Tailoring heated intraperitoneal mitomycin C for peritoneal metastases originating from colorectal carcinoma: a translational approach to improve survival

Background:

Patients with peritoneal metastases (PMs) originating from colorectal carcinoma (CRC) are curatively treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC). We aim to improve patient selection for HIPEC by predicting MMC sensitivity.

Methods:

The MMC sensitivity was determined for 12 CRC cell lines and correlated to mRNA expression of 37 genes related to the Fanconi anaemia (FA)–BRCA pathway, ATM–ATR pathway and enzymatic activation of MMC. Functionality of the FA–BRCA pathway in cell lines was assessed using a chromosomal breakage assay and western blot for key protein FANCD2. Bloom syndrome protein (BLM) was further analysed by staining for the corresponding protein with immunohistochemistry (IHC) on both CRC cell lines (n=12) and patient material (n=20).

Results:

High sensitivity correlated with a low BLM (P=0.01) and BRCA2 (P=0.02) at mRNA expression level. However, FA–BRCA pathway functionality demonstrated no correlation to MMC sensitivity. In cell lines, weak intensity staining of BLM by IHC correlated to high sensitivity (P=0.04) to MMC. Low BLM protein expression was significantly associated with an improved survival in patients after CRS and HIPEC (P=0.04).

Conclusions:

Low BLM levels are associated with high MMC sensitivity and an improved survival after HIPEC.     

Bone‐induced c‐kit expression in prostate cancer: A driver of intraosseous tumor growth

Loss of BRCA2 function stimulates prostate cancer (PCa) cell invasion and is associated with more aggressive and metastatic tumors in PCa patients. Concurrently, the receptor tyrosine kinase c‐kit is highly expressed in skeletal metastases of PCa patients and induced in PCa cells placed into the bone microenvironment in experimental models. However, the precise requirement of c‐kit for intraosseous growth of PCa and its relation to BRCA2 expression remain unexplored. Here, we show that c‐kit expression promotes migration and invasion of PCa cells. Alongside, we found that c‐kit expression in PCa cells parallels BRCA2 downregulation. Gene rescue experiments with human BRCA2 transgene in c‐kit‐transfected PCa cells resulted in reduction of c‐kit protein expression and migration and invasion, suggesting a functional significance of BRCA2 downregulation by c‐kit. The inverse association between c‐kit and BRCA2 gene expressions in PCa cells was confirmed using laser capture microdissection in experimental intraosseous tumors and bone metastases of PCa patients. Inhibition of bone‐induced c‐kit expression in PCa cells transduced with lentiviral short hairpin RNA reduced intraosseous tumor incidence and growth. Overall, our results provide evidence of a novel pathway that links bone‐induced c‐kit expression in PCa cells to BRCA2 downregulation and supports bone metastasis.     

脑转移瘤合理治疗模式的Meta分析

目的 应用Meta分析的方法探讨脑转移瘤的合理治疗模式.方法 以中英文关键词检索中外数据库,检索时限为自各数据库建立起至2012年12月30日.以Jadad评分评价文献质量,采用RevMan5.0软件完成统计分析.共纳入25篇文献,2 750例患者,依据不同的治疗方法进行分组.结果 与单一治疗相比,综合治疗能提高患者的1年生存率(OR =0.58,95％ CI为0.46 ～0.71,P＜0.000 01);在综合治疗组中,与2种联合治疗方式相比,3种联合治疗方式能提高患者的1年生存率(OR=0.63,95％ CI为0.50～0.80,P=0.000 1);与局部治疗相比,全身+局部治疗能提高患者的1年生存率(OR=0.68,95％ CI为0.53 ～0.86,P=0.001);与全身治疗相比,全身+局部治疗能提高患者的1年生存率(OR =0.59,95％ CI为0.41 ～0.86,P=0.006);在全身+局部治疗中,与2种联合治疗方式相比,3种联合治疗方式能提高患者的1年生存率(OR=0.52,95％ CI为0.35 ～0.78,P=0.002);与非靶向治疗相比,分子靶向药物治疗能提高患者的1年生存率(OR=0.76,95％ CI为0.67 ～0.87,P＜0.000 1).结论 脑转移瘤的合理治疗模式为手术、放疗、化疗3种治疗方式结合,即全身+局部治疗,如果具有应用分子靶向药物的指征,在原方案基础上联合分子靶向药物效果更佳.     

胃癌骨转移97例临床病理分析

目的 探讨胃癌骨转移患者的临床特征及预后.方法 回顾性分析江西省肿瘤医院2008-01-01-2012-12-31收治的97例胃癌骨转移患者的临床资料.结果 97例患者,占同期收治胃癌病例的2.7％(97/3 612),其中30例(30.9％)为同时性骨转移,67例(69.1％)为异时性骨转移.单发骨转移者20例(20.6％),多发骨转移77例(79.4％).骨转移最常见的部位为脊柱(77.3％)、骨盆(41.2％)和肋骨(35.1％).97例患者中,16例(16.5％)患者以骨转移为唯一远处转移灶,81例(83.5％)合并其他部位转移.76例(78.3％)患者接受了化疗,姑息放疗者17例(17.5％),81例(83.5％)患者进行了双膦酸盐的治疗.发生骨转移后患者中位生存时间为6.3个月(95％CI:4.94～7.66),1年生存率为23.7％;化疗组与未接受化疗组患者中位生存时间分别为7.2和4.5个月,x2=11.504,P=0.001.单因素分析显示,ECOG评分、同时性骨转移、单发骨转移、合并其他部位转移以及化疗与胃癌骨转移患者的预后有关,P值均＜0.05.多因素分析显示,合并其他部位转移、ECOG评分和化疗是影响患者预后的独立因素,P值均＜0.05.结论 胃癌骨转移患者的预后较差,尤其是合并其他部位转移和评分较差患者,化疗可能给部分患者带来生存获益.     

Traitement systémique des métastases cérébrales de mélanome

Melanomas have a high rate of brain metastases. Both the functional prognosis and the overall survival are poor in these patients. Until now, surgery and radiotherapy represented the two main modalities of treatment. Nevertheless, due to the improvement in the management of the extracerebral melanoma, the systemic treatment may be an option in patients with brain metastases. Immunotherapy with anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) – ipilimumab – or BRAF (serine/threonine-protein kinase B-raf) inhibitors – vemurafenib, dabrafenib – has shown efficacy in the management of brain metastases in a- or pauci-symptomatic patients. Studies are ongoing with anti-PD1 (programmed cell death 1) and combinations of targeted therapies associating anti-RAF (raf proto-oncogene, serine/threonine kinase) and anti-MEK (mitogen-activated protein kinase kinase).     

CpG oligodeoxynucleotides potentiate the antitumor activity of anti‐BST2 antibody

Numerous monoclonal antibodies (mAb) targeting tumor antigens have recently been developed. Antibody‐dependent cellular cytotoxicity (ADCC) and antibody‐dependent cellular phagocytosis (ADCP) via effector cells such as tumor‐infiltrating natural killer (NK) cells and macrophages are often involved in mediating the antitumor activity of mAb. CpG oligodeoxynucleotides (ODN) have a potent antitumor activity and are considered to increase tumor infiltration of NK cells and macrophages. Our group previously reported significant antitumor activity of anti‐bone marrow stromal antigen 2 (BST2) mAb against BST2‐positive endometrial cancer cells through ADCC. In this study, we evaluated the synergistic antitumor activity of combination therapy with anti‐BST‐2 mAb and CpG ODN using SCID mice and elucidated the mechanisms underlying this activity. Anti‐BST2 mAb and CpG ODN monotherapy had a significant dose‐dependent antitumor activity (P = 0.0135 and P = 0.0196, respectively). Combination therapy with anti‐BST2 mAb and CpG ODN had a significant antitumor activity in SCID mice (P < 0.01), but not in NOG mice. FACS analysis revealed significantly increased numbers of NK cells and macrophages in tumors treated with a combination of anti‐BST2 mAb and CpG ODN and with CpG ODN alone in SCID mice (P < 0.05 and P < 0.01, respectively). These results suggested that the combination therapy with anti‐BST2 mAb and CpG ODN has a significant antitumor activity and induces tumor infiltration of NK cells and macrophages. Combination therapy with CpG ODN and anti‐BST2 mAb or other antitumor mAb depending on ADCC may represent a new treatment option for cancer.