Low-Dose-Rate and High-Dose-Rate Brachytherapy for Localized Prostate Cancer in ABO-Incompatible Renal Transplant Recipients.

BACKGROUND: Brachytherapy is one of the standard treatments for localized prostate cancer (CaP). However, the feasibility of brachytherapy for renal transplant recipients (RTRs) is still uncertain. MATERIALS AND METHODS: Between August 2007 and March 2018, all patients who had undergone low-dose-rate (LDR) brachytherapy or high-dose-rate (HDR) brachytherapy for clinically localized CaP at our institution were retrospectively identified (n = 394). Of these patients, 3 had a history of renal transplantation. We reviewed all available clinical data retrospectively. RESULTS: All of the RTRs received ABO-incompatible renal grafts from their spouses and had stable renal graft function before the diagnosis of CaP. The median age at diagnosis of CaP was 65 years (range, 60-67 years). The median time between transplantation and brachytherapy was 7 years (range, 4-10 years). In all of the patients, clinical stage was cT1cN0M0. Two patients received 125I LDR-brachytherapy (dose, 145 Gy) and 1 patient was treated by 192Ir HDR brachytherapy (dose, 19 Gy in 2 fractions) combined with external beam radiation therapy of 39 Gy in 13 fractions. The median follow-up period after brachytherapy was 44 months (range, 34-50 months). During the follow-up period, none of the patients developed disease progression including biochemical recurrence or clinically significant adverse events associated with radiation therapy. CONCLUSIONS: LDR brachytherapy and HDR brachytherapy are safe and technically feasible in RTRs with CaP, and oncological outcomes in RTRs do not appear to be inferior to those of patients who did not receive renal transplant.

Expression of androgen receptor through androgen-converting enzymes is associated with biological aggressiveness in prostate cancer.

AIMS: The association between the expression of androgen receptor (AR) or androgen-converting enzymes and malignant potential in prostate cancer (PCa) was examined. METHODS: PCa specimens from 44 cases of stage II, 10 cases of stage III, four cases of stage IV and two recurrent cases were semi-quantitatively studied with immunohistochemistry for AR and androgen-converting enzymes. RESULTS: The expression scores for AR, 5alpha-reductase type 1 (SRD5A1), 5alpha-reductase type 2 (SRD5A2), and aldo-keto reductase family 1 member C3 (AKR1C3) in the metastatic lesion of stage IV or recurrent cancer (n = 6) were 284.2 (30.1), 300 (0.0), 279.2 (51) and 254.2 (74.9), respectively; these scores were significantly higher than the respective scores of 121.8 (82.1), 135.1 (59.7), 167.0 (66.4) and 150.5 (62.8) for stage II and III cancer (n = 54) (p<0.001, p<0.001, p = 0.002 and p = 0.018, respectively). The expression scores for AR and SRD5A1 in stage II and III cancer with Gleason score 7 (n = 19) were 128.7 (72.3) and 150.5 (52.9); these were significantly higher than the scores of 78.8 (67.2) and 100.0 (39.6), respectively, for cancers with a Gleason score of < or =6 (n = 20) (p = 0.032 and p = 0.002, respectively). The expression scores for AR, SRD5A1 and AKR1C3 in stage II and III cancer with primary Gleason pattern > or =4 (n = 21) were 158.1 (84.3), 158.3 (61.1) and 173.8 (64.8); these were significantly higher than the scores of 98.6 (72.8), 120.3 (54.7) and 135.6 (57.6), respectively, for cancers with primary Gleason pattern < or =3 (n = 33) (p = 0.011, p = 0.026 and p = 0.034, respectively). Within Gleason score 9 cancer, the expression scores for AR and SRD5A1 in the primary lesion of stage IV (n = 3) were 276.7 (5.8) and 283.3 (28.9); these scores were significantly higher than the scores of 182.1 (86.0) and 140.0 (56.6), respectively, for stage II and III cancer (n = 7) (p = 0.027 and p = 0.001, respectively). CONCLUSIONS: Both AR and androgen-converting enzymes were upregulated in high-grade or advanced PCa.

Importance of the intracrine metabolism of adrenal androgens in androgen-dependent prostate cancer.

The metabolic pathways of androgens and processes by which androgens induce re-growth after androgen deprivation therapy in prostate cancer have not been fully elucidated. In this study, finasteride decreased PSA secretion in medium containing testosterone, androstenedione, androstenediol and dehydroepiandrosterone, whereas dihydrotestosterone (DHT)- and hydroxy-flutamide-induced PSA production was not inhibited by finasteride in LNCaP-FGC cells. The present data show that adrenal androgen precursors do not directly interact with androgen receptors (ARs) but are converted to DHT via the intraprostatic metabolic pathways, resulting in the induction of LNCaP activity. This is the first report confirming this mechanism experimentally and also suggest the use of combined therapies that target ARs and prevent the formation of DHT within prostate cancer cells to achieve optimal therapeutic efficacy.

Absence of Bcl-2 and Fas/CD95/APO-1 predicts the response to immunotherapy in metastatic renal cell carcinoma.

Immunotherapy is the only available treatment for metastatic renal cell cancer (RCC), but the response rate is only about 20% and the treatment is occasionally associated with severe adverse effects. Thus, the selection of patients with a high susceptibility to immunotherapy is needed; however, there is no promising molecular marker that can predict the response to immunotherapy for RCC. This study was carried out to elucidate the potential role of apoptosis-related molecules Bcl-2 and Fas, as well as apoptotic and proliferating indexes (AI, PI) as predictors of the susceptibility of metastatic RCC to immunotherapy. Immunohistochemical examination of tumour tissues from 40 patients with metastatic RCC undergoing postoperative immunotherapy after radical nephrectomy was performed. Patients with progressive disease (PD) after immunotherapy presented with decreased survival (P=0.006). Progressive disease correlated with higher PI in the primary lesion (P=0.0087). All primary tumours of CR or PR patients were negative for Bcl-2, whereas among NC+PD patients, 40.6% were positive for Bcl-2 (P=0.0373). Patients in whom the primary tumours were both Bcl-2- and Fas-negative showed significantly better responses to immunotherapy in comparison with the remaining group (P=0.0022). The Bcl-2 and Fas status of the primary lesion may become useful criteria for the selection of patients with metastatic RCC for immunotherapy.

Prognostic impact of FAS/CD95/APO-1 in urothelial cancers: decreased expression of Fas is associated with disease progression.

The death receptor Fas (Apo1/CD95) and Fas ligand (FasL) system is recognised as a major pathway for the induction of apoptosis in vivo, and antiapoptosis via its blockade plays a critical role in carcinogenesis and progression in several malignancies. However, the function of Fas-FasL system in urothelial cancer (UC) has not been elucidated. We therefore investigated the expression of Fas, FasL and Decoy receptor 3 for FasL (DcR3) in UC specimens and cell lines, and examined the cytotoxic effect of an anti-Fas-activating monoclonal antibody (mAb) in vitro. Immunohistochemical examinations of Fas-related molecules were performed on 123 UC and 30 normal urothelium surgical specimens. Normal urothelium showed Fas staining in the cell membrane and cytoplasm. In UC, less frequent Fas expression was significantly associated with a higher pathological grade (P < 0.0001), a more advanced stage (P = 0.023) and poorer prognosis (P = 0.010). Fas and the absence thereof were suggested to be crucial factors with which to select patients requiring more aggressive treatment. Moreover, low-dose anti-Fas-activating mAb sensitised resistant cells to adriamycin, and this synergistic effect could be applied in the development of new treatment strategy for UC patients with multidrug-resistant tumours.

Impact of frequent Bcl-2 expression on better prognosis in renal cell carcinoma patients.

Previously, we reported that Bcl-2 was frequently expressed in renal cell carcinoma (RCC) specimens, but p53 mutation was a rare event. However, it was unclear whether Bcl-2 positivity was associated with the clinicopathological characteristics and prognosis in RCC. Therefore, we investigated the expression of Bcl-2 protein and its roles in 101 RCC specimens. In addition, the proliferation index (PI), apoptotic index (AI), caspase-3 and p53 expression were examined. The immunohistochemical method was applied for Bcl-2, caspase-3 and p53 protein expression. To investigate the proliferation activity and apoptosis of tumour cells, PI and AI were calculated based on Ki-67 and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL)-positive cells, respectively. Bcl-2 expression was detected in 72 out of 101 (71.3%) specimens. Bcl-2 positivity was inversely correlated with PI (P<0.0001) and AI (P=0.0074). Furthermore, Bcl-2 positivity was significantly correlated with better survival (P=0.0014), and was associated with lower stage (P=0.0301) and grade (P=0.0020). In RCC, frequent Bcl-2 expression was correlated with favourable character without higher PI and AI. Thus, Bcl-2 expression might be applied as a novel predictor of better prognosis in RCC patients.

[Usefulness of semi-skeletonized right gastroepiploic artery].

The right gastroepiploic artery (RGEA) could be harvested easily and safely by using an ultrasonic scalpel. It is easier and faster not to remove a satellite vein from RGEA than to skeletonize it fully. And blood flow of the vein is important, because it is the flow of vasa vasorum of RGEA. Among 70 patients who have bypassed to right coronary arteries (RCA), 25 patients were treated with semi-skeletonized RGEA (SSK-RGEA), the other 45 patients were operated with pedicled RGEA or (if pedicled RGEA was short and small) with the other grafts. An availability of SSK-RGEA for RCA was 100%. And that of pedicled RGEA was 47% (p < 0.001). Twenty-eight patients were operated without a pump. Twenty-three of them (82%) were bypassed with RGEA. In the on-pump cases (42 patients), RGEA were used for 13 (31%) cases (p < 0.05). Early post-operative angiographies revealed 1 occlusion. But the site of occlusion was the origin of RGEA branch from a gastro-duodenal artery, and the anastomotic site was patent. This graft was supposed to be occluded post-operatively by arteriosclerosis. Flow competition occurred in two grafts. In conclusion, the SSK-RGEA was useful for RCA bypass grafting. The reliability of RGEA should increase the indication of off-pump coronary artery bypass grafting.

[A randomized cross-over comparative study of granisetron alone and combination of granisetron, methylprednisolone and droperidol as antiemetic prophilaxis in CDDP-based chemotherapy for gynecologic cancer].

A cross-over clinical trial was carried out to compare the efficacy and safety of granisetron alone (40 micrograms/kg) as a "single" group, with that of granisetron, methylprednisolone (250 mg/ body) and droperidol (0.5 ml/body) as a "cocktail" group for control of emesis and vomiting induced by CDDP-based chemotherapy in 68 courses of 34 patients with gynecologic malignancies. At the first course, "single" or "cocktail" drugs were administered at day 1, 2, and 3 of chemotherapy, and at the second course, "cocktail" or "single" drugs in as cross-over fashion. We examined the degree of nausea and frequency of vomiting during the first 7 days of chemotherapy. As for the severity of nausea, the "single" group showed prominent nausea immediately after CDDP and the most severe level at the 3rd or 4th day. The "cocktail" group showed mild symptoms from the next day and it lasted for several days. Vomiting started 12 hours later in the "single" group and the most frequent peak was the 2nd day, whereas the "cocktail" group showed less than one vomiting at the 2nd or 3rd day throughout the treatment. Clinical response (extremely good, good) in the current series of 68 courses of chemotherapy was also evaluated to be 45% and 35% in the "single" group, respectively, against 75% and 20% in the "cocktail" group, respectively. There was no clinical toxicity or side effects in either treatment group. We conclude that the cocktail treatment is very useful for not only acute, but also late emesis in CDDP-based chemotherapy in gynecologic malignancies.

Coronary artery revascularization concomitant with vascular surgery.

Patients with vascular disease and coronary disease are usually treated initially by coronary artery bypass grafting (CABG), and vascular surgery is generally performed later. In this study we assessed the feasibility of combined CABG and vascular surgery in a single operation. Between 1988 and 1995, 16 patients received combined operations for vascular and cardiac lesions and the clinical results were assessed. There were no operative or hospital deaths. The mean time for operation was 421 min and the duration of the stay in the intensive care unit (ICU) was a mean of 3.6 days. In one patient with an ischemic left leg, the left internal thoracic artery (ITA) had become a collateral source of the ischemic leg, and the need for preoperative angiography of the ITA in such patients was indicated. The combined operation clearly takes longer than either vascular surgery or CABG alone, but the length of the postoperative intensive care unit stay was essentially the same as that after a single operation and the patient was still managed safely after the combined operation. In patient requiring both operations, the combined procedure therefore appears to be safe and to have a good clinical outcome.

Antineoplaston AS2-1 for maintenance therapy in liver cancer.

Antineoplaston AS2-1 exhibits cytostatic growth inhibition of human hepatocellular carcinoma cells in vitro and showed minimum adverse effects in a phase I clinical trial. Liver cancer is difficult to control because of multicentricity and underlying liver disease. We reviewed two clinical cases of liver cancer (hepatocellular carcinoma and multiple liver metastases from colon cancer) in whom we believe antineoplaston A2-1 was useful as a maintenance therapy after transcatheter arterial embolization (TAE) and microwave coagulation necrosis (MCN). The two patients have continued to be in good condition for more than two years without limitation of their normal activities. Antineoplaston AS2-1 may be effective and useful as a maintenance agent after TAE and MCN in patients with liver cancer.

Inhibitory effect of antineoplaston A10 and AS2-1 on human hepatocellular carcinoma.

Antineoplastons, first described by Burzynski, are naturally occurring peptides and amino acid derivatives which control neoplastic growth. Antineoplaston A10 (3-pehnylacetylamino-2,6-piperidinedion) is the first chemically identified antineoplastons and when it is administered orally it is hydrolysed in pancreatic juice to phenylactylglutamine and phenylacetylisoglutamine in the ration of 4 to 1. These metabolites are water soluble and have antitumor effect, they are further degraded to pehnylacetic acid. The mixture of phenylacetylglutamine and phenylacetylisoglutamine in the ratio of 4 to 1 was formulated as Antineoplaston A10 injectable formulation. The mixture of phenylacetylglutamine and phenylacetic acid in the ratio of 1 to 4 was also shown to have antitumor effect in tissue culture study, then formulated as Antineoplaston AS2-1. The reported cytostatic inhibitory effect of A10 on human hepatocellular carcinoma cells and differentiation inducing effect of AS2-1 on various tumor cells suggest potential benefit for the treatment of human hepatocellular carcinoma since this tumor recurs frequently despite initial successful treatment. We report here the effects of Antineoplaston A10 and AS2-1 on cell proliferation, cell morphology, cell cycle, and DNA in human hepatocellular carcinoma cell lines. Both agents inhibited cell proliferation and increased the number of cells in G0 and G1 phases and Antineoplaston AS2-1 induced apoptosis, we also describe our clinical experience of a hepatocellula carcinoma (HCC) patient whose tumor, after incomplete trancathere arterial embolization (TAE) for a 7cm 7cm HCC, has been stable for more than 15 months during which time he has been taking Antineoplaston AS2-1 continuously without any serious adverse effects.

[Partial brachiocephalic perfusion in aortic arch replacement].

Twenty patients with aneurysm or dissection of the aortic arch underwent surgical treatment using partial brachiocephalic perfusion (PBP). The right subclavian artery (SA) and common femoral artery were separately cannulated and perfused by individual pump heads. The flow to SA was 4.5-11 (9.9 +/- 1.4) ml/min/kg. The mean distal stump pressure of the left superficial temporal arteries before beginning the CPB were 36-64 (50.6 +/- 8.3) mmHg. The rectal temperature during PBP was maintained at 20.1-25.0 degrees C. The PBP time ranged 32 to 157 min. We studied the oxygen saturation of left internal jugular vein (SjO2) and cerebral circulatory index (CCI) during the PBP. SjO2 ranged from 72.9 to 99.4% and CCI were maintained at more than twice the CCI measured before beginning the CPB. We applied this simplified method (PBP) to the 20 patients with aortic aneurysms. No neurological complication were seen in these 19 patients without one patient. These clinical studies suggest that the PBP under hypothermic CPB is a safe and reliable method of cerebral protection for replacement of the aortic arch.

[A case of spontaneous rupture of the ascending aorta].

We report a rare case of spontaneous rupture of the ascending aorta without any evidence of aneurysm formation or aortic dissection. A woman aged 64 was admitted to our cardiac care unit as an emergency patient with severe chest pain. Her face was pale and systolic blood pressure was 70 mmHg in spite of intravenous administration of dopamine (10 micrograms/kg/min). She had a history of hypertension for two years under good medical control. No trace of the chest trauma was noted before her admission. Physical examination revealed neck vein engorgement and distant heart sounds. Chest X-ray film showed enlargement of the cardiac silhouette. ECG showed no evidence of acute coronary syndrome. Pericardial effusion with a floating hematoma-like mass was detected by 2-dimensional echocardiogram. Pericardiocentesis revealed bloody pericardial fluid (Ht: 26%). Aortagraphy was performed resulting in a clinical diagnosis of acute aortic dissection, but there were no signs of a false lumen, aneurysm formation or extravasation of the contrast medium. Although continuous pericardial drainage was performed, she suddenly lost consciousness, collapsed and died. A longitudinal intimal laceration 5 cm long was observed in the ascending aorta. Pathological examination revealed cystic medial necrosis and irregularity of the elastic fibers in the media. No atheromatous plaque was noted in the intima. Spontaneous rupture of the aorta is a life-threatening condition that requires urgent surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Sequence specific block of in vitro DNA synthesis with isopropyl phosphotriesters in template oligodeoxyribonucleotides.

We have synthesized four oligodeoxyribonucleotides each bearing an isopropyl phosphotriester at a defined position. These oligomers were used as templates for in vitro DNA synthesis catalyzed by Escherichia coli DNA polymerase I large fragment. Results showed that the phosphotriester inhibits the DNA chain elongation and the level of the inhibition is dependent on the base 5' to the phosphotriester.

Partial brachiocephalic perfusion under hypothermic cardiopulmonary bypass. An experimental study.

We studied electrophysiological, oxygen metabolic, and histological variables in dogs to establish the reliability and safety of partial brachiocephalic perfusion (PBP) under hypothermic cardiopulmonary bypass (CPB) at 23 degrees-25 degrees C. Sixteen mongrel dogs were divided into two groups. Six (control group) underwent typical hypothermic CPB for 90 min, and 10 (PBP group) underwent PBP under hypothermic CPB for 90 min. During core cooling on the CPB, a progressive reduction in voltage and slowing of frequency of the electroencephalogram (EEG) was observed. At around 23 degrees C nasopharyngeal temperature the tracing became almost flat and remained so throughout the hypothermic CPB or the PBP under hypothermic CPB. Consistent recovery of the EEG was, however, observed during the period of rewarming on the CPB, and the voltage and frequency of the EEG recovered to control levels on weaning off CPB at 36 degrees C in both groups. In the PBP group, the cerebral arteriovenous oxygen (AVO2) difference was 12.4 +/- 4.0 vol% before beginning the CPB, and it was 5.6 +/- 2.7, 5.7 +/- 3.1, 5.4 +/- 3.3, and 4.9 +/- 2.9 vol% at 10, 30, 60, and 90 min respectively after commencement of the PBP under hypothermic CPB. The cerebral AVO2 difference measured 10 min after commencement of the PBP was significantly less than that in the control group (P less than 0.05), but otherwise there were no significant differences between cerebral AVO2 differences in the two groups. Concentration of serum creatine kinase-BB (CK-BB) gradually increased in proportion to the duration of CPB in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cardiovascular surgery in patients seventy years of age and older].

During 10 years between 1981 and 1990 surgical treatment was performed in 77 elderly patients (emergency 19) for cardiovascular disease at the 2nd Dept of Kurume Univ. Hospital. The 58 elective patients were studied. There were CABG in 29; valve replacement in 18; aneurysm operation in 11. The control patients were consisted of CABG in 60; valve replacement in 40; and aneurysm operation in 20 patients whose age were under 60 years. In the elderly group, operative mortality was 3 in 58 (5.2%) and there were no significant differences compared to that in the control patients. However, low output syndrome or respiratory complication was relatively prevented in the elderly patients and careful post operative management was required. The late results in the elderly patients NYHA or exercise tolerance was improved well. The 5 years actuarial survival rate was 93.3% in ischemic heart disease group, 87.7% in valvular heart disease group, and 90.0% in thoracic aneurysm group. No significant difference was seen compared to these results in control patients and no significant differences among these diseases.

[Coronary artery bypass grafting combined with operation for non-cardiac disease].

During the last two years and six months, ten patients underwent operation for both coronary artery disease and non-cardiac surgery. There were six patients with vascular disease, three with gastric cancer and one with cholelithiasis. Six patients had simultaneous operation of both coronary artery bypass grafting (CABG) and non-cardiac surgery, and four underwent non-cardiac surgery mean of 105 days after CABG. The number of significant lesions of coronary artery in patients with simultaneous or two-staged operation was 2.2 +/- 0.8 or 2.8 +/- 0.5 per patient, respectively. The operative time in patients with simultaneous operation was 361 +/- 49 minutes. However, in patients with staged operation the time for cardiac surgery was 380 +/- 36 minutes and the time for non-cardiac operation was 388 +/- 83 minutes. There were no patients with complications after either cardiac or non-cardiac operation. In patients having surgical indications for both coronary artery and non-cardiac diseases, CABG should be performed prior to the non-cardiac surgery. In patients with normal cardiac function and sufficient operative time after CABG, concomitant operation seemed to be recommended. In case with advanced malignant disease or incompetent cardiac function, staged operation would be selected for good surgical result.

Primary anastomosis for acute ascending aortic dissection.

Intimal tear resection and primary anastomosis of the aorta were used for the treatment of eight patients with DeBakey I and II type acute aortic dissection. Five patients were of DeBakey I type, and three patients were of the II type. Moderate or severe aortic regurgitation (AR) was observed in six of eight patients. The site of the intimal tear was diagnosed by intraoperative echocardiography, and the adventitia corresponding to the intimal tear was transversely opened under total cardiopulmonary bypass. While resuspension of the aortic valve was performed on only one of six patients, AR disappeared in four, postoperatively. Two of eight patients died early postoperatively. The cause of death was postoperative cardiac tamponade in one patient and cerebral herniation in the remaining one. The other six patients have been observed for a mean period of 27 months. There is no late death, and they show no dilatation of the aortic root and deterioration of AR. We believe that this operative method is a simple and safe emergency procedure for DeBakey I and II type acute aortic dissection.

Spontaneous rupture of the ascending aorta.

A case of spontaneous non-traumatic rupture of the thoracic aorta in a hypertensive patient is presented. The clinical findings suggested acute aortic dissection, and a large pericardial effusion was detected by echocardiography. The typical angiographic features of aortic dissection were not found. Autopsy revealed a longitudinal intimal tear and a rupture in the postero-lateral aspect of the ascending aorta. No false lumen was seen in the ascending aorta. When acute intrapericardial or intrapleural bleeding develops with no evidence of aortic aneurysm or dissection, spontaneous aortic rupture should be suspected.