Initial Experience With Hand-Assisted Laparoscopic Living Donor Nephrectomy: Training and Clinical Practice as a General Surgeon.

BACKGROUND: To analyze our initial results of hand-assisted laparoscopic living donor nephrectomy, executed by a skilled gastrointestinal surgeon. METHODS: A total of 22 consecutive patients underwent the hand-assisted laparoscopic living donor nephrectomy between December 2014 and January 2017. We retrospectively analyze the patient's perioperative clinical data, which were collected prospectively. RESULTS: The right kidney was harvested in 12 patients. The mean operative time and intraoperative blood loss was 241.0 ± 43.4 minutes (range, 140-310 min) and 293.2 ± 203.1 mL (range, 50-700 mL), respectively. The mean warm ischemic time was 288.4 ± 103.4 seconds (range, 179-610 s). Postoperative complications included chyle leakage in 2 patients who were left kidney donors and oliguria in 1 patient who was a right kidney donor. All patients recovered with conservative care, and the mean hospital stay was 7.5 ± 1.7 days. The mean creatinine level was 0.7 ± 0.2 mg/dL before surgery, 1.1 ± 0.3 mg/dL at postoperative day (POD) 1, and 1.0 ± 0.2 mg/dL after discharge. The mean glomerular filtration rate was 97.9 ± 18.2 mL/min/1.73 m2 before surgery, 60.7 ± 10.4 at POD 1, and 67.3 ± 11.1 after discharge. Operation time was not associated with patient body mass index and case number. No significant differences, other than postoperative complications, were found in the perioperative data for the side of kidney donation. CONCLUSION: A skilled surgeon with experience in laparoscopic abdominal surgery (such as gastrectomy or colectomy) might safely perform hand-assisted donor nephrectomy. However, we could not identify a clear case number to complete the learning curve.

Importance of Timed and Detailed Evaluation of Kidney Transplantation Candidates.

Kidney transplant recipients are at increased risk of cardiovascular morbidity and malignant neoplasm, and meticulous evaluation of potential recipients is needed to minimize risks of complications after transplantation. The purpose of this study was to analyze the results of preoperative assessments and document the importance of timed and detailed examinations. METHODS: Medical records of patients evaluated as kidney transplant candidates from January 2015 to September 2017 were retrospectively collected and analyzed. RESULTS: Of the 216 patients evaluated during the study period, 135 (62.5%) were male, 112 (51.9%) had diabetes mellitus, 163 (75.5%) had hypertension, 31 (14.4%) had a cardiovascular event history, and 7 (3.2%) had previous history of malignant neoplasms. Mean (SD) patient age was 50.7 (10.8) years. All 216 recipient candidates underwent echocardiography. Mean (SD) ejection fraction was 57.8% (5.9%), and 48 candidates (22.2%) showed regional wall motional abnormality. Coronary angiography was performed on 81 candidates, and in 57 (70.4%) of these, coronary artery disease was detected. Malignant neoplasms were detected in 10 (4.6%) candidates. Kidney transplantation was performed on 55 candidates. One recipient died of Pneumocystis jirovecii pneumonia at 15 months after kidney transplant, but there was no death-censored graft failure, newly detected malignant neoplasm, or cardiovascular event over a mean (SD) follow-up duration of 15.5 (8.6) months. CONCLUSION: Evaluation of kidney transplant candidates resulted in diagnoses of malignant neoplasms in 4.6% of patients and coronary artery disease in 26.4% of patients. The results of this study demonstrate candidates for kidney transplant should undergo detailed preoperative evaluation.

Chemopreventive efficacy of arylalkyl isothiocyanates and N-acetylcysteine for lung tumorigenesis in Fischer rats.

The purpose of this study is to evaluate the efficacy of three promising sulfur-containing compounds, 6-phenylhexyl isothiocyanate (PHITC), phenethyl isothiocyanate (PEITC), and N-acetylcysteine (NAC), as chemopreventive agents in a long-term bioassay for lung tumorigenesis in F344 rats. PEITC occurs as a constituent of certain cruciferous vegetables, PHITC is a synthetic homologue, and NAC is an endogenous substance. Male F344 rats were treated with the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by s.c. injection at a dose of 1.5 mg/kg body weight three times weekly for 20 weeks. This dose regimen induced a 67% tumor incidence in the lung, a major target organ of NNK. PHITC or PEITC administered in the diet for 22 weeks, a period covering from 1 week before to 1 week after the NNK treatment, exhibited significant inhibition of lung tumorigenesis induced by NNK. The lung tumor incidences in the NNK-treated groups, fed a diet containing 4 mmol/kg (876 ppm) or 2 mmol/kg (438 ppm) PHITC, were 24 and 19% and were 9 and 17% in groups fed PEITC at concentrations of 8 mmol/kg (1304 ppm) or 4 mmol/kg (652 ppm), respectively. In contrast to isothiocyanates, NAC given in the diet at 80 mmol/kg (13056 ppm) or 40 mmol/kg (6528 ppm) exerted no inhibitory effects on the NNK-induced lung tumorigenesis. At the dose studied, NNK did not induce liver and pancreatic tumors in the treated animals, but a significant increase of nasal cavity tumor incidence was observed in the NNK-treated group. However, none of the test compounds showed any effect on the tumorigenesis in this tissue. This study demonstrated that PHITC and PEITC were potent chemopreventive agents for the NNK-induced lung tumorigenesis in F344 rats, whereas NAC was not active at all. These results support further evaluation of these compounds in chemoprevention studies.

Structure-activity relationships of isothiocyanates as mechanism-based inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in A/J mice.

A structure-activity relationship study was carried out to identify structural features in arylalkyl and alkyl isothiocyanates that are associated with the inhibitory potency of these compounds against lung tumorigenesis induced in A/J mice by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These features include the alkyl chain length, phenyl substitution, and secondary isothiocyanates. The naturally occurring allyl isothiocyanate, phenethyl isothiocyanate, and the synthetic analogues such as 6-phenylhexyl isothiocyanate, 8-phenyloctyl isothiocyanate, 10-phenyldecyl isothiocyanate, 1,2-diphenylethyl isothiocyanate, 2,2-diphenylethyl isothiocyanate, and alkyl isothiocyanates (with 1-hexyl, 2-hexyl, and 1-dodecyl as alkyl moieties) were assayed in mice for their tumor inhibitory potential. The isothiocyanates were given in corn oil by gavage at doses of either 0.04, 0.1, and 0.2 mumol or 1 and 5 mumol 2 h prior to a single i.p. injection of 10 mumol NNK. Mice were sacrificed 16 weeks later and lung adenomas were counted. At 0.2 mumol, 8-phenyloctyl isothiocyanate and 10-phenyldecyl isothiocyanate were stronger inhibitors than the previously tested 6-phenylhexyl isothiocyanate, but the difference in potency was not obvious at the lower doses. At both 1 and 5 mumol, allyl isothiocyanate was inactive, while the other five synthetic isothiocyanates were considerably more potent than phenethyl isothiocyanate. In the alkyl isothiocyanate series, 2-hexyl isothiocyanate was more potent than 1-hexyl isothiocyanate, while 1-dodecyl isothiocyanate was the most potent at 1 mumol, reducing tumor multiplicity in the group treated with NNK alone from 11.1 to the background level. Also, 1,2-diphenylethyl isothiocyanate appeared to be a stronger inhibitor than 2,2-diphenylethyl isothiocyanate. In this study we have shown that the phenyl moiety is not essential for the inhibitory activity since alkyl isothiocyanates exhibit strong inhibitory effects against lung tumorigenesis. We have also shown that secondary isothiocyanates possess a higher potency than their structural isomers bearing a primary isothiocyanate. From results of this study and of seven previously studied isothiocyanates, we conclude that the observed inhibitory potency of isothiocyanates in the A/J mouse lung tumor model is correlated with their partition coefficients (log P) and the pseudo first order rate constants for the reaction of isothiocyanates toward glutathione (kobs). These results reveal that both high lipophilicity and low reactivity of isothiocyanates are important for inhibitory activity toward NNK-induced lung tumorigenesis. These observations provide a structural basis for the discovery of more effective chemopreventive agents.

Structure-activity relationships for inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone lung tumorigenesis by arylalkyl isothiocyanates in A/J mice.

Phenethyl isothiocyanate (PEITC), 3-phenylpropyl isothiocyanate (PPITC), 4-phenylbutyl isothiocyanate (PBITC), and the newly synthesized 5-phenylpentyl isothiocyanate (PPeITC), 6-phenylhexyl isothiocyanate (PHITC), and 4-(3-pyridyl)butyl isothiocyanate (PyBITC) were tested for their abilities to inhibit tumorigenicity and DNA methylation induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the lungs of A/J mice. Mice were administered isothiocyanates by gavage for 4 consecutive days at doses of 5, 1, or 0.2 mumol/day prior to administration of 10 mumol of NNK by i.p. injection. Mice were sacrificed 16 weeks after NNK administration and pulmonary adenomas were quantitated, PEITC effectively inhibited NNK-induced lung tumors at a dose of 5 mumol/day but was not inhibitory at doses of 1 or 0.2 mumol/day. PPITC, PBITC, PPeITC, and PHITC were all considerably more potent inhibitors of NNK lung tumorigenesis than PEITC. While virtually no differences in inhibitory activity could be ascertained for PPITC, PBITC, and PPeITC, PHITC appeared to be the most potent tumor inhibitor of all of the compounds. At a dose of 0.2 mumol/day, PHITC pretreatment reduced tumor multiplicity by 85%. PyBITC, an analogue of both NNK and PBITC, was ineffective as an inhibitor. Using the same protocol, the compounds were found to have qualitatively similar inhibitory effects on NNK-induced DNA methylation when administered at 1 mumol/day. These results extend our previous findings that increased alkyl chain length enhances the inhibitory activity of an arylalkyl isothiocyanate toward NNK lung tumorigenesis and demonstrate the exceptional chemopreventive potentials of two new isothiocyanates, PPeITC and PHITC.

Effects of deuterium substitution on the tumorigenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in A/J mice.

Bioassays and DNA-binding studies of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its analogs with deuterium substitution at the positions alpha to the nitrosamino group ([4,4-D2]NNK and [CD3]NNK) were carried out in A/J mice in order to assess the potential importance of DNA methylation or pyridyloxobutylation in lung tumor induction. The tumorigenic activities of the major NNK metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its analog with deuterium at the carbinol carbon ([1-D]NNAL) were also determined. Groups of A/J mice were given single i.p. injections of either 10 or 5 mumol of NNK, [4,4-D2]NNK, [CD3]NNK, NNAL and [1-D]NNAL, and were killed 16 weeks later. Lung tumor multiplicities were as follows in mice treated with 10 mumol: NNK, 7.3 +/- 3.5; [4,4-D2]NNK, 1.4 +/- 1.6; [CD3]NNK, 11.7 +/- 5.4; NNAL, 3.2 +/- 2.0; [1-D]NNAL, 3.2 +/- 2.0. Similar relative tumorigenic activities were observed in mice treated with 5 mumol of these compounds. These results demonstrated that [4,4-D2]NNK was less tumorigenic than NNK and [CD3]NNK was more tumorigenic than NNK. NNAL was less tumorigenic than NNK; substitution of deuterium at the carbinol carbon did not affect its activity. Levels of O6-methylguanine (O6-mG) were measured in pulmonary DNA of A/J mice treated with 10 mumol of NNK, [4,4-D2]NNK or [CD3]NNK, and killed 2 or 24 h later. O6-mG levels were lower in mice treated with [4,4-D2]NNK than in those treated with NNK; no difference in O6-mG levels was observed between those treated with NNK and [CD3]NNK. The results of this study support the hypothesis that O6-mG formation in pulmonary DNA is the key step in lung tumor induction by NNK in A/J mice.

Rapid single-dose model for lung tumor induction in A/J mice by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and the effect of diet.

This paper describes the development of a relatively rapid single-dose model for induction of lung adenomas in female A/J mice by the tobacco-specific nitrosamine 4-(methylnitros-amino)-1-(3-pyridyl)-1-butanone (NNK). Mice maintained on AIN-76A semi-synthetic diet were given a single i.p. dose of 2.5, 5 or 10 mumol NNK in saline and killed 3-7 months later. Maximum lung tumor induction, measured by lung tumors per mouse (tumor multiplicity), occurred in 3.5 months. There was no significant increase in tumor multiplicity between 3.5 and 7 months. Four months after treatment, numbers of lung tumors per mouse were 11.9 +/- 1.0 (10 mumol NNK), 3.6 +/- 0.4 (5 mumol), 0.9 +/- 0.4 (2.5 mumol) and 0.07 +/- 0.1 (saline). Lung tumor multiplicity in mice treated with a single dose of 10 mumol NNK and maintained on AIN-76A diet was significantly higher (8.3 +/- 0.5) than in mice treated with NNK and maintained on NIH-07 diet (2.5 +/- 0.3). The results of this study establish a useful bioassay for identification of compounds that can modify NNK-induced lung tumorigenesis.

Transfer of the tobacco-specific carcinogens N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene into the milk of lactating rats.

The extent to which some of the more prevalent and potent carcinogens in cigarette smoke could be transferred from circulating blood into the milk of lactating rats was determined. One hour after i.v. administration of benzo[a]pyrene (BaP), N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to the dams, the levels of these carcinogens were determined in both blood and milk specimens. The average amount of radioactivity detected 1 h after administration of 14C-labeled BaP was 0.21% of the administered dose per ml of milk as compared with 0.17% per ml of blood. The amount of NNN in milk ranged from 0.20 to 0.36% of the administered dose per ml which closely paralleled the levels detected in blood. NNK is readily converted in vivo to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). The sum of NNK and NNAL was similar in the blood and milk of treated dams. There was, however, a major difference in the ratio of NNAL/NNK as detected in milk and blood. The ratio of NNAL/NNK in blood ranged from 1.3:1 to 1.9:1 while the ratio in milk ranged from 2.4:1 to 3.3:1. In a comparative study of the levels of NNN in the blood and milk of lactating rats at less than 1.0, 20, 60, 120 and 240 min after administration, it was confirmed that similar concentrations of NNN are present in blood and milk 1 h after administration. These data indicate that these carcinogens, which are present in both cigarette smoke and tobacco, can be transferred into the milk of lactating rats.

Effect of dietary Laminaria angustata (brown seaweed) on azoxymethane-induced intestinal carcinogenesis in male F344 rats.

The effect of dietary Laminaria angustata (brown seaweed) on azoxymethane (AOM)-induced intestinal carcinogenesis was studied in male F344 rats. Five-week old rats were fed semipurified diets containing 0 and 10% seaweed. When the rats were 7 weeks old, all except the vehicle-treated groups received weekly subcutaneous injections of AOM in normal saline for two weeks (20 mg/kg body wt/week). All animals were fed the experimental diets until the termination of the experiment, which was 28 weeks after the last AOM injection. The incidence (percent of animals with tumors) and multiplicity (tumors/animal) of small intestinal tumors did not differ significantly between the control and seaweed groups. The incidence and multiplicity of colon adenomas along with the size of colon tumors were increased in rats fed the seaweed diet compared with those fed the control diet. Dietary seaweed had no major effect on the concentration of fecal bile acids; however, the concentration of fecal cholesterol and total neutral sterols was decreased in the seaweed group. These results suggest that dietary seaweed increases the risk for colon tumors.