Primary Gastrointestinal Diffuse Large B-cell Lymphoma Research Articles

PET Radiomics Score Generated By Cross-Combination Approach for Treatment Response and Prognosis Prediction in Primary Gastrointestinal Diffuse Large B-Cell Lymphoma Patients

Background: Current risk stratification for primary gastrointestinal diffuse large B-cell lymphoma（PGI-DLBCL） relies on mainly on clinical factors. Radiomics score (RadScore) associated with survival outcomes have been developed for other cancer types, however few studies have thus far examined the role of radiomics in PGI-DLBCL. Objective: In this study, we investigated the value of PET RadScore constructed using a machine learning cross-combination approach in predicting the early treatment response and prognosis of patients with primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) treated with the R-CHOP-like regimen. Methods: A retrospective analysis was conducted on 108 PGI-DLBCL patients diagnosed through histopathological examination at two independent medical centers from March 2011 to March 2023, with 86 patients in the training cohort and 22 patients in the validation cohort. Seven different machine learning models were used to generate 49 feature selection-classification candidates, and the optimal candidate was selected based on the area under curve of ROC to establish RadScore. Risk factors were identified through logistic regression, and a radiomics nomogram was constructed by combining RadScore with the selected risk factors. The model was evaluated through calibration curves and decision curve analysis (DCA) using the training cohort and validation cohort. Results：A total of 111 radiomics features were extracted, and 19 features with strong predictive performance were selected to generate RadScore. The results suggest that RadScore can stratify patient prognosis.The logistic regression analysis results in the training cohort showed that elevated lactate dehydrogenase (LDH) level (OR=3.53, 95%CI: 1.21-10.31, p=0.021), intestinal involvement (OR=3.04, 95%CI: 1.04-8.88, p=0.042), and total lesion glycolysis (TLG) (OR=6.73, 95%CI: 2.23-20.29, p＜0.001) were independent risk factors for predicting early treatment response. A multi-parameter model incorporating clinical risk factors, metabolic factors, and RadScore was constructed (training cohort AUC: 0.834; validation cohort AUC: 0.902), and the performance of the model was evaluated. Conclusion：The RadScore, constructed based on a cross-combination approach using machine learning, can predict the survival of PGI-DLBCL patients. When RadScore is combined with clinical risk factors and metabolic factors, it forms a combinatorial model suitable for predicting early treatment response to R-CHOP-like chemotherapy regimens. Larger studies will be needed to validate these results. Keywords ： Primary gastrointestinal diffuse large B-cell lymphoma · [18F]FDG PET/CT · Early treatment response · Prognosis · Machine learning

Prognosis and complications of patients with primary gastrointestinal diffuse large B-cell lymphoma: Development and validation of the systemic inflammation response index-covered score.

This study aimed to evaluate the predictive value of systemic inflammation response index (SIRI) in primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) patients and establish a highly discriminating risk prediction model. This retrospective analysis included 153 PGI-DCBCL patients diagnosed between 2011 and 2021. These patients were divided into a training set (n=102) and a validation set (n=51). Univariate and multivariate Cox regression analyses were conducted to examine the significance of variables on overall survival (OS) and progression-free survival (PFS). An inflammation-covered score system was established according to the multivariate results. The presence of high pretreatment SIRI (≥1.34, p < 0.001) was significantly associated with poorer survival and identified as an independent prognostic factor. Compared with NCCN-IPI, the prognostic and discriminatory capability of the novel model SIRI-PI showed a more precise high-risk assessment with ahigher area under the curve (AUC) (0.916 vs 0.835) and C-index (0.912 vs 0.836) for OS in the training cohort, and similar results were obtained in the validation cohort. Moreover, SIRI-PI also showed good discriminative power for efficacy assessment. This new model identified patients at risk of developing severe gastrointestinal complications following chemotherapy. The results of this analysis suggested that the pretreatment SIRI may be a potential candidate for identifying patients with apoor prognosis. And we established and validated a better-performing clinical model, which facilitated the prognostic stratification of PGI-DLBCL patients and can serve as a reference for clinical decision-making.

S3393 Diffuse Large B Cell Lymphoma Presenting as Bleeding and Hypoalbuminemia: A Case Report

Introduction: Diffuse large B cell lymphoma (DLBCL) accounts for 38-57% of primary gastrointestinal (GI) lymphomas. Initial presentation can include nonspecific symptoms, such as weight loss, fatigue, and nausea. Imaging studies are typically nonspecific as well. Therefore, patients are commonly misdiagnosed or diagnosis is delayed. 20-30% of GI lymphomas are in the small intestine but are rarely in the jejunum. We present a rare case of jejunal DLBCL and illustrate the diagnostic difficulties. Case Description/Methods: A 49-year-old male presented with weeks of dizziness, dyspnea, hematochezia, and 30-pound unintentional weight loss over 4 months. Labs were notable for anemia and severe hypoalbuminemia (1.9 g/dL). Esophagogastroduodenoscopy and colonoscopy revealed diverticulosis and hemorrhoids, which were the presumed etiology of his symptoms. One month later, the patient presented similarly. Imaging demonstrated bilateral pulmonary emboli and intramural thickening of the jejunum. For worsening hypoalbuminemia (1.3 g/dL), the patient was scheduled for outpatient work-up. However, he presented again for acute GI bleed and severe anemia. Push enteroscopy revealed patchy mucosal changes in the jejunum and biopsies were consistent with DLBCL. The patient was started on chemotherapy and reported improvement in symptoms and resolution of his GI bleed. Discussion: Primary GI DLBCL is rarely found in the jejunum due to the lack of lymphoid tissue, making this case noteworthy. GI DLBCL is difficult to diagnose, since patients may be asymptomatic or present with nonspecific symptoms. Small intestinal DLBCL can present with GI bleeding, which can easily lead to a misdiagnosis of a diverticular or hemorrhoidal bleed. Imaging studies can be nonspecific and obtaining confirmation through biopsy can prove difficult due to its location, further complicating the diagnosis. One unique aspect of this case that led to the diagnosis was the severity of hypoalbuminemia. The patient was not malnourished, had no clinically apparent protein-losing enteropathy, and no proteinuria or liver failure, making underlying malignancy likely. Differential diagnoses of small bowel wall thickening on imaging is wide and includes infections, primary inflammatory processes such as IBD, and neoplastic lesions. DLBCL may have unusual clinical presentations, subtle laboratory findings and may not be easily diagnosed with initial imaging; thus, clinicians should remain vigilant of this possible diagnosis.

Serum miR-21 predicts the prognosis of patients with primary gastrointestinal diffuse large B-cell lymphoma.

Primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) lacks specific clinical manifestations and its malignancy renders prognostication and choice of treatment strategy difficult. The aim of this study was to evaluate microRNA (miR)-21 as potential non-invasive biomarkers for prognosis in PGI-DLBCL patients. Serum miR-21 expression in de novo PGI-DLBCL patients, consecutively enrolled for this study, was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Relative expression was calculated using the comparative Ct method. Statistical significance was determined using the Mann-Whitney rank sum and Fisher's exact test. Survival analysis was conducted using the Kaplan-Meier method. Compared with healthy controls, serum miR-21 levels were significantly elevated in the PGI-DLBCL patients (n=156). The high expression level of serum miR-21 at diagnosis was associated with worse progression-free survival (PFS) (30 (9-42) vs 42 (12-52) months in high and low miR-21 groups) and overall survival (OS) (35 (15-52) vs 48 (17-61) months in high and low miR-21 groups) and was an independent risk factor for PFS and OS (hazard ratios 4.345 and 3.311, respectively). Furthermore, Bcl-2, Bcl-6 and Ki-67 were independently and positively associated with miR-21 expression. Our results suggest that miR-21 is a potential prognostic marker to predict clinical outcomes in PGI-DLBCL patients and a high miR-21 level is associated with poor outcomes.

Radiomics signature from [18F]FDG PET images for prognosis predication of primary gastrointestinal diffuse large B cell lymphoma.

To investigate the prognostic value of PET radiomics feature in the prognosis of patients with primary gastrointestinal diffuse large B cell lymphoma (PGI-DLBCL) treated with R-CHOP-like regimen. A total of 140 PGI-DLBCL patients who underwent pre-therapy [18F] FDG PET/CT were enrolled in this retrospective analysis. PET radiomics features obtained from patients in the training cohort were subjected to three machine learning methods and Pearson's correlation test for feature selection. Support vector machine (SVM) was used to build a radiomics signature classifier associated with progression-free survival (PFS) and overall survival (OS). A multivariate Cox proportional hazards regression model was established to predict survival outcomes. A total of 1421 PET radiomics features were extracted and reduced to 5 features to build a radiomics signature which was significantly associated with PFS and OS (p < 0.05). The combined model incorporating radiomics signatures, metabolic metrics, and clinical risk factors showed high C-indices in both the training (PFS: 0.825, OS: 0.834) and validation sets (PFS: 0.831, OS: 0.877). Decision curve analysis (DCA) demonstrated that the combined models achieved the most net benefit across a wider reasonable range of threshold probabilities for predicting PFS and OS. The newly developed radiomics signatures obtained by the ensemble strategy were independent predictors of PFS and OS for PGI-DLBCL patients. Moreover, the combined model with clinical and metabolic factors was able to predict patient prognosis and may enable personalized treatment decision-making. • Radiomics signatures generated from the optimal radiomics feature set from the [18F]FDG PET images can predict the survival of PGI-DLBCL patients. • The optimal radiomics feature set is constructed by integrating the feature selection outputs of LASSO, RF, Xgboost, and PC methods. • Combined models incorporating radiomics signatures from18F-FDG PET images, metabolic parameters, and clinical factors outperformed clinical models, and NCCN-IPI.

Systemic Inflammation Response Index (SIRI) Predicts Clinical Outcome and Improves NCCN-IPI Scoring in Primary Gastrointestinal Diffuse Large B-Cell Lymphoma

Background: Systemic inflammation response index (SIRI) is a novel inflammatory hallmark that is proposed as an adverse prognosticator in a variety of malignancies. Nevertheless, the correlation between SIRI and primary gastrointestinal diffuse large B cell lymphoma (PGI-DLBCL) remains unknown. Our study aimed to evaluate the prognostic value of SIRI in PGI-DLBCL patients treated with CHOP-based therapies and establishing a highly discriminating risk prediction model compared with the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score.Methods: This retrospective analysis incorporated 102 PGI-DCBCL patients (57 patients with gastric DLBCL and 45 patients with intestinal DLBCL) newly diagnosed between January 2011 and June 2020. The SIRI was calculated by utilizing the peripheral blood neutrophil (N), monocyte (M), and lymphocyte (L) counts collected in the last ≤3 days before the initiation of the immunochemotherapy: SIRI= N × M/L. Pretreatment SIRI cutoff that may distinguish the study population into two gatherings with distinctive overall survival (OS) results which was calculated by the receiver operating characteristic (ROC) curve analysis. The prognostic factors associated with OS, the primary endpoint, were screened by multivariate Cox regression analyses and log-rank test as well as progression-free survival (PFS), the secondary endpoint. Performances of the novel model were compared using the area under the curve (AUC) and C-index in the cohort.Results: Among the 102 patients analyzed, there were 64 (62.7%) males and 38 (37.3%) females. The median follow-up time was 39.5 months (95% CI: 30.7-48.2), ranging from 2 to 102 months. A total of 33 patients (32.4%) presented B symptoms at the initial assessment, 74 (72.5%) of patients revealed stage III or IV disease, and 24 (23.5%) of patients had more than one extranodal involvement. Twenty-seven patients (26.5%) showed ECOG PS>2. The optimal SIRI cutoff was identified as 1.34 value by OS outcome, which divided patients into two groups. There were not significant differences in clinical characteristics between two groups (Table 1).Based on the cut-off value of SIRI, the outcomes of patients were distinct within two groups, which was shown in Figure 1. At a median follow-up of 39.5 (95% CI: 30.7-48.2) months, 86 (84.3%) patients were still alive (98.4% for SIRI <1.34 vs 62.5% for SIRI ≥1.34; p < 0.001). Cox regression analysis found three negative prognostic factors on OS: SIRI≥ 1.34 (P=0.001), B symptom (P=0.001), LDH>ULN (P=0.005). Accordingly, SIRI≥ 1.34 (P=0.002), age>60 (P=0.011) and LDH>ULN (P=0.002) emerged to be the indicators in relation to considerably inferior PFS times. Consequences of the multivariate analyses revealed that the prognostic significance of the SIRI on OS and PFS outcomes was independent of other confounders.SIRI could be used to combine with NCCN-IPI and develop a risk score to improve the NCCN-IPI score and identify PGI-DLBCL patients with poor prognosis. Patients with SIRI≥1.34 were allocated 2 points as a risk factor which was calculated in terms of the β coefficients compared with the effect of LDH level (>ULN) in the multivariate analysis of OS. This established an integrated scoring model with a maximum of 10 points when we combined NCCN-IPI with SIRI. Patients were divided into four risk groups and identified as low-risk group (0−3 points), low-intermediate-risk group (4−5 points), high-intermediate-risk group (6−7 points), and high-risk group (≥8 points). As a result, the prognostic and discriminatory capability of the NCCN-IPI plus SIRI was superior to NCCN-IPI alone (AUC: 0.858 vs. 0.814 and C-index: 0.826 vs. 0.801) based on OS in this patient population (Figure 2). Regarding the PFS, SIRI-PI also surpassed the NCCN-IPI with superior AUC (0.766 vs 0.709) and C-index (0.736 vs. 0.709) in discrimination.Conclusion: The results of this retrospective analysis suggested that the pretreatment SIRI was a potent and independent prognostic indicator that may be a potential candidate for identifying patients with poor prognosis in the future clinical practice of PGI-DLBCL.Keywords: Aggressive lymphoma, Clinically relevant, Systemic inflammation response index [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Increased MALAT1 expression predicts poor prognosis in primary gastrointestinal diffuse large B-cell lymphoma.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is involved in the pathogenesis and progression of several cancers. However, the potential effect of MALAT1 in primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) has not been elucidated. This study aimed to explore the prognostic value of MALAT1 in patients with PGI-DLBCL. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine the expression of MALAT1 in 90 patients with PGI-DLBCL. MALAT1 was remarkably upregulated in PGI-DLBCL tissues compared to paired adjacent non-tumor tissues (P < 0.001), and the area under the receiver operating characteristic (ROC) curve (AUC) was 0.838. MALAT1 expression was further increased in the non-germinal center B-cell-like (non-GCB), advanced stage (stages IIE-IV) and International Prognostic Index (IPI) score (3-5) groups (P = 0.01, P < 0.001 and P < 0.001, respectively). Furthermore, Kaplan-Meier analysis showed that elevated MALAT1 expression correlated with inferior overall survival (OS) and progression-free survival in PGI-DLBCL patients (P < 0.001 and P < 0.001, respectively), and our multivariate analysis results suggested that upregulation of MALAT1 and high IPI score (3-5) were two unfavorable prognostic factors for PGI-DLBCL. In conclusion, our results demonstrate that MALAT1 may serve as a novel prognostic biomarker and an ideal therapeutic target for patients with PGI-DLBCL.

Analysis of the Predictive Value of EZH2 Expression Level on the Clinical Efficacy and Long-term Prognosis of Patients with Primary Gastrointestinal Diffuse Large B-cell Lymphoma

To investigate the predictive value of methyltransferase EZH2 expression level on the clinical efficacy and long-term prognosis of patients with primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL). 161 patients with newly treated PGI-DLBCL in our hospital from August 2013 to July 2019 were selected. The expression level of EZH2 protein was detected by immunohistochemistry, and the short-term efficacy and long-term survival differences of patients with different levels of EZH2 were compared. The predictive values of EZH2 expression level on the short-term efficacy and long-term prognosis of PGI-DLBCL patients were analyzed by Log-rank test and COX risk proportional regression model. Chi-square test and Logistic regression analysis were used to analyze the influencing factors of EZH2 expression level. The complete response (CR) and overal response(OR) rates of those with high EZH2 expression were significantly lower than those with low EZH2 expression (P<0.001). The median OS and PFS of EZH2 high-level and low-level expression group was 37, 31 months and 49, 42 months, respectively. The cumulative OS and PFS rates of the high-level expression group were significantly lower than those of the low-level expression group, and the differences were statistically significant (P<0.05). The high expression levels of H3K27me3, EZH2, BCL-2, BCL-6, c-MYC were closely related to the shortening of OS and PFS, while the high expression level of Ki-67 was closely related to the shortening of OS (P<0.05), of which the high expression levels of H3K27me3, EZH2, BCL-2, and BCL-6 were independent risk factors for shortening of OS and PFS. The expression level of EZH2 was positively correlated with the expression level of H3K27me3, BCL-6, c-MYC and Ki-67 (r=0.741, r=0.837, r=0.809, r=0.772), and the high expression levels of H3K27me3, BCL-6 and Ki-67 were independent factors influencing the high expression of EZH2. In patients with PGI-DLBCL, the high expression of EZH2 significantly reduces the short-term CR and OR rates, which is an independent risk factor for the shortening of long-term OS and PFS rates, and it is independently related to the high expression of H3K27me3 and BCL6.

Role of MUM-1 immunohistochemistry in prognosis of primary gastrointestinal diffuse large cell lymphoma

: Diffuse large B-cell lymphoma (DLBCL) is the most common type of primary gastrointestinal lymphomas. It is a clinically heterogenous disease as most patients respond well to therapy, however a significant proportion of these patients become refractory or eventually relapse. Different prognostic factors for response and survival have been described for DLBCL. Immunophenotypic algorithms with small panels of biomarkers have been developed to translate the robust information from molecular studies into a routine clinical.platform. One of these biomarkers is MUM-1 which is used as a marker for classification of diffuse large B cell lymphoma into ABC type and its expression is associated with poorer overall survival as stated by various studies. We aim to study the expression pattern of MUM-1 IHC in primary gastrointestinal diffuse large B cell lymphomas and its role in prognosis and survival outcome. It was a five-year retrospective study where 40 cases of primary gastrointestinal DLBCL were identified, and MUM-1 IHC was done in 29 cases. Follow up and subsequent survival analysis was done.MUM-1 was positive in 7 (24%) and negative in 22 (76%) cases of primary gastrointestinal DLBCL. The overall survival of patients with DLBCL with MUM-1 expression (42.9%) was shorter than those without MUM-1 expression (72.7%). This suggested that MUM-1 expression in cases with DLBCL is associated with poorer prognosis.Multicentre large studies are warranted to study the role of MUM-1 IHC in prognosis of primary gastrointestinal DLBCL.

Texture Analysis Improves the Value of Pretreatment 18F-FDG PET/CT in Predicting Interim Response of Primary Gastrointestinal Diffuse Large B-Cell Lymphoma.

Objectives To explore the application of pretreatment 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) texture analysis (TA) in predicting the interim response of primary gastrointestinal diffuse large B-cell lymphoma (PGIL-DLBCL). Methods Pretreatment 18F-FDG PET/CT images of 30 PGIL-DLBCL patients were studied retrospectively. The interim response was evaluated after 3-4 cycles of chemotherapy. The complete response (CR) rates in patients with different clinicopathological characteristics were compared by Fisher's exact test. The differences in the maximum standard uptake value (SUVmax), metabolic tumor volume (MTV), and texture features between the CR and non-CR groups were compared by the Mann–Whitney U test. Feature selection was performed according to the results of the Mann–Whitney U test and feature categories. The predictive efficacies of the SUVmax, MTV, and the selected texture features were assessed by receiver operating characteristic (ROC) analysis. A prediction probability was generated by binary logistic regression analysis. Results The SUVmax, MTV, some first-order texture features, volume, and entropy were significantly higher in the non-CR group. The energy was significantly lower in the non-CR group. The SUVmax, volume, and entropy were excellent predictors of the interim response, and the areas under the curves (AUCs) were 0.850, 0.805, and 0.800, respectively. The CR rate was significantly lower in patients with intestinal involvement. The prediction probability generated from the combination of the SUVmax, entropy, volume, and intestinal involvement had a higher AUC (0.915) than all single parameters. Conclusions TA has potential in improving the value of pretreatment PET/CT in predicting the interim response of PGIL-DLBCL. However, prospective studies with large sample sizes and validation analyses are needed to confirm the current results.

Overexpression of microRNA-130a predicts adverse prognosis of primary gastrointestinal diffuse large B-cell lymphoma.

Primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) is a highly heterogeneous type of non-Hodgkin lymphoma. A number of studies have demonstrated that microRNA-130a (miR-130a) serves a role in the tumorigenesis and prognosis of numerous human tumors. However, to the best of our knowledge, the prognostic significance of miR-130a in PGI-DLBCL remains unknown. The present study explored the association between miR-130a and the clinical outcomes of PGI-DLBCL. Relative miR-130a expression was assessed by reverse transcription-quantitative PCR. Immunohistochemistry was used to detect expression levels of BCL-2, c-MYC, neprilysin, B-cell lymphoma 6 protein, PWWP domain-containing DNA repair factor 3A and proliferation marker protein Ki-67. A receiver operating characteristic curve was constructed to analyze the specificity and sensitivity of microRNA levels in the diagnosis of PGI-DLBCL. Survival curves were constructed using the Kaplan-Meier method. In the present study, miR-130a expression was notably higher in patients with PGI-DLBCL compared with in the controls (P<0.0001). miR-130a overexpression was closely associated with a high International Prognostic Index score (3–5) and drug resistance (P=0.017 and P=0.044, respectively). No significant difference in other clinical features was observed. Patients with increased expression levels of miR-130a had lower overall survival [hazard ratio (HR), 2.998; 95% CI, 1.347-6.673; P=0.007] and progression-free survival (HR, 3.325; 95% CI, 1.488-7.429; P=0.003) compared with patients who had lower expression levels of miR-130a. Furthermore, multivariate Cox regression analysis suggested that miR-130a was a negative prognostic parameter in PGI-DLBCL. Therefore, upregulation of miR-130a could become a potential prognostic marker for PGI-DLBCL. Additionally, further study of these results may have important guiding significance for the prognosis of patients with PGI-DLBCL in the clinical setting.

Significance of Peripheral Blood Lymphatic to Monocyte Ratio in the Progress of PGI-DLBCL

To explore the significance of lymphocyte to monocyte ratio (LMR) in the disease progress of primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL). The clinical data of 43 patients diagnosed as PGI-DLBCL in our hospital from January 2011 to December 2015 were collected, and the disease progress was followed up. According to the ROC curve, the threshold value of LMR for 2 years PFS (%) of PGI-DLBCL patients was 2.6. Unvariate analysis showed that LMR (P＜0.05), large enclosed mass lesion (P＜0.01) and IPI (P＜0.05) were prognostic factors affecting PFS, the COX regression model multivariate analysis showed that LMR＜2.6 [ (risk ratio (RR)=3.083, 95%CI 1.828-8.313, P＜0.01], and large enclosed mass lesions (RR=2.718, 95%CI 1.339-6.424, P＜0.05) were the independent adverse prognostic factor for two years PFS. Both LMR＜2.6 and large enclosed mass lesions relate with the progress of PGI-DLBCL.

Evaluation of different staging systems and prognostic analysis of 110 primary gastrointestinal diffuse large B cell lymphoma

Objective: To compare the prognostic efficiency of Lugano staging, TNM staging and Musshoff staging systems in patients with primary gastrointestinal diffuse large B-cell lymphoma(PGI-DLBCL) and investigate its clinical features and prognosis. Methods: The clinical data of 110 patients with PGI-DLBCL in Tianjin Medical University Cancer Institute and Hospital from May 2008 to August 2017 was retrospectively analyzed. The stage of lymphoma was assessed following Lugano staging, TNM staging and Musshoff staging systems respectively. The prognostic value was compared mainly according to the situation of 5-year overall survival (OS)and the influence of different clinical features on prognosis of patients was also investigated. Results: The median age of the whole study was 55(range 17-92) years old. With a median follow-up time of 36 (range 1-115) months, the median progression-free survival (PFS) was 35 (range 0-86) months, and the median overall survival was 37 (range 2-104) months. The 5-year OS rate of Lugano stagingⅠ, Ⅱ, Ⅲ and Ⅳ were 77.6%, 73.4%, 69.7%, 12.2% (χ(2)=63.395, P<0.001) respectively. The 5-year OS rate of TNM staging Ⅰ, Ⅱ, Ⅲ and Ⅳ were 77.6%, 75.9%, 25.0%, 9.3% (χ(2)=65.802, P<0.001) respectively. The 5-year OS rate of Musshoff stagingⅠ, Ⅱ, Ⅲ and Ⅳ were 84.5%, 68.4%, 25.0%, 9.3% (χ(2)=66.966, P<0.001) respectively. By Cox multiple-factors analysis, Lugano staging system was the only independent prognosis risk factor for PFS (HR=4.987, 95%CI: 1.421-17.498, P=0.009) and OS (HR=5.659, 95%CI: 1.563-20.485, P=0.008) of PGI-DLBCL. Univariated analysis revealed that the factors affecting PFS and OS of patients with PG-DLBCL include B-symptom, Eastern Cooperative Oncology Group performance status (ECOG PS), the number of extranodal lesions, serum lactate dehydrogenase (LDH), International prognostic index (IPI) score, staging and therapeutic regimen(all P values of PFS and OS<0.05). Patients with PG-DLBCL who received chemotherapy alone showed a better survival than others (PFS P=0.004; OS P<0.001); the factors affecting PFS and OS of patients with PI-DLBCL include β2-microglobulin(β2-MG), serum albumin(ALB) levels, LDH and staging (all P values of PFS and OS<0.05). Therapeutic regimen didn't affect those patients' survival (PFS P=0.661, OS P=0.720). The additional use of Rituximab failed to improve the survival of patients with PG-DLBCL and PI-DLBCL respectively (all P values of PFS and OS>0.05). Conclusions: Compared with TNM staging and Musshoff staging systems, Lugano staging system provides the best prognostic value in PFS and OS for patients with PGI-DLBCL. Accompany with B-sympto, higher ECOG PS score, more extranodal lesions, increased LDH, higher IPI score and later period are negative factors for PG-DLBCL. Increased β2-MG and LDH, lower ALB level and later period are negative factors of PI-DLBCL.

Primary Gastrointestinal De Novo CD5+ CD23+ Diffuse Large B-Cell Lymphoma (DLBCL): A Different Treatment Approach

Primary gastrointestinal lymphoma is a very rare entity, constituting only about 1%- 4% of all gastrointestinal malignancies. Diffuse large B cell lymphoma (DLBCL) represents the most common histological subtype of primary gastrointestinal lymphoma. Aggressive CD5+ CD23+ primary gastrointestinal DLBCL is a very rare lymphoma representing a unique immunophenotypic and molecular subtype of DLBCL.2547_A Figure 1. CT scan showing primary ileocecal lymphomaThis is a 50-year-old gentleman who presented with symptomatic anemia secondary to severe iron deficiency. On imaging, he was found to have an exophytic soft tissue mass in the cecal tip adjacent to the appendix. His colonoscopy was consistent with a near circumferential large polypoid mass at the ileocecal valve extending into the terminal ileum. Biopsy of the ileocecal mass showed diffuse infiltrate of large (centroblast -like) lymphoid cells positive for CD20, CD5, CD23, CD43, BCL-2, BCL-6, c-MYC, MUM-1 and with Ki-67 of 60%. Fluorescent In Situ Hybridization (FISH) did not show any evidence for MYC, CCND1-IGH, BCL2-IGH, BCL-6 rearrangements. An abnormal hybridization pattern was detected in 50% of cells consistent with loss of 3' region of the MYC gene, which confers poor prognosis. The immunohistochemical and flow cytometry analysis resembled Richter syndrome although chronic lymphocytic leukemia was not pre-existing. His bone marrow biopsy was negative for any involvement of lymphoma and he did not have any evidence of lymphadenopathy or splenomegaly on imaging. His diagnosis was consistent with primary gastrointestinal de novo CD5+ CD23+ diffuse large B-cell lymphoma of activated B cell type with low to intermediate IPI (International Prognostic Index) score. Denovo CD5+ DLBCL lymphoma is a rare variant of lymphoma with a poor prognostic feature. Diagnosis and treatment is always a challenge in these subtypes due to a critical gap in the understanding of optimal management approaches due to the rarity of these tumors. Early tumor stage, right-sided lesion, the diffuse large B-cell histological pattern seems to be the clinical characteristics of optimal surgical candidates. Surgical resection followed by chemotherapy might be an effective treatment strategy with the acceptable quality of life (QOL) for localized intestinal DLBCL. Combined modality approach reduces the risk of treatment-related perfusion and also minimizes the exposure to toxic effects of chemotherapy by decreasing the duration of chemotherapy.2547_B Figure 2. Biopsy of ileocecal mass demonstrating large centroblast like lymphoid cells with positive B cell markers2547_C Figure 3. Laparoscopic resection of the ileocecal diffuse large B-cell lymphoma

Effect of Lymphocyte/Monocyte Ratio on Clinical Features and Prognosis of Patients with Primary Gastrointestinal Diffuse Large B Cell Lymphoma

To analyze the effect of lymphocyte/monocyte ratio(LMR) on clinical features and prognosis of patients with primary gastrointestinal diffuse large B cell lymphoma(PGI-DLBCL). The clinical data of 38 PGI-DLBCL patients with complete follow-up data in our hospital were analyzed retrospectively. The absolute lymphocyte count(ALC), absolute monocyte count(AMC) and LMR were counted by automating complete blood cell count statistics in newly diagnosed patients, and then the LMR cut off value was obtained by ROC curve. All patients were divided into ≤3.9 group and >3.9 group according to cut off value. Out of 38 patients 21 male and 17 female with a median age 55 old years (29-73 years), 7 cases died, the clinical B symptom occurred in 7 cases (18.4%); the pathologic type of 13 cases (34.2%) belonged to germinal center B-cell like, the primary gastral and intestinal DLBCL were observed in 18 and 20 cases respectively. The chisquare test showed that the LMR associated with of clinical stage and tumor size of PGI-DLBCL. The median survival time was 44 months (7-100 months), and 5-year overrall survival(OS) rate was 78.3% for 38 PGI-DLBCL cases. The univariate analysis showed that age (P=0.021), stage (P=0.012), IPI score (P=0.001), LDH level (P<0.001), tumor size (P=0.037) and LMR (P=0.026) all associate with the 5 years OS rate(%), and the difference was between them statistically significant, but the multivariate analysis showed that only clinical staging is independent risk factors for the OS. LMR shows an important effect on clinical features and prognosis of PGI-DLBCL.

The Lymphocyte-Monocyte Ratio and the Platelet-Lymphocyte Ratio at Diagnosis as Independent Prognostic Factors in Primary Gastrointestinal Diffuse Large B Cell Lymphoma.

To study the role of the absolute lymphocyte count (ALC), absolute monocyte count (AMC), platelet count (PLT), lymphocyte-monocyte ratio (LMR) and the platelet-lymphocyte ratio (PLR) in the prognosis of primary gastrointestinal diffuse large B cell lymphoma (PGI-DLBCL). We retrospectively analyzed the prognostic value of the ALC, AMC, PLT, LMR, PLR at diagnosis in 173 PGI-DLBCL patients through histopathological examination from March 2009 to February 2015. In total, 173 patients with histopathological diagnosis of PGI-DLBCL in this study, the median age was 51years (range 12-90years), median follow-up time was 44months (range 7-89months). In univariate analysis, age <60years, B symptoms, Lugano stage I-II, low international prognostic index (IPI) or low age-adjusted international prognostic index (aaIPI), normal lactate dehydrogenase (LDH), normal β2-microglobulin (β2m), Hb≥11g/dL, ALC≥1.5×109/L, AMC≤0.50×109/L, LMR≥2.5, PLR≤170 were related with superior overall survival (OS) and progression-free survival (PFS) (p≤0.05). Multivariate analysis suggested that ALC, LMR, LDH were related with PFS (p≤0.05). Similarly, age and LMR were related with OS (p≤0.05). The parameters (ALC, AMC, LMR, PLR) may be valuable prognostic factors in PGI-DLBCL patients. LMR, PLR at diagnosis are expected to be independent prognostic factors for PGI-DLBCL patients.

Clinical characteristics and prognostic analysis of 195 primary gastrointestinal diffuse large B-cell lymphoma

Objective To explore the clinicopathological features and prognostic factors in patients with primary gastrointestinal diffuse large B cell lymphoma (PGI-DLBCL). Methods From January 2007 to January 2014, 195 patients with PGI-DLBCL in initial treatment were enrolled and clinical data of them were collected. Clinicopathological features, overall survival situation and the effects of therapeutic strategy on prognosis were retrospectively analyzed. Kaplan-Meier method was performed for survival analysis. Log-rank test was used for univariate analysis and the Cox proportional hazard regression model was used in multivariate factor analysis. Results Among 195 patients with PGI-DLBCL (117 male and 78 female patients, median age, 55 years), the tumors of 123 patients (63.1%) were located in stomach, 64 cases were in intestinal tract (32.8%, 24 cases in small intestine, 19 cases in ileocecum and 21 cases in colorectum) and eight cases (4.1%) had multiple gastrointestinal tract involvement. The one-year, three-year and five-year overall survival (OS) rates of 184 cases with complete follow-up data were 81.7%, 66.2% and 61.0%, respectively. The results of univariate analysis revealed that the prognostical factors affecting OS period included age, Eastern Cooperative Oncology Group performance status (ECOG PS), lesion location, large mass lesion, Lugano staging system, international prognostic index (IPI) score, the lactate dehydrogenase, β2-microglobulin, peripheral blood absolute lymphocyte/monocyte ratio (ALC/AMC) and serum albumin levels. The multivariate analysis by Cox proportional hazard regression model indicated that multiple gastrointestinal tract involvement (relative risk (RR)=1.378, 95% confidence interval (CI)1.144 to 1.661, P=0.001), end-stage by Lugano staging (RR=3.731, 95%CI 1.657 to 8.398, P=0.001) and ALC/AMC<2.6 (RR=1.816, 95%CI 1.055 to 3.127, P=0.031) were the independent adverse prognosis risk factors. The five-year accumulate OS rates of surgery group and non-surgery group were 65.0% and 53.3%, respectively, and the difference was not statistically significant (χ2=2.159, P=0.142). The five-year accumulate OS rates of combined with and without radiotherapy group were 77.5% and 58.0%, respectively, and the difference was not statistically significant (χ2=3.667, P=0.056). The five-year accumulate OS rates of combined with and without rituximab treatment group were 62.4% and 58.6%, respectively, and the difference was not statistically significant (χ2=1.352, P=0.243). Conclusions The prognosis is poor in PGI-DLBCL patients with multiple gastrointestinal tract involvement, later stage of Lugano staging and lower ALC/AMC. Neither surgery nor radiotherapy could improve OS of patients with PGI-DLBCL. Key words: Gastrointestinal tract; Lymphoma, large B-cell, diffuse; Clinical features; Prognosis

Mad2 overexpression is associated with high cell proliferation and reduced disease-free survival in primary gastrointestinal diffuse large B-cell lymphoma

Objectives: Primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) is a rare hematological malignancy with limited results on carcinogenesis and clinical characteristics. The aims of the current study were to examine mitotic arrest deficiency protein 2 (Mad2) expressions in PGI-DLBCL, and assess its association with Ki-67 expression, Helicobacter pylori (H. pylori) infection, BCL-6 gene rearrangement, and clinicopathological variables.Methods: Cancer tissues from 38 PGI-DLBCL patients were examined for Mad2, Ki-67, and H. pylori expression by immunohistochemistry, using normal gastrointestinal tissues and nodal DLBCL as controls. BCL-6 gene translocation was analyzed by fluorescence in situ hybridization (FISH), and Mad2 expression status was evaluated along with clinicopathological characteristics.Results: Mad2 expression was increased in PGI-DLBCL patients when compared with controls. The expression of Mad2 was 51.55 ± 22.88% in PGI-DLBCL, which was higher than reactive lymph node (28.77 ± 10.89%) and lymphoid nodule in normal gastrointestinal tissue (26.41 ± 11.30%) (P = 0.002), while it was comparable to nodal DLBCL (57.23 ± 20.79%) (P = 0.358). Mad2 overexpression had a positive correlation with Ki-67 proliferation index (r = 0.55, P = 0.01) in PGI-DLBCL, and patients with BCL-6 gene rearrangement had lower Mad2 expression (P = 0.032) than patients with intact BCL-6, while no relation was found between Mad2 expression and H. pylori infection. PGI-DLBCL patients with higher Mad2 expression had lower estimated disease-free survival (DFS) (17.10% vs. 53.00%) (P = 0.049). However, no correlation was found between Mad2 expression levels and overall survival (OS) (P = 0.443).Conclusions: Aberrant Mad2 expression was associated with cell proliferation and genetic instability, which may contribute to the carcinogenesis of PGI-DLBCL. Mad2 overexpression indicated a poor DFS and may be a potential biomarker for estimating prognosis for PGI-DLBCL patients.

Overexpression of DNA methyltransferase 1 as a negative independent prognostic factor in primary gastrointestinal diffuse large B-cell lymphoma treated with CHOP-like regimen and rituximab.

The aims of the present study were to elucidate the transcript levels of DNA methyltransferase (DNMT)1, DNMT3a and DNMT3b by quantitative polymerase chain reaction in patients with primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL), and determine the association of their expression with the clinical parameters and prognostic values of the disease. The results revealed that the expression of DNMT1 in patients with PGI-DLBCL was significantly higher than that in healthy controls (P=0.04), while the expression of DNMT3a and DNMT3b were significantly lower (P<0.001 and P=0.001, respectively). The increased expression of DNMT1 was significantly correlated with shorter overall survival and progression-free survival rates (P=0.018 and P=0.008, respectively). The multivariate analysis demonstrated that the level of DNMT1 was an independent prognostic factor. In conclusion, DNMT1 was identified to be an independent prognostic factor for predicting the survival of patients with PGI-DLBCL; this suggests that it could be used as a marker to indicate the prognosis of PGI-DLBCL.

Coexpression of MYC and BCL-2 predicts prognosis in primary gastrointestinal diffuse large B-cell lymphoma.

To investigate whether MYC and BCL-2 coexpression has prognostic significance in primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) patients, and explore its associations with patients' clinical parameters. Fresh and paraffin-embedded tumor tissue samples from 60 PGI-DLBCL patients who had undergone surgery at the Tianjin Medical University Cancer Institute and Hospital from January 2005 to May 2010 were obtained, and 30 lymphoid tissue samples from reactive lymph nodes of age- and sex-matched patients represented control samples. Staging and diagnostic procedures were conducted according to the Lugano staging system. All patients had been treated with three therapeutic modalities: surgery, chemotherapy, or radiotherapy. Expression of MYC and BCL-2 were detected at both protein and mRNA levels by immunohistochemistry and real-time RT-PCR. Positive expression levels of MYC and BCL-2 proteins were detected in 35% and 45% of patients, respectively. MYC+/BCL-2+ protein was present in 30% of patients. MYC and BCL-2 protein levels were correlated with high MYC and BCL-2 mRNA expression, respectively (both P<0.05). We found that advanced-stage disease (at IIE-IV) was associated with MYC and BCL-2 coexpression levels (P<0.05). In addition, MYC+/BCL-2+ patients had more difficulty in achieving complete remission than others (P<0.05). Presence of MYC protein expression only affected overall survival and progression-free survival (PFS) when BCL-2 protein was coexpressed. The adverse prognostic impact of MYC+/BCL-2+ protein on PFS remained significant (P<0.05) even after adjusting for age, Lugano stage, international prognostic index, and BCL-2 protein expression in a multivariable model. MYC+/BCL-2+ patients have worse chemotherapy response and poorer prognosis than patients who only express one of the two proteins, suggesting that assessment of MYC and BCL-2 expression by immunohistochemistry has clinical significance in predicting clinical outcomes of PGI-DLBCL patients.