A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma: continuous infusion doxorubicin,vincristine, and etoposide with daily mitotane as a P-glycoprotein antagonist

BACKGROUND: Adrenocortical carcinoma (ACC) is rare, nearly always fatal, and to the authors' knowledge has few nonsurgical treatment options. Based on in vitro studies demonstrating the efficacy of mitotane as a P-glycoprotein (Pgp) antagonist, and expression of high levels of Pgp in ACC, the authors conducted a study of infusional doxorubicin, vincristine, and etoposide with oral mitotane +/- surgical resection in patients with metastatic ACC. METHODS: Thirty-six patients with metastatic ACC received daily oral mitotane (mean, 4.6 g/day) and 96-hour infusional doxorubicin (10 mg/m(2)/day), etoposide (75 mg/m(2)/day), and vincristine (0.4 mg/m(2)/day). Four responding patients (11%) underwent surgery. RESULTS: Thirty-five patients were evaluable; all had metastatic disease. Eleven patients had not undergone resection of the primary tumor. Approximately 53% of patients had functional tumors. A total of 190 cycles were administered to 36 patients. Responses were observed in 8 patients (22%): 1 complete, 4 partial, and 3 minor responses. The mean duration of response was 12.4 months. Using a landmark method, the median survival of patients who did not respond to chemotherapy was 11.6 months from a point 4 months after the initiation of therapy, whereas that of 8 patients who demonstrated a response to chemotherapy was 34.3 months from that same landmark. High levels of Pgp expression were documented in nine of nine tumors. Mitotane levels > 10 microg/mL, previously shown to antagonize Pgp in vitro, were achieved in 25 of 36 patients (69%). However, rhodamine efflux from CD56-positive cells was not impaired, suggesting poor in vivo Pgp inhibition. The predominant Grade 3/4 toxicity (according to the Common Toxicity Criteria of the National Cancer Institute) was neutropenia in 66% of cycles; however, fever occurred in only 3% of cycles. Daily mitotane was associated with Grade 1/2 nausea, diarrhea, fatigue, and neuropsychiatric changes in 31 of 36 patients (86%). CONCLUSIONS: Using a combination regimen of daily mitotane with infusional doxorubicin, vincristine, and etoposide in patients with metastatic ACC, responses were observed in 22% of patients. The superiority of this combination over single-agent mitotane is uncertain. The side effects of mitotane made treatment difficult. More effective Pgp antagonists are needed.     

A concomitant tumour boost in bladder irradiation: patient suitability and the potential of intensity-modulated radiotherapy.

BACKGROUND AND PURPOSE: In radiotherapy (RT) of bladder cancer, dose escalation without increased adverse effects could be achieved with a concomitant bladder tumour boost. In this study we quantified (1) the fraction of patients suitable for this approach, and (2) the potential of intensity-modulated RT (IMRT) to achieve this boost while also sparing normal tissues. MATERIALS AND METHODS: The fraction of patients suitable for this boost approach was quantified using both a series of 30 radical therapy candidates, and a series of 15 consecutive RT patients. IMRT plans with 3, 5, 7 and 9 equi-spaced beams were set up for the patients in the RT series found suitable for a boost. Two sets of targets were defined, with (i) wide and (ii) narrow margins around both the tumour (prescribed 120% dose) and the non-involved bladder (prescribed 100% dose). The inverse planning optimisation minimised the dose deviation across the targets whilst fulfilling dose-volume histogram (DVH) constraints--based on what could be achieved with conformal RT (CRT)--for both the normal tissues and the targets. RESULTS: Fourteen of the 30 radical therapy candidates (47%) and 10 of the 15 RT patients (67%) were suitable for a boost. The 20% boost could be obtained while maintaining target coverage with at least one IMRT plan in 9 of 10 cases with wide margins and for all 10 cases with narrow margins. Using wide margins, all 3-field plans were unacceptable, the 5-field plans were acceptable for 5 of 10, and the 7- and 9-field plans for 9 of the 10 patients. The normal tissue volumes receiving doses >100% were on average reduced by a factor of 3-4 compared with CRT. The normal tissue volumes receiving intermediate doses (73-88%) decreased slightly, whereas volumes receiving the lowest doses (30-48%) increased with the number of beams. The use of narrow margins resulted in markedly lower normal tissue irradiation. CONCLUSION: This study has shown bladder tumour boosting to be both clinically relevant and technically feasible using IMRT. This approach is ready for clinical implementation, although further improvement could be expected if integrated with target localisation techniques.     

Induction of hepatic cell proliferation and unscheduled DNA synthesis in mouse hepatocytes following in vivo treatment

We have modified the in vivo-in vitro hepatocyte DNA repairassay for measurement of unscheduled DNA synthesis (UDS) andhepatic cell proliferation in B6C3F1 mice. Dimethylnitros-amineand methylmethane sulfonate produced significant increases inUDS in both rats and mice. 2-Acetylaminofluorene induced a significantincrease in UDS in rats, but not in mice. The mouse hepatocarcinogens,carbon tetrachloride, trichloroethylene, polybrominated biphenylsand 2,6-dichloro-p-phenylenediamine all failed to induce UDSin male and female mice, but all induced significant elevationsin hepatic cell proliferation. Increased cell turnover in theliver may therefore be an important mechanism in hepatocarcinogenicityin the mouse.     

A non-living nasal influenza vaccine can induce major humoral and cellular immune responses in humans without the need for adjuvants

Twenty-eight healthy adult volunteers were immunized intranasally with an inactivated whole-virus influenza vaccine based on the strain A/New Caledonia/20/99 (H1N1), either in saline or mixed with formaldehyde-inactivated Bordetella pertussis as a mucosal adjuvant, or in a thixotropic vehicle with mucoadhesive properties. After four doses, all groups of vaccinees developed significant IgG- and IgA-antibody responses, measured by ELISA, in respectively serum and nasal secretions. None of the volunteers had demonstrable hemagglutination inhibition (HAI) antibodies in serum before being immunized, whereas more than 80% of them reached HAI titers>or=40, considered protective, after immunizations. In addition, cellular immune responses, measured as significant increases in CD4+ T-cell proliferation and granzyme B-producing cytotoxic T-cells, were detected against the vaccine strain as well as against heterologous virus strains (H3N2). However, no additive effect on these responses could be demonstrated with use of B. pertussis or the thixotropic substance in the present vaccines. It appeared, actually, that the mucoadhesive vehicle containing the thixotropic substance was less efficient than were the two other formulations. An influenza vaccine made as a simple particulate formulation of inactivated virus, and given repeatedly onto the nasal mucosa, may thus be an attractive alternative to currently available vaccines.     

Alterations in T-Cell Subset Frequency in Peripheral Blood in Obesity

Background: Obesity affects the regulation of immune and inflammatory responses. This study characterizes differences in peripheral blood lymphocyte phenotype in obese humans. Methods: Frequencies of lymphocyte subsets among peripheral blood mononuclear cells were compared between 10 obese (BMI ≥35) and 10 lean subjects, as determined by antibodies directed against cluster differentiation (CD) markers. Results: Obese patients demonstrated an increased frequency of CD3+CD4+ T-cells (mean difference 12%, P=0.004), a decreased frequency of CD3+CD8+ T-cells (mean difference 9.4%, P=0.016) and an increased frequency of CD3+CD8+CD95+ T-cells (mean difference 13.3%, P=0.032). No other differences among T-cell or monocyte subsets were noted. Conclusions: Obesity is associated with alterations in frequencies of peripheral CD4+ and CD8+ T-cells and aberrations in the expression of CD95 among CD8+ T-cells. These data suggest both CD4+ and CD8+ T-cell compartments, as well as the regulation of CD95 expression on CD8+ T-cells, as targets for further study into obesity's effects on the immune system.