Combined radiofrequency ablation and doxorubicin-eluting polymer implants for liver cancer treatment

Previously, biodegradable polymer implants (polymer millirods) to release chemotherapeutic agents directly into tumors have been developed. The purpose of this study is to evaluate local drug distribution from these implants in liver tumors treated with radiofrequency (RF) ablation and determine if the implants provide a therapeutic improvement over RF ablation alone. Cylindrical implants were fabricated using 65% poly(D,L-lactide-co-glycolide) (PLGA), 21.5% NaCl, and 13.5% doxorubicin. Control or drug-containing millirods were implanted inside VX2 liver tumors (11 mm diameter) in rabbits after RF ablation. Therapeutic efficacy was assessed 4 and 8 days after treatment using tumor size, histology, and fluorescence measurement of drug distribution. Tumors in both test groups recurred at the boundary of the ablated region. Therapeutic doxorubicin concentrations were found in more than 80% of the ablated area, but concentrations declined rapidly at the boundary between normal and ablated tissue. This region was characterized by a developing fibrous capsule with resolving inflammation, which restricted drug transport out of the ablated zone. The intratumoral doxorubicin implants delivered high concentrations of drug within the ablated region but only limited amounts outside the ablation zone. Future studies will focus on overcoming the fibrotic transport barrier and enhancing drug delivery to the periphery of the ablation region to prevent tumor progression.     

Combination chemotherapy with 5-fluorouracil and heptaplatin as first-line treatment in patients with advanced gastric cancer

Heptaplatin is a recently developed platinum derivative. This agent has been reported to have a response rate of 17% as a single agent, and tolerable toxicity in the treatment of advanced gastric cancer. The aim of this study was to evaluate the efficacy and toxicity of a combination of 5-fluorouracil (5-FU) and heptaplatin in patients with advanced gastric cancer. Forty-seven chemotherapy-naive patients with advanced or recurred gastric cancer were recruited. 5-FU was administered over 120 hr by continuous intravenous infusion from day 1 to 5, at a daily dose of 1,000 mg/m2 and heptaplatin was administered over 1 hr by intravenous infusion on day 1 at 400 mg/m2, and this cycle was repeated every 4 weeks. The response rate was 21%, median progression-free survival was 1.9 months (95% CI, 1.6 to 2.2 months). Median overall survival was 6.2 months (95% CI, 4 to 8.4 months) and the 1-yr survival rate was 29% for all patients. The most frequent toxicity was proteinuria. Toxicities were generally mild and reversible. This study demonstrates that the combination of 5-FU/heptaplatin combination is less active but tolerated in patients with advance gastric cancer.     

Hepatic arterial infusion chemotherapy prior to standard systemic chemotherapy in patients with highly advanced unresectable liver metastases from colorectal cancer: a report of three patients

We administered hepatic arterial infusion chemotherapy (HAIC) prior to FOLFOX to three patients with unresectable liver metastases from colorectal cancer. The patients' disease state was found to be highly advanced based on both computed tomography findings and liver function tests. The treatment strategy included an initial administration of HAIC to control liver metastases and improve liver function in order to facilitate the subsequent safe administration of FOLFOX without drug loss. As the HAIC regimen, 1,000 mg/m2 of 5-FU was administered weekly by continuous 5-h infusion after performing laboratory investigations through an implanted port-catheter system. After 3 HAIC cycles administered over 3 consecutive weeks, the mean alkaline phosphatase levels decreased from 969.3IU/l to 422IU/l due to shrinkage of the liver metastases. Thereafter, FOLFOX without drug loss could be safely initiated for all patients. Two patients succumbed 488 and 333 days after HAIC was initiated;the third patient is still alive and has been followed-up for 1215 days. The combined use of HAIC and standard systemic chemotherapy could be a feasible and efficacious treatment in highly advanced cases of liver dysfunction.     

Liver-directed chemotherapy of cetuximab and bevacizumab in combination with oxaliplatin is more effective to inhibit tumor growth of CC531 colorectal rat liver metastases than systemic chemotherapy

Colorectal carcinoma is, through to its high rate of liver metastasis (mCRC), the second most cause of cancer death worldwide. Tumor resection represents the only potential cure. In cases of unresectable disease systemic chemotherapy (sCHT) remains the therapy of choice. Modern sCHT regimens including biological agents can induce tumor response that leads to curative surgery of initially unresectable mCRC. However, liver-directed therapy via hepatic arterial infusion (HAI) may produce higher response rates than sCHT. Herein we studied whether a HAI of cetuximab (CE) plus bevacizumab (BE) with or without oxaliplatin (OX) can inhibit tumor growth in a rat model. WAG/Rij rats underwent subcapsular hepatic tumor implantation. After 10 days animals received either HAI or sCHT of CE plus BE, OX or all three drugs. Saline-treated animals served as controls. Tumor growth was estimated at day 10 and 13. On day 13 liver and tumor tissue was studied histologically and immunohistochemically. In controls the tumors grew about 50 %. OX alone was not capable of inhibiting tumor growth. In contrast, CE plus BE given as HAI significantly reduced tumor growth compared to sCHT (p < 0.05). HAI of CE plus BE combined with OX yielded an even more pronounced inhibition of tumor growth. Immunohistochemistry revealed a decreased tumor cell proliferation and tumor vascularization. The present study demonstrates that HAI of CE plus BE is effective to inhibit tumor growth. This effect is even more pronounced in combination with OX. Systemic application of these agents cannot achieve comparable effects.     

特殊或高危部位原发性小肝癌超声引导下腹腔镜射频消融术治疗效果及术后免疫状况分析

目的 探讨超声引导下腹腔镜射频消融术(LRFA)治疗特殊或高危部位原发性小肝癌患者术后的免疫状况及临床疗效。方法 回顾性分析2012年1月—2017年12月鄂东医疗集团市中心医院肝胆胰腺外科60例特殊或高危部位原发性小肝癌患者的临床资料,其中行超声引导下LRFA 32例(LRFA组),行腹腔镜肝切除术(LH)治疗28例(LH组)。LRFA组男25例、女7例,年龄38~84(61.13±12.30)岁;LH组男23例、女5例,年龄35~80(60.07±12.90)岁。比较两组患者术后根治率、免疫状况、术后并发症及无瘤生存率。结果 两组患者均成功实施手术,无围手术期死亡病例。LRFA组和LH组的手术根治率分别为96.9%(31/32)和100.0%(28/28),差异无统计学意义(P＞0.05)。两组患者术后均随访3~72(46.8±18.5)个月。与LH组相比,LRFA组术后4周、8周CD3⁺、CD4⁺、CD8⁺、CD4⁺/CD8⁺均较高,差异均有统计学意义(P值均＜0.05);LRFA组术后8周外周血CD3⁺、CD4⁺、CD8⁺、CD4⁺/CD8⁺与术前比较显著升高,Treg显著降低,差异均有统计学意义(P值均＜0.05)。两组患者术后并发症发生率差异无统计学意义(P＞0.05)。LRFA组无瘤生存时间明显长于LH组,两组患者术后1、2、3年无瘤生存率分别为93.7%、81.3%、56.3%和82.1%、71.5%、42.9%,差异均有统计学意义(P值均＜0.05)。结论 LRFA可精确定位、动态观察消融过程,拓宽了射频消融的适用范围,增强机体免疫功能,延长患者无瘤生存期。LRFA已成为特殊或高危部位原发性小肝癌微创治疗的主要手段。     

Recent progress towards development of effective systemic chemotherapy for the treatment of malignant brain tumors

Systemic chemotherapy has been relatively ineffective in the treatment of malignant brain tumors even though systemic chemotherapy drugs are small molecules that can readily extravasate across the porous blood-brain tumor barrier of malignant brain tumor microvasculature. Small molecule systemic chemotherapy drugs maintain peak blood concentrations for only minutes, and therefore, do not accumulate to therapeutic concentrations within individual brain tumor cells. The physiologic upper limit of pore size in the blood-brain tumor barrier of malignant brain tumor microvasculature is approximately 12 nanometers. Spherical nanoparticles ranging between 7 nm and 10 nm in diameter maintain peak blood concentrations for several hours and are sufficiently smaller than the 12 nm physiologic upper limit of pore size in the blood-brain tumor barrier to accumulate to therapeutic concentrations within individual brain tumor cells. Therefore, nanoparticles bearing chemotherapy that are within the 7 to 10 nm size range can be used to deliver therapeutic concentrations of small molecule chemotherapy drugs across the blood-brain tumor barrier into individual brain tumor cells. The initial therapeutic efficacy of the Gd-G5-doxorubicin dendrimer, an imageable nanoparticle bearing chemotherapy within the 7 to 10 nm size range, has been demonstrated in the orthotopic RG-2 rodent malignant glioma model. Herein I discuss this novel strategy to improve the effectiveness of systemic chemotherapy for the treatment of malignant brain tumors and the therapeutic implications thereof.     

Comparison of percutaneous microwave ablation and laparoscopic resection in the prognosis of liver cancer

The effect of percutaneous microwave ablation and laparoscopic resection on the prognosis of liver cancer was investigated. Ninety patients with liver cancer treated at our hospital from March 2010 to March 2012 were divided into group A and group B (n=45) by using a random number table, and the surgical conditions and the prognosis were compared. The surgical conditions of patients in group A were significantly better than those in group B (P<0.05). The incidence of complications in group A was 6.67%, which was obviously lower than that of group B (P<0.05). The local recurrence rate of group A was 20.00%, and that of group B was 8.89%, which showed a significant difference (P<0.05). The two groups did not differ significantly in terms of either total recurrence rate (P>0.05) or 1-year, 2-year and 3-year survival (P>0.05). Both percutaneous microwave ablation and laparoscopic resection had a good long-term efficacy in liver cancer. However, percutaneous microwave ablation was superior as it caused less invasiveness, reduced the incidence of complications and improved prognosis of liver cancer.     

The distribution of liver metastases from colonic cancer

Summary 54 livers of patients with colonic cancer were investigated in a postmortem study. 26 livers contained metastases from colon carcinoma. Assessment of the number, size and location of metastases was made. The possible interdependence of the site of the colonic primary and the location of its secondaries in the liver was examined. Results suggest an approximately homogenous distribution of metastases from colonic cancer in the hepatic parenchyma, irrespective of the location of the primary tumour.     

The tumour biology of synchronous and metachronous colorectal liver metastases: a systematic review

Forty to fifty percent of colorectal cancer (CRC) patients develop colorectal liver metastases (CLM) that are either synchronous or metachronous in presentation. Clarifying whether there is a biological difference between the two groups of liver metastases or their primaries could have important clinical implications. A systematic review was performed using the following resources: MEDLINE from PubMed (1950 to present), Embase, Cochrane and the Web of Knowledge. Thirty-one articles met the inclusion criteria. The review demonstrated that the majority of studies found differences in molecular marker expression between colorectal liver metastases and their respective primaries in both the synchronous and metachronous groups. Studies investigating genetic aberrations demonstrated that the majority of changes in the primary tumour were ‘maintained’ in the colorectal liver metastases. A limited number of studies compared the primary tumours of the synchronous and metachronous groups and generally demonstrated no differences in marker expression. Although there were conflicting results, the colorectal liver metastases in the synchronous and metachronous groups demonstrated some differences in keeping with a more aggressive tumour subtype in the synchronous group. This review suggests that biological differences may exist between the liver metastases of the synchronous and metachronous groups. Whether there are biological differences between the primaries of the synchronous and metachronous groups remains undetermined due to the limited number of studies available. Future research is required to determine whether differences exist between the two groups and should include comparisons of the primary tumours.     

微创治疗中脊柱转移瘤椎体成形骨水泥注入及射频消融和放射疗法

背景：微创技术的发展明显降低了脊柱转移瘤手术并发症,目前微创治疗方法主要有椎体骨水泥增强、射频消融联合椎体成形、术中放疗联合椎体成形3大类。 目的：总结上述3大类微创治疗脊柱转移瘤的研究进展。 方法：以“脊柱转移瘤,椎体成形,射频消融,放射治疗;spinal metastases,vertebroplasty,radiofrequency ablation,radiotheray”为关键词,检索PubMed、万方数据库文献。 结果与结论：骨水泥增强技术应用广泛、止痛效果很好,有效率达80%-90%,但骨水泥产热杀灭肿瘤的效果非常有限,不能控制肿瘤生长;射频消融及放疗能够杀灭肿瘤,但不能重建稳定性,将不同技术结合可以提高脊柱肿瘤的治疗效果。术中应用放射线、植入放射性粒子或放射性骨水泥是近年发展起来的新技术,因报道较少,缺乏长期随访,目前还不能得出优于单纯骨水泥增强技术的结论。尤其是针对椎体后壁破坏及部分侵入椎管的转移瘤患者,虽然做了很多尝试,但骨水泥渗漏导致神经功能加重的风险依旧很高,所以目前还没有一种完善的微创治疗方法。中国组织工程研究杂志出版内容重点：生物材料;骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性;组织工程全文链接：     

CT导向下经皮无水乙醇消融在复杂性肾癌治疗中的临床应用

目的 探讨CT导向下经皮无水乙醇消融(PEA)在复杂性癌治疗中的临床价值.方法 对7例复杂性肾癌患者,其中孤立肾肾癌2例,单侧肾肾癌5例,病灶数11个,肿瘤直径1.7～8.4 cm,在CT引导、局麻下进行经皮穿刺无水乙醇消融治疗,常规行螺旋CT平扫和增强扫描进行随访评价疗效.结果 患者平均每人2次PEA治疗,随访12～26个月,中位时间15个月.1例孤立肾肾癌患者经2次PEA治疗后,已随访1年9个月未见复发;1例孤立肾多发肾癌患者4次PEA治疗后肾衰死亡;2例肾癌伴腰痛血尿症状经PEA治疗后病灶消融完全,血尿症状缓解;其他3例肾癌患者分别随访1年6个月、2年2个月和1年,1例死于远处转移,其他2例CT复查未见肿瘤进展.全部患者无1例出现尿瘘、出血、肠穿孔或针道转移等并发症.结论 CT导向下无水乙醇消融治疗对复杂性肾癌是一种微创、疗效确切、可供选择的局部治疗方法 ,但对于孤立肾肾癌,PEA治疗须谨慎.     

p53 and HLA class-I expression are not down-regulated in colorectal cancer liver metastases

p53 overexpression occurs in more than 50% of colorectal carcinomas, which makes it an interesting target for immunotherapy. HLA class I expression on tumor cells is required for the presentation of p53 peptides and an effective T-cell mediated-immune response to ensue. To analyze to which extent p53 and HLA-I expression in a primary tumor reflects expression in liver metastases, we investigated p53, HLA-A and HLA-B/C expression in 82 colorectal carcinomas and 143 associated liver metastases of 82 patients. We used the monoclonal antibodies DO-7 (p53), HCA2 (HLA-A) and HC-10 (HLA-B/C) on formalin-fixed, paraffin embedded tissue. The percentage of expressing cells was estimated. P53 was overexpressed in 73% of the colorectal carcinomas and 66% of liver metastases. HLA-A was expressed in 98% and 96% and HLA-B/C in 100% and 94% of colorectal cancers and liver metastases respectively. There were no significant differences between the primary tumors and the liver metastases for each marker. The concordance was also very high in those cases in which more than one metastasis was available. Discordant cases consisted of tumors in which expression of p53 or HLA-A was lost in the liver metastases, whereas it was present in only a few tumor cells in the primary tumor. The combined analysis of p53 and HLA-I expression in liver metastases demonstrated that both molecules were expressed in 63% of the cases. P53 and HLA-I were expressed in the majority of primary tumors and their associated liver metastases. This allows to select patients for p53-immunotherapy on the basis of p53 and HLA-I expression in the primary tumor.     

等离子低温射频消融术联合鼻内镜治疗慢性鼻-鼻窦炎疗效分析

目的探讨等离子低温射频消融术联合鼻内镜治疗慢性鼻-鼻窦炎疗效。方法对我院自2010年1月至2012年1月收治的慢性鼻-鼻窦炎98例患者采用前瞻性研究,按照随机分配原则分为观察组和对照组,观察组(49例)采用等离子低温射频消融术联合鼻内镜进行治疗,对照组(49例)仅采用鼻内镜进行治疗,对2组的疗效进行比较。结果观察组术后1个月和1年的总有效率分别为为91.84%、89.80%,对照组术后1个月和1年的总有效率分别为77.55%和73.47%,2组比较差异有统计学意义(P0.05)。结论等离子低温射频消融术联合鼻内镜治疗慢性鼻-鼻窦炎近远期疗效显著,值得临床推广应用。     

Des-gamma carboxy prothrombin (PIVKA-II) and alpha-fetoprotein producing gastric cancer with multiple liver metastases

We describe the case of an 87-year-old woman who presented to Tokyo Kousei Nenkin Hospital because of appetite loss and general fatigue. Multiple liver masses and Borrmann type 2 gastric tumor were detected. A clinical diagnosis of hepatocellular carcinoma and gastric cancer was made based on the patient's high levels of serum alpha-fetoprotein (AFP; 490 200 ng/mL) and protein induced by vitamin K absence or antagonist-II (PIVKA-II, 2284 mAU/mL). The patient's general condition worsened gradually and she died 42 days after admission. Autopsy revealed that the predominant histological structure of the gastric tumor was trabecular or sheet-like, although a tubular structure was also found. Venous invasion was prominent. Immunohistochemically, the tumor tissue was positive for AFP and a few tumor cells were positive for PIVKA-II. The histological appearance and immunohistochemical features of the hepatic tumors resembled that of the gastric tumor. This case was pathologically diagnosed as AFP- and PIVKA-II-producing gastric carcinoma with multiple liver metastases. When tumors are found in the stomach and liver and serum PIVKA-II level is abnormally high, the possibility of PIVKA-II-producing gastric cancer with liver metastasis should be considered, especially when hepatitis virus markers are negative and liver cirrhosis is not present.     

Proposal for novel histological findings of colorectal liver metastases with preoperative chemotherapy

This study aimed to clarify the histological characteristics related to preoperative chemotherapy for colorectal liver metastases (CRLM). Sixty‐three patients with CRLM were divided into two groups: CRLM with chemotherapy (41 cases, group A) and CRLM without chemotherapy (22 cases; surgical treatment alone, group S) to identify the histological differences associated with chemotherapy. In addition, we investigated the effects of combination chemotherapy on the histology of metastatic lesions. Infarct‐like necrosis (ILN), three‐zonal changes, and cholesterol clefts were more frequent in group A than in group S (P < 0.05). ILN and three‐zonal changes were more common in the 5‐FU with leucovorin and oxaliplatin (FOLFOX), or 5‐FU with leucovorin and irinotecan (FOLFIRI) with or without additional bevacizumab groups than in group S (P < 0.05). Cholesterol clefts in the FOLFOX or FOLFIRI with bevacizumab group and foamy macrophages in the FOLFOX or FOLFIRI group were more common than in group S (P < 0.05). Cases with more than three of the four histological findings—i.e. ILN, three‐zonal changes, cholesterol clefts, and foamy macrophages—were more frequent in the FOLFOX or FOLFIRI with or without additional bevacizumab groups than in group S (P < 0.05). We showed histological findings for every representative chemotherapy regimen for CRLM to clarify the effects of preoperative chemotherapy.     

Decrease in intrahepatic CD56+ lymphocytes in gastric and colorectal cancer patients with liver metastases

Gulubova M, Manolova I, Kyurkchiev D, Julianov A, Altunkova I. Decrease in intrahepatic CD56⁺ lymphocytes in gastric and colorectal cancer patients with liver metastases. APMIS 2009; 117: 870–9. The aim of the study was to examine the main intrahepatic lymphocyte subpopulations, namely CD3⁺ lymphocytes, natural killer (NK)‐like T lymphocytes (NKT) expressing the CD3⁺ CD56⁺ phenotype, CD56⁺ NK cells, CD4⁺, and CD8⁺ T cells in livers of patients with gastric and colorectal cancer with and without hepatic metastases. The proportion of each lymphocyte subset was determined in 34 patients with gastric or colorectal cancer (18 with and 16 without liver metastasis) by two‐color flow cytometry after extraction of hepatic mononuclear cell fraction. The distribution of lymphocyte subpopulations in selected areas of liver metastases and adjacent liver tissue was evaluated using immunohistochemistry for CD4, CD8, and CD56. Flow cytometry analysis revealed a significant decrease in the proportion of CD3⁺ CD56⁺ cells in metastatic livers, but not in nonmetastatic livers (11.9 ± 10.3 vs 24.2 ± 13.6%, p = 0.02). The percentage of intrahepatic CD3^?CD56⁺ cells was also decreased in patients with metastases compared to those without (10.1 ± 11.6 vs 16.6 ± 8.9%, p = 0.039). Immunohistochemically, three types of lymphocytes (CD4⁺, CD8⁺, and CD56⁺) were present in the metastatic tissue, although the number of CD56⁺ cells was almost twice lower. We found a low prevalence of tumor‐infiltrating CD4⁺, CD8⁺, and CD56⁺ cells in livers with multiple metastases, whereas in cases with solitary metastasis a higher degree of lymphocyte infiltration was observed. The number of CD3^?CD56⁺ and CD3⁺ CD56⁺ cells was decreased in metastatic livers compared to those unaffected by metastases. Therefore the prevalence of tumor‐infiltrating lymphocytes seems to be related to the progression of metastatic liver disease. Depletion of hepatic innate lymphocytes may reveal susceptibility to metastatic liver disease and could be a reason for the escape of metastatic cells from the mechanisms of liver immune control.     

Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer

BACKGROUND: Two years after undergoing resection of liver metastases from colorectal cancer, about 65 percent of patients are alive and 25 percent are free of detectable disease. We tried to improve these outcomes by treating patients with hepatic arterial infusion of floxuridine plus systemic fluorouracil after liver resection. METHODS: We randomly assigned 156 patients at the time of resection of hepatic metastases from colorectal cancer to receive six cycles of hepatic arterial infusion with floxuridine and dexamethasone plus intravenous fluorouracil, with or without leucovorin, or six weeks of similar systemic therapy alone. Patients were stratified according to previous treatment and the number of liver metastases identified at operation. The study end points were overall survival, survival without recurrence of hepatic metastases, and survival without any metastases at two years. RESULTS: The actuarial rate of overall survival at two years was 86 percent in the group treated with local plus systemic chemotherapy and 72 percent in the group given systemic therapy alone (P=0.03). The median survival was 72.2 months in the combined-therapy group and 59.3 months in the monotherapy group, with a median follow-up of 62.7 months. After two years, the rates of survival free of hepatic recurrence were 90 percent in the monotherapy group and 60 percent in the monotherapy group (P<0.001), and the respective rates of progression-free survival were 57 percent and 42 percent (P=0.07). At two years, the risk ratio for death was 2.34 among patients treated with systemic therapy alone, as compared with patients who received combined therapy (95 percent confidence interval, 1.10 to 4.98; P=0.027), after adjustment for important variables. The rates of adverse effects of at least moderate severity were similar in the two groups, except for a higher frequency of diarrhea and hepatic effects in the combined-therapy group. CONCLUSIONS: For patients who undergo resection of liver metastases from colorectal cancer, postoperative treatment with a combination of hepatic arterial infusion of floxuridine and intravenous fluorouracil improves the outcome at two years.