The role of cetuximab in treatment‐related hematologic toxicity is not clear. We performed a meta‐analysis of published randomized controlled trials (RCTs) to determine the overall risk of ≥grade 3 hematologic toxicity events (HTEs) associated with cetuximab. PubMed, EMBASE, and Web of Knowledge databases as well as abstracts presented at American Society of Clinical Oncology conferences and ClinicalTrials.gov were searched to identify relevant studies. Eligible studies included RCTs in which cetuximab in combination with chemotherapy or chemoradiotherapy was compared with chemotherapy or chemoradiotherapy alone. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using fixed‐ or random‐effects models. A total of 11,234 patients with a variety of advanced solid tumors from 18 RCTs were included in the meta‐analysis. Compared with chemotherapy alone, the addition of cetuximab was associated with increased risks of ≥grade 3 leucopenia/neutropenia and anemia events in colorectal cancer, with RRs of 1.16 (95% CI 1.05–1.27, p = 0.002; incidence, 21.0 vs. 18.0%) and 2.67 (95% CI 1.53–4.65, p = 0.01; incidence, 4.0 vs. 2.0%), respectively. Cetuximab was also associated with an increased risk of leucopenia/neutropenia in nonsmall cell lung cancer (NSCLC) (RR: 1.15; 95% CI 1.08–1.22, p < 0.01). Additionally, K‐ras wild type in the case of colorectal cancer patients was more vulnerable to ≥grade 3 leucopenia or neutropenia events in cetuximab group (RR: 1.31; 95% CI 1.11–1.54, p = 0.001). With present evidence, cetuximab in conjunction with chemotherapy or chemoradiotherapy, compared with chemotherapy or chemoradiotherapy alone, was associated with increased slight risk of ≥grade 3 HTEs, especially in colorectal cancer and NSCLC.

The traditional Chinese medicinal formula BDL301 has been used to inhibit inflammation for hundreds of years. The development of colorectal cancer and chronic inflammation are closely related. In this study, we investigated whether BDL301 could inhibit tumor growth. We found that angiogenesis and tumor growth were both inhibited in vivo. In addition, apoptosis was induced and the signal transducer and activator of transcription-3 (STAT3) pathway were suppressed in the colorectal cancer cells in vitro and in vivo by BDL301. This study demonstrates that BDL301 exerted significant anticancer activity by inhibiting the STAT3 pathways and inducing apoptosis in colorectal cancer cells.

Abstract Background: The UGT1A1*28 polymorphism is known as a biomarker of irinotecan-induced neutropenia in Caucasians. However, in Asians, the UGT1A1*28 mutation is much less frequent. Methods: A meta-analysis was performed to assess the association of the UGT1A1*6 and UGT1A1*28 with neutropenia in Asians. Results: In a combination test of the two variations, patients with severe neutropenia displayed a 155% higher mutational load than those that were not neutropenic (ORG = 2.55; 95% CI: 1.82–3.58). Conclusions: In Asians, a combination test of UGT1A1*6 and UGT1A1*28 might be a potential biomarker of irinotecan-induced neutropenia, an observation that will need additional trials for confirmation.

Recent research indicates that the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway may play an important role in chronic inflammation which promotes cancer progression, yet the mechanism is not clear. The present study aimed to investigate the role of the JAK/STAT3 pathway in the growth and cancer-related inflammation (CRI) of esophageal squamous cell carcinoma (ESCC) by studying the crosstalk between the JAK/STAT3 pathway and nuclear factor-κB (NF-κB) and cyclooxygenase-2 (COX-2) which are important inflammatory factors associated with tumorigenesis. Cell growth and the cell cycle were assessed by CCK-8 assays and flow cytometry, respectively. The protein levels of STAT3, phosphorylated STAT3, VEGF, NF-κB p65, phosphorylated NF-κB p65 and COX-2 in ESCC cells following treatment with JAK2 inhibitor for 48 h or interleukin-6 (IL-6) for 24 h were detected. RT-PCR was performed to study the interaction among STAT3, NF-κB and COX-2 by transfection of siRNAs targeted at STAT3 and NF-κB. STAT3 was activated in 3 ESCC cell lines at different levels. Blocking the JAK/STAT3 pathway inhibited cancer growth through regulation of cell growth, cell cycle and angiogenesis. Likewise, abrogation of the JAK/STAT3 pathway decreased CRI by downregulating levels of NF-κB p65 phosphorylation, COX-2 and IL-6 concentration. In addition, CRI and cancer growth were accelerated by IL-6 through stimulation of the JAK/STAT3 and NF-κB p65 pathway. Moreover, STAT3 and NF-κB both regulated COX-2 as a downstream gene. The JAK/STAT3 pathway is an important pathway which links CRI and cancer growth through IL-6 and crosstalk with the NF-κB p65 subunit and COX-2. The STAT3 pathway could be a novel target both for cancer treatment and prevention in ESCC.

Several studies have reported that C-reactive protein (CRP), an inflammation biomarker, may be associated with the prognosis of prostate cancer (PCa). The objective of this systematic review is to summarize the predictive role of CRP for survival in PCa as reported in previous studies. Related studies were identified, and evaluated for quality through multiple search strategies. Data was collected from studies comparing overall and cancer-specific survival (CSS) in patients with elevated CRP levels and those having lower levels. However, for progression-free survival (PFS), data were collected according to the log of CRP. The hazard ratio (HR) and its 95% confidence interval (CI) were used to assess the strength of associations. A total of nine studies (n = 1,497) were evaluated in this meta-analysis (five for overall survival (OS), four for CSS and two for PFS). For OS and PFS, the pooled HR of CRP was statistically significant at 1.51 (95% CI, 1.28-1.79) and 1.50 (95% CI, 1.25-1.81), respectively. For CSS, the pooled HR was 1.91 (95% CI, 1.36-2.69) with higher CRP expression in PCa, which strongly indicates poorer survival in PCa. This study demonstrates that CRP may have a critical prognostic value in patients with prostatic cancer.

Background: The potential prognostic value of human equilibrative nucleoside transporter1 in pancreatic cancer receiving gemcitabine-based chemotherapy is variably reported.Objective: The objective of this study was to conduct a systematic review of literature evaluating human equilibrative nucleoside transporter1 expression as a prognostic factor in pancreatic cancer receiving gemcitabine-based chemotherapy and to conduct a subsequent meta-analysis to quantify the overall prognostic effect.Methods: Related studies were identified and evaluated for quality through multiple search strategies. Only studies analyzing pancreatic cancer receiving gemcitabine-based chemotherapy were eligible for inclusion. Data were collected from studies comparing overall, disease-free and progression-free survival (OS, DFS and PFS) in patients with low human equilibrative nucleoside transporter1 levels and those having high levels. The hazard ratio (HR) and its 95% confidence interval (95%CI) were used to assess the strength of associations. Hazard ratios greater than 1 reflect adverse survival associated with low human equilibrative nucleoside transporter1 levels.Results: A total of 12 studies (n = 875) were involved in this meta-analysis (12 for OS, 5 for DFS, 3 for PFS). For overall and disease-free survival, the pooled HRs of human equilibrative nucleoside transporter1 were significant at 2.93 (95% confidence interval [95% CI], 2.37-3.64) and 2.67 (95% CI, 1.87-3.81), respectively. For progression-free survival, the pooled HR in higher human equilibrative nucleoside transporter1 expression in pancreatic cancer receiving gemcitabine-based chemotherapy was 2.76 (95% CI, 1.76-4.34). No evidence of significant heterogeneity or publication bias was seen in any of these studies.Conclusion: These results support the case for a low human equilibrative nucleoside transporter1 level representing a significant and reproducible marker of adverse prognosis in pancreatic cancer receiving gemcitabine-based chemotherapy.

Dear Editor, We present here a rare case of primary malignant lymphoma of the glans penis that was detected in a 72-year-old man. Additionally, we have reviewed the literature for reports of primary malignant lymphoma of the penis. This is most likely the forty-ninth case of primary malignant lymphoma of the penis reported in the medical literature. Lymphomas typically originate from the lymph nodes and lymph tissues; however, the tonsils, spleen and bone marrow are also vulnerable sites. Due to the presence of lymph nodes and lymph tissue throughout the human body, primary malignant lymphomas of glans penis occur rarely. The diagnosis of this rare lymphoma may be difficult and delayed without specific symptoms, and treatment modalities are controversial because of the limited number of patients. A 72-year-old male patient was referred to our hospital due to a mass on the left side of the glans penis in May 2007. A physical examination identified two masses, one on the left tip and one on the right tip of his penis. The left lump measured approximately 8 mm in diameter, was hard in nature, and was cystic, reddish in colour and covered the surface of the glans penis with ill-defined margins. There was no visible ulceration and no tenderness on palpation. The cystic mass on the right side measured 15 mm; the lesion was firm in nature, did not protrude from the surface and had no palpable tenderness. The liver and spleen were not palpable, and no other sites of lymphadenopathy were observed; B symptoms were absent. Anti-inflammatory treatment was administered at another hospital, but it was unsuccessful. On 17 May 2007, the two masses were resected with penile preservation. The pathological examination showed the presence of a malignant lymphoma originating from B cells (diffuse large B), as shown in Figure 1. The patient was diagnosed with diffuse large B-cell lymphoma of the glans penis, stage IE, according to the Ann Arbor classification. No obvious distal metastasis was found by chest X-ray or abdominal ultrasonography before the surgery. Figure 1 Diffuse penile cellular infiltration with atypical lymphoid large-size cells with polymorphic nuclei. Scale bar=200 µm. Four cycles of systemic chemotherapy with a monthly CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen were administered from June 2007 to September 2007. A follow-up of the patient in September 2007, including a chest X-ray, abdominal CT and pelvic CT, showed no obvious abnormalities. Immunotherapy with interferon α-2b was then administered until November 2007. The patient was asymptomatic and in good general condition with no obvious distant metastasis. In November 2007, his lactate dehydrogenase (LDH) level was 1133 U l−1. On 12 December 2007, PET/CT revealed a treated glans penis carcinoma. Bone marrow 18F-fluorodeoxyglucose showed slightly increased metabolism, and after clinical correlation with the patient's history, it was diagnosed as post-chemotherapy reactive hyperplasia. Moreover, whole-body PET showed no abnormal metabolic increase in the 18F-fluorodeoxyglucose uptake focus. At a later date in December 2007, the patient started having night sweats and a dry cough with no apparent fever (B symptoms). His LDH level on 22 December 2007 was 1347 U l−1. From 7 January 2008 to 14 March 2008, four cycles of systemic chemotherapy with R-CHOP were administered. In March 2008, his LDH was 457 U l−1, and his health status had improved with decreased symptoms. In December 2008, the patient developed fever with an LDH level of 783 U l−1. The patient presented with transient obnubilation, left limb hypodynamia, mild headache, nausea and vomiting. Beginning 1 January 2009, prednisolone and rituximab were administered intravenously. The patient's fever and appetite improved, but he subsequently went into a comatose state. On 21 February 2009, Magnatic Resonance Imaging (MRI) showed many space-occupying lesions with different shapes and sizes in the bilateral hemispheres of the brain. On the right side, larger and more numerous lesions were observed with low signal intensity in T1-weighted imaging and diffusion-weighted imaging and high signal intensity in fluid-attenuated inversion recovery images with obvious oedema. The lesions were significantly strengthened after enhancement, although the area of oedema was not (Figure 2). On 22 February 2009, the patient died as a result of the ineffectiveness of the above treatment. Figure 2 The MRI shows many space occupying lesions with different shapes and sizes in bilateral hemispheres of the brain. On the right side, there are more and bigger ones which are low signal in T1WI, DWI and high signal in FLAIR with obvious edema. These lesions ... The first case of primary malignant lymphoma of the penis was reported in 1962.1 To the best of our knowledge, only 48 cases of primary malignant penile lymphoma have been reported in the medical literature (Supplementary Table 1). The mean reported patient age was 51.6 years (range: 4–91 years). Only two patients were younger than 18 years of age, and 11 patients were younger than 60 years of age. Of the 48 cases, pathological examinations were reported for only 38 cases. The pathological results showed that diffuse large B-cell lymphoma (DLBCL) was the most frequent subtype (14/38);2 the other reported types included 10 cases of T-cell lymphoma (TCL), one case of lymphoblastic lymphoma in 2001 and one case of primitive T cell-rich B-cell lymphoma of the glans penis reported in 2003.3 ALK+ anaplastic large cell lymphoma (ALCL) of the penis was first reported in 1997.4 Additionally, one patient with extranodal marginal B-cell lymphoma of the glans penis reported in 2004 had a good prognosis.5 Two cases with mixed small and large type lymphoma have been reported, and one primary reticulum cell sarcoma type was reported in 1962.1 Metastasis has been reported in the liver and lung, among other locations, but there have been few reports of brain metastases. The most common complaint was a mass or nodule in the penis (15/32). Three patients complained primarily of priapism, although one complained of erectile dysfunction. A mass or nodule on the penis and organ dysfunction should be closely monitored and evaluated. In total, 23 of 33 cases from the literature had a reported prognosis of 6 months to 4 years without recurrence and dissemination or complete remission. In our case, the disease-free survival was 21 months, and the overall survival was 25 months. Non-Hodgkin's lymphoma is more common than Hodgkin's lymphoma in these cases, and the exact subtype and stage are the main determinants of the outcome. Determining whether the prognosis for this particular carcinoma was in agreement with the current published National Comprehensive Cancer Network (NCCN) malignant lymphoma prognostic factors (e.g. age, lactate dehydrogenase level, tumour stage, Performance Status (PS) score and extranodal invasion) will require additional clinical data for verification. Currently, there is no standard treatment for malignant lymphoma of the penis; 15 of the 42 reported cases underwent surgery, and 3 of 15 were treated solely with surgery. Additionally, 33 of the 42 reported cases were treated with chemotherapy or immunotherapy, and 9 of the 41 underwent radiotherapy. In addition to radical surgery, many cases showed that penile preservation strategies were also effective treatments for the patients. Delicato et al.6 suggested that conservative therapy could be considered as the first-choice approach with a curative goal because of the aesthetic problems and erectile dysfunction caused by surgery. Combined-modality treatments were used in some cases. Rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone, was the most common choice of systemic chemotherapy. The absence of lymphoid tissue in the penis suggests that penile lymphoma is a manifestation of occult nodal disease or part of a systemic process, and this is the rationale for combined treatment modalities.7 However, patients sometimes undergo surgery that could have been avoided if the diagnosis had been considered.8 Similar relevant reports are rare, but in recent years, there have been a growing number of reports, which should make clinicians more aware of the poorly understood circumstances for the specific aetiology and pathogenesis of this disease and how to avoid misdiagnosis. Thus, early recognition of this disease and its clinical management will be maximised. Identifying a standard treatment for such patients still requires support from further clinical studies and more detailed information.

OBJECTIVE:To observe the changes in the expressions of STAT3 and NF-KB in PC-3 cells after IL-6 stimulation and to verify the effects of the NF-KB inhibitor caffeic acid phenethyl ester (CAPE) on the expressions of p-STAT3 and IL-6 in the PC-3 prostate cancer cell line.METHODS:PC-3 prostate cancer cells were treated with IL-6 at 20 ng/ml for 5, 10, 20, 30 and 45 min. The protein and mRNA expressions of STAT3 and NF-kappaB were measured by Western blot and real time PCR, respectively, and the cell cycle was detected by flow cytometry. The PC-3 cells were exposed to TNF-alpha or TNF-alpha + CAPE, followed by determination of the IL-6 expression in the supernatant of the cells by ELISA and the expression of p-STAT3 by Western blot.RESULTS:After IL-6 stimulation, both the expression of p-STAT3 protein and the proliferation index of the PC-3 cells were significantly increased, and so were the expressions of IL-6 and p-STAT3 protein in the supernatant after TNF-alpha treatment (P < 0.05). TNF-alpha + CAPE induced statistically lower expressions of IL-6 and p-STAT3 than TNF-alpha alone (P < 0.05).CONCLUSION:CAPE can inhibit IL-6 secretion induced by TNF-alpha in PC-3 cells and thus suppress STAT3 translocation. Therefore, by inhibiting the expression of NF-kappaB and affecting STAT3 and other related cell signaling pathways, CAPE may become a new therapeutic option for prostate cancer.

Objective To investigate the relationship between STAT3 activity and sensitivity to cisplatin in prostate cancer cell lines.Methods STAT3 activity was examined by immunocytochemistry and Western blotting analysis in three prostate cancer cell lines: LNCaP,PC3 and DU145.Androgen-independent cell lines PC3 and DU145 were selected to examine the inhibitory effect of various concentrations of cisplatin(2 ng/ml,20 ng/ml,200 ng/ml,2 μg/ml and 20 μg/ml).STAT3 activity of DU145 cell line was re-examined by Western blotting analysis after treatment with low concentration of cisplatin.Results The STAT3 activity of androgen-independent cell lines PC3 and DU145 was higher than that of androgen-dependent cell line LNCaP.The sensitivity of DU145 cells to cisplatin was lower than that of PC3 cells with lower STAT3 activity.Treatment with low concentration of cisplatin for a long period caused STAT3 activation in DU145.Conclusion Our results suggest that STAT3 may play a role in regulating the sensitivity of prostate cancer cells to cisplatin.

Objective To observe the immunomodulatory effects of thymosin combined with antineoplastic traditional Chinese medicine(injection containing Radix Sophora Flavescentis, Cinobufacini) in cancer patients.Methods Fifty-four cancer patients accepted thymosin 80-120 mg/d intravenously for 5 consecutive days per month in combination with antineoplastic traditional Chinese medicine.Total T cells,T cells/induce cells,CD4/CD8,B cells,NK cells,immunoglobulins IgG, IgA,IgM and complements CHso,C3,C4 were measured before and after treatment.Results The levels of peripheral blood lymphocyte(total T cells,T cells/induce cells,CD4/CD8,B cells and NK cells),immunoglobulins IgG,IgA and complements C3,C4 were significantly higher after treatment than those before treatment(P 0.05) except for CHso and IgM.Conclusion The immunological function of cancer patients is maintained and enhanced by thymosin treatment in combination with antineoplastic traditional Chinese medicine.

[Purpose] To compare the hematological toxicity of gemcitabine between fix dose rate(FDR) infusion and 30-minute infusion in the treatment for malignancy.[Methods] Twenty-five cases with malignancy histopathologically or cytologically proven.All patients received chemotherapy with gemcitabine alone or combined with other chemotherapy agents.Patients were randomly divided into FDR infusion [10mg/(m2·min)](FDR group) or over 30 minutes infusion(standard group).The cycle was repeated every 21 days.Hematologic toxicity was evaluated at the end of each cycle.[Results] A total of 28 cycles was completed in 13 patients with FDR group,and 32 cycles in 12 patients with standard group.All patients were evaluable for hematological toxicity.There was significantly different of leucopenia grade Ⅲ/Ⅳ between the 2 groups(14.3% vs 0,P0.05),and no significant difference of neutropenia,thrombocytopenia and hemoglobin suppression grade Ⅲ/Ⅳ between the 2 groups(P0.05).[Conclusion] Hematologic toxicity of gemcitabine at a fix dose rate for malignancy is tolerable.