腹腔热灌注化疗治疗胃癌恶性腹水的临床与基础研究
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摘要
第一部分腹腔热灌注化疗治疗胃癌恶性腹水的临床研究
研究目的：
1.探讨应用BR-TRG-I型体腔热灌注治疗系统进行腹腔热灌注化疗(HIPEC)对患者呼吸、循环等生理功能的影响,评估HIPEC技术方法的临床安全性。
2.初步探讨腹腔镜辅助HIPEC治疗胃癌恶性腹水的安全性和可行性,评估其疗效。
3.初步探讨B超引导下HIPEC治疗恶性腹水的安全性和可行性,评估其疗效。
资料与方法：
1.临床安全性研究临床资料：我院收治的25例恶性肿瘤患者,所有患者均经病理检查诊断证实,无严重心脑血管疾病及出血倾向。其中胃癌根治切除术7例、姑息性切除4例,结直肠癌根治切除术5例、姑息性切除2例,卵巢癌完全减瘤术5例,不完全减瘤术2例。
2. HIPEC技术方法：将5-Fu1500mg、生理盐水3000～5000ml加入HIPEC专用袋内,根据患者腹腔容积续加生理盐水至腹腔全部充满灌注液。开动HIPEC设备,设定治疗温度43℃,治疗时间60min,灌注速度500ml/min。HIPEC结束后灌注液自然引出,全部放出体外。
3.监测患者HIPEC前0min及术中15min、30mmin、45min、60min各时间点HIPEC进水口、出水口及患者体表、直肠、鼓膜的温度；监测各相应时间的血压、心率、呼吸、血氧饱和度等生命体征,分析43℃治疗温度腹腔热灌注治疗对患者体表、直肠、鼓膜的温度和生命体征的影响。
4.腹腔镜辅助HIPEC组的临床资料：胃癌恶性腹水患者18例(未手术9例、术后9例),经剖腹探查、纤维内窥镜检查、血清肿瘤标志物检查(CEA, CA199, CA125)、腹水细胞学检查诊断原发病。所有患者均经影像学检查有大量腹腔积液,B超检查评估腹水量4000-9000m1,12例患者经多次腹腔穿刺抽液无明显缓解。12例患者腹水内可查见大量游离癌细胞,2例腹水呈明显血性、1例呈乳糜性。
5.腹腔镜辅助HIPEC技术方法：术前准备,气管内插管麻醉,脐下0.5cm作-1cm横行切口,插入Veress气腹针,吸尽腹腔内积液后,闭合法建立人工气腹,气腹压力13mmHg (1mmHg=0.133KPa),经脐下戳孔插入10mm、30°腹腔镜,探查腹腔内脏器,在腹腔镜引导下于右侧和左侧锁骨中线脐上两横指平面处各作5mm的第二、第三戳孔,在左侧锁骨中线脐下两横指平面处各作5mm的第四戳孔；先行腹腔镜辅助腹腔探查了解肿瘤的部位、大小、临床分期、可否手术根治切除,对腹腔镜腹腔探查证实腹膜弥散种植转移、已不适合切除的患者进行HIPEC治疗,在腹腔镜引导下自第二、第三、第四戳孔放入灌注和流出导管至左上腹、右上腹、左下腹,最后将腹腔镜放至右下腹Trocar充分深入,拔出腹腔镜,在Trocar引导下将灌注管放至右下腹。
6.B超引导下HIPEC组的临床资料：18例腹腔恶性肿瘤患者(胃癌1例、胃癌术后腹膜弥漫种植转移4例、卵巢癌1例、卵巢癌术后4例、结肠癌1例、结肠癌术后腹膜弥漫种植转移4例,胰腺癌1例、肝癌肝移植术后腹膜种植转移1例、胃肠道间质瘤术后1例)。经既往剖腹探查、影像学、纤维内窥镜检查、血清肿瘤标志物检查、腹水细胞学检查诊断原发病。所有患者均经影像学检查有大量腹腔积液,B超检查评估腹水量3500～9000ml。
7.B超引导下HIPEC技术方法：静脉镇静基础麻醉下患者取平卧位,B超检查确定腹水量,常规消毒铺巾,B超引导下分别在左上腹、右上腹、左下腹、右下腹部位检查,选择腹水较深、腹壁与腹腔内组织无粘连的部位作为穿刺点,注意避开原腹壁手术切口部位。0.5%利多卡因局麻后在穿刺点作-1cm横切口,直径1cm腹腔镜专用Trocar穿刺入腹腔,见腹水流出后调整Trocar放入腹腔的角度,在Trocar引导下将有多个侧孔的灌注管(内径0.8cm,外径1.0cm,长度120cm)分别放至左上腹、右上腹,引流管(规格同灌注管,可互换)放至左下腹、右下腹,放入长度约40～80cm。如患者腹水量不多,可借助体位使腹水积聚于左下腹选择第一个穿刺孔,放入灌注道管后向腹腔内灌入适量生理盐水使腹部隆起,再选择其他穿刺位点进行穿刺置管。
结果：
1. HIPEC过程中患者体表、直肠、鼓膜温度和生命体征监测值如表1示。从表1中的研究结果可以看出：HIPEC前至治疗60min结束时患者的腋窝、鼓膜、直肠温度平均分别上升了0.9℃、0.7℃、0.9℃,这表明,以43℃的治疗温度、60min的治疗时间、500ml/min的灌注速度进行HIPEC,虽然可引起患者体温稍微升高,但均在正常范围内；同时HIPEC过程中各时间点血压、心率、呼吸、血氧饱和度等数值均在正常范围内,治疗前及治疗过程中无明显变化,这也表明43℃治疗温度、60min治疗时间、500ml/min灌注速度进行腹腔热灌注治疗对血压、心率、呼吸、血氧饱和度等生命体征无明显影响。
2.腹腔镜辅助组HIPEC:患者第一次HIPEC后腹水引出量一般为100～300ml,以后逐日减少,一周后腹水引出量一般为5～30ml/d。18例患者两周后复查至随访结束,CR15例(83.3%)；PR3例(16.7%),总有效率100%(CR+PR18例)。术后两周KPS评分为60-90,较术前明显升高(P<0.01)；患者持HIPEC后一般状况、精神状态好转,食欲改善,体重增加,贫血症状明显缓解,近期临床疗效满意；但术后2例患者出现触控种植转移。
3.B超引导组HIPEC:18例患者手术均进行顺利,B超引导下放置灌注和引流管平均时间20～45min,平均放管时间35min。患者经第一次HIPEC放出腹水后第二天腹水引出量一般为100～300ml,以后逐日减少,一周后腹水腹水引出量一般为5-30ml/d。本组18例中两周后复查至随访结束,CR17例(94.4%)；PR1例(5.6%),总有效率100%(CR+PR18例)。HIPEC治疗后患者KPS评分上升10-30%,中位上升数20%,一般状况、精神状态好转,食欲改善,体重增加,贫血症状明显缓解,近期临床疗效满意。
第二部分腹腔热灌注化疗治疗胃癌恶性腹水的基础研究
研究目的：
研究胃癌患者在HIPEC前后血清及腹水标本内miRNA的表达变化,初步建立胃癌HIPEC相关的特征性miRNA表达谱。
资料与方法：
收集进展期胃癌行HIPEC患者的5例血清和腹水标本,取HIPEC前为对照组,热灌注化疗后为实验组,共5组。每组取血浆2ml,用mirVana PARIS试剂盒分别抽提实验组和对照组的RNA。测定浓度后使用Exiqon MicroRNA低密度芯片分别检测实验组和对照组的microRNA谱。使用SDS2.3软件分析TLDA芯片数据。对比分析腹腔热灌注治疗前后两组之间microRNA表达的差异。
结果：
微阵列技术共检测到270个microRNA分子。聚类结果分析显示,相对于热疗前的血清标本,热疗后有169个miRNA表达上调,上调3倍以上的有19个,其中以hsa-miR-218-2-3p、hsa-miR-135a-5p、hsa-miR-377-5p、 hsa-miR-409-3p和hsa-miR-4326表达上调明显。101个miRNA表达下调,14个明显下调,其中以hsa-let-7a-5p、hsa-let-7b-5p、hsa-let-7c、hsa-miR-96-5p下调明显。
结论：
第一部分结论：
1.以BR-TRG-I型体腔热灌注治疗系统进行43℃治疗温度、60min治疗时间、500ml/min灌注速度的HIPEC治疗,对患者血压、心率、呼吸、血氧饱和度等生命体征无明显影响,临床安全可行。
2.腹腔镜辅助HIPEC可先在腹腔镜下探查腹腔了解肿瘤情况,可充分应用微创外科技术的优势,对腹腔探查证实癌细胞腹膜广泛种植转移、不适合进行肿瘤切除的患者进行HIPEC,是临床不可手术切除胃癌伴恶性腹水患者一种安全易行而有效的治疗方法,有着很好的临床应用前景。
3.B超引导下HIPEC可发挥B超检查无创伤,对腹水诊断具有特异性的优点,具有创伤小、患者痛苦少、术后恢复快、疗效肯定、费用低廉等优点,具有很好的临床应用前景。
第二部分结论：胃癌患者行HIPEC后可引起多种miRNA的表达上调和下调,提示上述miRNAs的异常表达可能与胃癌HIPEC治疗的疗效和胃癌的发生发展相关,进一步研究这些异常表达的miRNA有望找到相关的调控胃癌的靶基因和相关信号传导通路,为胃癌恶性腹水的靶向治疗提供新的研究思路。
Part one:The clinical research about hyperthermic intraperitoneal chemotherapy (HIPEC) on gastric cancer with malignant ascites.
Objective:
1. To explore the impact of HIPEC in patients with respiratory, circulatory and other physiological functions with the BR-TRG-I type body cavity perfusion treatment system.
2. To investigate the measurement, feasibility and clinic effect of laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of gastric cancer with malignant ascites from peritoneal carcinomatosis.
3. To investigate the measurement, feasibility and clinic effect of B ultrasound guided hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of malignant ascites from peritoneal carcinomatosis.
Materials and Methods:
1. Clinical data:25patients with malignant tumors in our hospital, all patients were diagnosed by pathological examination confirmed serious cardiovascular and cerebrovascular diseases and bleeding tendency.7cases of gastric cancer resection, palliative resection in4cases, radical resection of colorectal cancer5cases, palliative resection in2cases, ovarian cancer in complete cytoreductive surgery for five cases, incomplete cytoreductive surgery two cases.
2. HIPEC methods:5-Fu1500mg and saline3000-5000ml to join the special bag for HIPEC, and add volume normal saline to the abdominal cavity filled with perfusion fluid. Switched on the equipment, set the intraperitoneal hyperthermic perfusion chemotherapy in the treatment temperature43℃, with the treatment time of60min, infusion rate of500ml/min. Solution naturally leads out after the HIPEC. Monitoring the temperature in the inlet, outlet of the HIPEC Pipeline and the body surface, rectum, and tympanic on the patients at each time point of HIPEC0min,15min,30min,45min,60min. Monitoring the blood pressure, heart rate, vital signs such as respiration, oxygen saturation on each corresponding time, analysis the impact of43℃temperature HIPEC treatment to the patients with body surface, rectal, tympanic membrane temperature and vital signs.
3. The clinical data of the laparoscopic-assisted HIPEC group:Of the18patients in this study, there were7men and9women. There were9primary cases of gastric cancer and9cases of postoperative gastric cancer, which were diagnosed by laparotomy, gastric fiberoptic endoscopy, serum tumor markers (CEA and CA199) and ascite cytology. Ultrasonic B and laparoscopic examinations displayed4000-9000mL seroperitoneum in all the patients.12patients had no apparent palliation was found after repeated abdominal puncture drainage,12patients had numerous free cancer cells within the ascites,2cases presented obvious bloody ascites, and1case presented chyle-like ascites.
4. Laparoscopic-assisted HIPEC technique and methods:After endotracheal anesthesia, a transverse cut (10mm long) was performed at the belly,5mm below the umbilicus. The seroperitoneum was extracted as completely as possible; artificial pneumoperitoneum was established via an open procedure with a pressure of13mmHg (1mmHg=0.133kPa); a10-mm Trocar was inserted into the abdominal cavity via the working port. Thereafter, the laparoscope (10mm and30°) was inserted via the10mm Trocar to examine the abdominal viscera and tumors. The site, size and clinical stages of tumors were examined laparoscopically. Patients with peritoneal diffusive seeding and unresectable tumors were advised to receive laparoscope assisted HIPEC. In the process of laparoscope-assisted HIPEC, three new ports were prepared under the guidance of a laparoscope. On the right side, the second and third ports (both10mm long) were prepared at the cross-point of the midclavicular line and transverse surfaces, with two finger spaces above and below the umbilicus, respectively. On the left side, the fourth port (10mm long) was prepared at the cross-point of the mid-clavicular line and transverse surface, with two finger spaces below the umbilicus. Thereafter, under the guidance of laparoscope. a10mm Trocar was inserted into the abdominal cavity via the working port. Two perfusion catheters were placed in the right superior abdominal cavity via the third and fourth working ports, respectively. One drainage catheter was placed in the Douglas' cavity of the lowest place in the pelvic cavity via the second working port. Then, the laparoscope was placed in the inferior abdomen and the Trocar was inserted. Subsequently, the laparoscope was pulled out, and the perfusion catheter was placed in the Douglas' cavity of the lowest place in the pelvic cavity under the guidance of the Trocar.
5. Clinical data of the B ultrasound-guided group:18cases of patients with abdominal malignancy (1case of gastric,4cases of diffuse gastric cancer postoperative peritoneal metastasis,1case of ovarian cancer,4patients ovarian cancer after surgery,1cases of colon cancer,4cases of colon cancer peritoneal diffuse metastasis,1case of the pancreascarcinoma,1case of hepatocellular carcinoma after liver transplantation in peritoneal metastasis, and1case of gastrointestinal stromal tumor after surgery). Diagnosis of the primary disease by laparotomy, imaging, fiber endoscopy. serum tumor markers checked. All patients have a large number of malignant ascites inspected with imaging studies. B-ultrasound assessment the amount of ascites was3500-9000ml.
6. B ultrasound-guided HIPEC technique and methods:The basis intravenous anesthesia was given for the supine patient, B-ultrasonic examination to determine the amount of ascites. conventional prepped and draped, B-ultrasound guided in the left upper quadrant, right upper quadrant, left lower quadrant, right lower abdomen to check, select the ascites deep enough abdominal wall as the puncture point, and avoid the original abdominal incision site. Left lower quadrant, right lower quadrant puncture point placed on the perfusion tube to the orientation of the left upper quadrant, right upper quadrant; the left upper quadrant, right upper quadrant puncture point to place the drainage tube to the orientation to the left lower quadrant, right lower quadrant. At the puncture site for a1-cm transverse incision after0.5%lidocaine local anesthesia,1cm in diameter laparoscopic Trocar puncture into the abdominal cavity, adjust the angle of the Trocar into the abdominal cavity when seen the ascites outflow, the perfusion tube (0.8cm in inner diameter, outer diameter1.0cm, length120cm) were placed to the left upper quadrant, right upper quadrant with the guide of Trocar, the drainage tube put to the left lower quadrant, right lower quadrant, into the length about40-80cm. If the ascites was not enough, we can take the advantage of the position to accumulate the ascites in the left lower quadrant options, after poured into the appropriate amount of saline to the abdominal cavity after abdominal bulge, and then select the other puncture sites for catheter insertion.
Results:
1. HIPEC process in patients with body surface, rectal, tympanic temperature and vital signs monitoring values such as shown in Table1. The axillary, tympanic membrane, rectal average temperature of the patients rise0.9℃,0.7℃,0.9℃Before and after HIPEC, which showed that the treatment temperature of43℃for60min,500ml/min infusion rate HIPEC, can cause patients body temperature slightly elevated, but were within the normal range; The blood pressure, heart rate, respiration, blood oxygen saturation values were within the normal range before and during the treatment, which suggests that this therapy had no significant effect to the patient blood pressure, heart rate, respiratory, oxygen saturation and other vital signs.
2. The laparoscopic-assisted HIPEC group:After the first laparoscopeassisted HIPEC, the daily amount of ascite outflow was100-300ml. After the first day, ascite outflow gradually decreased. A week later, daily outflow was5-30ml. During the period from two weeks after laparoscope-assisted HIPEC to the end of follow-up, clinical CR of ascites and related symptoms were achieved in15of the18treated patients (83.3%), and PR was achieved in3patients (16.7%). Thus the objective remission rate (ORR=CR+PR) was100%. The Karnofsky mark indicating patient quality of life was60-90, which was increased significantly in comparison with before laparoscope-assisted HIPEC (P<0.01). The general status of patients improved after the third laparoscope-assisted HIPEC. Mental status, appetite and body weight improved, and symptoms of anemia were obviously alleviated. Thus, satisfactory initial clinical efficacy has been achieved in these patients treated by laparoscope-assisted HIPEC.
3. The B ultrasound-guided group:The operations of18patients were carried out smoothly, B ultrasound-guided placement of perfusion and drainage tube an average of20to45min, the average discharge pipe for35min. Patients with ascites after the first HIPEC on the next day ascites releas was generally100to300ml, then gradually declined, a week later ascites leads to generally5to30ml/d. After the review of18cases in two weeks to the end of follow-up, the CR in17cases (94.4%); the PR in1case (5.6%), the total efficiency of100%(CR+PR18cases). HIPEC treatment in patients with KPS score increased by10to30percent, the median rose20percent, general status, mental status improved, to improve appetite, weight gain, anemia and symptom relief, short-term clinical results were satisfactory.
Part two:The basic research of hyperthermic intraperitoneal chemotherapy (HIPEC) on gastric cancer with malignant ascites.
Objectives:
1. To investigate the expression changes of microRNA (miRNA) in the blood of advanced gastric cancer before and after HIPEC, establish the distinctive circulating miRNA spectrum related to gastric cancer with the treatment of HIPEC.
Materials and Methods:
1. This study had collected five advanced gastric cancer patients' serum and ascite before and after HIPEC from January2010to December2011. All patients were confirmed by pathology and the clinical stages were all stage Ⅳ. The blood samples were drawn with empty stomach and then centrifugated. Plasma was aspirated and then frozened under-80℃condition.2ml plasma's RNA from each group was extracted by mirVana PARIS kit. After the saturation evaluation and the quality control, the total RNA of each group was examined by Exiqon MicroRNA low density assay respectively. The result was analyzed by SDS2.3software.
Results:
1. Two hundred and seventy miRNAs were detected in the two groups before and after HIPEC totally. According to the judgment standard analysis,169miRNAs were upregulated including19miRNAs upregulated more than3times such as hsa-miR-218-2-3p, hsa-miR-135a-5p, hsa-miR-377-5p, hsa-miR-409-3p and hsa-miR-4326.101miRNAs were downregulted including14miRNAs downregulated significantly such as hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c and hsa-miR-96-5p.
Conclusions:
Conclusions of part one:
1. Treatment temperature of43℃for60min,500ml/min infusion rate of HIPEC with the BR-TRG-I type body cavity perfusion treatment system, had no significant effect to the patient blood pressure, heart rate, respiratory, oxygen saturation and other vital signs, clinical application is safety and feasible.
2. Laparoscope-assisted HIPEC could explore the tumor in the abdominal cavity with the help of laparoscope, which can fully apply the advantages of minimally invasive surgical techniques, confirmed and then given HIPEC for patients whose cancer cell extensive peritoneal metastasis, is not suitable for tumor resection. HIPEC is a safe and easy and effective treatment for clinical non-resected gastric cancer patients with refractory ascites, with good prospects for clinical application.
3. B ultrasound-guided HIPEC has non-invasive, and the advantages of specific diagnosis for malignant ascites, with less trauma, less pain, and postoperative recovery faster, more effective, low-cost advantages, etc. It has good prospects for clinical application.
Conclusions of part two:
1. Patients with gastric cancer given the therapy of HIPEC can cause the upregulation and downregulation of multiple miRNAs, which implied the dysfunction of miRNA might lead to the abnormal expression targeted gene and played an important role betweeen gastric cancer and HIPEC. Further study of these abnormal expression of miRNA is expected to find the target genes and of the regulation of gastric cancer signals transduction pathways; miRNA microarray technology is an effective high-throughput detection methods.
研究目的：
1.探讨应用BR-TRG-I型体腔热灌注治疗系统进行腹腔热灌注化疗(HIPEC)对患者呼吸、循环等生理功能的影响,评估HIPEC技术方法的临床安全性。
2.初步探讨腹腔镜辅助HIPEC治疗胃癌恶性腹水的安全性和可行性,评估其疗效。
3.初步探讨B超引导下HIPEC治疗恶性腹水的安全性和可行性,评估其疗效。
资料与方法：
1.临床安全性研究临床资料：我院收治的25例恶性肿瘤患者,所有患者均经病理检查诊断证实,无严重心脑血管疾病及出血倾向。其中胃癌根治切除术7例、姑息性切除4例,结直肠癌根治切除术5例、姑息性切除2例,卵巢癌完全减瘤术5例,不完全减瘤术2例。
2. HIPEC技术方法：将5-Fu1500mg、生理盐水3000～5000ml加入HIPEC专用袋内,根据患者腹腔容积续加生理盐水至腹腔全部充满灌注液。开动HIPEC设备,设定治疗温度43℃,治疗时间60min,灌注速度500ml/min。HIPEC结束后灌注液自然引出,全部放出体外。
3.监测患者HIPEC前0min及术中15min、30mmin、45min、60min各时间点HIPEC进水口、出水口及患者体表、直肠、鼓膜的温度；监测各相应时间的血压、心率、呼吸、血氧饱和度等生命体征,分析43℃治疗温度腹腔热灌注治疗对患者体表、直肠、鼓膜的温度和生命体征的影响。
4.腹腔镜辅助HIPEC组的临床资料：胃癌恶性腹水患者18例(未手术9例、术后9例),经剖腹探查、纤维内窥镜检查、血清肿瘤标志物检查(CEA, CA199, CA125)、腹水细胞学检查诊断原发病。所有患者均经影像学检查有大量腹腔积液,B超检查评估腹水量4000-9000m1,12例患者经多次腹腔穿刺抽液无明显缓解。12例患者腹水内可查见大量游离癌细胞,2例腹水呈明显血性、1例呈乳糜性。
5.腹腔镜辅助HIPEC技术方法：术前准备,气管内插管麻醉,脐下0.5cm作-1cm横行切口,插入Veress气腹针,吸尽腹腔内积液后,闭合法建立人工气腹,气腹压力13mmHg (1mmHg=0.133KPa),经脐下戳孔插入10mm、30°腹腔镜,探查腹腔内脏器,在腹腔镜引导下于右侧和左侧锁骨中线脐上两横指平面处各作5mm的第二、第三戳孔,在左侧锁骨中线脐下两横指平面处各作5mm的第四戳孔；先行腹腔镜辅助腹腔探查了解肿瘤的部位、大小、临床分期、可否手术根治切除,对腹腔镜腹腔探查证实腹膜弥散种植转移、已不适合切除的患者进行HIPEC治疗,在腹腔镜引导下自第二、第三、第四戳孔放入灌注和流出导管至左上腹、右上腹、左下腹,最后将腹腔镜放至右下腹Trocar充分深入,拔出腹腔镜,在Trocar引导下将灌注管放至右下腹。
6.B超引导下HIPEC组的临床资料：18例腹腔恶性肿瘤患者(胃癌1例、胃癌术后腹膜弥漫种植转移4例、卵巢癌1例、卵巢癌术后4例、结肠癌1例、结肠癌术后腹膜弥漫种植转移4例,胰腺癌1例、肝癌肝移植术后腹膜种植转移1例、胃肠道间质瘤术后1例)。经既往剖腹探查、影像学、纤维内窥镜检查、血清肿瘤标志物检查、腹水细胞学检查诊断原发病。所有患者均经影像学检查有大量腹腔积液,B超检查评估腹水量3500～9000ml。
7.B超引导下HIPEC技术方法：静脉镇静基础麻醉下患者取平卧位,B超检查确定腹水量,常规消毒铺巾,B超引导下分别在左上腹、右上腹、左下腹、右下腹部位检查,选择腹水较深、腹壁与腹腔内组织无粘连的部位作为穿刺点,注意避开原腹壁手术切口部位。0.5%利多卡因局麻后在穿刺点作-1cm横切口,直径1cm腹腔镜专用Trocar穿刺入腹腔,见腹水流出后调整Trocar放入腹腔的角度,在Trocar引导下将有多个侧孔的灌注管(内径0.8cm,外径1.0cm,长度120cm)分别放至左上腹、右上腹,引流管(规格同灌注管,可互换)放至左下腹、右下腹,放入长度约40～80cm。如患者腹水量不多,可借助体位使腹水积聚于左下腹选择第一个穿刺孔,放入灌注道管后向腹腔内灌入适量生理盐水使腹部隆起,再选择其他穿刺位点进行穿刺置管。
结果：
1. HIPEC过程中患者体表、直肠、鼓膜温度和生命体征监测值如表1示。从表1中的研究结果可以看出：HIPEC前至治疗60min结束时患者的腋窝、鼓膜、直肠温度平均分别上升了0.9℃、0.7℃、0.9℃,这表明,以43℃的治疗温度、60min的治疗时间、500ml/min的灌注速度进行HIPEC,虽然可引起患者体温稍微升高,但均在正常范围内；同时HIPEC过程中各时间点血压、心率、呼吸、血氧饱和度等数值均在正常范围内,治疗前及治疗过程中无明显变化,这也表明43℃治疗温度、60min治疗时间、500ml/min灌注速度进行腹腔热灌注治疗对血压、心率、呼吸、血氧饱和度等生命体征无明显影响。
2.腹腔镜辅助组HIPEC:患者第一次HIPEC后腹水引出量一般为100～300ml,以后逐日减少,一周后腹水引出量一般为5～30ml/d。18例患者两周后复查至随访结束,CR15例(83.3%)；PR3例(16.7%),总有效率100%(CR+PR18例)。术后两周KPS评分为60-90,较术前明显升高(P<0.01)；患者持HIPEC后一般状况、精神状态好转,食欲改善,体重增加,贫血症状明显缓解,近期临床疗效满意；但术后2例患者出现触控种植转移。
3.B超引导组HIPEC:18例患者手术均进行顺利,B超引导下放置灌注和引流管平均时间20～45min,平均放管时间35min。患者经第一次HIPEC放出腹水后第二天腹水引出量一般为100～300ml,以后逐日减少,一周后腹水腹水引出量一般为5-30ml/d。本组18例中两周后复查至随访结束,CR17例(94.4%)；PR1例(5.6%),总有效率100%(CR+PR18例)。HIPEC治疗后患者KPS评分上升10-30%,中位上升数20%,一般状况、精神状态好转,食欲改善,体重增加,贫血症状明显缓解,近期临床疗效满意。
第二部分腹腔热灌注化疗治疗胃癌恶性腹水的基础研究
研究目的：
研究胃癌患者在HIPEC前后血清及腹水标本内miRNA的表达变化,初步建立胃癌HIPEC相关的特征性miRNA表达谱。
资料与方法：
收集进展期胃癌行HIPEC患者的5例血清和腹水标本,取HIPEC前为对照组,热灌注化疗后为实验组,共5组。每组取血浆2ml,用mirVana PARIS试剂盒分别抽提实验组和对照组的RNA。测定浓度后使用Exiqon MicroRNA低密度芯片分别检测实验组和对照组的microRNA谱。使用SDS2.3软件分析TLDA芯片数据。对比分析腹腔热灌注治疗前后两组之间microRNA表达的差异。
结果：
微阵列技术共检测到270个microRNA分子。聚类结果分析显示,相对于热疗前的血清标本,热疗后有169个miRNA表达上调,上调3倍以上的有19个,其中以hsa-miR-218-2-3p、hsa-miR-135a-5p、hsa-miR-377-5p、 hsa-miR-409-3p和hsa-miR-4326表达上调明显。101个miRNA表达下调,14个明显下调,其中以hsa-let-7a-5p、hsa-let-7b-5p、hsa-let-7c、hsa-miR-96-5p下调明显。
结论：
第一部分结论：
1.以BR-TRG-I型体腔热灌注治疗系统进行43℃治疗温度、60min治疗时间、500ml/min灌注速度的HIPEC治疗,对患者血压、心率、呼吸、血氧饱和度等生命体征无明显影响,临床安全可行。
2.腹腔镜辅助HIPEC可先在腹腔镜下探查腹腔了解肿瘤情况,可充分应用微创外科技术的优势,对腹腔探查证实癌细胞腹膜广泛种植转移、不适合进行肿瘤切除的患者进行HIPEC,是临床不可手术切除胃癌伴恶性腹水患者一种安全易行而有效的治疗方法,有着很好的临床应用前景。
3.B超引导下HIPEC可发挥B超检查无创伤,对腹水诊断具有特异性的优点,具有创伤小、患者痛苦少、术后恢复快、疗效肯定、费用低廉等优点,具有很好的临床应用前景。
第二部分结论：胃癌患者行HIPEC后可引起多种miRNA的表达上调和下调,提示上述miRNAs的异常表达可能与胃癌HIPEC治疗的疗效和胃癌的发生发展相关,进一步研究这些异常表达的miRNA有望找到相关的调控胃癌的靶基因和相关信号传导通路,为胃癌恶性腹水的靶向治疗提供新的研究思路。
Part one:The clinical research about hyperthermic intraperitoneal chemotherapy (HIPEC) on gastric cancer with malignant ascites.
Objective:
1. To explore the impact of HIPEC in patients with respiratory, circulatory and other physiological functions with the BR-TRG-I type body cavity perfusion treatment system.
2. To investigate the measurement, feasibility and clinic effect of laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of gastric cancer with malignant ascites from peritoneal carcinomatosis.
3. To investigate the measurement, feasibility and clinic effect of B ultrasound guided hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of malignant ascites from peritoneal carcinomatosis.
Materials and Methods:
1. Clinical data:25patients with malignant tumors in our hospital, all patients were diagnosed by pathological examination confirmed serious cardiovascular and cerebrovascular diseases and bleeding tendency.7cases of gastric cancer resection, palliative resection in4cases, radical resection of colorectal cancer5cases, palliative resection in2cases, ovarian cancer in complete cytoreductive surgery for five cases, incomplete cytoreductive surgery two cases.
2. HIPEC methods:5-Fu1500mg and saline3000-5000ml to join the special bag for HIPEC, and add volume normal saline to the abdominal cavity filled with perfusion fluid. Switched on the equipment, set the intraperitoneal hyperthermic perfusion chemotherapy in the treatment temperature43℃, with the treatment time of60min, infusion rate of500ml/min. Solution naturally leads out after the HIPEC. Monitoring the temperature in the inlet, outlet of the HIPEC Pipeline and the body surface, rectum, and tympanic on the patients at each time point of HIPEC0min,15min,30min,45min,60min. Monitoring the blood pressure, heart rate, vital signs such as respiration, oxygen saturation on each corresponding time, analysis the impact of43℃temperature HIPEC treatment to the patients with body surface, rectal, tympanic membrane temperature and vital signs.
3. The clinical data of the laparoscopic-assisted HIPEC group:Of the18patients in this study, there were7men and9women. There were9primary cases of gastric cancer and9cases of postoperative gastric cancer, which were diagnosed by laparotomy, gastric fiberoptic endoscopy, serum tumor markers (CEA and CA199) and ascite cytology. Ultrasonic B and laparoscopic examinations displayed4000-9000mL seroperitoneum in all the patients.12patients had no apparent palliation was found after repeated abdominal puncture drainage,12patients had numerous free cancer cells within the ascites,2cases presented obvious bloody ascites, and1case presented chyle-like ascites.
4. Laparoscopic-assisted HIPEC technique and methods:After endotracheal anesthesia, a transverse cut (10mm long) was performed at the belly,5mm below the umbilicus. The seroperitoneum was extracted as completely as possible; artificial pneumoperitoneum was established via an open procedure with a pressure of13mmHg (1mmHg=0.133kPa); a10-mm Trocar was inserted into the abdominal cavity via the working port. Thereafter, the laparoscope (10mm and30°) was inserted via the10mm Trocar to examine the abdominal viscera and tumors. The site, size and clinical stages of tumors were examined laparoscopically. Patients with peritoneal diffusive seeding and unresectable tumors were advised to receive laparoscope assisted HIPEC. In the process of laparoscope-assisted HIPEC, three new ports were prepared under the guidance of a laparoscope. On the right side, the second and third ports (both10mm long) were prepared at the cross-point of the midclavicular line and transverse surfaces, with two finger spaces above and below the umbilicus, respectively. On the left side, the fourth port (10mm long) was prepared at the cross-point of the mid-clavicular line and transverse surface, with two finger spaces below the umbilicus. Thereafter, under the guidance of laparoscope. a10mm Trocar was inserted into the abdominal cavity via the working port. Two perfusion catheters were placed in the right superior abdominal cavity via the third and fourth working ports, respectively. One drainage catheter was placed in the Douglas' cavity of the lowest place in the pelvic cavity via the second working port. Then, the laparoscope was placed in the inferior abdomen and the Trocar was inserted. Subsequently, the laparoscope was pulled out, and the perfusion catheter was placed in the Douglas' cavity of the lowest place in the pelvic cavity under the guidance of the Trocar.
5. Clinical data of the B ultrasound-guided group:18cases of patients with abdominal malignancy (1case of gastric,4cases of diffuse gastric cancer postoperative peritoneal metastasis,1case of ovarian cancer,4patients ovarian cancer after surgery,1cases of colon cancer,4cases of colon cancer peritoneal diffuse metastasis,1case of the pancreascarcinoma,1case of hepatocellular carcinoma after liver transplantation in peritoneal metastasis, and1case of gastrointestinal stromal tumor after surgery). Diagnosis of the primary disease by laparotomy, imaging, fiber endoscopy. serum tumor markers checked. All patients have a large number of malignant ascites inspected with imaging studies. B-ultrasound assessment the amount of ascites was3500-9000ml.
6. B ultrasound-guided HIPEC technique and methods:The basis intravenous anesthesia was given for the supine patient, B-ultrasonic examination to determine the amount of ascites. conventional prepped and draped, B-ultrasound guided in the left upper quadrant, right upper quadrant, left lower quadrant, right lower abdomen to check, select the ascites deep enough abdominal wall as the puncture point, and avoid the original abdominal incision site. Left lower quadrant, right lower quadrant puncture point placed on the perfusion tube to the orientation of the left upper quadrant, right upper quadrant; the left upper quadrant, right upper quadrant puncture point to place the drainage tube to the orientation to the left lower quadrant, right lower quadrant. At the puncture site for a1-cm transverse incision after0.5%lidocaine local anesthesia,1cm in diameter laparoscopic Trocar puncture into the abdominal cavity, adjust the angle of the Trocar into the abdominal cavity when seen the ascites outflow, the perfusion tube (0.8cm in inner diameter, outer diameter1.0cm, length120cm) were placed to the left upper quadrant, right upper quadrant with the guide of Trocar, the drainage tube put to the left lower quadrant, right lower quadrant, into the length about40-80cm. If the ascites was not enough, we can take the advantage of the position to accumulate the ascites in the left lower quadrant options, after poured into the appropriate amount of saline to the abdominal cavity after abdominal bulge, and then select the other puncture sites for catheter insertion.
Results:
1. HIPEC process in patients with body surface, rectal, tympanic temperature and vital signs monitoring values such as shown in Table1. The axillary, tympanic membrane, rectal average temperature of the patients rise0.9℃,0.7℃,0.9℃Before and after HIPEC, which showed that the treatment temperature of43℃for60min,500ml/min infusion rate HIPEC, can cause patients body temperature slightly elevated, but were within the normal range; The blood pressure, heart rate, respiration, blood oxygen saturation values were within the normal range before and during the treatment, which suggests that this therapy had no significant effect to the patient blood pressure, heart rate, respiratory, oxygen saturation and other vital signs.
2. The laparoscopic-assisted HIPEC group:After the first laparoscopeassisted HIPEC, the daily amount of ascite outflow was100-300ml. After the first day, ascite outflow gradually decreased. A week later, daily outflow was5-30ml. During the period from two weeks after laparoscope-assisted HIPEC to the end of follow-up, clinical CR of ascites and related symptoms were achieved in15of the18treated patients (83.3%), and PR was achieved in3patients (16.7%). Thus the objective remission rate (ORR=CR+PR) was100%. The Karnofsky mark indicating patient quality of life was60-90, which was increased significantly in comparison with before laparoscope-assisted HIPEC (P<0.01). The general status of patients improved after the third laparoscope-assisted HIPEC. Mental status, appetite and body weight improved, and symptoms of anemia were obviously alleviated. Thus, satisfactory initial clinical efficacy has been achieved in these patients treated by laparoscope-assisted HIPEC.
3. The B ultrasound-guided group:The operations of18patients were carried out smoothly, B ultrasound-guided placement of perfusion and drainage tube an average of20to45min, the average discharge pipe for35min. Patients with ascites after the first HIPEC on the next day ascites releas was generally100to300ml, then gradually declined, a week later ascites leads to generally5to30ml/d. After the review of18cases in two weeks to the end of follow-up, the CR in17cases (94.4%); the PR in1case (5.6%), the total efficiency of100%(CR+PR18cases). HIPEC treatment in patients with KPS score increased by10to30percent, the median rose20percent, general status, mental status improved, to improve appetite, weight gain, anemia and symptom relief, short-term clinical results were satisfactory.
Part two:The basic research of hyperthermic intraperitoneal chemotherapy (HIPEC) on gastric cancer with malignant ascites.
Objectives:
1. To investigate the expression changes of microRNA (miRNA) in the blood of advanced gastric cancer before and after HIPEC, establish the distinctive circulating miRNA spectrum related to gastric cancer with the treatment of HIPEC.
Materials and Methods:
1. This study had collected five advanced gastric cancer patients' serum and ascite before and after HIPEC from January2010to December2011. All patients were confirmed by pathology and the clinical stages were all stage Ⅳ. The blood samples were drawn with empty stomach and then centrifugated. Plasma was aspirated and then frozened under-80℃condition.2ml plasma's RNA from each group was extracted by mirVana PARIS kit. After the saturation evaluation and the quality control, the total RNA of each group was examined by Exiqon MicroRNA low density assay respectively. The result was analyzed by SDS2.3software.
Results:
1. Two hundred and seventy miRNAs were detected in the two groups before and after HIPEC totally. According to the judgment standard analysis,169miRNAs were upregulated including19miRNAs upregulated more than3times such as hsa-miR-218-2-3p, hsa-miR-135a-5p, hsa-miR-377-5p, hsa-miR-409-3p and hsa-miR-4326.101miRNAs were downregulted including14miRNAs downregulated significantly such as hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c and hsa-miR-96-5p.
Conclusions:
Conclusions of part one:
1. Treatment temperature of43℃for60min,500ml/min infusion rate of HIPEC with the BR-TRG-I type body cavity perfusion treatment system, had no significant effect to the patient blood pressure, heart rate, respiratory, oxygen saturation and other vital signs, clinical application is safety and feasible.
2. Laparoscope-assisted HIPEC could explore the tumor in the abdominal cavity with the help of laparoscope, which can fully apply the advantages of minimally invasive surgical techniques, confirmed and then given HIPEC for patients whose cancer cell extensive peritoneal metastasis, is not suitable for tumor resection. HIPEC is a safe and easy and effective treatment for clinical non-resected gastric cancer patients with refractory ascites, with good prospects for clinical application.
3. B ultrasound-guided HIPEC has non-invasive, and the advantages of specific diagnosis for malignant ascites, with less trauma, less pain, and postoperative recovery faster, more effective, low-cost advantages, etc. It has good prospects for clinical application.
Conclusions of part two:
1. Patients with gastric cancer given the therapy of HIPEC can cause the upregulation and downregulation of multiple miRNAs, which implied the dysfunction of miRNA might lead to the abnormal expression targeted gene and played an important role betweeen gastric cancer and HIPEC. Further study of these abnormal expression of miRNA is expected to find the target genes and of the regulation of gastric cancer signals transduction pathways; miRNA microarray technology is an effective high-throughput detection methods.
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