volume overload (71.4%), and organomegaly (72.6%). Of the 84 patients, 75 received initial treatment (local radiotherapy, 6 8.0%; chemotherapy, 17 22.7%; both chemotherapy and local radiotherapy, 9 12.0%), upfront autologous stem cell transplantation (ASCT), 43 (57.3%; with induction chemotherapy, n = 12, 16.0%; without induction chemotherapy, n = 31, 41.3%). The median follow-up duration was 40.7 months. The 5-year overall survival (OS) was 78%, and the 5-year progression-free survival (PFS) was 55%. Patients who underwent upfront ASCT and were diagnosed after 2014 had a longer OS and PFS.
The demographics of Korean patients with POEMS syndrome were similar to those reported previously. Because of the introduction of new treatment agents and the reduced rate of transplant-related mortality related to ASCT, the treatment outcomes of Korean patients with POEMS syndrome have improved in recent years.
Background
Epstein–Barr virus (EBV) is etiologically associated with ~ 10% of all gastric carcinomas. However, the molecular mechanisms and roles of EBV miRNAs in gastric carcinoma oncogenesis are ...yet to be elucidated.
Methods
MicroRNA microarray and TaqMan quantitative real-time RT-PCR were conducted. RT-PCR and luciferase reporter assay for PIAS3, western blotting for 20 proteins, immunofluorescence for STAT3, transfection with miRBART5-5p-plasmid, STAT3-plasmid, miRBART5-5p mimic, or PIAS3-siRNA, and in vitro assays for biological effects of PD-L1 were implemented. In situ hybridization for EBV-encoded small RNAs and immunohistochemistry were performed on gastric carcinoma tissues.
Results
Transfecting miR-BART5-5p into EBV(−) gastric carcinoma cell lines caused a decrease in PIAS3 3′-UTR reporter activity, PIAS3 downregulation, and subsequent STAT3 activation followed by PIAS3/pSTAT3-dependent PD-L1 upregulation. Interestingly, due to PD-L1 knockdown, apoptosis was increased, while the rate of cell proliferation, invasion capacity, and migration were decreased in miR-BART5-5p-transfected cells. In EBV(+) gastric carcinoma cells, anti-miR-BART5-5p reduced PD-L1 levels through PIAS3/pSTAT3 control. Among 103 patients with EBV-associated gastric carcinomas, overall survival was significantly shortened for those with PD-L1(+) tumors compared to those with PD-L1(−) tumors (
P
= 0.049).
Conclusions
Our findings imply that miR-BART5-5p directly targets PIAS3 and augments PD-L1 through miR-BART5/PIAS3/pSTAT3/PD-L1 axis control. This contributes to antiapoptosis, tumor cell proliferation, invasion and migration, as well as immune escape, furthering gastric carcinoma progression and worsening the clinical outcome, especially in the PD-L1(+) group of patients with EBV-associated gastric carcinomas. miR-BART5-5p may, therefore, be amenable to PD-1/PD-L1 immune checkpoint inhibitor therapy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Epstein-Barr virus (EBV) is associated with several tumors and generates BamHI A rightward transcript (BART) microRNAs (miRNAs) from BART transcript introns. These BART miRNAs are expressed at higher ...levels in EBV-associated epithelial malignancies than in EBV-infected B lymphomas. To test the effects of EBV miRNA on the cell cycle and cell growth, we transfected miR-BART1-3p, a highly expressed EBV-associated miRNA, into gastric carcinoma cells. We found that miR-BART1-3p induced G0/G1 arrest and suppressed cell growth in gastric carcinoma cells. As our microarray analyses showed that E2F3, a cell cycle regulator, was inhibited by EBV infection, we hypothesized that miR-BART1-3p regulates E2F3. Luciferase assays revealed that miR-BART1-3p directly targeted the 3'-UTR of E2F3 mRNA. Both E2F3 mRNA and encoded protein levels were reduced following miR-BART1-3p transfection. In contrast, E2F3 expression in AGS-EBV cells transfected with a miR-BART1-3p inhibitor was enhanced. As E2F3 has been shown to regulate the expression of highly conserved miR-17-92 clusters in vertebrates, we examined whether this expression is affected by miR-BART1-3p, which can downregulate E2F3. The expression of E2F3, miR-17-92a-1 cluster host gene (MIR17HG), and miR-17-92 cluster miRNAs was significantly reduced in EBV-associated gastric carcinoma (EBVaGC) patients compared with EBV-negative gastric carcinoma (EBVnGC) patients. Further, miR-BART1-3p as well as the siRNA specific to E2F3 inhibited the expression of the miR-17-92 cluster, while inhibition of miR-BART1-3p enhanced the expression of the miR-17-92 cluster in cultured GC cells. Our results suggest a possible role of miR-BART1-3p in cell cycle regulation and in regulation of the miR-17-92 cluster through E2F3 suppression.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We compared efficacy and safety, according to frailty, of elderly patients with relapsed and refractory multiple myeloma (RRMM) treated with lenalidomide and dexamethasone (Rd), for whom bortezomib ...treatment had failed. Patients, 164 (52.9%) and 146 (47.1%), were classified as non-frail and frail using a simplified frailty scale. The overall response rates (ORR) and survival outcomes were lower in frail than in non-frail patients (ORR: 56.2% vs. 67.7%,
P
= 0.069; median progression free survival: 13.17 vs. 17.80 months,
P
= 0.033; median overall survival: 23.00 vs. 36.27 months,
P
= 0.002, respectively). The number of treatment emergent adverse events in grade 3 or worse was higher in frail than in non-frail patients (41.8% vs. 24.4%,
P
= 0.002, respectively). In frail patients, independent poor prognostic factors for survival were two or more Charlson comorbidity index (CCI) score, prior to exposure to both bortezomib and thalidomide, and achieved less than partial response In conclusion, frailty could predict clinical outcomes of Rd treatment in elderly patients with RRMM who had failed prior bortezomib. In frail patients, lower CCI in addition to less previous treatment exposure and deep response were associated with better survival.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Plasmacytoma has been reported to be associated with a poor prognosis in patients with multiple myeloma (MM). In this study, we evaluated the incidence of relapse with plasmacytoma and survival ...outcomes after upfront autologous stem cell transplantation (ASCT). This study retrospectively analyzed the data of 303 patients with MM who underwent upfront ASCT between April 2000 and April 2018 at eight institutes in the Republic of Korea. In total, 52 patients (17.1%) had plasmacytoma at MM relapse after upfront ASCT, of whom, 27 had paramedullary plasmacytoma (PMD) and 25 had extramedullary plasmacytoma (EMD). Patients with initial plasmacytoma were more likely to have plasmacytoma at MM relapse than those without initial plasmacytoma (37.1% vs. 11.2%). Over a median follow-up of 66.0 months, patients with plasmacytoma at relapse had significantly inferior overall survival (OS) than those without plasmacytoma (43.9 vs. 100.7 months,
P
< 0.001), but the OS did not significantly differ between patients with EMD and those with PMD (42.2 vs. 56.6 months,
P
= 0.464). After MM relapse, all patients received salvage therapy, and progression-free survival after relapse was significantly shorter in patients with plasmacytoma than in those without (6.4 vs. 12.4 months,
P
= 0.007). This study showed that plasmacytoma frequently developed at MM relapse after upfront ASCT in patients with plasmacytoma at the time of diagnosis. Plasmacytoma at relapse was significantly associated with a poor prognosis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Lenalidomide plus dexamethasone (LD) is currently the mainstay of treatment for both untreated and relapsed or refractory multiple myeloma (RRMM). Although lenalidomide-associated venous ...thromboembolism (VTE) is a major clinical concern, its incidence and prognostic impact have not been delineated. In this nationwide retrospective cohort study, we aimed to determine the cumulative incidence of VTE and its prognostic value using two consecutive cohorts of LD-treated RRMM patients: the KMM151 cohort (
N
= 542) and the HIRA cohort (
N
= 1559). Data were collected from medical records for the KMM151 cohort and healthcare insurance claims database for the HIRA cohort. Throughout the study period, 24 patients (4.4%) in the KMM151 cohort and 80 patients (5.1%) in the HIRA cohort developed VTE. The cumulative incidence reached a plateau approximately 2 years after LD initiation. The 2-year incidence was 4.9% in the KMM151 cohort and 8% in the HIRA cohort. Higher starting dose of lenalidomide, previous history of VTE, and older age were associated significantly with an increased VTE risk. Early-onset VTE was associated significantly with poor survival. In conclusion, VTE occurred in 5–8% of RRMM patients treated with LD over 2 years, and early-onset VTE was a strong indicator of poor prognosis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The effectiveness of early treatment for biochemical relapse of multiple myeloma (MM) is unclear. To clarify this issue, this retrospective study was performed to evaluate the survival outcomes of ...315 patients with relapsed MM after upfront autologous stem cell transplantation (ASCT). Over a median follow-up of 66.6 months (range, 15.1–195.5 months), 48.2% of patients showed biochemical relapse, 41.3% showed clinical relapse, and 10.5% showed significant biochemical relapse. Progression-free survival (PFS) and overall survival (OS) were inferior for patients with clinical relapse compared to the other patients. Multivariate analysis showed that clinical relapse was an independent prognostic factor for OS. In patients with biochemical relapse, there was no significant difference in survival between patients treated while asymptomatic and those treated once clinical symptoms had appeared. Relapse type after upfront ASCT was a significant prognostic factor in patients with MM. In addition, no survival benefit of early treatment at biochemical relapse was observed, but a triplet regimen may be beneficial for MM patients with biochemical relapse.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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