Clinical and prognostic significance of apoptotic profile in patients with newly diagnosed nodal diffuse large B-cell lymphoma (DLBCL)

Background: Apoptosis‐related proteins might play an important role in the pathogenesis of lymphoma and sensibility to chemotherapy (CH) in patients with non‐Hodgkin’s lymphoma. We have analyzed the relationship between expression of two proapoptotic (CD95, caspase‐3) and four antiapoptotic proteins (c‐FLIP, bcl‐2, survivin, and XIAP) and clinical outcome of patients with nodal diffuse large B‐cell lymphoma (DLBCL). Methods: We have analyzed lymph node biopsy specimens obtained from 78 patients with newly diagnosed nodal DLBCL. The expression of apoptotic parameters was analyzed using the standard immunohistochemical method (antibodies against caspase‐3, CD95, c‐FLIP, XIAP, survivin, and bcl‐2) on formalin‐fixed and routinely processed paraffin‐embedded lymph node specimens. The expression of immunohistochemical parameters has been evaluated semiquantitatively as a percentage of tumor cells. Results: Immunoexpression of caspase‐3, CD95, c‐FLIP, survivin, XIAP, and bcl‐2 has been found in 48 (61.5%), 39 (50%), 45 (57.7%), 41 (52.6%), 43 (55.12%), and 39 (50.0%) patients, respectively. The therapy response was achieved in 53 (67.9%) patients. Besides numerous clinical parameters, survivin and XIAP positivity along with CD95 negativity were found to be unfavorable factors for therapy response and shorter survival in univariate analysis. According to this finding, an ‘apoptotic score’ that includes unfavorable apoptotic parameters has been defined. In multivariate analysis, only International Prognostic Index (IPI) and apoptotic score remained independent prognostic predictors for the chance to reach the complete remission (P = 0.003 and P = 0.044, respectively) and longer overall survival (OS) (P = 0.002 and P = 0.046, respectively). Significantly, the better response to immunochemotherapy (ICH) in comparison with CH has been achieved in patients with expression of caspase‐3, c‐FLIP, and survivin and in patients without the immunoexpression of XIAP. In addition, ICH was superior to CH in both bcl‐2‐positive and bcl‐2‐negative patients. Conclusion: The results of this study showed that the dysregulation of apoptosis can appear on different places of apoptotic cascade in DLBCL. Apoptotic score is a more useful tool in predicting therapy response and OS of patients with DLBCL than single apoptotic parameters and along with IPI could help to identify a high‐risk group of newly diagnosed nodal DLBCL.     

Pemetrexed plus platinum or gemcitabine plus platinum for advanced non‐small cell lung cancer: final survival analysis from a multicentre randomized phase II trial in the East Asia region and a meta‐analysis

Background and Objective: Pemetrexed plus platinum has shown efficacy as a first‐line treatment for advanced non–small cell lung cancer (NSCLC), but little is known about its efficacy and safety in East Asian patients. We report the final analysis of overall survival (OS) from a multicentre, randomized, phase II trial in chemotherapy‐naive Chinese patients with advanced NSCLC. An additional meta‐analysis was performed to systematically evaluate pemetrexed/platinum as first‐line treatment for advanced NSCLC. Methods: Eligible patients received up to six cycles of pemetrexed, 500 mg/m² plus cisplatin, 75 mg/m² (day 1) or gemcitabine, 1000 mg/m² (days 1 and 8) plus cisplatin, 75 mg/m² (day 1). OS and toxicity were assessed. Results: A total of 254 patients were randomized, and 251 were eligible for inclusion in the efficacy and safety analyses. Median OS in the pemetrexed/cisplatin arm was 15.3 months, compared with 16.9 months in the gemcitabine/cisplatin arm [hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.80–1.48; log‐rank P = 0.4888). There was a trend towards improved survival in both arms. Patients in the pemetrexed/cisplatin arm showed a lower incidence of drug‐related grade 3 to 4 leukopenia and thrombocytopenia. Meta‐analysis showed that pemetrexed‐platinum treatment was associated with 19% longer survival among females (HR 0.81; 95% CI 0.69–0.96) and 17% longer survival among patients with non‐squamous cell lung cancer (HR 0.83; 95% CI 0.73–0.95). Conclusions: In Chinese patients with advanced NSCLC, pemetrexed/cisplatin treatment resulted in comparable OS outcomes and was better tolerated than gemcitabine/cisplatin. Meta‐analysis supports the use of pemetrexed‐platinum as first‐line treatment for female patients and those with the non‐squamous cell subtype of advanced NSCLC.     

胸腺素β4在老年晚期非小细胞肺癌中的表达及其对化疗疗效的影响

目的:探讨胸腺素β4(Tβ4)在老年晚期非小细胞肺癌(NSCLC)中的表达与临床病理学因素及一线含铂类化疗疗效的关系。方法:选取94例晚期的老年NSCLC患者病理组织标本,采用免疫组化的方法检测Tβ4的表达水平,分析临床病理特征,采用实体瘤客观疗效评价标准(RECIST)评价化疗效果,进行生存随访。分析Tβ4的阳性表达与无进展生存期(PFS)及总生存期(OS)的关系。结果:在94例老年晚期NSCLC患者中,Tβ4的高表达率为39.4%(37例/94例)。相关性分析表明,Tβ4的高表达与性别、分化程度、病理类型、TNM分期、化疗方案及T分期等因素无关(P<0.05),与化疗疗效(r=0.327,P=0.001)、PFS(r=0.387,P=0.002)及OS(r=0.404,P=0.001)显著相关。多因素Logistic回归分析表明,Tβ4表达为NSCLC患者疗效的影响因素(P<0.05)。COX多因素分析表明Tβ4表达水平是化疗反应率及PFS的预测因素(P<0.05)。结论:Tβ4的高表达与老年晚期NSCLC一线含铂化疗疗效及生存期相关。Tβ4对于老年晚期NSCLC一线含铂化疗方案的疗效预测具有一定的临床意义。     

Early on-treatment predictions of clinical outcomes using alpha-fetoprotein and des-gamma-carboxy prothrombin responses in patients with advanced hepatocellular carcinoma

Background and Aim: The clinical utility of alpha‐fetoprotein (AFP) and des‐γ‐carboxy prothrombin (DCP) as a predictor of treatment outcome in patients with advanced hepatocellular carcinoma (HCC) receiving hepatic artery infusional chemotherapy (HAIC) or concurrent chemoradiation therapy (CCRT) has been poorly defined. Methods: Between January 2003 and December 2007, we enrolled 127 treatment‐naïve patients who received HAIC (n = 60) or CCRT (n = 67) as an initial treatment modality. An AFP or DCP response was defined as a reduction of more than 20% from the baseline level. Results: AFP responders showed significantly better overall survival (OS) than non‐responders among patients with HAIC (median 17.3 vs 6.4 months, P < 0.001) and with CCRT (median 17.6 vs 8.7 months, P = 0.014). DCP responders in the CCRT group also showed significantly better progression‐free survival (PFS) than non‐responders (median 9.2 vs 3.1 months, P < 0.001). Multivariate Cox regression analyses showed that AFP response was independently predictive of OS in both groups (P = 0.009 in HAIC and P = 0.008 in CCRT) whereas DCP only predicted PFS in patients with CCRT (P = 0.015). Conclusions: Early on‐treatment AFP response was predictive of OS in treatment‐naïve patients with advanced HCC receiving HAIC and CCRT as an initial treatment modality. Furthermore, DCP response was useful for predicting PFS in patients with CCRT.     

High immunohistochemical expression of p‐AKT predicts inferior survival in patients with diffuse large B‐cell lymphoma treated with immunochemotherapy

Chemotherapy and rituximab (R) is current standard therapy in diffuse large B‐cell lymphoma (DLBCL), but a substantial proportion of patients still fail to reach sustained remission. In vitro studies have indicated that rituximab resistance could be accompanied by dysregulated apoptotic pathways, such as the phosphatidylinositol 3‐kinase (PI3K)/AKT signaling pathway, which can be constitutively activated in DLBCL. In this retrospective, immunohistochemical study on 106 patients treated with R‐CHO(E)P (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab [+etoposide]), we investigated the prognostic role of proteins involved in different apoptotic pathways; phosphorylated AKT (p‐AKT), bcl‐2, MCL1, bcl‐xL, Bax and Bak. High p‐AKT expression (>108 cells/mm², highest quartile, n = 27) predicted worse progression‐free (PFS) (P = 0·02) and overall (OS) (P = 0·01) survival, independent of International Prognostic Index and sex. Also bcl‐2+ (cut‐off 50%) predicted worse PFS (P = 0·005) and OS (P = 0·05) but after adjustment for clinical factors only the influence on PFS (P = 0·03) remained significant. The prognostic impact of p‐AKT overexpression was independent of bcl‐2 status. MCL1, bcl‐xL, Bax and Bak expression did not add any prognostic information. Our results suggest that high p‐AKT expression predicts worse outcome, possibly indicating that inhibition of the activated PI3K/AKT pathway could be of clinical interest in DLBCL patients. In addition, bcl‐2 status could have prognostic importance also in the era of immunochemotherapy.     

Extranodal NK/T‐cell lymphoma,nasal type: Clinical features,outcome, and prognostic factors in 101 cases

Objectives

We aimed to define the clinical features, outcome, and prognostic factors for extranodal NK/T‐cell lymphoma (ENKTL) patients in Taiwan.

Methods

We retrospectively reviewed 101 ENKTL patients diagnosed between February 1998 and October 2015.

Results

The median age of 101 patients was 52 years old (range 22‐85); 76.2% of patients were Ann Arbor stage I/II disease. The 5‐year progression‐free survival (PFS) and overall survival (OS) were 49.9% and 54.8%, respectively. Patients with log[EBV‐DNA] ≥ 3.8 and bone marrow hemophagocytosis at diagnosis had inferior PFS and OS. Most stage I/II patients received combined chemoradiotherapy with anthracycline‐containing regimen, with overall response rate of 96.7%, complete response rate 86.9%, 5‐year PFS 65%, and OS 72%. The relapse rate was 29.3% with a short median disease‐free survival of 6.2 months. In advanced stage patients, overall response rate was only 13.6%, with median PFS 2.3 months, and OS 4.8 months. Age ≥ 60 (HR 3.773, 95% CI 1.733‐8.215, P = 0.001) and stage III/IV (HR 7.785, 95% CI 2.312‐26.213, P = 0.001) were unfavorable prognostic factors for PFS and OS by multivariate analyses.

Conclusions

Age ≥ 60 and stage III/IV are independent poor prognostic factors for PFS and OS. Early‐stage ENKTL patients had good response to combined chemoradiotherapy with anthracycline‐containing regimen but with a high relapse rate and short disease‐free survival. Anthracycline‐containing regimen in advanced stage had poor response and dismal outcome.

     

Prognostic value of 18F‐FDG PET for hepatocellular carcinoma patients treated with sorafenib

Background: Sorafenib (Nexavar) is an orally active multikinase inhibitor that is approved for the treatment of hepatocellular carcinoma (HCC). In this study, we used ¹⁸F‐2‐fluoro‐2‐deoxyglucose (¹⁸F‐FDG) with positron emission tomography (PET) to predict the treatment outcome of sorafenib in patients with advanced HCC. Materials and methods: A total of 29 patients with HCC were included. Baseline ¹⁸F‐FDG PET scans were performed a median of 14 days before sorafenib treatment. Sorafenib was administered orally at a dose of 400 mg twice daily. For statistical analysis, the standardized uptake value (SUV) of the most hypermetabolic lesion was obtained and assigned as the SUVmax for each patient. Results: Among 29 patients, one patient achieved partial remission and 14 patients showed stable disease. The overall survival (OS) and progression free survival (PFS) were 5.1 months [95% confidence interval (CI): 0.0–12.0] and 3.8 months (95% CI: 1.4–6.2). The multivariate analysis of OS showed that four indices, Eastern Cooperative Oncology Group performance status, α‐fetoprotein (AFP) concentration, portal vein thrombosis and SUVmax were significant prognostic factors (P=0.030, P=0.024, P=0.020 and P=0.015 respectively). AFP concentration and SUVmax were independent prognostic factors for PFS, too (P=0.003 and P=0.026 respectively). When the patients were divided into two groups: low SUVmax (n=10; <5.00) and high SUVmax (n=19;≥5.00), the low SUV group showed significantly longer OS and PFS (P=0.023 and P=0.042 respectively). Conclusion: Our study showed that the degree of FDG uptake is an independent prognostic factor in patients with HCC who undergo sorafenib treatment.     

Favourable outcomes of poor prognosis diffuse large B‐cell lymphoma patients treated with dose‐dense Rituximab,high‐dose Methotrexate and six cycles of CHOP‐14 compared to first‐line autologous transplantation

The optimal therapeutic approach for young diffuse large B‐cell lymphoma (DLBCL) patients with high‐intermediate and high‐risk age‐adjusted international prognostic index (aaIPI) remains unknown. Hereby we report a 10‐year single‐centre study of 63 consecutively treated patients. To optimize outcome, two approaches were carried out: Cohort 1 patients received four cycles R‐CHOP‐21 (rituximab, cyclophosphamide, daunorubicin, vincristine, prednisolone over 21 days) followed by first‐line high‐dose chemotherapy with autologous stem‐cell support (HDCT‐ASCT), resulting in 2‐year progression‐free (PFS) and overall survival (OS) of 60·6% and 67·9%. 39·4% of those patients were not transplanted upfront, mainly due to early progressive disease (24·2%). Cohort 2 patients received an early intensified protocol of six cycles of CHOP‐14 (cyclophosphamide, daunorubicin, vincristine, prednisolone over 14 days) with dose‐dense rituximab and high‐dose methotrexate resulting in promising overall response‐ (93·3%) and complete remission (90%) rates and sustained survival (2‐year PFS and OS: 93·3%). In an intention‐to‐treat analysis, 2‐year PFS (60·6% vs. 93·3%, hazard ratio [HR] 7·2, P = 0·009) and OS (69·7% vs. 93·3%, HR 4·95, P = 0·038) differed significantly, in favour of the early intensified protocol (Cohort 2). In a multivariate Cox‐regression model, PFS (HR 8·12, 95% confidence interval [CI] 1·83–35·9, P = 0·006) and OS (HR 5·86, 95% CI 1·28–26·8, P = 0·02) remained superior for Cohort 2 when adjusted for aaIPI3 as the most important prognostic factor. Survival of young poor‐prognosis DLBCL patients appears superior after early therapy intensification.     

Absolute lymphocyte count at the time of first relapse predicts survival in patients with diffuse large B‐cell lymphoma

Peripheral blood absolute lymphocyte count (ALC) is a survival prognostic factor in hematological malignancies. No reports have addressed whether ALC at the time of first relapse (ALC‐R) predicts survival. Thus, we assessed the prognostic significance of ALC‐R in diffuse large B‐cell lymphoma (DLBCL). Patients were required to have been diagnosed with first relapsed DLBCL, have ALC‐R values, and to be followed at Mayo Clinic, Rochester. From Feb 1987 until March 2006, 97 first relapsed DLBCL patients qualified for the study. The overall survival (OS) and progression‐free survival (PFS) were measured from the time of first relapse. The value of ALC‐R ≥ 1.0 × 10⁹/L was used for the analysis. Both groups (ALC‐R ≥ 1 or < 1 × 10⁹/L) were balanced for the international prognostic index at relapse (IPI‐R) (P = 0.3), and for autologous stem cell transplantation (P = 0.4). Superior OS and PFS were observed with an ALC‐R ≥ 1.0 × 10⁹/L (N = 60) versus ALC‐R < 1.0 × 10⁹/L (N = 37) [median OS: 28.7 months, 5 years OS rates of 39% versus median OS: 10.2 months, 5 years OS rates of 14%, P < 0.002; and median PFS: 14.8 months, 5 years PFS rates of 21% versus median PFS: 6.5 months, 5 years PFS rates of 8%, P < 0.004, respectively]. ALC‐R was an independent prognostic factor for OS [RR = 0.4, P < 0.01] and PFS [RR = 0.5, P < 0.005]. ALC‐R predicts survival suggesting that host immunity is an important variable predicting survival in first relapsed DLBCL. Am. J. Hematol. 2009. © 2008 Wiley‐Liss, Inc.     

THP‐COP regimen for the treatment of peripheral T‐cell lymphoma and adult T‐cell leukemia/lymphoma: a multicenter phase II study

Objective: The efficacy of pirarubicin (THP)‐COP was previously compared with cyclophophamide + doxorubicin + vincristine + prednisolone (CHOP) in elderly patients with lymphoma. The subset analysis showed that T‐cell lymphoma had a significantly better response with THP‐COP, whereas no such difference was observed in B‐cell lymphoma. The aim of this study is to confirm the efficacy of THP‐COP in the treatment of T‐cell lymphoma. Methods: We underwent a multicenter phase II study of THP‐COP as a first‐line treatment for T‐cell lymphoma. The overall response rate, survival period, and toxicity were analyzed. Results: Fifty‐three patients were enrolled in this study. Seventeen patients had peripheral T‐cell lymphoma (PTCL), including nine of PTCL not otherwise specified (PTCL‐NOS) and eight of angioimmunoblastic T‐cell lymphoma (AITL). Thirty‐six patients had adult T‐cell leukemia/lymphoma (ATLL), including 20 of acute type and 16 of lymphoma type. A treatment response was obtained in 35 (66%) patients, including 17 (32%) complete responses. Median overall survival (OS) and progression‐free survival (PFS) times were 14.3 months and 5.2 months, respectively. Patients with ATLL showed a tendency to obtain low response rate (61% vs. 77%, P = 0.27) and had a significantly inferior OS (13.3 vs. 28.6 months, P = 0.04) and PFS (4.6 vs. 8.1 months, P = 0.01) in comparison with PTCL. Grade 3 to 4 neutropenia, anemia, and thrombocytopenia occurred in 72%, 34%, and 58% of the patients, respectively. Febrile neutropenia was observed in 51% and grade 3 non‐hematological toxicities in 2–9% of the patients. Conclusion: The efficacy of THP‐COP is equivalent to that of CHOP for the first‐line therapy in T‐cell lymphoma.     

Improved survival for relapsed diffuse large B cell lymphoma is predicted by a negative pre‐transplant FDG‐PET scan following salvage chemotherapy

The utility of ^[18F]fluoro‐2‐deoxy‐ d ‐glucose positron‐emission tomography (FDG‐PET) for predicting outcome after autologous stem cell transplantation (ASCT) for diffuse large B cell lymphoma (DLBCL) is uncertain – existing studies include a range of histological subtypes or have a limited duration of follow‐up. Thirty‐nine patients with primary‐refractory or relapsed DLBCL with pre‐ASCT PET scans were analysed. The median follow‐up was 3 years. The 3‐year progression‐free survival (PFS) for patients with positive PET scans pre‐ASCT was 35% vs. 81% for those who had negative PET scans (P = 0·003). The overall survival (OS) in these groups was 39% and 81% (P = 0·01), respectively. In a multivariate analysis, PET result, number of salvage cycles and the presence of relapsed or refractory disease were shown to predict a longer PFS; PET negativity (P = 0·04) was predictive of a longer OS. PET is useful for defining those with an excellent prognosis post‐ASCT. Although those with positive scans can still be salvaged with current treatments, PET may useful for selecting patients eligible for novel consolidation strategies after salvage therapies.     

Factors associated with long-term survival of patients with advanced non-small cell lung cancer

Background and objective: Only a small proportion of patients with advanced non‐small cell lung cancer (NSCLC) have a life expectancy greater than 2 years. The aim of this study was to identify the factors associated with long‐term survival of patients with advanced NSCLC. Methods: Patients who had received chemotherapy for stage IIIb or IV NSCLC that was not amenable to radiotherapy were studied retrospectively. Data were gathered prospectively from a comprehensive database. Long‐term survivors (>2 years) were compared with the other patients, with respect to clinical, biological and tumour–node–metastasis criteria. Results: Data for 245 consecutive patients were collected. Thirty nine patients (15.9%) survived for more than 2 years. Long‐term survivors were more likely to have had metastases at fewer sites (P = 0.008), an absence of bone metastases (P = 0.01), a performance status (PS) of 0–1 at first progression of the tumour (P = 0.002), a tumour that was controlled with first (P < 0.0001) and second‐line (P = 0.004) chemotherapy, maintenance therapy (P = 0.001), curative surgery (P < 0.0001), time to first progression of the tumour of >3 months (P < 0.0001), normal LDH levels at diagnosis (P = 0.049), and a haemoglobin concentration >110 g/L at first progression of the tumour (P = 0.02). In multivariate analysis, surgery, maintenance treatment, time to first progression of the tumour of >3 months, a PS of 0–1 at first progression, the number of chemotherapy agents received, and LDH levels, were significant predictors of long‐term survival. Conclusions: Assessment of these factors, and the use of maintenance therapy, when possible, may identify a population of patients with NSCLC that is likely to have a prolonged life expectancy.     

Reduction in C‐reactive protein indicates successful targeting of the IL‐1/IL‐6 axis resulting in improved survival in early stage multiple myeloma

We report the long‐term follow‐up results of a phase II trial of IL‐1 receptor antagonist and low‐dose dexamethasone for early stage multiple myeloma (MM). Patients were eligible if they had smoldering multiple myeloma (SMM) or indolent multiple myeloma (IMM) without the need for immediate therapy. Forty seven patients were enrolled and subsequently treated with IL‐1Ra; in 25/47 low‐dose dexamethasone (20 mg weekly) was added. The primary endpoint was progression‐free survival (PFS). In the clinical trial, three patients achieved a minor response (MR) to IL‐1Ra alone; five patients a partial response (PR) and four patients an MR after addition of dexamethasone. Seven patients showed a decrease in the plasma cell labeling index (PCLI) which paralleled a decrease in the high sensitivity C‐reactive protein (hs‐CRP). The median PFS for the 47 patients was 1116 days (37.2 months). The median PFS for patients without (n = 22) and with (n = 25) a decrease in their baseline hs‐CRP was 326 days (11 months) vs. 3139 days (104 months) respectively (P <0.0001). The median overall survival (OS) for the 47 patients was 3482 days (9.5 years). The median OS for patients without and with a decrease in their baseline hs‐CRP was 2885 days (7.9 years) vs. median not reached, respectively (P = 0.001). In SMM/IMM patients at risk for progression to active myeloma, reduction in the hs‐CRP indicates successful targeting of the IL‐1/IL‐6 axis resulting in improved PFS and OS. (Clinical Trials.gov Identifier: NCT00635154) Am. J. Hematol. 91:571–574, 2016. © 2016 Wiley Periodicals, Inc.     

High Ki-67 expression in diffuse large B-cell lymphoma patients with non-germinal center subtype indicates limited survival benefit from R-CHOP therapy

Objectives: Rituximab has significantly improved the survival of patients with DLBCL, especially those with non‐germinal center B‐cell‐like (non‐GCB) subtype. The impact of Ki‐67 expression, an index of proliferation, on the clinical outcomes of patients with DLBCL has largely been unexplored. This study aimed to investigate whether Ki‐67 expression is an indicator of outcome in DLBCL patients (especially non‐GCB DLBCL patients) treated with standard chemotherapy combined with rituximab. Methods: Expression of Ki‐67 protein was examined immunohistochemically in 118 tumor specimens from patients newly diagnosed with DLBCL and treated with R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Results: Overall survival (OS) and progression‐free survival (PFS) were lower in patients with high Ki‐67 expression than in those with low Ki‐67 expression (3‐year OS: 65.2% vs. 81.7%, P = 0.030; 3‐year PFS: 56.4% vs. 73.3%, P = 0.020), similar in patients with GCB subtype and those with the non‐GCB subtype (OS: P = 0.330; PFS: P = 0.287). According to Ki‐67 expression status by immunophenotype subgroups, patients with high Ki‐67 expression in non‐GCB subgroup had the most unfavorable PFS and OS, comparing with the other three subgroups (P = 0.004 and P = 0.002, respectively). In multivariate analysis, non‐GCB with high Ki‐67 expression was an independent prognostic predictor of inferior survival in DLBCL patients treated with R‐CHOP. Conclusion: For DLBCL patients with non‐GCB DLBCL and high Ki‐67 expression, the survival benefit from R‐CHOP therapy is limited.     

Hodgkin lymphoma post‐transplant lymphoproliferative disorder: A comparative analysis of clinical characteristics,prognosis, and survival

Hodgkin lymphoma post‐transplant lymphoproliferative disorder (HL‐PTLD) is an uncommon PTLD with unclear prognosis and differences between HL‐PTLD and immunocompetent HL are not well defined. Patient characteristics were compared among 192 patients with HL‐PTLD from the Scientific Registry of Transplant Recipients and 13,847 HL patients in SEER (HL‐SEER). Overall survival (OS) and disease‐specific survival (DSS) were compared after exact matching. Additionally, multivariable analyses were used to identify prognostic markers of survival and associations between treatment and survival. Median time from transplant to HL‐PTLD diagnosis was 88 months. When compared with HL‐SEER, patients with HL‐PTLD were older (median age, 52 vs. 36 years, P = 0.001), more likely male (73% vs. 54%, P < 0.001), Caucasian (81% vs. 70%, P = 0.02), and had extranodal disease (42% vs. 3%, P < 0.001). Five‐year OS for patients with HL‐PTLD was 57% versus 80% for HL‐SEER (P < 0.001); DSS was also inferior (P < 0.001). For patients with HL‐PTLD, the use of any chemotherapy was associated with decreased hazard of death (HR = 0.36, P < 0.001). Furthermore, patients who received no chemotherapy or nontraditional HL regimens had increased hazard of death (aHR = 2.94, P = 0.001 and 2.01, P = 0.04) versus HL‐specific chemotherapy regimens. In multivariable analysis, advanced age and elevated creatinine were associated with inferior OS (aHR = 1.26/decade P < 0.001 and 1.64/0.1 mg/dL increase P = 0.02). A prognostic score based on the number of these adverse factors (0, 1, 2) was associated with 10‐year OS rates of 79%, 53%, and 11%, respectively (P < 0.001). Altogether, HL‐PTLD patients have inferior survival when compared with HL‐SEER. Furthermore, treatment with HL‐specific chemotherapy was associated with improved OS, whereas age and creatinine identified patients with markedly divergent survival. Am. J. Hematol. 91:560–565, 2016. © 2016 Wiley Periodicals, Inc.     

A phase III randomized trial of high‐dose CEOP + filgrastim versus standard‐dose CEOP in patients with non‐Hodgkin lymphoma: 10‐year follow‐up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial

Increasing dose intensity (DI) of chemotherapy for patients with aggressive non‐Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3‐weekly standard (s) or intensive (i) chemotherapy: s‐CEOP–cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m² all on day 1, and prednisolone 100 mg days 1–5; i‐CEOP–cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m² all on day 1, and prednisolone 100 mg days 1–5. Primary endpoint was 5‐year overall survival (OS). Relative to s‐CEOP patients, i‐CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5‐year OS (56.7% i‐CEOP; 55.1% s‐CEOP; P = 0.80), 5‐year progression free survival (PFS; 41% i‐CEOP; 43% s‐CEOP; P = 0.73), 5‐year time to progression (TTP; 44% i‐CEOP; 47% s‐CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i‐CEOP; 59% s‐CEOP; P = 0.64). Long‐term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i‐CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6‐month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity. Am. J. Hematol. 89:536–541, 2014. © 2014 Wiley Periodicals, Inc.     

Serum interleukin-18 level is associated with the outcome of patients with diffuse large B-cell lymphoma treated with CHOP or R-CHOP regimens

Background: We have previously reported that serum interleukin‐18 (IL‐18) concentration predicted the clinical outcome of patients with aggressive non‐Hodgkin’s lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). When rituximab (R) was added to this regimen, the prognosis of diffuse large B‐cell lymphoma (DLBCL) was markedly improved. Patients and Methods: In this study, we re‐evaluated the prognostic significance of serum IL‐18 in 227 DLBCL patients. Seventy‐three patients received CHOP before R‐era, and 154 patients received rituximab‐cyclophosphamide, doxorubicin, vincristine, and prednisolone (R‐CHOP) recently. Result: Four‐year overall survival (4‐yr OS) rates for patients in CHOP group with IL‐18 ≥ 720 pg/mL and <720 pg/mL were 8.2% and 67.3% (P < 0.0001), respectively, and 4‐yr OS rates with IL‐18 ≥ 590 and <590 pg/mL in R‐CHOP group were 53.4% and 77.8% (P = 0.0008), respectively. Multivariate analysis revealed that serum IL‐18 correlated most significantly with OS and progression‐free survival (PFS) in both groups (OS: P < 0.0001, PFS: P < 0.0001, in CHOP group; OS: P = 0.0147, PFS: P = 0.0084 in R‐CHOP group). The high serum IL‐18 patients with poor prognostic group in revised IPI or with non‐germinal center B‐cell phenotype had a very poor prognosis. Conclusion: Serum IL‐18 might be a powerful prognostic factor for DLBCL in R‐era.     

F‐18 FDG‐PET predicts outcomes for patients receiving total lymphoid irradiation and autologous blood stem‐cell transplantation for relapsed and refractory Hodgkin lymphoma

Total lymphoid irradiation (TLI) followed by high‐dose chemotherapy and autologous haematopoietic stem cell transplant (aHSCT) is an effective strategy for patients with relapsed/refractory classical Hodgkin lymphoma (HL). We report outcomes for patients with relapsed/refractory HL who received TLI followed by high‐dose chemotherapy and aHSCT. Pre‐transplant fludeoxyglucose positron emission tomography (FDG‐PET) studies were scored on the 5‐point Deauville scale. Of 51 patients treated with TLI and aHSCT, 59% had primary refractory disease and 63% had active disease at aHSCT. The 10‐year progression‐free survival (PFS) and overall survival (OS) for all patients was 56% and 54%, respectively. Patients with complete response (CR) by PET prior to aHSCT had a 5‐year PFS and OS of 85% and 100% compared to 52% and 48% for those without CR (P = 0·09 and P = 0·007, respectively). TLI and aHSCT yields excellent disease control and long‐term survival rates for patients with relapsed/refractory HL, including those with high‐risk disease features. Achievement of CR with salvage therapy is a powerful predictor of outcome.     

Total body computed tomography scan in the initial work‐up of Binet stage A chronic lymphocytic leukemia patients: Results of the prospective,multicenter O‐CLL1‐GISL study

Total body computed tomography (TB‐CT) scan is not mandatory in the diagnostic/staging algorithm of chronic lymphocytic leukemia (CLL). The aim of this study was to determine the value and prognostic significance of TB‐CT scan in early stage CLL patients. Baseline TB‐CT scan was performed in 240 Binet stage A CLL patients (179 Rai low‐ and 61 Rai intermediate‐risk) included in a prospective multicenter observational study ( clinicaltrial.gov ID:NCT00917549). The cohort included 69 clinical monoclonal B lymphocytosis (cMBLs). Patients were restaged considering only radiological data. Following TB‐CT scans, 20% of cases reclassified as radiologic Binet (r‐Binet) stage B. r‐Binet B patients showed a higher incidence of unfavorable cytogenetic abnormalities (P = 0.027), as well as a shorter PFS (P = 0.001). At multivariate analysis, r‐Binet stage [HR = 2.48; P = 0.004] and IGHV mutational status [HR = 3.01; P = 0.002] retained an independent predictive value for PFS. Among 179 Rai low‐risk cases, 100 were redefined as r‐Rai intermediate‐risk based upon TB‐CT scan data, showing a higher rate of cases with higher ZAP‐70 (P = 0.033) and CD38 expression (P = 0.029) and β2‐microglobulin levels (P < 0.0001), as well as a shorter PFS than those with r‐Rai low‐risk (P = 0.008). r‐Rai stage [HR = 2.78; P = 0.046] and IGHV mutational status [HR = 4.25; P = 0.009] retained a significant predictive value for PFS at multivariate analysis. Forty‐two percent of cMBL patients were reclassified as r‐small lymphocytic lymphomas (r‐SLLs) by TB‐CT scan. TB‐CT scan appears to provide relevant information in early stage CLL related to the potential and the timing of patients to progress towards the more advanced disease stages. Am. J. Hematol. 88:539–544, 2013. © 2013 Wiley Periodicals, Inc.     

Role of surgery in the management and prognosis of limited‐stage small cell carcinoma of the esophagus

Small cell carcinoma of the esophagus (SCCE) is a rare, highly aggressive tumor characterized by early dissemination and a poor prognosis. Surgery, chemotherapy, and radiotherapy have been used alone or in combination for the treatment of this rare disease. The aim of this retrospective study was to analyze the role of surgery in the management of limited‐stage SCCE at a high‐volume center. We retrospectively evaluated 73 patients with limited‐stage SCCE who received an esophagectomy at our center from January 1994 to December 2011. The clinical characteristics, median survival times (MSTs), overall survival (OS), and relevant prognostic factors were analyzed. The overall MST was 23.0 months, and the 1‐, 2‐, 3‐, and 5‐year OS rates were 61.6%, 47.9%, 22.7%, and 10.6%, respectively. The MST for patients without lymph node involvement (33.0 months) was greater than the MST for patients with lymph node involvement (17.0 months) (P = 0.014). Similarly, patients who underwent radical resection had a greater MST (25.0 months) than patients who underwent palliative resection (7.0 months) (P = 0.004). Patients who received chemotherapy had a greater MST (27.0 months) than patients who did not receive chemotherapy (13.0 months) (P = 0.021). Survival analysis confirmed that a radical operation, chemotherapy, and lymph node involvement were independent prognostic factors. This study suggests that radical resection combined with chemotherapy should be recommended for patients with limited‐stage SCCE, especially patients with negative regional lymph nodes. A lack of lymph node metastasis was a good prognostic factor because patients without lymph node involvement had greater OS.