Dose-finding/phase II trial: bevacizumab, immunotherapy, and chemotherapy (BIC) in metastatic renal cell cancer (mRCC). Antitumor effects and variations of circulating T regulatory cells (Treg).

The aim of this study was to explore the efficacy and toxicities of a combined regimen of bevacizumab plus immunotherapy and chemotherapy (BIC) and the circulating T regulatory cells (Treg) in metastatic renal cell cancer (mRCC). Nephrectomized mRCC patients were enrolled into a multicenter single-arm dose-finding study with five escalated dose levels of chemotherapy with intravenous gemcitabine and 5-fluorouracil associated with fixed intravenous doses of bevacizumab, subcutaneous low doses of interleukin-2, and interferon-α-2a. An expanded cohort (phase II study) was treated at the recommended dose for additional safety and efficacy information according to minimax Simon two-stage design. Blood samples for Treg were collected and evaluated by fluorescence-activated cell sorting (FACS) analysis on cycle 1. Fifty-one patients were entered to receive one of five dose levels. Median age was 58 years (male 67 %, pretreated 49 %): 15 patients were low risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) criteria, while 27 and nine were respectively intermediate- and high-risk patients. More frequent grade 3 and 4 toxicities included nonfebrile neutropenia, thrombocytopenia, and fever. Among patients evaluable for response (49), 29.5 % had partial response and 37 % stable disease. Overall median time to progression and median overall survival were 8.8 and 22.67 months, respectively. We observed a rapid increase in the percentage of Treg after immunotherapy and a reduction after bevacizumab only in patient who obtained a partial response or stable disease. The BIC was feasible, well tolerated, and shown interesting activity. Further studies are needed to explore if Treg could have a role in clinical response in mRCC treated with bevacizumab.

Forty-slice MDCT enteroclysis: evaluation after oral administration of isotonic solution in Crohn's disease.

OBJECTIVE: The aim of this study was to evaluate the accuracy of multidetector computed tomography (MDCT) enteroclysis after oral hyperhydration with isotonic solution in detecting bowel wall alterations in patients with Crohn's disease. MATERIALS AND METHODS: Twenty-eight patients with a diagnosis of Crohn's disease established by ileocolonoscopy and histology were enrolled in the study; 15 patients with negative ileocolonoscopy served as controls. In all cases, MDCT enteroclysis was performed after oral administration of 2,000 ml of isotonic solution and intravenous administration of N-butylscopolamine. Axial, isotropic multiplanar and volume-rendered reconstructions were used to evaluate bowel wall thickness, ulceration, contrast enhancement, extraparietal involvement and possible complications. RESULTS: MDCT enteroclysis identified the typical signs of Crohn's disease in 26 patients (92.8%), with sensitivity of 92.8%, specificity of 100%, positive predictive value 100% and negative predictive value 75%. CONCLUSIONS: MDCT enteroclysis after oral hyperhydration with isotonic solution showed a high level of accuracy in detecting small bowel changes in patients with Crohn's disease. It can be considered a safe and effective alternative to conventional radiography and small-bowel spiral computed tomography enema, especially in patients who refuse nasojejunal intubation.

Identification of RPE65 in transformed kidney cells.

The protein RPE65 has an important role in retinoid processing and/or retinoid transport in the eye. Retinoids are involved in cell differentiation, embryogenesis and carcinogenesis. Since the kidney is known as an important site for retinoid metabolism, the expression of RPE65 in normal kidney and transformed kidney cells has been examined. The RPE65 mRNA was detected in transformed kidney cell lines including the human embryonic kidney cell line HEK293 and the African green monkey kidney cell lines COS-1 and COS-7 by reverse transcription PCR. In contrast, it was not detected in human primary kidney cells or monkey kidney tissues under the same PCR conditions. The RPE65 protein was also identified in COS-7 and HEK293 cells by Western blot analysis using a monoclonal antibody to RPE65, but not in the primary kidney cells or kidney tissues. The RPE65 cDNA containing the full-length encoding region was amplified from HEK293 and COS-7 cells. DNA sequencing showed that the RPE65 cDNA from HEK293 cells is identical to the RPE65 cDNA from the human retinal pigment epithelium. The RPE65 from COS-7 cells shares 98 and 99% sequence identity with human RPE65 at the nucleotide and amino acid levels, respectively. Moreover, the RPE65 mRNA was detected in three out of four renal tumor cultures analyzed including congenital mesoblastic nephroma and clear cell sarcoma of the kidney. These results demonstrated that transformed kidney cells express this retinoid processing protein, suggesting that these transformed cells may have an alternative retinoid metabolism not present in normal kidney cells.

Effects of the combination antibiotic--EDTA-Tris in the treatment of chronic bovine endometritis caused by antimicrobial-resistant bacteria.

The combined effects of the uterine infusion of EDTA-Tris solution and antibiotics have been evaluated in 75 cases of slight, moderate or severe bovine endometritis which did not respond to local routine antimicrobial therapy. Antibiotic-resistant bacteria were isolated from uterine swabs. The cows were divided into three groups on the basis of the severity of endometritis and treated with 100 ml of sterile EDTA-Tris solution (250 mM EDTA and 50 mM tris, pH 8) and the same antibiotic used in the first unsuccessful treatment (oxytetracycline, enrofloxacin, lincomycin-spectinomycin or amikacin). Control groups consisting of six animals treated with antibiotic alone were used. Clinical evaluations performed 2, 15, 21, 42 and 63 days after treatment revealed good therapeutic results, as 53 cows showed a complete recovery with renormalization of the subsequent oestrus cycle. Artificial insemination was followed by pregnancy in about 90% of treated cows. In control animals the second treatment performed using only the antibiotic gave variable and unsatisfactory results, particularly in animals affected by severe endometritis.

Potentiating effect of EDTA-Tris on the activity of antibiotics against resistant bacteria associated with otitis, dermatitis and cystitis.

Possible synergistic effects of the combination of EDTA-tromethamine (EDTA-Tris) and three antimicrobial agents (cephaloridine, kanendomycin and enrofloxacin) against resistant Gram-positive and Gram-negative bacteria are reported. Bacteria were isolated from eight cases of chronic otitis externa, five cases of chronic dermatitis and four cases of recurrent cystitis in dogs which had previously been treated with one of the three antibiotics without success. Animals exposed to EDTA-tromethamine plus the antibiotic recovered completely within 10 days, and were controlled clinically and bacteriologically for 180 days. Local irrigation with EDTA-tromethamine solution was well tolerated and no side effects were recorded.

Efficacy of transarterial targeted treatments on survival of patients with hepatocellular carcinoma. An Italian experience.

BACKGROUND: Most patients with hepatocellular carcinoma (HCC) are not suitable for surgical therapy. Systemic chemotherapy, immunotherapy, and hormonotherapy have not had convincingly acceptable results. Therefore, transarterial catheter-targeted therapies such as intraarterial chemotherapy (IAC), possibly followed by transcatheter arterial chemoembolization (TACE), have been proposed. METHODS: A survival analysis curve was drawn using the Kaplan-Meier method for 164 patients, 100 with HCC who underwent TACE (69) or IAC (31), and a matched historic group of 64 who did not receive specific antineoplastic treatment. RESULTS: A significantly more favorable survival was observed for TACE-treated patients compared with IAC-treated patients (P < 0.001); TACE- and IAC-treated patients had a statistically superior survival than that of untreated patients (P < 0.001 and P < 0.025, respectively). This difference was still significant (P < 0.001) when the patients were subdivided into Classes A and B and Stages I and II following Child's and Okuda's criteria. The TACE- and IAC-treated groups had a good relationship between technical efficacy of therapy and survival. Stratifying the patients according to the degree of iodized oil (Lipiodol Ultrafluid, Guerbet, Aulnay-Sous-Bois, France) uptake in the three groups with Group 1 having an uptake greater than 75% of tumor mass, Group 2 having an uptake of 50%-75%, and Group 3 having an uptake less than 50%, survival at 6, 12, 24, 36, and 48 months was calculated as 94%, 88%, 67%, 53%, and 30%, respectively, for Group 1; 86%, 68%, 13%, 13%, and 0% for Group 2, and 43%, 23%, 6%, 6%, and 0% for Group 3 (Group 1 vs. Group 2: P < 0.001; Group 1 vs. Group 3: P < 0.001; Group 2 vs. Group 3: P < 0.001, respectively). The most important side effects after the intraarterial procedure were fever (46.2%), abdominal pain (36.6%), chemical cholecystitis (8%), and pancreatitis (1.7%). Death strictly related to treatment occurred in two patients; one had massive bleeding due to ruptured esophageal varices, and the other had a subphrenic abscess of a superficial HCC of the VIII segment. CONCLUSIONS: Transcatheter arterial chemoembolization and IAC were effective and relatively safe, and the authors believe that they have a primary role in treating patients with unresectable HCC larger than 5 cm; iodized oil uptake can be considered a suitable prognostic marker.

Cisplatin and 5-fluorouracil combination chemotherapy in advanced and/or metastatic colorectal carcinoma: a phase II study.

The possible synergism of cisplatin (P) and 5-fluorouracil was studied in 38 consecutive patients with advanced or metastatic colorectal carcinoma. Cisplatin 60 mg/m2 i.v.q. 4 weeks and fluorouracil 600 mg/m2 i.v. weekly were administered for at least 2 cycles, on an out-patient basis, to 24 males and 14 females with a median age of 57 years and a median PS of 80 (Karnofsky). Evaluable lesions were: primary unresectable tumor in 2 patients, local recurrence in 11, liver, lung, bone and soft tissue metastases in 21, 7, 2 and 3 patients respectively. With a median number of 3 cycles administered to 35 evaluable patients, 6 partial responses, 16 unchanged and 13 progressions were observed. Responses were observed in the liver (2 patients), lungs (1) and soft tissues (3). Median remission duration was 15 weeks, median duration of 'unchanged' was 12 weeks. The overall median survival was 24 weeks (30.5 weeks for responders and 22.5 weeks for non-responders). Six patients were pretreated with chemotherapy not containing cisplatin (mainly adjuvant 5-FU). None of them responded. Toxicity was very tolerable with moderate nausea, vomiting and alopecia in the majority of the patients; bone marrow toxicity was generally mild with no blood transfusions required, no complications of myelosuppression (sepsis or bleeding) and no chemotherapy-related deaths. In this experience the combination of low dose cisplatin with fluorouracil, does not appear to significantly enhance 5-FU toxicity and the response rate is not superior to that reported with 5-FU alone. However, better designed schedule combinations with optimal doses, sequences and exposure time of the 2-drug regimen, seem necessary to obtain the biochemical events that support the potentiation.