Primary breast diffuse large B-cell lymphoma characterized by CNS relapse and successful hematopoietic stem cell transplantation salvage therapy.

BACKGROUND: Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is rare, with a high incidence of central nervous system (CNS) relapse. This study aims to investigate clinical characteristics, prognostic factors, and outcomes in Taiwanese PB-DLBCL patients and review the literature on PB-DLBCL. METHODS: Thirty-one PB-DLBCL patients diagnosed between 2000 and 2021 were retrospectively enrolled for analysis. RESULTS: The median age was 49 (range 26-79) years. The complete remission (CR) rate was 90.3%. Nine (90%) of the ten patients who experienced relapse had CNS involvement at the time of relapse. The one-year, two-year, and five-year progression-free survival (PFS) rates were 86.6% (95% confidence interval [CI] 75.2-99.8), 75.8% (95% CI 61.6-93.2), and 45.1% (95% CI 29.5-68.9), respectively. The five-year overall survival (OS) rate was 64.1% (95 % CI 48.4-85.0). A stage-modified International Prognostic Index (mIPI) less than two (five-year PFS rate 52.5% vs. 17.1%, P = 0.02) and the achievement of CR after first-line treatment (two-year PFS rate 80.3% vs. 33.3%, P < 0.001) were significant favorable prognostic factors for PFS. Hematopoietic stem cell transplantation (HSCT) after the first relapse was associated with significantly improved post-relapse OS (five-year OS rate 85.7% vs. 20.0%, P = 0.02) and PFS (five-year PFS rate 85.7% vs. 20.0%, P = 0.02). CONCLUSION: Patients with low-risk mIPI scores, CR after first-line treatment, and those who underwent HSCT after the first relapse had significantly better survival. Intrathecal chemotherapy conferred no benefit in preventing CNS relapse. Further research is needed to assess frontline HSCT's effectiveness in improving outcomes and preventing CNS relapses in PB-DLBCL patients.

Application of comprehensive geriatric assessment in predicting early mortality among elder patients with B-cell lymphoma receiving immunochemotherapy.

OBJECTIVES: Early mortality, defined as death within 120 days after initiated antitumor therapy, is an important issue especially for elder patients with B-cell lymphoma. This study aimed to evaluate the clinical value of comprehensive geriatric assessment (CGA) in early mortality prediction in elderly patients with B-cell lymphoma receiving immunochemotherapy. METHODS: Seventy-six consecutive patients with newly diagnosed B-cell lymphoma receiving immunochemotherapy from a medical center in Taiwan were prospectively enrolled. Patients were divided into fit (n = 49) and frail (n = 27) groups per pretreatment CGA for early mortality comparison. RESULTS: The early mortality rate in our patient cohort was 16% (n = 12): from 6% in patients with no CGA domain impairment to 43% in patients with ≥4 CGA domain impairment. The early mortality rate was 6% and 33% in fit and frail patients (odds ratio, 7.67; 95% CI, 1.86-31.6; P = .005), respectively. Frailty was the significant predictor for early mortality in univariate and multivariate analysis. CONCLUSION: In this study, the number of geriatric domain impairment is positively associated with the early mortality risk in elderly patients with B-cell lymphoma. Therefore, CGA can help clinicians to identify the risk of early mortality in elderly patients and provide alternative treatment.

Correction: Huang et al. Systemic Anticoagulation and Inpatient Outcomes of Pancreatic Cancer: Real-World Evidence from U.S. Nationwide Inpatient Sample. Cancers 2023, 15, 1985.

In the original publication [...].

Features and allele frequency of JAK2 Exon 12-mutated polycythemia vera in comparison with JAK2V617F-mutated disease.

BACKGROUND AND AIM: JAK2 exon 12 mutation status and the clinical characteristics of patients with polycythemia vera (PV) in Asia remain to be defined. METHOD: We analyzed the clinical, molecular, and genetic features and outcomes of patients with PV harboring exon 12 mutation and compared them with the JAK2V617F-mutated patients in Taiwan. JAK2V617F with allele burden was measured by pyrosequencing and/or RT/qPCR. The allele frequency of exon 12 mutation was analyzed by next-generation sequencing in JAK2V617F-negative patients. RESULTS: A total of 532 patients diagnosed with PV were enrolled. The JAK2V617F mutation was present in 94.9% and exon 12 mutations in 5.1%. At diagnosis, patients with exon 12 mutation had higher hemoglobin (p = 0.012), and hematocrit levels (p = 0.003), and lower platelet (p < 0.001), and leukocyte counts (p < 0.001) compared to patients with JAK2V617F mutations. Patients harboring the JAK2V617F mutation had a higher incidence of high allele burden (p < 0.001), disease risk (p= 0.014), and bleeding events (p= 0.013) compared to patients with PV with exon 12 mutations. These patients showed similar outcomes (overall survival, leukemia-free, myelofibrosis and thrombosis-free survival) to those with JAK2V617F mutations. An allele frequency ≥ 52.5% conferred an inferior overall survival compared to ≤ 52.5% in both exon 12-mutated (p = 0.029) and JAK2V617F patients with PV (p = 0.038). CONCLUSION: Taiwanese patients with PV showed differences in blood count, risk group, and bleeding events between exon 12 and JAK2V617F patients. Higher mutant allele burden had a negative impact on overall survival for both mutation types.

Major impact of prognosis by age and sex in patients with primary mediastinal large B­cell lymphoma.

The effective prognostic factors for primary mediastinal large B-cell lymphoma (PMLBCL) vary among published studies. The aim of the present study was to explore the factors influencing the overall survival (OS) and progression-free survival (PFS) of patients with PMLBCL at a single institute in Taiwan. This retrospective study was conducted to analyze the prognostic impact of age, sex, disease stage, International Prognostic Index (IPI) score, treatment modality and initial response. A total of 72 patients with a median age of 28 years were included in the study. The mean OS and PFS were 171.40 and 159.77 months, respectively. Female sex, age ≤60 years, receiving radiotherapy (RT) and achieving a complete response were found to be associated with a significantly improved OS and PFS. In addition, high-intensity chemotherapy and an IPI score ≤1 were associated with longer OS, and early-stage disease was associated with a PFS superior to that of advanced-stage disease. The predictive value of IPI is limited in PMLBCL. Therefore, it is necessary to develop a novel prognostic system. The present study revealed the impact of sex on prognosis and, therefore, this factor should be considered in future prognostic evaluations. Since a complete post-treatment response was found to be important, high-intensity chemotherapy is recommended. However, low-intensity treatment followed by RT consolidation appears to be a feasible approach in elderly patients.

Different patterns of failure in two treatment regimens for primary central nervous system lymphoma, a retrospective analysis of 124 cases in Taiwan.

To explore prognostic factors and outcomes of primary central nervous system lymphoma (PCNSL) of diffuse large B-cell lymphoma (DLBCL) in Taiwan, 124 PCNSL-DLBCL patients (from 1995 to 2021) were retrospectively analyzed. Mainly, two treatment modalities including sandwich chemoradiotherapy and modified MATRix regimen were employed in these patients. Overall survival (OS) was determined by log-rank test and time-dependent Cox analysis. Median OS of all patients was 27.1 months. 47 (37.9%) patients who underwent sandwich chemoradiotherapy had a complete remission (CR) rate of 87.2%, median OS of 53.9 months, and progression free survival (PFS) of 42.9 months. 11 (8.9%) patients who underwent modified MATRix regimen had CR rate of 72.7%, median OS of 18.9, and PFS of 11.2 months. There are no significant OS differences between treatment groups or addition of Rituximab. Patients treated with the modified MATRix regimen experienced a higher early mortality rate followed by a survival plateau. IELSG low-risk group had significantly improved OS and PFS than IELSG intermediate- or high-risk group. In multivariant analysis, age > 60 years old and bilateral cerebral lesions are associated with significantly inferior OS. Sandwich chemoradiotherapy demonstrated better early survival and reduced treatment-related toxicity for PCNSL patients compared to the modified MATRix regimen. However, the long-term follow-up revealed a higher rate of treatment failure events in the sandwich chemoradiotherapy group. IELSG and MSKCC scores served as reliable risk assessment models. Incorporating bilateral cerebral lesions as a risk factor further improved risk evaluation.

Comparison of Clinical and Molecular Features Between Patients With Essential Thrombocythemia and Early/Prefibrotic Primary Myelofibrosis Presenting With Thrombocytosis in Taiwan.

OBJECTIVES: The clinical presentations of essential thrombocythemia (ET) may be quite similar to early/prefibrotic primary myelofibrosis (pre-PMF), especially in pre-PMF presenting with thrombocytosis (pre-PMF-T), but may be associated with a different outcome. It is very important to distinguish these two entities. The aim of this study was to address the clinical and prognostic relevance of distinguishing pre-PMF-T from ET. METHODS: All patients, including 258 with ET and 105 with pre-PMF-T, received JAK2V617F, MPL (exon 10), and CALR (exon 9) mutation analysis and allele burden measurement for JAK2V617F and CALR mutants. RESULTS: Patients with pre-PMF-T had an older age and higher leukocyte and platelet counts but lower hemoglobin levels than patients with ET. Patients with pre-PMF-T had a shorter overall, leukemia-free, and thrombosis-free survival compared with patients with ET. Patients with ET had a higher rate of cerebral ischemic stroke, whereas patients with pre-PMF-T tended to have splanchnic vein thrombosis. The frequencies of JAK2V617F, CALR, and MPL mutations and CALR allele burden were no different, but JAK2V617F allele burden was significantly higher in pre-PMF-T. Patients with pre-PMF-T with the JAK2V617F mutation had an inferior overall survival and thrombosis-free survival, whereas the status of driver gene mutations did not influence the outcomes of patients with ET. CONCLUSIONS: ET and pre-PMF-T were two distinct disease entities and exhibited different clinical phenotype, genotype, and outcomes.

Systemic Anticoagulation and Inpatient Outcomes of Pancreatic Cancer: Real-World Evidence from U.S. Nationwide Inpatient Sample.

Background: Pancreatic cancer can induce a hypercoagulable state which may lead to clinically apparent thrombosis. However, the effect of anticoagulants remains ambiguous. This study aimed to investigate the potential effect of long-term systemic anticoagulant usage on hospitalization outcomes of patients with pancreatic cancer. Methods: This retrospective study extracted all data from the U.S. Nationwide Inpatient Sample (NIS) database from 2005 to 2018. We included hospitalized adults ≥18 years old with a pancreatic cancer diagnosis identified by International Classification of Diseases ninth revision (ICD-9) and tenth revision (ICD-10) codes. We utilized diagnostic codes ICD9 V58.61 and ICD10 Z79.01, i.e., 'long-term use of anticoagulant', to identify individuals who were on a long-term systemic anticoagulant. The study cohort were then further grouped as being with or without long-term systemic use of an anticoagulant. Propensity score matching was performed to balance the characteristics of the two groups. The risks of life-threatening events, e.g., acute myocardial infarction (AMI), acute heart failure (AHF), sepsis, shock, and acute kidney injury (AKI), in-hospital death, and prolonged length of stay (LOS) in the hospital were compared between the groups by univariable and multivariable logistic regression analyses. Results: The study population consisted of 242,903 hospitalized patients with pancreas cancer, 6.5% (n = 15,719) of whom were on long-term systemic anticoagulants. A multivariable regression analysis showed that long-term systemic anticoagulant use was independently associated with lower odds of sepsis (aOR: 0.81, 95% CI: 0.76-0.85), shock (aOR: 0.59, 95% CI: 0.51-0.68), AKI (aOR: 0.86, 95% CI: 0.81-0.91), in-hospital mortality (aOR: 0.65, 95% CI: 0.60-0.70), and prolonged LOS (aOR: 0.84, 95% CI: 0.80-0.89). Conclusions: Long-term systemic anticoagulant use is associated with better clinical outcomes in terms of decreased risks of some life-threatening events, in-hospital death, and prolonged LOS among hospitalized patients with pancreatic cancer in the U.S.

Beta2-microglobulin is a valuable marker and identifies a poor-prognosis subgroup among intermediate-risk patients with diffuse large B cell lymphoma.

Prognosis of diffuse large B cell lymphoma (DLBCL) can be predicted by various factors. The most widely used tool for prediction is the international prognostic index (IPI). ß2-microglobulin is a tumor marker commonly used in hematological malignancies. ß2-microglobulin is well correlated with outcome of DLBCL. It has been used as an adjunctive tool in some scoring systems for prognostication of DLBCL. In this study, we collected data of patients with diagnosis of DLBCL between 2015 and 2019 in our institute. For each patient, IPI was calculated according to published literature. At diagnosis, serum levels of ß2-microglobulin were measured in the clinical laboratory and the results were retrieved from medical records. A total of 516 patients (269 male and 247 female) were enrolled for retrospective analysis. The median age was 64 (range 22-96). The median follow-up period was 32.2 months. The median level of ß2-microglobulin was 2319 µg/L (normal range < 2366 µg/L in the clinical laboratory). Level of ß2-microglobulin was significantly different between survivors and patients who succumbed to the disease. ß2-microglobulin level was correlated with tumor stage, extranodal involvement, B symptoms and IPI, suggesting that it may be a good surrogate marker for disease severity and outcome prediction. We selected the intermediate-risk patients for further analysis. Patients with intermediate-risk IPI and high ß2-microglobulin levels have overall survival comparable to patients with high-risk IPI, suggesting an important role of ß2-microglobulin in subdivision of DLBCL patients. In conclusion, ß2-microglobulin levels correlated with outcome of DLBCL. It may be used independently as a prognostic factor. Subdivision of patients with intermediate-risk IPI may identify a group of high-risk patients, which can be helpful in refining plans of treatment and follow-up.

Changing profile of platelet activity and turnover indices during treatment response of immune thrombocytopenia.

Both platelet count and function change after treatment of immune thrombocytopenia. Platelet function can be measured by plasma markers, including platelet activity [e.g., soluble P-selectin (sP-selectin) and soluble CD40 ligand (sCD40L)] and platelet turnover markers [e.g., glycocalicin (GC)]. Patients were classified into no response (NR, including new diagnosis), partial response (PR) and complete response (CR). One hundred and sixteen samples (29 CR, 32 PR, 55 NR) from 79 patients were collected. Plasma markers (sP-selectin, sCD40L and GC) were measured by ELISA. Platelet counts and mean platelet volume (MPV) were obtained in the clinical laboratory using GenS System-2. The results showed that responsive patients (PR + CR) had higher levels of sP-selectin (P = 0.026) and sCD40L (P = 0.001). Although there was no difference in MPV (P = 0.077) or GC (P = 0.078), there was a marked decrease of GC index (P < 0.001) in responsive patients. Paired sample analysis showed no difference in sP-selectin, sCD40L, MPV or GC but significant difference in GC index (P = 0.017) between NR and PR. Another paired sample analysis showed no difference in sP-selectin, sCD40L, MPV or GC but significant difference in GC index (P = 0.029) between PR and CR. Patients with refractory and newly diagnosed disease had a significant difference in GC (P = 0.020) and sCD40L (P = 0.001), despite similarly low platelet counts. In conclusion, platelet activity markers (sP-selectin and sCD40L) and GC indices change in parallel with treatment response. Plasma levels of GC and sCD40L may be predictors of treatment response.

Measurable Residual Disease Monitoring by Locked Nucleic Acid Quantitative Real-Time PCR Assay for IDH1/2 Mutation in Adult AML.

Locked nucleic acid quantitative Real-Time PCR (LNA-qPCR) for IDH1/2 mutations in AML measurable residual disease (MRD) detection is rarely reported. LNA-qPCR was applied to quantify IDH1/2 mutants MRD kinetics in bone marrow from 88 IDH1/2-mutated AML patients, and correlated with NPM1-MRD, clinical characteristics, and outcomes. The median normalized copy number (NCN) of IDH1/2 mutants decreased significantly from 53,228 (range 87−980,686)/ALB × 106 at diagnosis to 773 (range 1.5−103,600)/ALB × 106 at first complete remission (CR). IDH1/2 LNA-qPCR MRD was concordant with remission status or NPM1-MRD in 79.5% (70/88) of patients. Younger patients and patients with FLT3 mutations had higher concordance. The Spearman correlation coefficient (rs) and concordance rate between the log reduction of IDH1/2 LNA-qPCR and NPM1-MRD were 0.68 and 81% (K = 0.63, 95% CI 0.50−0.74), respectively. IDH1/2-MRD > 2 log reduction at first CR predicted significantly better relapse-free survival (3-year RFS rates 52.9% vs. 31.9%, p = 0.007) and cumulative incidence of relapse (3-year CIR rates 44.5% vs. 64.5%, p = 0.012) compared to IDH1/2-MRD ≤ 2 log reduction. IDH1/2-MRD > 2 log reduction during consolidation is also associated with a significantly lower CIR rate than IDH1/2-MRD ≤ 2 log reduction (3-year CIR rates 42.3% vs. 68.8%, p = 0.019). LNA-qPCR for IDH1/2 mutation is a potential MRD technique to predict relapse in IDH1/2-mutated AML patients, especially for those with IDH1/2 MRD > 2 log reduction at first CR or a concurrent FLT3 mutation.

Clinical features, outcome and prognostic factors of 87 patients with angioimmunoblastic T cell lymphoma in Taiwan.

We retrospectively analyzed 87 patients with angioimmunoblastic T cell lymphoma (AITL) in Taiwan. The median age was 68 (range 18-89) years. Of these patients, 74 % was at an advanced stage. The most common extra-nodal site involved was bone marrow (36 %). Of these patients, 77 % were International Prognostic Index (IPI) >1 and 79 % had a prognostic index for peripheral T-cell lymphoma (PIT) >1. Of 75 patients who received systemic chemotherapy, the complete remission rate was 60 %, the relapse rate was 47 %, and the 2-year progression-free survival rate was 37.4 %. The 2-year overall survival (OS) rate for all patients was 51.9 %. By multivariate analysis, bone marrow involvement (P < 0.001) and ECOG >1 (P = 0.007) were independent adverse factors for OS. A simplified prognostic index efficiently stratified patients into the following three groups: 2-year OS rates 79.8 % (0 factor), 28.3 % (1 factor), and 10.2 % (2 factors) by using bone marrow involvement and ECOG >1 (P < 0.001). In conclusion, AITL patients were older and had poorer prognosis in Taiwan. Bone marrow involvement, EOCG >1, IPI >1 and PIT >1 had adverse impact on OS. The usefulness of this simplified prognostic index needs further validation.

CD5 positivity is an independent adverse prognostic factor in elderly patients with diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. Age over 60 years is one of the five parameters of the International Prognostic Index (IPI), which is the most important clinical prognostic predictor in DLBCL. A previous study on German DLBCL patients over 60 years of age showed that immunoblastic morphology, but not germinal center B cell-like (GCB)/non-GCB subtype, correlated with short survival. We collected 174 DLBCL cases over 60 years of age in Taiwan and performed immunophenotyping and detection of Epstein-Barr virus (EBV)-encoded RNA (EBER) by in situ hybridization. Of the cases, 5.2 % were positive for CD5 and 5.7 % positive for EBER. Neither immunoblastic morphology nor GCB/non-GCB subtype correlated with survival. In univariate analysis, adverse prognostic factors included IPI ≥ 3 (P < 0.000001), B symptoms (P = 0.000075), bone marrow/peripheral blood involvement (P = 0.017), EBER positivity (P = 0.0013), and CD5 positivity (P = 0.016). In multivariate analysis, CD5 positivity was the only independent adverse prognostic factor (HR = 3.16; 95 % CI = 1.34-7.47; P = 0.0087) in addition to IPI ≥ 3 (HR = 3.07; 95 % CI = 1.84-5.11; P = 0.000018). Surprisingly, despite an overall 5.2 % incidence of central nervous system (CNS) relapse in our patients, none of the CD5+ cases experienced CNS relapse (P = 1.00). This is in stark contrast to the more frequent CNS relapse in Japanese CD5+ DLBCL patients. EBER positivity was associated with IPI ≥ 3 (P = 0.010), stage III-IV (P = 0.0082), and B symptoms (P = 0.011). In multivariate analysis, EBER positivity was not an independent adverse prognostic factor (P = 0.81), its effect being due likely to accompanying adverse clinical parameters.

Primary breast lymphoma: a single-institute experience in Taiwan.

BACKGROUND: Breast is an uncommon location of lymphoma involvement. The most common type of primary breast lymphoma (PBL) is diffuse large B-cell lymphoma (DLBCL). Rituximab is the widely used monoclonal antibody against CD20+ B-cell lymphoma, especially DLBCL. We aimed to analyze the clinical features, prognostic factors, and treatment outcome with or without rituximab in primary breast DLBCL. METHODS: We retrospectively analyzed patients diagnosed with PBL from October 1987 to March 2012 in our hospital, excluding metastasis by whole-body computed tomography and bone marrow study. RESULTS: Twenty-three patients were diagnosed with PBL. All were females. Eighteen patients were stage IE and five were stage IIE according to the Ann Arbor staging system. Two patients had lymphoma other than DLBCL. The median age of primary breast DLBCL patients was 48 years (range 27-79). Two were excluded from the analysis due to refusal or ineligibility for chemotherapy. No significant prognostic factor was found. Patients receiving chemotherapy with (RC) or without (C) rituximab were not significantly different in the 5-year overall survival (RC: 57.1%; C: 58.3%; p = 0.457) or progression-free survival (RC: 57.1%; C: 50.0%; p = 0.456). A high incidence of relapse in the central nervous system (CNS) (17.6%) was observed. CONCLUSIONS: In accordance with prior literature reports, our Taiwanese cohort of primary breast DLBCL seemed younger than those reported in Japan, Korea, and Western societies. Relapse in the CNS was not uncommon. The benefit of rituximab in addition to chemotherapy was not statistically significant. Treatment modality remained to be defined by further large-scale studies.

Expression of Nuclear Receptor Coactivators in the Human Fetal Membranes at Term before and after Labor.

Human fetal membranes play an important role in term and preterm labor and are responsive to steroids. We examined the expression of steroid receptor coactivators in fetal membranes obtained prior to and following labor at term. Proteins were localized by immunohistochemistry, Western analysis was carried out in nuclear extracts, and mRNA levels were determined by real-time RT-PCR. SRC-1, SRC-2, p300, and PCAF proteins were present in all nuclear extracts. The amnion nuclei expressed higher levels of SRC-1, p300, and PCAF than nuclei from the chorion-decidua, whereas the reverse was true for SRC-2. Chorion-decidua from patients before labor expressed higher levels of SRC-1 than those from patients after labor. Also, the PCAF level was higher in the amnion obtained before labor than the same tissue obtained after labor. In contrast to the protein expression, mRNA levels of SRC-1 and p300 were higher in the chorion-decidua compared to the amnion, whereas there was no difference in levels of SRC-2 and PCAF mRNAs between these two tissues. These data underline that the regulation of the expression of the coactivators in these tissues occurs during labor and is complex and tissue specific.