Hepatic arterial infusion of verapamil and doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration: pharmacological evaluation of reduction in systemic drug exposure and assessment of hepatic toxicity.

Tumour resistance to chemotherapeutic drugs through expression of the multidrug resistance phenotype is a major impediment in the treatment of hepatic malignancies. We performed hepatic arterial infusion of verapamil (at a dose known to block P-glycoprotein activity) and doxorubicin combined with complete hepatic venous isolation and extracorporeal chemofiltration in non-tumour-bearing pigs with normal livers to evaluate the pharmacology and toxicology of this drug combination. The complete hepatic venous isolation-chemofiltration system significantly reduced system exposure to both verapamil and doxorubicin (P < 0.01). Hepatic arterial infusion of verapamil (2 mg/kg) alone did not result in hepatocellular toxicity. However, the combination of verapamil and doxorubicin (3 mg/kg or 5 mg/kg) produced significant elevations in liver enzymes (P < 0.01), and gross histological evidence of liver damage in 90% of the treated animals. The results of this study indicate that hepatic arterial infusion of verapamil and doxorubicin, in an attempt to improve treatment response in unresectable liver tumours expressing the multidrug resistance phenotype, may not be tolerated by patients with limited hepatic reserve.

Metabolic effects of single-dose pamidronate administration in prostate cancer patients with bone metastases.

BACKGROUND: Increased osteolysis usually accompanies sclerotic bone metastases from prostate cancer. This provides a rationale for the use of bisphosphonates to treat bone pain and prevent skeletal complications. METHODS: The fasting urinary levels of calcium, hydroxyproline (OHPRO), pyridinolines (PYD), deoxypyridinolines (DPYD), collagen cross-linked N-telopeptide (NTX) and the serum values of calcium, total alkaline phosphatase and relevant bone isoenzyme, bone gla protein (BGP), carboxy-telopeptide of type I collagen (ICTP) and parathyroid hormone (PTH) were determined at baseline and on the 15th, 30th, 60th and 90th days after single-dose (90 mg) pamidronate administration in 35 consecutive prostate cancer patients with bone metastases. These biochemical indices and serum interleukin 6 (IL-6) were also measured after four days in the last consecutive 17 cases. RESULTS: PYD, DPYD and NTX showed a significant decrease lasting four weeks (p<0.01, <0.01 and <0.001, respectively). OHPRO and ICTP did not change significantly. The NTX decline was greater than that of PYD and DPYD (maximum percent decrease: -71.3, -23.1 and -28.2, respectively). Bone formation markers and serum calcium did not change significantly. Serum PTH showed a rapid initial increase followed by a slow decrease (p<0.001). DPYD and NTX patterns did not correlate with changes in bone pain. As observed in the last 17 cases, the maximum osteolysis inhibition after pamidronate occurred on the fourth day after drug infusion. Serum IL-6 levels showed a short-lived decrease preceded by a transient rise on the fourth day. CONCLUSIONS: Pamidronate is able to induce a decrease in bone resorption without significantly influencing bone formation. The maximum decrease in bone resorption occurs very early. NTX is the most sensitive bone resorption marker in bisphosphonate therapy monitoring. Changes in IL-6 but not bone resorption markers may be useful in the prediction of symptomatic response.

Different measures of energetic efficiency and their phenotypic relationships with growth, feed intake, and ultrasound and carcass merit in hybrid cattle.

Residual feed intake (RFI) has been proposed as an index for determining beef cattle energetic efficiency. Although the relationship of RFI with feed conversion ratio (FCR) is well established, little is known about how RFI compares to other measures of efficiency. This study examined the phenotypic relationships among different measures of energetic efficiency with growth, feed intake, and ultrasound and carcass merit of hybrid cattle (n = 150). Dry matter intake, ME intake (MEI), ADG, metabolic weight (MWT), and FCR during the test averaged 10.29 kg/d (SD = 1.62), 1,185.45 kJ/(kg0.75 x d) (SD = 114.69), 1.42 kg/d (SD = 0.25), 86.67 kg0.75 (SD = 10.21), and 7.27 kg of DM/kg of gain (SD = 1.00), respectively. Residual feed intake averaged 0.00 kg/d and ranged from -2.25 kg/d (most efficient) to 2.61 kg/d (least efficient). Dry matter intake (r = 0.75), MEI (r = 0.83), and FCR (r = 0.62) were correlated with RFI (P < 0.001) and were higher for animals with high (>0.5 SD) RFI vs. those with medium (+/-0.5 SD) or low (<0.5 SD) RFI (P < 0.001). Partial efficiency of growth (PEG; energetic efficiency for ADG) was correlated with RFI (r = -0.89, P < 0.001) and was lower (P < 0.001) for high- vs. medium- or low-RFI animals. However, RFI was not related to ADG (r = -0.03), MWT (r = -0.02), relative growth rate (RGR; growth relative to instantaneous body size; r = -0.04), or Kleiber ratio (KR; ADG per unit of MWT; r = -0.004). Also, DMI was correlated (P < 0.01) with ADG (r = 0.66), MWT (r = 0.49), FCR (r = 0.49), PEG (r = -0.52), RGR (r = 0.18), and KR (r = 0.36). Additionally, FCR was correlated (P < 0.001) with ADG (r = -0.63), PEG (r = -0.83), RGR (r = -0.75), and KR (r = -0.73), but not with MWT (r = 0.07). Correlations of measures of efficiency with ultrasound or carcass traits generally were not different from zero except for correlations of RFI, FCR, and PEG, respectively, with backfat gain (r = 0.30, 0.20, and -0.30), ultrasound backfat (r = 0.19, 0.21, and -0.25), grade fat (r = 0.25, 0.19, and -0.27), lean meat yield (r = -0.22, -0.18, and 0.24), and yield grade (r = 0.28, 0.24, and -0.25). These phenotypic relationships indicate that, compared with other measures of energetic efficiency, RFI should have a greater potential to improve overall production efficiency and PEG above maintenance, and lead to minimal correlated changes in carcass merit without altering the growth and body size of different animals.

Molecular biology in uro-oncology: clinical application. Prognostic factors in bladder cancer.

In the bladder cancer the most important prognostic factors are the stage, the grade, the presence or absence of lymph nodal metastasis, the response to therapy with B. C. G. etc.... In any case, even in the context of the same clinical stage, it is not possible to correctly evaluate the evolution of the disease. The Author did a literature revision and got a personal contribution about the effective utility of same biological prognostic factors. In a study about superficial bladder tumor using monoclonal antibody MIB-1 (Ki-67) a correlation between proliferation index (P.I.) and grade was noted. In particular the presence of a P.I. above 40% correlated with greater precocity and frequency of recurrences. A similar study showed that the expression of protein p21 correlated with a greater precociousness and with recurrence frequency. In conclusion, we have also carried out an evaluative study on the expression of oncosuppressor gene p53. In superficial bladder cancer this study showed up a correlation between the expression of protein p53 and a greater precociousness and frequency of recurrences.

Intravesical bacillus calmette-guerin (BCG) as inducer of tumor-suppressing proteins p53 and p21 Waf1-Cip1 during treatment of superficial bladder cancer.

PURPOSE: Previous in vitro investigations recorded an inhibition of cell proliferation by BCG when added to different cell cultures. The induction of apoptosis by BCG is controversial. Our study aimed to evaluate the influence of BCG on the expression of tumor suppressing proteins p53 and p21Waf1-Cip1 and apoptosis of the urothelial cells in vivo. MATERIALS AND METHODS: Twenty-one cases of superficial bladder cancer, treated with TUR and subsequent intravesical BCG, were studied retrospectively. The assays evaluated the expression of p53 and p21Waf1-Cip1 by immunochemistry (IHC), and the presence of apoptosis by TUNEL assay. The estimates were performed, in each case, on the following specimens: one tumor sample and one non-neoplastic sample collected during the TUR which preceded the administration of BCG; one non-neoplastic sample collected 3 months after the diagnosis; and one non-neoplastic sample collected in the first 2 weeks after the completion of the treatment. Samples of 6 cancer recurrences detected during BCG were examined too. RESULTS: As usual for non-neoplastic urothelium, the pre-BCG samples displayed poor p53 and p21Waf1-Cip1 immunoreactivity. By contrast, the samples collected during and in the aftermath of BCG showed an overall increase of the expression of both proteins. The rare occurrence of apoptosis proved to be chronologically unrelated to the BCG treatment. DISCUSSION: The relationship between changes of the IHC features and BCG suggests that BCG, at least under some circumstances, can induce the activation of wild type p53 and p21Waf1-Cip1 in the urothelium. The mechanism of the BCG-p53 status interaction and its role in the antitumor activity of BCG remain to be clarified.

Prognostic value of the involvement of the urinary collecting system in renal cell carcinoma.

OBJECTIVES: The prognostic role of the invasion of the urinary collecting system (UCS) by renal cell carcinoma (RCC) has not attracted a notable amount of attention. The aim of this study was to investigate incidence and prognostic value of UCS involvement in RCC. MATERIAL AND METHODS: All pathological reports of radical nephrectomies performed in two centres of urology from November 1983 to December 1999 were reviewed in order to evaluate the invasion of the UCS (calices, renal pelvis, ureter). Patients were divided into two groups according to presence (Group 1) or absence (Group 2) of UCS invasion. The stage was determined according to the TNM 6th edition. Overall and cause-specific survival rates were evaluated. Univariate and multivariate analyses were performed. RESULTS: The evaluable specimens were 671 from the 735 examined; in 64 cases it was not possible to ascertain or to exclude UCS involvement. Invasion of the UCS was found in 59 cases (8.8%). Median follow-up was 59.0 months (range 0-216). Tumours invading the UCS were usually symptomatic, with high nuclear grade and predominantly high stage. At univariate analysis the 5 year overall and cause-specific survival rates of tumours invading the UCS were significantly lower when compared to those without UCS invasion (42.8% versus 60.8% and 45.5% versus 64.7%, respectively). When groups were stratified, according to the pT category, the 5-year cause-specific survival rate was only significantly different for the pT2 category (33.3% versus 76.9%). At the multivariate analysis TNM staging, symptoms at diagnosis and tumour grade were the only independent prognostic factors. CONCLUSION: The invasion of the UCS by RCC is unusual, particularly in small tumours. UCS involvement does not represent an independent prognostic factor. However, in organ-confined tumours (i.e. pT2) UCS involvement has an influence on the prognosis and should be taken into account when planning adjuvant treatments and follow-up.

The number of lymph nodes examined and staging accuracy in renal cell carcinoma.

OBJECTIVE: To determine the number of lymph nodes that need to be examined to accurately stage the pN variable in patients undergoing radical nephrectomy (RN) for renal cell carcinoma (RCC). PATIENTS AND METHODS: We reviewed the operative and pathology reports of 725 patients with RCC submitted for RN. All tumours were classified using the fifth edition of the Tumour-Nodes-Metastasis classification. For each patient the number of lymph nodes removed was recorded. The patients were divided into five different groups according to the number of nodes removed, i.e. group 1, 1-4; group 2, 5-8; group 3, 9-12; group 4, 13-16; and group 5, >or= 17. We evaluated the factors that affected the number of lymph nodes removed with nodal dissection and the variables that influenced the incidence of nodal involvement. RESULTS: Lymphadenectomy was performed in 608 patients (83.8%); in these patients the rate of lymph node metastases was 13.6%. The median (range) number of nodes removed was 9 (1-43); there was a statistically significant correlation between the number of nodes removed and the percentage of nodal involvement (r = 0.6; P < 0.01). The rate of pN+ was significantly higher in the patients with >or= 13 than in those with < 13 nodes examined (20.8% vs 10.2%; P < 0.001). For organ-confined and locally advanced tumours there was a statistically significant difference in the pN+ rate between patients with < 13 or >or= 13 nodes examined (3.4% vs 10.5%, and 19.7% vs. 32.2%, respectively). CONCLUSIONS: The proportion of tumours classified as pN+ increased with the number of lymph nodes examined. In RCC,> 12 lymph nodes need to be assessed for optimal staging.

Complete hepatic venous isolation and extracorporeal chemofiltration as treatment for human hepatocellular carcinoma: a phase I study.

BACKGROUND: We performed a phase I study of a novel system of complete hepatic venous isolation and extracorporeal chemofiltration in patients with unresectable hepatocellular carcinoma (HCC) to determine (a) whether systemic exposure to doxorubicin could be limited after high-dose hepatic arterial infusion (HAI), and (b) the hepatic maximum tolerated dose (MTD) of doxorubicin. METHODS: Ten patients with biopsy-proven HCC were treated with 20-min HAI of doxorubicin (17 total treatments). Two patients were treated with doxorubicin 60 mg/m2, three patients were treated at 90 mg/m2, and five patients received 120 mg/m2. A newly developed dual-balloon vena cava catheter was advanced from the femoral vein, and the balloons were inflated to isolate and capture total hepatic venous outflow. The hepatic venous blood was pumped through extracorporeal carbon chemofilters before return of the blood to the systemic circulation. RESULTS: Peak systemic doxorubicin levels were an average 85.6% lower than were peak prefilter levels (p < 0.01). Because all catheters were placed percutaneously and because the chemofiltration markedly limited systemic chemotherapy exposure, patients were discharged 1 day after 16 of the 17 treatments. The hepatic and systemic MTD of doxorubicin in this treatment protocol was 120 mg/m2. CONCLUSIONS: This novel system of complete hepatic venous isolation and chemofiltration limits systemic chemotherapy toxicity and will allow use of higher doses of chemotherapeutic agents to treat HCC.