The Role of Surgery in the Management of Intestinal Diffuse Large B-Cell Lymphoma (DLBCL): A Propensity Score-Matched Analysis.

The Pretreatment Controlling Nutritional Status (CONUT) Score Is an Independent Prognostic Factor in Elderly Patients with Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease and the most common gastrointestinal lymphoma. The prognostic/predictive indicators among patients with gastric and intestinal DLBCL (giDLBCL) are controversial beyond their anatomical sites. We compared giDLBCL cases and investigated the clinical utility of newly emerging indicators with an emphasis on programmed cell death ligand 1 (PD-L1) expression. This retrospective study included 174 patients with primary gastric (n = 129) or intestinal (n = 45) DLBCL treated with rituximab-containing chemotherapy between 1995 and 2018. Compared with gastric DLBCL (gDLBCL) cases, patients with intestinal DLBCL (iDLBCL) had a significantly higher rate of advanced Lugano stage (71% vs 37%, P < 0.001), perforation (13% vs. 0.8%, P = 0.001), PD-L1 expression on microenvironment immune cells (miPD-L1, 70% vs 46%, P = 0.008), CD10 positivity (47% vs 28%, P = 0.027), and CD5 positivity (9% vs 1.6%, P = 0.040). The iDLBCL patients showed significantly worse progression-free survival (PFS) and overall survival (OS) than gDLBCL cases (P = 0.0338 and P = 0.0077, respectively). PD-L1 expression on tumor cells was detected in only 3 (2%) of 174 cases with early relapse and/or an aggressive clinical course; whereas, miPD-L1-positive cases had significantly better OS than the miPD-L1-negative gDLBCL and iDLBCL cases (P = 0.0281 and P = 0.0061, respectively). Multivariate analysis revealed that miPD-L1 negativity (P = 0.030) was an independent adverse prognostic factor for OS in giDLBCL. The anatomical site of disease did not influence outcome in giDLBCL cases treated with rituximab-containing chemotherapy; while, miPD-L1 expression had a favorable impact on the outcome.

Objective To investigate the prognostic value of 18F-FDG PET-CT in patients with diffuse large B-cell lymphoma (DLBCL). Methods The clinical data of 130 DLBCL patients from June 2009 to May 2015 and pretreatment 18F-FDG PET-CT were retrospectively analyzed. Results The 130 DLBCL patients' median of maximal standard uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) was 19.93, 34.45 cm3, 459.92 respectively. Univariate analysis showed that the affecting factors of progression-free survival (PFS) and overall survival (OS) rate included Eastern Cooperative Oncology Group (ECOG) grade, Ann Arbor stage, β2-MG, lactate dehydrogenase level, tumor diameter, bone marrow involvement, National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), MTV and TLG (all P < 0.05), while age was related with PFS rate (P < 0.05). As MTV and TLG were strongly correlated, only TLG measure was used for multivariate analysis. The result showed that ECOG grade, Ann Arbor stage, NCCN-IPI and TLG were statistically significant predictors of PFS rate, and NCCN-IPI and TLG were independent factors of OS rate (all P < 0.05). According to TLG and NCCN-IPI, the patients were divided into three groups: low risk group, mediate risk group and high risk group. The 3-year PFS rates of these groups were 66.0%, 36.8% and 26.1% respectively (P < 0.05), and the 3-year OS rates of these groups were 70.0%,49.1% and 39.1% respectively (P < 0.05). Conclusion TLG in 18F-FDG PET-CT is an independent prognostic factor for PFS and OS in patients with DLBCL, which has a reference value for prognosis of DLBCL. Key words: Lymphoma, large B-cell, diffuse; Prognosis; Tomography, X-ray computed; Fluorodeoxyglucose F18

The potential role of visceral adipose tissue (VAT) as a prognostic factor in patients with diffuse large B cell lymphoma (DLBCL) treated with frontline rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) immunochemotherapy was explored. Total adipose tissue and VAT were measured by analyzing positron emission tomography (PET)/computed tomography (CT) images obtained during the initial staging of patients with DLBCL. The VAT ratio was calculated as follows: VAT ratio = VAT area/total adipose tissue area. Body mass index (BMI), sex, and International Prognostic Index (IPI) were also incorporated as co-variates in the final model of multivariate Cox regression analysis for survival. A total of 156 patients with DLBCL, who were treated with frontline R-CHOP, were enrolled in our study. The median patient age was 61 years, and 81 patients were male (51.9 %). The median cycle of R-CHOP was six. The IPI risk group was a strong prognostic factor for progression-free survival (PFS) and overall survival (OS) (p < 0.001). Obese BMIs were an independent prognostic factor for PFS, but not for OS in multivariate analyses, compared to patients with normal BMIs (HR = 0.43, 95 % CI = 0.19-0.98, and p = 0.046 for PFS). A high VAT ratio (third tertile) was an independent adverse prognostic factor for PFS and OS in multivariate analyses (HR = 2.87 and 2.66, 95 % CI = 1.30-6.32 and 1.30-5.44, and p = 0.009 and 0.007 for PFS and OS, respectively). VAT ratio was an independent prognostic factor for patients with DLBCL treated with first-line R-CHOP; thus, additional large prospective studies are warranted.

Many diffuse large B-cell lymphomas (DLBCLs) of the stomach are believed to represent high-grade transformation of low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type, which is of memory B-cell origin, displaying evidence for positive antigen selection and a low level of ongoing somatic mutation of the rearranged immunoglobulin heavy-chain variable region (V(H)) genes. The pattern of somatic mutation has been studied little in intestinal DLBCLs. To assess evidence for antigen selection and the levels of ongoing mutation, we analyzed the ratio of replacement to silent mutations, as well as the frequency of intraclonal sequence variation in gastric and small intestinal DLBCLs that showed no concomitant low-grade component. Genomic DNA was extracted from formalin-fixed paraffin blocks of gastric (n = 6) and small intestinal (n = 6) DLBCLs. The complementarity-determining region 2 and framework region 3 sequences (<200 base pairs) of the rearranged immunoglobulin V(H) gene were obtained from polymerase chain reaction-amplified product, and the ratio of replacement-to-silent mutations and the frequency of intraclonal sequence variation were determined. Clustering of replacement mutations in complementarity-determining region 2 with a high (>2.9) ratio of replacement-to-silent mutations was observed in 5 gastric DLBCLs, whereas it was recognized in only 1 intestinal DLBCL. Intraclonal sequence variation was observed in 6 intestinal and 5 gastric DLBCLs. The frequency of ongoing mutation was much higher in the intestinal (median, 0.33%) than in the gastric DLBCLs (median, 0.13%), but the difference was not statistically significant (P =.09). The mutation pattern was consistent with positive antigen selection in gastric DLBCLs, but not in the intestinal tumors. Ongoing mutation was much more frequent in the intestinal than in the gastric DLBCLs. These findings suggest that positive antigen selection plays a major role in a significant proportion of gastric tumors, whereas germinal center reaction with aberrant mutation is important in small intestinal DLBCLs.

CD47 overexpression is common in intestinal non-GCB type diffuse large B-cell lymphoma and associated with 18q21 gain

We conducted a retrospective analysis to evaluate the impact on clinical outcomes of adding rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) treatment for diffuse large B-cell lymphoma (DLBCL) patients in Japan. A propensity score method was used to compensate for the non-randomized study design. From January 2000 to December 2004, 378 patients who were newly diagnosed with DLBCL at 13 institutes were enrolled: 123 in the rituximab plus CHOP-based chemotherapy (R+) group, and 255 in the CHOP-based chemotherapy only (R-) group. The complete response rate was significantly higher in the R+ group than in the R- group (77.7 vs. 69.4%, P < 0.001). The progression-free survival (PFS) at 2 years was 62.4% in the R+ group and 57.0% in the R- group. The 2-year overall survival (OS) was 76.9% for the R+ group and 70.5% for the R- group. A multivariate analysis revealed that the addition of rituximab was a strong independent prognostic factor for PFS (hazard ratio 0.64, 95% CI 0.43-0.96, P = 0.031). A subgroup analysis revealed that R+ particularly benefited younger patients (hazard ratio 0.25, 95% CI 0.08-0.75, P = 0.013). IPI also showed significant impact for PFS (hazard ratio 1.82, 95% CI 1.55-2.14 for one score increase, P < 0.001) as well as OS (hazard ratio 2.10, 95% CI 1.71-2.57, P < 0.001). In summary, the addition of rituximab to CHOP-based chemotherapy results in better outcomes for Japanese DLBCL patients, particularly younger patients.

To determine the prognostic value of metabolic heterogeneity parameter coefficient of variation (COV) measured on baseline 18F-FDG positron emission tomography/computed tomography (PET/CT) in a series of newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) treated with the classical R-CHOP or R-CHOP-like chemotherapy. One hundred and three patients with histopathologically proven DLBCL, who underwent 18F-FDG PET/CT and had available follow-up results were retrospectively enrolled. The clinical data and baseline metabolic parameters of 18F-FDG PET/CT, including maximum standardized uptake value (SUVmax), tumor metabolic tumor volume (TMTV), bone marrow-to-liver ratio (BLR), COV, and 18F-FDG uptake in bone marrow (BM) involvement were collected and documented. Progression-free survival (PFS) and overall survival (OS) served as endpoints. The prognostic value of clinical data and metabolic parameters for PFS and OS was evaluated using Kaplan-Meier survival analysis. Based on the multivariate Cox regression analysis, two predictive models for PFS and OS were developed and their predictive performance was assessed. At a median follow-up time of 39.6 months (95%CI, 27.55-51.65), 40 patients (38.8%) experienced disease progression and 15 patients (14.6%) died. Patients with high COV had a shorter PFS (median PFS: 7.4 months vs. 'not reached', P < 0.001) and OS (no patients died in low COV group, P = 0.001). Based on the independent risk factors obtained from the multivariate Cox regression analyses for PFS (pathological BM involvement, TMTV and COV) and OS (pathological BM involvement and COV), two predictive models were constructed and visualized using nomogram. The calibration analysis and the decision curves demonstrated good performance of the models. 18F-FDG uptake of BM involvement was also a significant factor influencing PFS (P = 0.036) and OS (P = 0.019). Furthermore, the combination of COV and 18F-FDG uptake in BM involvement provided significant prognostic stratification for both PFS (P < 0.001) and OS (P = 0.001), successfully categorizing patients into three distinct risk groups. Metabolic heterogeneity parameter COV was a strong independent prognostic factor in DLBCL patients. Based on pathological BM involvement, TMTV and COV, two predictive models were established and their performance was evaluated for predicting PFS and OS. The risk stratification combining COV and 18F-FDG uptake in BM involvement also had significant prognosis value in PFS and OS. Our exploratory study revealed that metabolic heterogeneity parameters measured via 18F-FDG PET/CT can preliminarily distinguish DLBCL patients most responsive to standard R-CHOP or analogous chemotherapy regimens, providing a preliminary basis for prognostic stratification in this cohort.

Impact of Occult Bone Marrow Involvement on Outcome in Diffuse Large B-Cell Lymphoma Treated with R-CHOP

Background: Evidence regarding the need for surgery for primary intestinal non-Hodgkin lymphoma (PINHL) patients with chemotherapy is limited and controversial. However, there is a lack of large-scale multicenter studies for the specific analysis of this population. We aimed to investigate the specific impact of surgery on survival in a large cohort of PINHL patients (aged >18 years) with chemotherapy. Methods: For this retrospective cohort study, data from PINHL patients (aged >18 years) with chemotherapy between 1983 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database through strict acceptance and discharge standards. The primary and secondary objectives were to access improved overall survival (OS) and improved cancer-specific survival (CSS) with surgery, respectively. In addition to multiple regression analysis and stratification analysis adjusted for confounding factors, propensity score matching (PSM) analysis was used to explore the reliability of the results to further control for confounding factors. Findings: Data were collected from the SEER database for 8398 patients; 3537 met inclusion criteria. The median survival was 53 months. Multivariate regression analysis showed that patients with surgery and chemotherapy had significantly better OS (hazard ratio [HR] 0·83, 95% confidence interval [CI] 0·75–0·93; P=0·0009) and CSS (HR 0·87, 95% CI 0·77–0·99; P=0·0404) compared with the non-operation group after adjusting for age, gender, race, marital status, year of diagnosis, Ann Arbor stage, histology, tumor size, and radiation. In particular, histological subgroup analyses showed that patients with primary intestinal diffuse large B-cell lymphoma had a better prognosis with chemotherapy plus surgery compared with the non-operation group (HR 0·71, 95% CI 0·60–0·84; P for interaction=0·0067). After PSM analysis, compared with non-surgery, surgery remained associated with improved OS (HR 0·77, 95% CI 0·68–0·87; P<0·0001) and improved CSS (HR 0·82, 95% CI 0·72–0·95; P=0·008) adjusted for baseline differences. Interpretation: In the large cohort of PINHL patients with chemotherapy older than 18 years, surgery was associated with significantly improved OS and CSS before and after PSM analysis. Funding: Supported by grants from the National Natural Science Foundation of China (grant no. 81873147) and the Natural Science Foundation of Guangdong Province (grant no. 2020A1515011177). Declaration of Interest: All the authors declared that they have no conflict of interest.

The Outcome of Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with Rituximab-CHOP (R-CHOP) Is Not Predicted by 18-FDG-Positron Emission Tomography/Computerized Tomography (PET) Performed at Intermediate In-Course Evaluation, but Only by PET Assessed at the End of Therapy.

The aim of this study was to evaluate the prognostic effect of low triiodothyronine (T3) syndrome on patients with diffuse large B cell lymphoma (DLBCL). A hundred and eighty-eight patients with detailed thyroid hormone levels at diagnosis of DLBCL were enrolled. Low T3 syndrome was defined as a low serum free T3 (FT3) level with low or normal serum free tetraiodothyronine (FT4) and thyroid stimulating hormone levels. Multivariate Cox regression analysis was used to screen prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Receiver-operator characteristic curves and the corresponding areas under the curve were calculated to assess the predictive accuracy of International Prognostic Index (IPI) and low T3 syndrome. Twenty-four patients were diagnosed with low T3 syndrome, which was associated with worse PFS and OS in the rituximab era. It was an independent prognostic factor for PFS and OS, especially for those with IPI 0-2, extranodal sites ≤1 and stage III-IV. Synchronously low FT3 and FT4 had poorer survival outcome compared to only low FT3 and adding criterion of low T3 syndrome improved the prognostic capacity of IPI for predicting PFS and OS in DLBCL. Low T3 syndrome was found to be a strong prognostic predictor in DLBCL.

Prognostic value of pretreatment FDG PET in pediatric neuroblastoma

Improved Survival of R/R Double Hit/Triple Hit Lymphoma in the Era of CD19 Chimeric Antigen T Cell (CART) Therapy

To analyze the clinicopathological characteristics, treatment protocls and prognostic factors in patients with primary intestinal diffuse large B-cell lymphoma (DLBCL). The clinical data of 54 patients with DLBCL who were treated in Cancer Hospital of Chinese Academy of Medical Sciences in the period from August 2003 to November 2012 were retrospectively analyzed, and the relevant prognostic factors of DLBCL were analyzed. Of the 54 patients, there were 43 males and 11 females (male∶female ratio was 3.91∶1), with a median age of onset of 49 (7-76) years. Most patients (64.8%) were in Lugano stage Ⅰ-Ⅱ. Of all the patients, 50 were followed up for a median of 49 (1-118) months. The 1-, 3- and 5-year overall survival (OS) rates were 82.0%, 69.9% and 60.7%, respectively; the 1-, 3- and 5-year progression-free survival (PFS) rates were 68.0%, 58.0% and 53.4%, respectively. Univariate analysis showed that the factors affecting prognosis of DLBCL patients included Lugano stage, B symptom, International Prognostic Index (IPI) score, lactate dehydrogenase level, β2-microglobulin level, tumor size, and treatment protocols (all P<0.05). The 5-year OS rate was 67.1% in the patients treated with surgery plus chemoradiotherapy, and 40.0% in those treated with surgery or chemotherapy alone (P<0.05). In the patients treated with chemotherapy combined with rituximab, the 5-year OS rate was higher than in those treated with chemotherapy alone (71.2% vs 47.6%, P<0.05). Multivariate analysis indicated that tumor size (RR=7.686, P=0.022) and lactate dehydrogenase level (RR=10.131, P=0.017) were independent prognostic risk factors affecting OS. Primary intestinal DLBCL is a highly heterogeneous malignancy. Surgery combined with chemoradiotherapy and rituximab may help improve the overall prognosis of DLBCL patients.