Long-term studies of cisplatin-induced reductions in porcine renal functional reserve

Summary Mature Large White female pigs aged approx. 10 months received single intravenous doses of 1.5, 2, or 2.5 mg/kg cisplatin. The glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF) in individual kidneys were measured prior to and at 4-week intervals for up to 24 weeks after cisplatin administration by renography using [^99mTc]-diethylenetriamminepentaacetic acid (DTPA) and iodohippurate sodium I 131, respectively. The left kidney of each cisplatin-treated pig and that of three age-matched control pigs was then removed, and GFR and ERPF values were measured in the remaining kidney at 4-week intervals for a further 24 weeks after unilateral nephrectomy (UN). Pigs treated with cisplatin showed no significant reduction in GFR or ERPF for up to 24 weeks after drug infusion. As measured using inductively coupled plasma mass spectrometry, the mean renal platinum concentration in the left kidney removed at UN was 77.5±9.1 ng/g kidney per mg/kg cisplatin. Histological evaluation of these kidneys revealed narrow interconnecting rays of interstitial fibrosis in the deep cortex and medulla; in these areas, glomeruli exhibited thickened Bowman's capsules and occasionally shrunken sclerotic capillaries. In cisplatin-treated pigs, UN was associated with a marked reduction in the ability of the remaining kidney to increase its function in terms of GFR and, to a lesser exten, of ERPF. The increase seen in GFR following UN in the cisplatin-treated pigs was only ca. 50%–70% of that seen in age-matched UN controls. Histologically, these kidneys revealed resolution of the peritubular fibrosis observed at UN; occasional sclerotic glomeruli were also evident. Platinum remained detectable in these kidneys, the mean levels being 18.8±4.9 ng/g kidney per mg/kg cisplatin. These findings confirm previous observations and illustrate the need for caution in considering further treatment of patients who have previously received cisplatin along with a second potentially nephrotoxic agent.Supported by the Cancer Research Campaign and the Imperial Cancer Research Fund     

Effect of unilateral nephrectomy on tumor growth of the murine renal cell adenocarcinoma and neuroblastoma

Compensatory renal growth has been observed following contralateral nephrectomy in man and in certain animals. In a recent study of murine Wilms' tumor, tumor growth was observed to be affected by contralateral nephrectomy; therefore, a murine renal cell adenocarcinoma and neuroblastoma were evaluated. Comparison of tumors in sham-nephrectomized animals to tumors in mice who had undergone unilateral nephrectomy showed no significant increase in tumor weights. However, the contralateral kidney in the uninephrectomized animals had increased in weight as compared to that in tumor-bearing intact mice and the kidneys removed at uninephrectomy. This study demonstrates that factors influencing compensatory renal growth do not affect all renal tumors or other solid tumors.     

Acceleration of late radiation damage of the kidney by unilateral nephrectomy.

Both increased proliferation as measured by labeling index and the appearance of abnormally large nuclei in renal proximal tubule cells, which have been observed in mouse kidneys after irradiation, were enhanced by subsequent unilateral nephrectomy. Nephrectomy alone induced only a transient increase in labeling index, lasting less than 1 month, whereas nephrectomy after irradiation induced an increase above that of the irradiated kidneys without nephrectomy lasting as long as 9 months. The incidence of large nuclei in kidneys from mice unilaterally nephrectomized 1 week after irradiation showed a rapid increase with time, peaking at 4.6% at 6 months, compared to more gradual increases with peaks at about 4.0% at 9 or 12 months in irradiated kidneys without nephrectomy or those in which nephrectomy was done prior to irradiation. This result demonstrates that nephrectomy after irradiation accelerates the appearance of this indicator of radiation damage, rather than enhancing the maximum amount of damage. Unilateral nephrectomy after irradiation also increased kidney damage 9 months later, as indicated by kidney weight loss and increased blood urea nitrogen. These results are consistent with our model for radiation damage of the kidney in which radiation induces cell proliferation and the appearance of reproductively dead, large nuclear cells that are lost at subsequent attempts to divide; the acceleration of radiation damage by unilateral nephrectomy performed after radiation could very well be a result of nephrectomy-induced enhancement in the proliferation of proximal tubule cells.     

超声引导经皮气冷微波固化在活体猪肝的实验研究

背景与目的:超声引导经皮微波固化术创伤小且疗效确实,目前已广泛运用于治疗小肝癌,但微波天线高杆温阻碍了该治疗方法的发展。本研究探讨新式气冷微波固化仪在肝癌微波固化治疗的应用前景。方法:应用ECO-100增强型气冷微波固化仪,在超声引导下对6头猪的肝脏进行活体微波凝固试验。结果:实验显示,运用气冷却技术进行微波固化可以降低微波天线杆温,从而可以通过增大微波输出功率及延长固化时间来增大固化范围;当微波功率为80W,辐射时间为10min时,单点凝固范围达到4.0cm×4.3cm;当微波功率为80W,辐射时间为20min时,凝固范围可达到4.7cm×5.2cm。而且气冷微波固化组织无“拖尾”现象。结论:气冷微波固化术可以降低微波天线杆温,增大微波功率和延长辐射时间,提高固化效果。     

The response of the pig kidney to the combined effects of cisplatin and unilateral renal irradiation

Seven mature Large White female pigs, approximately 10 months of age received a single dose of cis-dichlorodiammineplatinum(II), c-DDP (2.5 mg/kg body weight). Prior to, and 4 weeks after c-DDP administration, individual kidney glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by [99mTc]DTPA and [131I]hippuran renography. Of the 5 pigs surviving the c-DDP treatment most exhibited a reduction in both GFR and ERPF; the mean reduction in GFR (36.2 +/- 18.9%) was more pronounced than that for ERPF (12.6 +/- 19.4%). However, the difference in the severity of the impairment in these two parameters was not significant (p greater than 0.55). Haematocrit, haemoglobin and red blood cell counts were markedly reduced 14 days after c-DDP infusion, and despite some recovery evident 21 days after treatment, all three haematological parameters were still reduced 28 days after c-DDP administration. The right kidneys of these 5 animals, plus 5 pigs which did not receive c-DDP, were irradiated with a single dose of 11.9 Gy of 60Co gamma-rays. Individual kidney GFR and ERPF was routinely measured up to 24 weeks after irradiation. Pigs in which only the right kidney was irradiated showed a marked increase in both GFR and ERPF values 2 weeks after irradiation. This was followed by a decline in function with a reduction of 50% in terms of ERPF 16 weeks after irradiation. Values then showed some evidence of a recovery in function. There was a concomitant compensatory response by the contralateral unirradiated kidney.(ABSTRACT TRUNCATED AT 250 WORDS)     

经腹腔肾癌根治术治疗肾细胞癌155例经验总结

背景与目的:肾细胞癌是泌尿系统常见恶性肿瘤,手术切除为主要治疗.但手术是经腹腔还是经腰部切口、是否同时作淋巴结清扫以及淋巴结清扫是扩大淋巴结清扫还是区域淋巴结清扫,均存在争议.本研究回顾性分析经腹腔肾癌手术的手术时间、出血量、术后住院日、并发症和患者的生存率,总结经腹腔肾癌手术的经验.方法:1999年10月至2005年12月对155例肾癌患者采用经腹腔根治性肾切除和区域淋巴结清扫术.对155例患者的手术时间、出血量、术后住院日、并发症和生存率进行回顾性统计和分析.结果:本组手术时间为60～360 min(中位时间155 min):术中出血量为50～10 000ml)(中位出血量为200 ml),输血16例,平均输血量为11.5个单位红细胞(1个单位红细胞由200 ml全血制备).术中出血量＞500 m1有23例(14.8%),其中5例同时取腔静脉癌栓,出血量为600～6 000 ml(中位出血量为1 100m1).术后住院日6～46天(中位术后住院15天).术中并发症有脾脏损伤2例,腔静脉撕裂并十二指肠损伤1例,血管损伤2例,均于术中处理无后遗症.术后并发症有心衰1例,不完全性肠梗阻2例,经保守治疗治愈,无手术死亡.随访1～78.6个月,中位随访时间20.0个月.1年、3年和5年总生存率分别为93.2%(145/155)、84.1%(131/155)、74.8%(116/155);病理分期为Ⅰ、Ⅱ、Ⅲ和Ⅳ期的患者1年生存率分别为100%(78/78)、100%(34/34)、88.2%(25/28)、53.8%(8/15),3年生存率分别为89.7%(70/78)、95.5%(33/34)、75.6%(21/28)、44.9%(7/15),5年生存率分别为Ⅰ期89.7%(70/78)、Ⅱ期86.8%(30/34)、Ⅳ期0%(0/15).结论:经腹腔根治性肾切除术由于能首先处理肾血管和便于区域淋巴结清扫,出血少,疗效确切以及术中术后严重并发症少,可作为肾癌根治性肾切除的标准术式之一.     

Short-term functional and oncological outcomes of partial nephrectomy for renal cell carcinoma in patients with an anatomically or functionally solitary kidney: single-center experience

Background

We retrospectively investigated short-term functional and oncological outcomes of partial nephrectomy (PN) for the anatomically or functionally solitary kidney in patients with renal cell carcinoma.

Methods

Between 1993 and 2011, 193 partial nephrectomies were performed and 16 (8.3 %) had an imperative indication in our institution. The patients’ characteristics, peri- and postoperative complications, surgical margin status and postoperative changes in estimated glomerular filtration rates (eGFR) were assessed.

Results

The median follow-up period was 31.2 months and median age was 69.5 years. Open and laparoscopic PN were performed for 13 and 2 patients, respectively. One patient received ex-vivo PN followed by autotransplantation. There was no case with a positive surgical margin. All patients survived at the final day of observation. Median preoperative eGFR was 48.67 mL/min/1.73 m² and the reduction rate of eGFR at 3 months after operation was 20.9 % (0–50.2). Three patients (18.8 %) required temporary hemodialysis after operation and all these patients had stage 4 chronic kidney disease (CKD) before operation. Only one patient needed chronic hemodialysis at 8 months after operation.

Conclusions

PN can be performed safely and provides feasible functional and oncological outcomes. Preoperative CKD stage 4 patients may have a risk of temporary hemodialysis in the perioperative period.     

Possible application to medium-term organ bioassays for renal carcinogenesis modifiers in rats treated with N-ethyl-N-hydroxyethylnitrosamine and unilateral nephrectomy.

The effects of the renal tumor promoters; beta-cyclodextrin (beta-C), DL-serine (DL-S), basic lead acetate (LA), trisodium nitrilotriacetate monohydrate (NTA) and potassium bromate (KB), and diethylene glycol (DEG) as a negative control, on early stage of renal carcinogenesis were investigated in unilaterally nephrectomized male Wistar rats after N-ethyl-N-hydroxyethylnitrosamine (EHEN) administration. Wistar male rats were fed 1000 ppm EHEN diet for 2 weeks and the left kidney was removed at week 3, then the animals were divided into 7 groups of 15 rats each. These groups received the following treatments: 1000 ppm LA, 10000 ppm NTA or 500 ppm KB diet for 18 weeks from week 3; 45 mg/100 g body wt./day of beta-C injected sc for 7 days; 100 mg/100 g body wt. of DL-S injected sc biweekly for 6 weeks; 5% DEG in drinking water as a negative control for two days. Five rats in each group were killed at weeks 8, 12 and 20 and their kidneys were examined histologically. At week 20, the average numbers of adenomatous hyperplasias seen as preneoplastic lesions in the beta-C, DL-S, LA, NTA or KB groups were significantly higher than those in the DEG or control groups. Thus within a relatively short period of 20 weeks, promoting effects of chemicals can be detected as a significant increase of adenomatous hyperplasias in this model.     

机器人辅助腹腔镜与后腹腔镜肾部分切除术治疗早期肾癌的疗效比较

目的 比较机器人辅助经腹腹腔镜肾部分切除术（RALPN）与后腹腔镜下肾部分切除术（RLPN）治疗早期肾癌的疗效和安全性,探讨RALPN的临床应用价值。方法 选取2010年5月至2013年10月收治的70例肾癌患者,根据术式的不同分为RALPN组（n=36）和RLPN组（n=34）。比较两组手术时间、肾动脉阻断时间、术中出血量、术中输血率、术后住院时间及术后并发症发生情况。结果 除RLPN组有2例术中转开放手术,两组均成功完成手术。RALPN组和RLPN组的手术时间、肾动脉阻断时间、术中出血量、术后住院时间分别为（90.5±12.6）min和（110.7±20.3）min、（15.2±5.8）min和（24.6±7.2）min、（50.2±9.5）ml和（130.2±22.4）ml、（6.1±1.7）d和（7.8±2.2）d,两组比较差异均有统计学意义（P＜0.05）。RALPN组和RLPN组的术中输血率分别为0和11.8%。RALPN组术后出现1例肾周血肿,RLPN组出现1例尿漏和2例继发性出血。两组在随访期间均为无瘤生存。结论RALPN是治疗肾癌安全、有效的微创术式。     

Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study

BACKGROUND: Chronic kidney disease is a graded and independent risk factor for substantial comorbidity and death. We aimed to examine new onset of chronic kidney disease in patients with small, renal cortical tumours undergoing radical or partial nephrectomy. METHODS: We did a retrospective cohort study of 662 patients with a normal concentration of serum creatinine and two healthy kidneys undergoing elective partial or radical nephrectomy for a solitary, renal cortical tumour (相似文献   

后腹腔镜根治性肾切除术治疗肾癌的临床分析

目的 评价后腹腔镜根治性肾切除术治疗肾癌的安全性及疗效.方法 回顾性分析后腹腔镜根治性肾切除术治疗53例肾癌的临床资料.结果 53例患者中,52例成功施行后腹腔镜根治性肾切除术,1例因粘连较重改行开放手术.手术时间75～220min,平均125min;术中出血50～420 ml,平均120ml;术后住院时间为6～12 d.发生手术并发症4例.病理检查显示,透明细胞癌47例,嫌色细胞癌5例,囊性肾细胞癌1例.随访1个月至5年,未见肿瘤复发转移.结论 后腹腔镜根治性肾切除术治疗T1～2N0M0期肾癌安全、有效.

Abstract：

Objective To evaluate the safety and efficacy of retroperitoneal laparoscopic radical nephrectomy in the treatment of renal cancer. Methods The clinical data of 53 cases who underwent retroperitoneal laparoscopic radical nephrectomy were analyzed retrospectively. Results Fifty-two cases achieved successful retroperitoneal laparoscopic radical nephrectomy, a conversion to open surgery was required in one case because of severe adhesion. The operation time was 75 min to 220 min ( mean, 125 min), the blood loss was 50 ml to 420 ml ( mean, 120 ml), and the postoperative hospital stay was 6 d to 12 d. Complications occurred in 4 cases. Pathological examination showed that 47 cases were of renal clear cell carcinoma, 5 of chromophobe carcinoma, and 1 of cystic renal cell carcinoma. Follow-up for 1 month to 5 years showed no mimor recurrence and metastasis. Conclusion Retroperitoneal laparoscopic radical nephrectomy is a safe and effective treatment for patients with stage T1 ～2N0M0 renal cell carcinoma.     

Results of a prospective study comparing the clinical efficacy of cryoablation of renal cell cancer followed by immediate partial nephrectomy

Purpose

Evaluation if cryoablation of small renal tumours (RT) would facilitate the technique of laparoscopic partial nephrectomy (LPN) in a prospective study.

Patients and methods

In a prospective non-randomised study between April 2007 and October 2009, 16 patients with a mean age of 68 years (48–80 years) and a peripherally located RT were candidates for nephron-sparing surgery (5 open partial nephrectomy (OPN), 11 LPN). Cryoablation of RT was followed in the same session by open (K-OPN) and laparoscopic (K-LPN) partial nephrectomy. Perioperative and follow-up parameters were estimated. A matched-pair cohort of 41 patients (20 OPN, 21 LPN) who underwent standard operations due to the same indication has been selected for retrospective comparison (controls).

Results

Mean age for K-OPN was 74 years (69–83) with mean blood loss 140 ml (50–200); for K-LPN: 66.6 years (48–80) with 100 ml (50–700). All procedures were completed successfully without conversions (K-LPN), transfusions or intra-operative complications. Compared to OPN/LPN, K-OPN and K-LPN were associated with a longer operative time (P < 0.05) and a comparable postoperative hospital stay. There were no early postoperative complications. Cryoablation has not affected the histopathological evaluation of tumours or resection margins. Histopathology showed cytologic changes suggesting fresh coagulative necrosis, glomerular vascular congestion and interstitial haemorrhages following cryotherapy. One patient (K-LPN) developed a pararenal abscess necessitating puncture after 7 weeks. The follow-up (9–42 months) was uneventful.

Conclusions

The current study shows that K-LPN is feasible without increasing procedure morbidity or compromising surgical and oncological outcomes. It adds no advantage to tumour excision. Pathological findings document early cryoablation effects but viable tissue.     

Subtotal submucosal cricoid resection: an experimental study

It has generally been considered that the cricoid cartilage is essential for maintaining airway continuity. The purpose of this experimental study was to test this concept by evaluating the effects of subtotal excision of the canine cricoid cartilage. Eight adult mongrel dogs were studied. They received general anesthesia and were intubated. By using a vertical midline incision, the cricoid cartilage was exposed. Subtotal cricoid resection was performed by submucosal dissection; the mucosal continuity was not violated. The resultant defect in the cricoid cartilage was reconstructed with a polytetrafluoroethylene (PTFE) graft which was sutured in place with prolene sutures. All the dogs were extubated immediately after surgery. None required tracheostomy or ventilatory support and none had any respiratory problems during the follow-up period. They were all able to eat soon after surgery. The animals were followed for up to 4 to 6 months and then sacrificed to permit evaluation of the condition of the airway and subglottic space. There was fibrous scarring outside the graft but no evidence of airway narrowing. Despite submucosal fibrosis, the mucosa appeared normal. The data documented that dogs tolerate subtotal cricoid resection very well and develop no subglottic stenosis. The resultant defect in the cricoid cartilage can readily be reconstructed with a PTFE graft.     

Radical partial renal irradiation. an alternative to partial nephrectomy in bilateral Wilms' tumor.

A 6-year-old girl with simultaneous bilateral Wilms' tumor was treated with a radical nephrectomy on the side of more extensive involvement, followed by postoperative renal bed irradiation (3500 rads over 32 days) and radical partial renal irradiation (4000 rads over 35 days) to the contralateral disease. Concurrent and subsequent adjuvant actinomycin-D and vincristine were given. She has remained disease-free for over 5 years after primary therapy, with satisfactory renal function. This case report suggest that radical partial renal irradiation may be an alternative to partial nephrectomy in the management of the lesser involved kidney in some patients with bilateral Wilms' tumor.     

经后腹腔途径与经腹腔途径腹腔镜下肾部分切除术治疗肾门肿瘤的疗效比较

目的探讨经后腹腔途径与经腹腔途径腹腔镜下肾部分切除术治疗肾门肿瘤的疗效。方法将80例肾门肿瘤患者按手术入路方式不同分为经腹腔入路组(43例)和经后腹腔入路组(37例),比较两组患者手术相关指标、肾功能[血清肌酐(Cr)、肾小球滤过率(GFR)]、炎性因子[白细胞(WBC)、血清C反应蛋白(CRP)]、免疫功能[CD4+、CD8+、CD4+/CD8+]指标。随访1年,比较两组并发症及复发转移情况。结果经后腹腔入路组患者手术时间、术后肠道功能恢复时间、住院时间均明显短于经腹腔入路组(P﹤0.05);经腹腔入路组患者WBC、CRP均高于经后腹腔入路组,CD4+、CD4+/CD8+均低于经后腹腔入路组(P﹤0.05);两组患者Cr、GFR、并发症及复发转移情况比较,差异均无统计学意义(P﹥0.05)。结论腹腔镜下经腹腔入路与经后腹腔入路肾部分切除术治疗肾门肿瘤患者均具有显著疗效,但相较于经腹腔入路,经后腹腔入路能够缩短手术时间,促进术后恢复进程,且具有免疫保护作用。     

Epigenetic sampling effects: nephrectomy modifies the clear cell renal cell cancer methylome

Purpose

Currently, it is unclear to what extent sampling procedures affect the epigenome. Here, this phenomenon was evaluated by studying the impact of artery ligation on DNA methylation in clear cell renal cancer.

Methods

DNA methylation profiles between vascularised tumour biopsy samples and devascularised nephrectomy samples from two individuals were compared. The relevance of significantly altered methylation profiles was validated in an independent clinical trial cohort.

Results

We found that six genes were differentially methylated in the test samples, of which four were linked to ischaemia or hypoxia (REXO1L1, TLR4, hsa-mir-1299, ANKRD2). Three of these genes were also found to be significantly differentially methylated in the validation cohort, indicating that the observed effects are genuine.

Conclusion

Tissue ischaemia during normal surgical removal of tumour can cause epigenetic changes. Based on these results, we conclude that the impact of sampling procedures in clinical epigenetic studies should be considered and discussed, particularly after inducing hypoxia/ischaemia, which occurs in most oncological surgery procedures through which tissues are collected for translational research.

     

5-Bromodeoxyuridine-induced carcinogenesis and its modification by persistent estrus syndrome, unilateral nephrectomy, and X-irradiation in rats

We showed earlier that 5-bromodeoxyuridine (BrdUrd), which can substitute for thymidine during DNA synthesis, inducing transition mutations, is incorporated into DNA of various tissues when administered to newborn rats and is not subjected to repair processes. The main purpose of the present experiment is to verify if a direct perturbation of DNA would be sufficient to initiate carcinogenesis. Rats aged 1, 3, 7, and 21 days were given BrdUrd s.c. at a dose of 3.2 mg/animal. At 2 months some of the females were subjected to treatment known to induce persistent estrus; at 1 month a group of males underwent removal of one kidney, and groups of males and females were exposed to a single total-body X-irradiation at a dose of 1.5 Gy (150 rads) per rat. In females, treatment with BrdUrd induced tumors of the ovaries, polyps in the uterus, and tumors of the soft tissues, nervous system, forestomach, glandular stomach, and salivary gland; no such tumor occurred in control females. Induction of persistent estrus increased the incidences of ovarian tumors and of malignant tumors of the uterus. Treatment with BrdUrd also increased the carcinogenic effect of X-rays on the mammary gland. In males, BrdUrd induced tumors of the testis (seminomas) and adenomas of the thyroid gland; solitary tumors of the kidney, nervous system, soft tissues, and bladder were also found. Unilateral nephrectomy reduced the incidences of tumors in the testis and pituitary gland, whereas subsequent treatment with X-rays did not alter the incidences of tumors induced by BrdUrd. These studies demonstrated for the first time that a nucleoside analogue, BrdUrd, has carcinogenic potential. Possible molecular mechanisms for its carcinogenicity and for the effects of the promoting factors are discussed.