Kai Xue

Predictive and prognostic value of KRAS mutations in metastatic colorectal cancer patients treated with cetuximab: A meta-analysis of 22 studies

The published data on the predictive and prognostic value of KRAS mutations in metastatic colorectal cancer (mCRC) treated with cetuximab seemed inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Systematic computerised searches of the PubMed, EMBase, BIOSIS, and SCOPUS were performed. A total of 22 studies were identified. Random-effects model or fix-effects model was used according to between-study heterogeneity. A total of 2188 mCRC patients were included in the final meta-analysis. The rate of KRAS mutations was 38% (829/2188). The overall response rate (ORR) of mutant KRAS patients was 14% (119/829), whereas the ORR of wild-type KRAS patients was 39% (529/1359). The overall pooled relative ratio (RR) for ORR was 0.24 (95% confidence intervals (CI): 0.16-0.38; P<0.01) when mutant KRAS patients were compared with wild-type KRAS patients. Median PFS was significantly shorter in mutant KRAS patients compared with that in wild-type KRAS patients (3.0 versus 5.8 months; HR=1.94; 95% CI: 1.62-2.33; P<0.01). Similarly, median OS was significantly shorter in mutant KRAS patients compared with that in wild-type KRAS patients (6.9 versus 13.5 months; HR=2.17; 95% CI: 1.72-2.74; P<0.01). The meta-analysis strongly suggests that KRAS mutations represent adverse predictive and prognostic biomarkers for tumour response and survival in mCRC patients treated with cetuximab. Patients with tumours that harbour mutant-type KRAS are more likely to have a worse response, PFS, and OS when treated with cetuximab.

Up-regulation of hexokinase II contributes to rituximab-chemotherapy resistance and is a clinically relevant target for therapeutic development

In order to identify cellular pathways associated with therapy-resistant aggressive lymphoma, we generated rituximab-resistant cell lines (RRCL) and found that the acquirement of rituximab resistance was associated with a deregulation in glucose metabolism and an increase in the apoptotic threshold leading to chemotherapy resistance. Hexokinase II (HKII), the predominant isoform overexpressed in cancer cells, has dual functions of promoting glycolysis as well as inhibiting mitochondrial-mediated apoptosis. We found that RRCL demonstrated higher HKII levels. Targeting HKII resulted in decreased mitochondrial membrane potential, ATP production, cell viability; and re-sensitization to chemotherapy agents. Analyzed gene expression profiling data from diffuse large B-cell lymphoma patients, high-HKII levels were associated with a shorter progression free survival (PFS) and/or overall survival (OS). Our data suggest that over-expression of HKII is associated with resistance to rituximab and chemotherapy agents in aggressive lymphoma and identifies this enzyme isoform as a potential therapeutic target.

Recombinant human endostatin in combination with CHOP regimen for peripheral T cell lymphoma.

Peripheral T cell lymphoma (PTCL) has a poor prognosis. Overexpression of vascular endothelial growth factor (VEGF) might contribute to the poor prognosis of PTCL and could be the target of novel therapy. The efficacy and safety of recombinant human endostatin (Endostar) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (ECHOP) have been explored in 15 PTCL patients. The objective response rate was 80%, with 53.3% patients having achieved complete response (CR) rate. The CR rate was 100% (3/3) in angioimmunoblastic T cell lymphoma (AITL) patients compared to only 36.4% (4/11) in PTCL not otherwise specified (PTCL-NOS) patients. With a median follow-up of 69 months, the 5-year progression-free survival and overall survival (OS) were 53% and 60%, respectively. The 5-year OS was 100% in AITL but was only 45% in PTCL-NOS. Seven out of 11 patients showed overexpression of VEGFR2 in their tumor vessels and had a better efficacy than those with low expression of VEGFR2. Grade 3 or 4 neutropenia is the most common toxicity observed. ECHOP was safe and might display potential benefit in AITL patients.

Cardiotoxicity as indicated by LVEF and troponin T sensitivity following two anthracycline-based regimens in lymphoma: Results from a randomized prospective clinical trial

Anthracycline-induced cardiotoxicity influences treatment selection and may negatively affect clinical outcomes in lymphoma patients. While epirubicin induced cardiotoxicity less often than the same dose of doxorubicin in breast cancer, higher doses of epirubicin are required in lymphoma regimens for equivalent efficacy. Whether a higher dosage of epirubicin also induces cardiotoxicity less often than doxorubicin in lymphoma remains unknown. We therefore administered 6-8 cycles of cyclophosphamide, vincristine and prednisone (CEpOP) +/− rituximab (R) with either epirubicin (CEpOP) or doxorubicin (CHOP) to patients (N=398) with untreated diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma grade 3 (FLG3). Left ventricular ejection fraction (LVEF) and high-sensitivity serum cardiac troponin T (HsTnT) were assessed at baseline and after 4 cycles of treatment. Epirubicin (70 mg/m2/dose) was equivalent to doxorubicin (50 mg/m2/dose) in terms of 3-year progression-free survival. The risk of decreased LVEF was similar between the two regimens. CEpOP+/−R induced HsTnT elevation less often than CHOP+/−R. We conclude that CEpOP+/−R is a more acceptable regimen with short-term efficacy similar to CHOP+/−R in lymphoma patients. Longer follow-up is needed to monitor the risk of cardiac dysfunction and determine whether differences in the induction of elevated HsTnT between epirubicin and doxorubicin justify changes in clinical practice.

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 waldeyers 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 Waldeyers 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]).

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

Abstract 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.

Sweyjawbu expression is a predictor of ALK rearrangement status in lymphoma

In recent years molecular subtyping has become an important tool for accurate diagnosis of many cancers; for example, the detection of ALK rearrangements in lymphoma and lung cancer helps clinicians provide more precise diagnosis and treatment. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are two routine approaches used to detect ALK rearrangements. However, difficulties with acquisition of biopsy samples, high costs, and long waiting time for results negatively impact the application of these methods. A rapid and inexpensive alternative would be a useful complement to current ALK rearrangement detection. We identified a novel gene, sweyjawbu, from Affymetrix microarray studies. Its expression correlated strongly with ALK in an analysis of 1037 cancer cell lines (correlation coefficient = 0.92). By comparing sweyjawbu transcript levels, it was possible to discriminate 12 ALK rearrangement-positive lymphoma samples from 64 ALK rearrangement-negative lymphomas. Moreover, combining measurements of sweyjawbu expression and the ratio of the 5’ and 3’ portions of the ALK transcript provided even more accurate identification of ALK rearrangement-positive lymphomas. This novel approach is an excellent complement or alternative to existing FISH and IHC methodologies.

Response-adapted therapy for limited stage diffuse large B-cell lymphoma based on interim PET-CT: preliminary results of a phase 2 study

Abstract Background Limited stage diffuse large B-cell lymphoma is curable with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) immunochemotherapy. For patients achieving complete response by interim 18F-fluorodeoxyglucose PET-CT, a previous study showed therapy could be safely de-escalated by omitting the subsequent chemotherapy or radiotherapy. We aimed to adapt the therapy on the basis of the response as assessed by the interim PET-CT. Methods We did this phase 2 study in patients with low risk (International Prognostic Index 0–2), limited stage diffuse large B-cell lymphoma. Patients were initially treated with four cycles of R-CHOP. PET-CT scans were done at baseline and after four cycles. Patients with negative PET (Deauville scores 1–2) received two cycles of rituximab monotherapy, unless they had any risk factors (primary mediastinal large B-cell lymphoma, primary extranodal non-Hodgkin lymphoma, and bulky disease). Patients with these risk factors received another two cycles of R-CHOP as routine practice. Patients with partial response received another four cycles of R-CHOP and a repeated PET-CT scan at the end of treatment. Patients with stable and progressive disease were managed by salvage chemotherapy. The primary endpoint was progression-free survival at 3 years. The trial is registered with ClinicalTrials, number NCT0180412 . Findings From December, 2012, to September, 2015, a total of 143 patients were enrolled and we analysed the 129 patients with baseline and interim PET-CT scans for efficacy. By local assessment, 114 PET-CT scans (88%) were reported as negative and 15 (12%) as positive. With a median follow-up time of 28·2 months (range 15·0–47·4), the estimated 3-year progression-free survival was 91%. Patients with negative interim PET-CT scans had a 3-year progression-free survival of 93% compared with 79% for patients with positive results (p=0·062). The estimated 3-year progression-free survival did not differ between patients with nodal and extranodal primaries (92% vs 91%, p=0·978). Interpretation For patients with limited stage diffuse large B-cell lymphoma, the results of interim PET-CT might predict progression-free survival and adapt the subsequent treatment. For complete response patients without risk factors, the extra two cycles of CHOP might be safely omitted without compromising the efficacy, which needs to be confirmed in a randomised study. Funding None.

A retrospective analysis of outcomes for primary mediastinal large B-cell lymphoma treated with RCHOP followed by radiotherapy or front-line autologous stem cell transplantation

ABSTRACT Objectives: Our aim was to retrospectively investigate the data from our institute the response rate and outcome in patients with primary mediastinal B-cell lymphoma (PMBL) who received the rituximab in combination with CHOP (RCHOP) followed by autologous stem cell transplantation (ASCT) or RCHOP followed by involved field radiation therapy (IFRT). Methods: Sixty five patients with PMBL received RCHOP as first-line chemotherapy between January 2005 and December 2010. Forty of the 65 patients completed the planned subsequent IFRT after initial chemotherapy. Thirteen of the 65 patients received the front-line ASCT after RCHOP. Twelve patients received RCHOP alone. Results: Thirty two of the 40 patients who received the RCHOP followed by IFRT have complete remission (CR) or CRu (CR/unconfirmed). All patients have CR or CRu after the ASCT. The progression free survival (PFS) and the estimated overall survival (OS) rate at 5 years for 32 CR/CRu patients in the RCHOP followed by IFRT group were 57 and 65%, respectively, as compared to RCHOP/ASCT group who were 94 and 100%, respectively. Twelve patients who received RCHOP alone had the same PFS and OS rate as the 40 patients who received RCHOP/IFRT (5-year PFS:62 vs. 65%, p = 0.068; 5-year OS:57 vs. 67%, p = 0.058). For all 65 patients, the age-adjusted international prognostic index (aaIPI) score remained the only predictor of a worse outcome. Conclusion: The PFS and OS rate of RCHOP/IFRT were found to be unsatisfied. RCHOP/ASCT showed a satisfactory PFS and OS rate.