Phase 2 study of pegylated liposomal doxorubicin plus cyclophosphamide, vincristine/vindesine, and prednisone in newly diagnosed PTCL: 8-year results.

BACKGROUND: Pegylated liposomal doxorubicin (PLD) is a liposome-encapsulated form of doxorubicin with equivalent efficacy and less cardiotoxicity. This phase 2 study evaluated the efficacy and safety of the PLD-containing CHOP regimen in newly diagnosed patients with aggressive peripheral T-cell lymphomas (PTCL). METHODS: Patients received PLD, cyclophosphamide, vincristine/vindesine, plus prednisone every 3 weeks for up to 6 cycles. The primary endpoint was the objective response rate at the end of treatment (EOT). RESULTS: From September 2015 to January 2017, 40 patients were treated. At the EOT, objective response was achieved by 82.5% of patients, with 62.5% complete response. As of the cutoff date (September 26, 2023), median progression-free survival (mPFS) and overall survival (mOS) were not reached (NR). The 2-year, 5-year, and 8-year PFS rates were 55.1%, 52.0%, and 52.0%. OS rate was 80.0% at 2 years, 62.5% at 5 years, and 54.3% at 8 years. Patients with progression of disease within 24 months (POD24) had worse prognosis than those without POD24, regarding mOS (41.2 months vs NR), 5-year OS (33.3% vs 94.4%), and 8-year OS (13.3% vs 94.4%). Common grade 3-4 adverse events were neutropenia (87.5%), leukopenia (80.0%), anemia (17.5%), and pneumonitis (17.5%). CONCLUSION: This combination had long-term benefits and manageable tolerability, particularly with less cardiotoxicity, for aggressive PTCL, which might provide a favorable benefit-risk balance. CLINICALTRIALS.GOV IDENTIFIER: Chinese Clinical Trial Registry, ChiCTR2100054588; IRB Approved: Ethics committee of Fudan University Shanghai Cancer Center (Date 2015.8.31/No. 1508151-13.

Imaging of Tumor Stroma Using 68Ga-FAPI PET/CT to Improve Diagnostic Accuracy of Primary Tumors in Head and Neck Cancer of Unknown Primary: A Comparative Imaging Trial.

The low detection rate of primary tumors by current diagnostic techniques remains a major concern for patients with head and neck cancer of unknown primary (HNCUP). Therefore, in this study, we aimed to investigate the potential role of 68Ga-labeled fibroblast activation protein inhibitor (68Ga-FAPI) PET/CT compared with 18F-FDG PET/CT for the detection of primary tumors of HNCUP. Methods: In this prospective comparative imaging trial conducted at Fudan University Shanghai Cancer Center, 91 patients with negative or equivocal findings of a primary tumor by comprehensive clinical examination and conventional imaging were enrolled from June 2020 to September 2022. The presence of a primary tumor was recorded by 3 experienced nuclear medicine physicians. Primary lesions were validated by histopathologic analysis and a composite reference standard. Results: Of the 91 patients (18 women, 73 men; median age, 60 y; age range, 24-76 y), primary tumors were detected in 46 (51%) patients after a thorough diagnostic work-up. 68Ga-FAPI PET/CT detected more primary lesions than 18F-FDG PET/CT (46 vs. 17, P < 0.001) and showed better sensitivity, positive predictive value, and accuracy in locating primary tumors (51% vs. 25%, 98% vs. 43%, and 51% vs. 19%, respectively). Furthermore, 68Ga-FAPI PET/CT led to treatment changes in 22 of 91 (24%) patients compared with 18F-FDG PET/CT. The Kaplan-Meier curve illustrated that patients with unidentified primary tumors had a significantly worse prognosis than patients with identified primary tumors (hazard ratio, 5.77; 95% CI, 1.86-17.94; P = 0.0097). Conclusion: 68Ga-FAPI PET/CT outperforms 18F-FDG PET/CT in detecting primary lesions and could serve as a sensitive, reliable, and reproducible imaging modality for HNCUP patients.

Development and Validation of Pretreatment Serum Total Bilirubin as a Biomarker to Predict the Clinical Outcomes in Primary Central Nervous System Lymphoma: A Multicenter Cohort Study.

Primary central nervous system lymphoma (PCNSL) is a predominantly aggressive neoplasm isolated to the central nervous system or vitreoretinal space. Bilirubin is an important biomarker reflecting hepatic function and oxidative stress status that is associated with the occurrence and development of various tumors. However, its prognostic role in PCNSL has yet to be evaluated. Therefore, we conducted a prospective-retrospective study to analyze the predictive value of serum total bilirubin (STB) in PCNSL patients. The association between the pretreatment STB and clinical outcomes in PCNSL was developed in the discovery cohort (retrospective [n = 44] and prospective [n = 45]) and validated in an independent retrospective cohort (n = 69). A generalized additive model, Kaplan-Meier curve, and Cox analysis were applied. In the discovery cohort, the STB showed a linear relationship with overall survival (OS, p = 0.011) and progression-free survival (PFS, p = 0.0476). The median STB level of 12.0 µmol/L was determined as the cutoff value to predict the clinical outcomes with area under the receiver operating characteristic curve (AUROC) values of 0.9205 and 0.8464 for OS and PFS, respectively. The median STB level resulted in similar accuracy for predicting the clinical outcomes in the validation cohort with AUROC values of 0.8857 and 0.8589 for OS and PFS, respectively. In both the discovery and validation cohorts, the Kaplan-Meier survival curve and Cox regression analysis showed that the upper median STB groups showed significantly worse OS than the lower median STB groups. In conclusion, the pretreatment STB could be considered a novel biomarker to predict the clinical outcomes in patients with PCNSL receiving high-dose methotrexate-based combination immunochemotherapy.

Serum miR-146a level is a potential biomarker in predicting the outcome of diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma with heterogenicity in clinical manifestation and prognosis. Some microRNAs can influence the development of tumors and may be related to the response of therapy or prognosis. This study aims to explore the role of serum miR-146a in predicting the prognosis of DLBCL. METHODS: A total of 72 de novo DLBCL patients received 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab combined CHOP (R-CHOP) regimen, and their serum samples were collected before treatment and after 4 cycles of chemotherapy. RESULTS: The results show that a high level of miR-146a is significantly associated with a good outcome in baseline and is more obvious in post-chemotherapy. In addition, a high level of miR-146a was associated with better progression-free survival and overall survival in patients treated with R-CHOP but has not been related to a superior outcome in patients treated with CHOP. Rituximab may improve the efficacy of therapy, especially in patients with high miR-146a levels. The level of miR-146a decreased in more patients after chemotherapy, and it seems patients with a decreased expression of miR-146a after chemotherapy tended a better outcome, but it is not statistically significant. CONCLUSION: Our results suggest that the level of serum miR-146a can serve as a potential prognostic biomarker for DLBCL patients.

Proposed new prognostic model using the systemic immune-inflammation index for primary central nervous system lymphoma: A prospective-retrospective multicohort analysis.

Purpose: The systemic immune-inflammation index (SII) has been considered a novel prognostic biomarker in several types of lymphoma. Our aims were to determine the best statistical relationship between pretreatment SII and survival and to combination of SII and the Memorial Sloan Kettering Cancer Center model (MSKCC) to derive the best prognostic mode in primary central nervous system lymphoma (PCNSL). Methods: Pretreatment SII and clinical data in 174 newly diagnosed PCNSL patients were included from two retrospective discovery cohorts (n = 128) and one prospective validation cohort (n = 46). A generalized additive model, Kaplan-Meier curve, and Cox analysis were performed. The high risk versus low risk of SII-MSKCC for the PCNSL cutoff point (0-1 vs. 2-4) was determined by the minimum P-value approach. Results: The SII showed a U-shaped relationship with the risk of overall survival (OS; P = 0.006). The patients with low SII or high SII had poorer OS and progression-free survival (PFS) than those with median SII. For PFS and OS, SII-MSKCC was a better predictor than MSKCC alone. The area under the receiver operating characteristic curve of the SII-MSKCC score was 0.84 for OS and 0.78 for PFS in the discovery cohorts. The predictive value of the SII-MSKCC score (OS, 0.88; PFS, 0.95) was verified through the validation cohort. Multivariable Cox analysis and Kaplan-Meier curve showed excellent performance for SII-MSKCC, with significant separation of two groups and better performance than MSKCC alone. Conclusions: We propose a new prognostic model using SII, age, and Karnofsky score that outperforms MSKCC alone and enables individualized estimates of patient outcome.

Prognostic significance of pretreatment red blood cell distribution width in primary diffuse large B-cell lymphoma of the central nervous system for 3P medical approaches in multiple cohorts.

Background/aims: Predicting the clinical outcomes of primary diffuse large B-cell lymphoma of the central nervous system (PCNS-DLBCL) to methotrexate-based combination immunochemotherapy treatment in advance and therefore administering the tailored treatment to the individual is consistent with the principle of predictive, preventive, and personalized medicine (PPPM/3PM). The red blood cell distribution width (RDW) has been reported to be associated with the clinical outcomes of multiple cancer. However, its prognostic role in PCNS-DLBCL is yet to be evaluated. Therefore, we aimed to effectively stratify PCNS-DLBCL patients with different prognosis in advance and early identify the patients who were appropriate to methotrexate-based combination immunochemotherapy based on the pretreatment level of RDW and a clinical prognostic model. Methods: A prospective-retrospective, multi-cohort study was conducted from 2010 to 2020. We evaluated RDW in 179 patients (retrospective discovery cohorts of Huashan Center and Renji Center and prospective validation cohort of Cancer Center) with PCNS-DLBCL treated with methotrexate-based combination immunochemotherapy. A generalized additive model with locally estimated scatterplot smoothing was used to identify the relationship between pretreatment RDW levels and clinical outcomes. The high vs low risk of RDW combined with MSKCC score was determined by a minimal P-value approach. The clinical outcomes in different groups were then investigated. Results: The pretreatment RDW showed a U-shaped relationship with the risk of overall survival (OS, P = 0.047). The low RDW (< 12.6) and high RDW (> 13.4) groups showed significantly worse OS (P < 0.05) and progression-free survival (PFS; P < 0.05) than the median group (13.4 > RDW > 12.6) in the discovery and validation cohort, respectively. RDW could predict the clinical outcomes successfully. In the discovery cohort, RDW achieved the area under the receiver operating characteristic curve (AUC) of 0.9206 in predicting the clinical outcomes, and the predictive value (AUC = 0.7177) of RDW was verified in the validation cohort. In addition, RDW combined with MSKCC predictive model can distinguish clinical outcomes with the AUC of 0.8348 for OS and 0.8125 for PFS. Compared with the RDW and MSKCC prognosis variables, the RDW combined with MSKCC scores better identified a subgroup of patients with favorable long-term survival in the validation cohort (P < 0.001). RDW combined MSKCC score remained to be independently associated with clinical outcomes by multivariable analysis. Conclusions: Based on the pretreatment RDW and MSKCC scores, a novel predictive tool was established to stratify PCNS-DLBCL patients with different prognosis effectively. The predictive model developed accordingly is promising to judge the response of PCNS-DLBCL to methotrexate-based combination immunochemotherapy treatment. Thus, hematologists and oncologists could tailor and adjust therapeutic modalities by monitoring RDW in a prospective rather than the reactive manner, which could save medical expenditures and is a key concept in 3PM. In brief, RDW combined with MSKCC model could serve as an important tool for predicting the response to different treatment and the clinical outcomes for PCNS-DLBCL, which could conform with the principles of predictive, preventive, and personalized medicine. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00290-5.

Clinical Characteristics and Prognostic Factors in Primary Breast Diffuse Large B-Cell Lymphoma.

Background: Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare subtype of non-Hodgkin lymphoma (NHL) with limited data on the clinical features and prognostic factors. Patients and Methods: A consecutive cohort of patients with PB-DLBCL was retrospectively analyzed in our hospital from February 1997 through July 2018. The primary endpoint is overall survival (OS) contributing to any cause. Results: A total of 76 patients were diagnosed with PB-DLBCL. The median age at diagnosis was 51 years (range: 25-80 years), with female prevalence (98.7%). Forty (52.6%) patients had right-sided breast involvement but no bilateral breast involvement at diagnosis. Overall, disease stages IE and IIE were seen in 55 (72.4%) and 21 (27.6%) patients, respectively. According to the stage-modified International Prognostic Index (IPI), 37 (48.7%) patients were classified in the very good risk group (IPI 0). Of the 72 patients available, the non-germinal center B-cell (non-GCB) subtype of DLBCL was observed in 66 (91.6%) patients. All patients received anthracycline-based chemotherapy, 56 (73.7%) with rituximab, 31 (40.8%) also with additional radiation therapy, and 14 (18.4%) patients received a prophylactic intrathecal injection. Seven (9.2%) patients had refractory disease. With a median follow-up of 6.8 years (range 0.4-25.0 years), 10 (13.2%) patients had a relapse in the central nervous system (CNS) site. The 5-year and 10-year OS of all the patients was 97.2% (95% CI: 99.3-89.5) and 84.8% (95% CI: 70.0-93.5), respectively. The median OS was not reached. The median progression-free survival (PFS) was 10.3 years for patients with PB-DLBCL. The 5-year PFS of all the patients was 76.3% (95% CI: 64.6-84.6). Univariate analysis revealed several prognostic factors, including stage-modified IPI, breast surgery, refractory disease, and CNS relapse. Multivariate analyses produced two independent prognostic factors for patients with PB-DLBCL, including stage-modified IPI score (2-3 versus 0) (hazard ratio: 19.114, 95% CI 1.841 to 198.451, p=0.013) and CNS relapse (hazard ratio: 5.522, 95% CI 1.059 to 28.788, p=0.043). Conclusion: In our cohort, PB-DLBCL clinical features are similar to prior literature reports. Stage-modified IPI score and CNS relapse were associated with overall survival.

Combined taxane, platinum, and cetuximab as a first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma: Retrospective study.

BACKGROUND: There is limited evidence supporting the use of taxane-based chemotherapy combined with cetuximab to treat recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). This retrospective study aimed to explore treatment efficacy and safety in a first-line setting. METHODS: Fifty-nine patients received ≤6 cycles of combined cetuximab, platinum compounds, and taxane (median follow-up, 352 days). Kaplan-Meier survival curves were constructed. RESULTS: The median patient age was 54 years (23-75 years; 50 males and 9 females). The most common distant metastatic site was the lung. Patients received ≥2 cycles chemotherapy (33 [55.9%] received cetuximab, paclitaxel, and carboplatin; 21 [35.5%] received cetuximab maintenance; median progression-free survival, 7 months; overall survival, 12 months). The most common hematological toxicity was Grade 3 or 4 neutropenia, which was successfully managed through growth-stimulating factors and dose modifications. No treatment-associated deaths occurred. CONCLUSIONS: Combined cetuximab, platinum, and taxane is effective and tolerable in R/M HNSCC.

Hexokinase II expression as a prognostic marker in diffuse large B-cell lymphoma: pre- and post-rituximab era.

We aimed to assess HKII expression and its prognostic significance in diffuse large B-cell lymphoma (DLBCL) patients. The HKII protein level was determined by immunohistochemistry in 159 newly diagnosed DLBCL patients, and its relationship with overall response rate, progression-free survival (PFS), and overall survival (OS) was analyzed. HKII was expressed in 95 DLBCL patients (59.7%). HKII-positive patients had poorer outcomes than negative patients for 5-y PFS (68% vs. 84%, p = 0.029) and 5-y OS (78% vs. 94%, p = 0.05). When only patients without no bulky disease, B symptoms, or extranodal involvement who had low IPI scores were considered, those with positive HKII had worse 5y-PFS and 5y-OS (p < 0.05). Multivariate analysis indicated that HKII status was an independent prognostic factor of OS. In subgroup analysis, HKII expression was associated with inferior OS in the CHOP group (p = 0.017). In CHOP group patients without bulky disease or extranodal involvement who had low LDH and low IPI scores (p < 0.05), positive HKII was associated with worse PFS and OS. No differences in PFS and OS, or any independent prognostic factors, were found in the RCHOP group. In DLBCL, HKII is valuable as a prognostic biomarker and may be useful as a tool for assessing disease risk.

Four cycles of R-CHOP followed by two applications of rituximab based on negative interim PET/CT: an analysis of a prospective trial.

BACKGROUND: R-CHOP with or without radiotherapy is the standard treatment for limited-stage diffuse large B-cell lymphoma (DLBCL). To prevent overtreatment, we assessed whether four cycles of CHOP plus six applications of rituximab was adequate with negative interim PET/CT and the role of consolidation radiotherapy specifically for patients with Waldeyer's ring DLBCL. One hundred and twenty-nine patients with limited-stage DLBCL were enrolled in this open-label, nonrandomized, single-arm, phase 2 clinical trial (NCT01804127). METHODS: All patients were initially treated with 4 cycles of R-CHOP and underwent interim PET/CT. Patients with negative PET/CT (Deauville scores 1-2) received 2 additional cycles of rituximab monotherapy, unless they had any risk factors (primary mediastinal large B-cell lymphoma, extranodal primary or bulky disease). Otherwise, patients received another 2 cycles of R-CHOP. Patients with partial response on interim PET/CT received another 4 cycles of R-CHOP. No radiotherapy was conducted in Waldeyer's ring DLBCL patients with negative PET/CT. The primary endpoint was 3-year progression-free survival (PFS). Overall survival (OS) in this study was compared with those from a historical study (NCT 00854568159). RESULTS: One hundred fifteen interim PET/CT scans (89.1%) were negative after 4 cycles of R-CHOP. An elevated lactate dehydrogenase level was significantly associated with positive interim PET/CT (P < 0.05). A trend of inferior outcome was observed in patients with positive interim PET/CT in terms of 3-year PFS (78.6% vs. 91.9%, P = 0.24) and 3-year OS (85.7% vs. 95.6%, P = 0.16). There were no PFS or OS differences found between patients treated with 4R-CHOP+2R and those treated with 6R-CHOP from a historical control study. Patients with Waldeyer's ring DLBCL and negative interim PET/CT achieved a 3-year PFS of 87.2% and a 3-year OS of 89.7%. CONCLUSIONS: Our results suggested that for interim PET/CT-negative patients without risk factors, the extra 2 cycles of CHOP might be omitted, and radiotherapy might also be omitted in patients with Waldeyer's ring DLBCL without compromising the efficacy. These results need to be confirmed in a randomized study. TRIAL REGISTRATION: clinicaltrials.gov , NCT01804127 . Date of first registration: 05/03/2013.

Deubiquitinase OTUD7B is a potential prognostic biomarker in diffuse large B-cell lymphoma.

OTUD7B is a deubiquitinase and has been reported as a prognostic factor in various solid tumors. However, its prognostic value in lymphoma patients remains unclear. We detected OTUD7B expression levels in 160 diffuse large B-cell lymphoma (DLBCL) tissue samples by immunohistochemistry, and analyzed correlations between its expression and clinic-pathologic parameters as well as clinical outcomes. We also investigated association between OTUD7B expression and chemotherapeutic drugs anti-tumor activity in vitro. We found that OTUD7B overexpressed in 129 (80.6%) cases, and patients with overexpression of OTUD7B experienced better overall survival comparing to those with OTUD7B low expression (P=0.021). Multivariate Cox regression analysis illustrated that OTUD7B was an independent prognostic indicator. In DLBCL cell lines, we found that Chidamide could up-regulate OTUD7B in several DLBCL cell lines, and also had synergistic effect with doxorubicin at low concentration. Our data illustrated that OTUD7B deficiency is a negative predictor of clinical outcome, and might be a potential therapeutic target in the treatment of diffuse large B-cell lymphoma.

Prognostic significance of clinical characteristics and 18Fluorodeoxyglucose-positron emission tomography/computed tomography quantitative parameters in patients with primary mediastinal B-cell lymphoma.

OBJECTIVE: Primary mediastinal B-cell lymphoma (PMBCL) lacks standard treatment regimens. This study aimed to identify the disease's clinical features and prognostic factors. METHODS: This retrospective study included 56 patients with PMBCL. Patient demographic details and clinicopathological characteristics were summarized, and their effects on progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: The median patient age was 29 years (range, 14-56). Twenty-two patients received DA-EPOCH-R (dose-adjusted etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone, as well as rituximab), and 34 patients received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Clinical/laboratory parameters, overall response rates, and 5-year PFS and OS rates did not differ between the treatment groups. Kaplan-Meier analysis indicated that late-stage disease and a higher International Prognostic Index (IPI) were associated with shorter PFS and OS. Furthermore, patients with B symptoms and first-line treatment non-responders exhibited worse OS. 18Fluorodeoxyglucose-positron emission tomography/computed tomography quantitative parameters, such as higher metabolic tumor volume (MTV) and total lesion glycolysis (TLG), were corrected with shorter PFS. CONCLUSIONS: This study revealed that stage IV disease, higher IPI, and B symptoms were poor prognostic factors in patients with PMBCL. Significantly, higher MTV and TLG portended worse PFS.

The Added Value of 68Ga-FAPI PET/CT in Patients with Head and Neck Cancer of Unknown Primary with 18F-FDG-Negative Findings.

18F-FDG PET/CT plays an important role in locating the primary tumor for patients with head and neck cancer of unknown primary (HNCUP). Nevertheless, in some cases it can be challenging to locate the primary malignancy on 18F-FDG PET/CT scans. Because 68Ga-radiolabeled fibroblast activation protein inhibitor (FAPI) PET/CT has promising results in detecting different tumor entities, our study aimed to evaluate the performance of 68Ga-FAPI PET/CT for detecting the primary tumor in HNCUP patients with negative 18F-FDG findings. Methods: Eighteen patients (16 men and 2 women; median age, 55 y; age range, 24-72 y) with negative 18F-FDG findings were enrolled in this study. All patients underwent 18F-FDG and 68Ga-FAPI PET/CT within 1 wk. Biopsy and histopathologic examinations were performed in the sites with positive 68Ga-FAPI PET/CT findings. Results:68Ga-FAPI PET/CT detected the primary tumor in 7 of 18 patients (38.89%). Among these 7 patients, primary tumor sites included the nasopharynx (n = 1), palatine tonsil (n = 2), submandibular gland (n = 2), and hypopharynx (n = 2). The primary tumors showed moderate to intensive uptake of 68Ga-FAPI (mean SUVmax, 8.79; range, 2.60-16.50) and excellent tumor-to-contralateral normal-tissue ratio (mean SUVmax ratio, 4.50; range, 2.17-8.21). In lesion-based analysis, 65 lymph nodes and 17 bone metastatic lesions were identified. The mean SUVmax of lymph node metastases was 9.05 ± 5.29 for 18F-FDG and 9.08 ± 4.69 for 68Ga-FAPI (P = 0.975); the mean SUVmax of bone metastases was 8.11 ± 3.00 for 18F-FDG and 6.96 ± 5.87 for 68Ga-FAPI (P = 0.478). The mean tumor-to-background ratios of lymph node and bone metastases were 10.65 ± 6.59 versus 12.80 ± 8.11 (P = 0.100) and 9.08 ± 3.35 versus 9.14 ± 8.40 (P = 0.976), respectively. Conclusion: We present the first evidence, to our knowledge, of a diagnostic role of 68Ga-FAPI PET/CT in HNCUP. Our study demonstrated that 68Ga-FAPI PET/CT has the potential to improve the detection rate of primary tumor in HNCUP patients with negative 18F-FDG findings. Moreover, 68Ga-FAPI had a performance in assessing metastases similar to that of 18F-FDG.

Phase II study of sequential chemoradiotherapy with L-asparaginase, dexamethasone, ifosfamide, cisplatin, and etoposide (DICE-L) in the early stage of extranodal natural killer (NK)/T-cell lymphoma.

BACKGROUND: To explore a more effective treatment strategy for newly diagnosed stage I and II extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, we conducted a prospective phase II study of sequential chemoradiotherapy with the L-asparaginase, dexamethasone, ifosfamide, cisplatin, and etoposide (DICE-L) regimen. METHODS: Patients with newly diagnosed stage I and II ENKTL in the upper-aerodigestive tract were enrolled. Treatment was comprised of up to 4 cycles of DICE-L followed by 50 Gy of intensity modulated radiation therapy (IMRT) to the involved field. The primary endpoint was the complete response (CR) rate. The secondary endpoints were the objective response rate (ORR), the 5-year overall survival (OS) rate, the 5-year progression-free survival (PFS) rate, and safety. RESULTS: A total of 81 patients were enrolled from June 2009 to May 2012 in Shanghai Cancer Hospital. Among these patients, 68 patients achieved CR and 1 patient achieved partial response (PR). The CR rate was 84%, and the ORR was 85.2%. With a median follow up of 88.1 months, the 5-year OS and 5-year PFS rates were 82.4% and 63.4%, respectively. The most common adverse events were grade 3 to 4 neutropenia (73.5%) and febrile neutropenia (21%). CONCLUSIONS: Sequential chemoradiotherapy using DICE-L followed by radiotherapy is an effective treatment modality for stage I to IIE ENKTL and is safe with acceptable toxicity.

Characterization of Artificial Pneumothorax-Unrelated Pyothorax-Associated Lymphoma.

Pyothorax-associated lymphoma (PAL) is a rare disease developing from a long-term pleural cavity inflammation. Most reported PAL cases have a history of artificial pneumothorax. However, the clinical features of artificial pneumothorax-unrelated PAL remain largely unknown. Here, we reported two PAL cases diagnosed from our center in the past ten years. One case developed from asymptomatic pyothorax after pneumonectomy with a latency of 28 years, while the other case showed a relatively short latency of one year. Then we reviewed the literature of artificial pneumothorax-unrelated PAL by searching PubMed and Google Scholar from 2007. In total, nine artificial pneumothorax-unrelated PAL cases were found, predominantly in old male with median age of 76 years (ranging from 51 to 88). Most cases were diagnosed with diffuse large B-cell lymphoma (DLBCL) (n = 8, 88.9%) and had evidence of Epstein-Barr virus (EBV) infection (n = 6, 66.7%) or tuberculous pleurisy (n = 5, 55.6%). Notably, four cases (44.4%) had short intervals (no more than two years) between pleuritis and PAL. Regarding the overall survival, one-third cases survived more than 5 years after the diagnosis of PAL. In conclusion, the features of artificial pneumothorax-unrelated PAL are comparable with the classic type of PAL, except for some patients with short duration of pleuritis, and need to be identified. Treatment guideline of DLBCL is recommended for the management of PAL.

The adhesion molecule ICAM-1 in diffuse large B-cell lymphoma post-rituximab era: relationship with prognostic importance and rituximab resistance.

Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface receptor contributing to lymphocyte homing, adhesion and activation. The prognostic significance of the protein is unknown in diffuse large B-cell lymphoma (DLBCL) in post-rituximab era. We detected expression of ICAM-1 immunohistochemically in 102 DLBCL tissue samples. Overexpression of ICAM-1 was found in 28 (27.5%) cases. In patients with low ICAM-1 expression levels, the addition of rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy resulted in an improved overall response rate, progression-free survival (PFS) and overall survival (OS) (P=0.019, 0.01, 0.02). In pre-clinical models, we found that chronic exposure of cell lines to rituximab led to downregulation of ICAM-1 and acquirement of a rituximab resistant phenotype. In vitro exposure of rituximab resulted in rapid aggregation of B-cells regardless of the ICAM-1 expression levels. MTT assay showed knockdown of ICAM-1 could cause rituximab resistance. Neutralization of ICAM-1 did not affect rituximab activity in vitro and in vivo. Our data illustrated that in post-rituximab era, R-CHOP significantly improved the ORR, PFS and OS in ICAM-1 negative subset patients. Downregulation of ICAM-1 may contribute to rituximab resistance, and that rituximab, by promoting cell-cell aggregation, may sensitize cells to the cytotoxic effects of chemotherapy agents.

Radiotherapy followed by DICEP regimen in treatment of newly diagnosed, stage IE/IIE, extranodal NK/T-cell lymphoma patients.

BACKGROUND: The optimal treatment strategies for extranodal natural killer/ T-cell lymphoma (ENKTL) have not been defined. We conducted this prospective, open-label, phase II, single-center study aimed to explore the efficacy and safety of radiotherapy followed by DICEP (Dexamethasone, ifosfamide, cisplatin, etoposide, and pegaspargase) regimen in the treatment of patients with untreated, stage IE/IIE, extranodal NK/T-cell lymphoma. METHODS: Thirty eligible patients were enrolled in this study, receiving radiotherapy of 50Gy/25fx, and followed by chemotherapy with DICEP regimen for 3 cycles if tolerated. Median follow-up time of this study was 70.8 months. We constructed Kaplan-Meier survival curves for survival analyses. RESULTS: The most common manifestations at the onset of disease were nasal obstruction (80%), with or without fever, and pharyngalgia (20%). The overall response rate (ORR) was 96.7% (29/30). Four patients (13.3%) had progression of the disease (PD), the estimated 5-year progression-free survival (PFS) rate was 86%. Four patients (13.3%) died of disease, and the estimated 5-year cumulative overall survival (OS) was 87%. The most common hematological toxicity was grade 3 or grade 4 neutropenia, which could be successfully managed via using growth-stimulating factors or dose modifications. Hypoalbuminemia and decreased fibrinogen are the top two nonhematologic toxicities. No treatment-related death occurred in this study. CONCLUSIONS: Our present study showed that radiotherapy followed by DICEP chemotherapy could be an effective and tolerable treatment modality for newly diagnosed, stage IE/IIE ENKTL patients. Adverse events were predictable and manageable. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01667302. Registered: 1 July 2012.

Prognostic Significance of LDH Ratio in Serum/Cerebral Spinal Fluid of Patients with Primary Testicular Diffuse Large B-Cell Lymphoma.

OBJECTIVE: Primary testicular diffuse large B-cell lymphoma (PT-DLBCL) is relatively rare, and risk factors of this disease are still not well understood. This study aims to identify clinical features and prognostic factors of PT-DLBCL patients. METHODS: Thirty-two patients were included in this retrospective study who were diagnosed as PT-DLBCL and treated in Fudan University Shanghai Cancer Center between November 2010 and May 2018. The demographic details, clinico-pathological characteristics of the patients were summarized, and the impact on progression-free survival (PFS) and overall survival (OS) was analyzed. RESULTS: The median age of the patients was 57 (range 36-76) years old. All patients received rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for 4-6 cycles and central nervous system (CNS) prophylaxis, with a CR rate 87.5% and an ORR 96.9%. Nineteen patients continued prophylactic contralateral testis radiation therapy (PCTRT) in our hospital. The 3-year PFS and OS rates were 79% and 92%, respectively. None of the 19 patients who received PCTRT experienced local recurrence. All three patients who suffered from CNS relapse were germinal center B-cell subtype. Kaplan-Meier analyses showed that PT-DLBCL patients with late-stage (Stage IV) (P =0.022), higher IPI score (IPI≥ 2) (P =0.017), B symptoms (P =0.004), and elevated LDH level (P =0.03) had a shorter PFS. More importantly, we found that patients with the ratio of the LDH level in serum to that in CSF ≥ 6.5 suffered from a worse PFS (P =0.028). CONCLUSION: Our work revealed that staging IV, IPI score ≥2, having B symptoms and elevated LDH level were risk factors for PT-DLBCL patients. Significantly, the PT-DLBCL patients with a high ratio of LDH level in serum to that in CSF were indicated to have a worse PFS.

The size and depth of lesions measured by endoscopic ultrasonography are novel prognostic factors of primary gastric diffuse large B-cell lymphoma.

Diffuse large B cell lymphoma is one of the predominant histological subtypes of primary gastric lymphomas. Factors that contribute to precise stratification and guide the treatment of this disease are still not well understood. We analyzed 73 primary gastric diffuse large B cell lymphoma patients retrospectively, and found that patients characterized by late stage, multiple localization, B symptoms, lower serum albumin level and elevated LDH level had a shorter overall survival through Univariate Cox regression analysis. Multivariate Cox regression analysis demonstrated that ALB ≤ 35g/L, staging ≥ IIE and multiple sites localization were independent adverse prognostic factors. Significantly, in 35 patients who received endoscopy at diagnosis, Kaplan-Meier analyses indicated that patients with large (≥3 cm) and deep lesions (≥11 mm) had an inferior OS (p = .01 and .039). These findings implicated that tumor size and depth are two indicators of prognosis under ultrasonography. Further randomized studies with large number of cases are needed.

Role of radiotherapy in patients with limited diffuse large B-cell lymphoma of Waldeyer's ring in remission after R-CHOP immunochemotherapy.

The standard treatment of waldeyer's ring DLBCL remains controversial. This retrospective study was designed to evaluate the role of consolidation radiotherapy (RT) in patients with stage I/II diffuse large B-cell lymphoma (DLBCL) limited in Waldeyer's ring (WR). We included 72 patients, 42 were treated with immunochemotherapy alone (CT group) and 30 were treated with immunochemotherapy followed by radiotherapy (CT + RT group). All patients received at least 3 cycles of R-CHOP regimen and achieved complete remission (CR) after immunochemotherapy. After 53 months median follow-up time, the 5-year progression-free survival (PFS) rates in CT + RT group vs. CT group were 93.3% vs. 92.5% (P = 0.896), the 5-year overall survival (OS) rates were 96.7% vs. 94.4% (P = 0.649). Patients with oropharyngeal primary had relatively better 5-year PFS and OS rates compared to nasopharyngeal primary (PFS: 98.2% vs. 73.3%, p = 0.001; OS: 100% vs. 79.0%, p < 0.001). Moreover, the primary site was the only independent prognostic factor for PFS in the multivariate analysis (p = 0.012, HR 16.858 [95% CI: 1.883-150.933]).