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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.

Background Antitumor immune response of programmed cell death ligand (PD-L1) has shown clinical value not only in Hodgkin lymphoma and EBV-associated lymphomas but also in EBV-negative diffuse large B cell lymphoma (DLBCL) of non-germinal center B cell-like (non-GCB) subtype. Signal transducer and activator of transcription 3 (STAT3) is known to induce PD-L1 in immune cells and its activated form, phosphorylated STAT3 (pSTAT3), is also frequently expressed in non-GCB DLBCL. Herein, we investigated associations between PD-L1 expression/gene alteration, pSTAT3 expression and clinicopathologic variables in EBV-negative DLBCL. Methods In 107 cases of DLBCLs with non-GCB subtype (67%; 72/107), GCB subtype (25%; 27/107) and unclassifiable cases (8%; 8/107), we performed PD-L1 and pSTAT3 immunohistochemistry and fluorescence in situ hybridization for PD-L1 gene translocation and copy number gain/amplification. Results PD-L1 was expressed in tumor cells (PD-L1t) in 21% (23/107; 30% cutoff), immune cells (PD-L1i) in 36% (38/107; 20% cutoff), and pSTAT3 in tumor nuclei in 41% (44/107; 40% cutoff). PD-L1 gene alteration was observed in 10% (10/102) including translocation in 6% (6/102) and copy number gain/amplification in 4% (4/102). Non-GCB subtype was associated with PD-L1t and pSTAT3 (p = 0.006 and p = 0.042), and tended to have PD-L1 gene alteration (p = 0.058). Tumoral PD-L1 expression without gene alteration (PD-L1t+ GA−) correlated with pSTAT3-positive tumor cell proportions (%) (p = 0.033). In survival analysis, pSTAT3 expression independently predicted shorter PFS in total cohort (p = 0.017) and R-CHOP-treated group (p = 0.007), and in pSTAT3-negative R-CHOP-treated subset, PD-L1 expression in immune cells (PD-L1i) correlated with shorter PFS (p = 0.042). Conclusions Gene alteration and protein expression of PD-L1 and pSTAT3 expression were closely related in DLBCL and constituted features of non-GCB subtype. In addition to known clinical significance of pSTAT3, immune cell expression of PD-L1 (PD-L1i) had also clinical value in pSTAT3-dependent manner. These findings may provide an insight into immunotherapeutic strategy and risk stratification in DLBCL patients.

PIK3CA mutations are frequently observed in various human cancers including gastric cancer (GC). This study was conducted to investigate the anti-tumor effects of alpelisib, a PI3K p110α-specific inhibitor, using preclinical models of GC. In addition, the combined effects of alpelisib and paclitaxel on GC were evaluated. Among the SNU1, SNU16, SNU484, SNU601, SNU638, SNU668, AGS, and MKN1 GC cells, three PIK3CA -mutant cells were predominantly sensitive to alpelisib. Alpelisib monotherapy decreased AKT and S6K1 phosphorylation and induced G 0 /G 1 phase arrest regardless of PIK3CA mutational status. The alpelisib and paclitaxel combination demonstrated synergistic anti-proliferative effects, preferentially on PIK3CA -mutant cells, resulting in increased DNA damage response and apoptosis. In addition, alpelisib and paclitaxel combination potentiated anti-migratory activity in PIK3CA- mutant cells. Alpelisib partially reversed epithelial–mesenchymal transition markers in PIK3CA -mutant cells. In a xenograft model of MKN1 cells, the alpelisib and paclitaxel combination significantly enhanced anti-tumor activity by decreasing Ki-67 expression and increasing apoptosis. Moreover, this combination tended to prolong the survival of tumor-bearing mice. Our data suggest promising anti-tumor efficacy of alpelisib alone or in combination with paclitaxel in PIK3CA -mutant GC cells.

Limited data is available regarding the pharmacological prophylaxis for venous thromboembolism (VTE) in Asian patients undergoing total knee arthroplasty or total hip arthroplasty (TKA/THA). We performed a population-based epidemiological study using the Health Insurance Review and Assessment Service database to estimate the rate of pharmacological thromboprophylaxis and its impact on VTE in Korean patients who underwent TKA/THA between 2009 and 2013. We identified 306,912 cases (TKA, 261,260; THA, 45,652). The pharmacological thromboprophylaxis rate was 57.16% (TKA, 58.32%; THA, 50.51%), which increased from 42.81% in 2009 to 65.92% in 2013 (P = 0.0165). Both low-molecular-weight-heparin (22.42%) and rivaroxaban (22.71%) were the most common drugs for prophylaxis. The number of patients aged ≥ 60 years (87.31% vs. 81.01%, P < 0.0001), cases requiring general anesthesia (20.70% vs. 18.37%, P < 0.0001), and cases requiring long hospital stay (median, 13 days vs. 12 days, P < 0.0001) were significantly greater in the pharmacological prophylaxis group. The incidence of VTE within 3 months of surgery was 1.52% (TKA, 1.46%; THA, 1.87%). Patients with pharmacological prophylaxis had higher VTE rates (TKA, 1.69% vs. 1.14%; THA, 2.30% vs. 1.43%) than those without prophylaxis, with advanced age, use of general anesthesia, and a longer hospital stay increasing the risk of VTE. However, rivaroxaban significantly reduced the incidence of VTE following TKA (0.82% vs. 1.14%; odd ratio [OR], 0.72; 95% CI, 0.65-0.79). Moreover, ≥ 10 days of pharmacological thromboprophylaxis was significantly associated with lower incidence of VTE after TKA (1.33% vs. 1.52%; OR, 0.87; 95% CI, 0.81-0.94). This represents the largest epidemiological study showing a gradual increase in the use of pharmacological prophylaxis in Korean patients undergoing TKA/THA. Although the incidence of VTE is still low without pharmacological prophylaxis, this study demonstrates that the incidence of VTE can be reduced further using appropriate pharmacological thromboprophylaxis strategies.

BACKGROUNDChronotherapy is a drug intervention at specific times of the day to optimize efficacy and minimize adverse effects. Its value in hematologic malignancy remains to be explored, in particular in adult patients.METHODSWe performed chronotherapeutic analysis using 2 cohorts of patients with diffuse large B cell lymphoma (DLBCL) undergoing chemotherapy with a dichotomized schedule (morning or afternoon). The effect of a morning or afternoon schedule of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on survival and drug tolerability was evaluated in a survival cohort (n = 210) and an adverse event cohort (n = 129), respectively. Analysis of about 14,000 healthy individuals followed to identify the circadian variation in hematologic parameters.RESULTSBoth progression-free survival (PFS) and overall survival (OS) of female, but not male, patients were significantly shorter when patients received chemotherapy mostly in the morning (PFS HR 0.357, P = 0.033; and OS HR 0.141, P = 0.032). The dose intensity was reduced in female patients treated in the morning (cyclophosphamide 10%, P = 0.002; doxorubicin 8%, P = 0.002; and rituximab 7%, P = 0.003). This was mainly attributable to infection and neutropenic fever: female patients treated in the morning had a higher incidence of infections (16.7% vs. 2.4%) and febrile neutropenia (20.8% vs. 9.8%) as compared with those treated in the afternoon. The sex-specific chronotherapeutic effects can be explained by the larger daily fluctuation of circulating leukocytes and neutrophils in female than in male patients.CONCLUSIONIn female DLBCL patients, R-CHOP treatment in the afternoon can reduce toxicity while it improves efficacy and survival outcome.FUNDINGNational Research Foundation of Korea (NRF) grant funded by the Korean government (grant number NRF-2021R1A4A2001553), Institute for Basic Science IBS-R029-C3, and Human Frontiers Science Program Organization Grant RGY0063/2017.

Background Sodium-glucose cotransporter 2 (SGLT-2) inhibitors, widely used for type 2 diabetes and cardiorenal conditions, may induce erythrocytosis, potentially increasing cardiovascular risk. This study investigates its prevalence, risk factors, and thrombotic implications. Methods In a single-center retrospective study, we analyzed 6787 patients prescribed SGLT-2 inhibitors (2014–2024). Erythrocytosis was defined as hemoglobin > 16.5 g/dL or hematocrit > 49% in men, > 16.0 g/dL or > 48% in women. We assessed prevalence, risk factors, and thrombotic events using logistic regression. Results Erythrocytosis occurred in 1145 patients (16.9%) over a median follow-up of 530 days (IQR, 277–981), with a median hemoglobin rise of 1.0 g/dL (IQR, 0.4–1.8). Male sex (OR 3.24, 95% CI 2.47–4.26), BMI ≥ 25 kg/m 2 (OR 1.97, 95% CI 1.63–2.39), and current smoking (OR 2.41, 95% CI 1.96–2.96) significantly increased risk (all p < 0.001), while age ≥ 70 years, hypertension, dyslipidemia, and chronic kidney disease were associated with reduced risk. Thrombosis was rare (0.5%, 33 patients) and associated with antiplatelet use (OR 3.57, 95% CI 1.60–7.97), anticoagulant use (OR 5.93, 95% CI 2.60–13.57), and baseline erythrocytosis (OR 3.75, 95% CI 1.41–9.96). Among 33 patients with thrombosis, five exhibited erythrocytosis at the time of the event and within the prior six months; all had arterial thrombosis associated with underlying conditions (atrial fibrillation, coronary calcification, atherosclerosis), not directly attributable to SGLT-2-induced erythrocytosis. Conclusions SGLT-2 inhibitors are associated with a 16.9% prevalence of erythrocytosis, but thrombotic risk appears primarily driven by pre-existing conditions. Graphical abstract

Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. The aim of this study was to investigate the effects of baseline plasma AREG levels in KRAS , NRAS , and BRAF wild-type metastatic colorectal cancer (CRC) on treatment outcome with palliative first-line cetuximab + FOLFIRI chemotherapy. Chemotherapy outcomes were analyzed based on baseline plasma AREG levels. The clinical findings were further validated using an in vitro model of CRC. Among 35 patients, the progression-free survival (PFS) was significantly inferior in patients with high AREG than in those with low AREG levels: 10.9 vs . 24.2 months, respectively ( p  = 0.008). However, after failure of first-line chemotherapy, AREG levels were associated with neither PFS (4.8 vs. 11.6 months; p  = 0.215) nor overall survival (8.4 vs. 13.3 months; p  = 0.975). In SNU-C4 and Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC cell lines tested, AREG significantly decreased the anti-proliferative effect of cetuximab ( p  < 0.05) via AKT and ERK activation. However, after acquiring cetuximab resistance with gradual exposure for more than 6 months, AREG neither increased colony formation nor activated AKT and ERK after cetuximab treatment. Our results suggest that plasma AREG is a potential biomarker to predict clinical outcomes after cetuximab-based chemotherapy.

Splanchnic vein thrombosis (SpVT) in solid tumors has not been well investigated. Therefore, the treatment guidelines for SpVT are not well established. We aimed to conduct this prospective study to investigate the clinical characteristics and risk factors influencing survival in patients with gastrointestinal cancer with SpVT. Fifty-one patients with gastrointestinal cancer diagnosed with SpVT were prospectively enrolled. The clinical characteristics and courses of SpVT were analyzed. SpVT occurred in various clinical situations (at the time of initial cancer diagnosis or tumor recurrence after curative therapy, in the postoperative period, during chemotherapy, or in the period of end-of-life care). Among the total patients, 90.2% had no SpVT-related symptoms at initial SpVT diagnosis, and 82.4% did not receive any anticoagulation therapy. The clinical course of SpVT during the follow-up varied: (1) spontaneous resorption without any anticoagulation (47.1%), (2) resorption with anticoagulation (3.9%), (3) persistent thrombosis without progression (17.6%), and (4) SpVT extension (31.4%). Although the SpVT showed extension in some cases, most of them did not cause symptoms or had little impact on the patient's cancer treatment course. During the follow-up period, 23 patients died, all of which were caused by tumor progression. In the multivariable analysis, performance status and clinical situation at the time of SpVT diagnosis were significant prognostic factors. Clinicians could adopt a strategy of close observation for incidentally detected SpVT in patients with gastrointestinal cancer. Anticoagulation should be considered only for SpVT cases selected strictly, weighing the risks and benefits.

Potential synergism between Bruton’s tyrosine kinase (BTK) inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab (R2A) in patients with aggressive relapsed/refractory aggressive (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint of this study is objective response rate (ORR), and the secondary endpoints are complete remission (CR) rate, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). A total of 66 patients are enrolled mostly with diffuse large B-cell lymphoma. The ORR is 54.5% and CR rate is 31.8% meeting the primary end point. The median DoR is 12.9 months, and 1-year PFS and OS rate is 33.1% and 67.5% respectively. Adverse events (AE) are manageable with the most frequent AE being neutropenia (31.8%). Patients with MYD88 mutations, subtypes known for NF-κB activation, and high BTK expression by immunohistochemistry respond well. Overall, these results show a significant efficacy of the R2A regimen in patients with aggressive R/R B-cell NHL, with exploratory biomarkers suggesting potential associations with response. (ClinicalTrials.gov 51 identifier: NCT04094142) Potential synergism between BTK inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab in patients with aggressive Relapsed/Refractory aggressive B-cell non-Hodgkin lymphoma.

Background/Aim: Bruton’s tyrosine kinase (BTK)-mediated B-cell-receptor signaling drives lymphomagenesis of diffuse large B-cell lymphoma (DLBCL). We investigated the clinicopathological significance of BTK positivity in DLBCL according to known molecules related to resistance to BTK inhibitors [BCL2 apoptosis regulator (BCL2)/MYC proto-oncogene, bHLH transcription factor (MYC)]. Patients and Methods: We evaluated BTK expression immunohistochemically in 106 DLBCLs considering their BCL2/MYC status. Results: Considering the whole cohort, BTK was expressed in 65.1%, including 70.4% (50/71) of non-germinal center B-cell-like (non-GCB) subtype; BCL2 expression was detected in 60.4%, MYC expression in 15.1%, MYC translocation in 4.2% (4/96) and MYC gain/amplification in 7.6% (8/105). Overall and in the non-GCB cohort, BTK positively correlated with high international prognostic index (both p=0.005) and stage (p=0.006 and p=0.002), and with BCL2 intensity (p=0.005 and p=0.026, respectively); MYC gain/amplification total cohort (p=0.038). Moreover, high risk, defined as co-expression of BTK and either or both BCL2/MYC, independently predicted shorter progression-free survival in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) (all R-CHOP-treated patients: hazard ratio=2.565, p=0.044; R-CHOP-treated non-GCB subgroup: HR=3.833, p=0.019). Conclusion: BTK expression may be utilized to stratify risk in patients with DLBCL.