Pharmacokinetics of etanidazole (SR-2508) in bladder and cervical cancer: evidence of diffusion from urine.

Following an IV infusion of 2.0 g/m2 of Etanidazole, the mean tumor concentration 40 min after injection was 126 micrograms/g in bladder cancer and 65 micrograms/g in cervical cancer. The tumor/plasma concentration ratio was 1.88 in bladder and 0.85 in cervical cancer. This high tumor concentration in bladder cancer could be accounted for by diffusion from a highly concentrated urine. This renders bladder cancer a suitable clinical model for testing this sensitizer.

Cell proliferation in carcinoma in bilharzial bladder: influence of pre-operative irradiation and clinical implications.

Cell proliferation in carcinoma in the bilharzial bladder was studied in 92 patients in terms of the in vitro labeling index (LI), cell density (CD) and labeled cell density (LCD) using the in vitro 3H-Tdr technique. Cell proliferation was much greater in high than in low grade tumors and in deep than in superficial parts of the tumor, but was much less dependent on cell type; transitional cell cancer had the highest activity followed by squamous cell and adenocarcinoma. The probability of local recurrence after cystectomy decreased markedly when the LI exceeded 5.0%. The influence of the following three pre-operative radiotherapy regimens was studied: split-course (SC): the initial course consisted of 20 Gy in 10 treatments with a similar course was given after one week, hyper-fractionation using 17 treatments 0.6 Gy each on two successive days, this 2-day course of 20 Gy was repeated after one week, and concentrated irradiation consisting of two treatments, 6.0 Gy each with a gap of one week. Cystectomy was performed 14-20 days after treatment in all groups. Preoperative irradiation was generally associated with an increased probability of local control. The unfavorable influence of a high pretreatment LI was not noted after pre-operative irradiation. The CD was also reduced in proportion to the pretreatment LI. It is proposed that the response to irradiation was proportional to the initial proliferation activity and hence the prognostic significance of tumor grade and pretreatment LI was masked. Postirradiation tumor volume reduction was a strong predictor of treatment outcome. Concentrated irradiation was the least efficient pre-operative irradiation regimen and was associated with the least tumor volume reduction.

Experience in the radical radiotherapy of cancer in the bilharzial bladder: the use of misonidazole.

The results of application of a protracted split-course radiotherapy regimen in T3 carcinoma in the bilharzial bladder are presented. A total dose of 70 Gy spread over 61 days was divided into four courses separated by gaps of 1, 2 and 1 week, respectively. Each of the first three sessions comprised eight fractions, 2.5 Gy each, while four such fractions were given during the fourth course. Patients were randomized between radiotherapy alone (32 patients) and radiotherapy plus misonidazole (MIS) (30 patients). The drug was given in a daily oral dose of 0.5 g/m2, 3.5 h prior to each radiation treatment. The treatment was well tolerated and MIS did not augment the radiation reaction. Mild or moderate peripheral neuropathy was experienced by 63% of patients of the group. Age and degree of upper obstructive uropathy were the most important determinants of the risk of neuropathy. The 2-year disease-free actuarial survival rates amounted to 58% and 44% in the MIS and radiotherapy alone groups respectively; the difference is not significant. The results were significantly better in case of transitional cell (67%) than squamous cell cancer (29%) but were independent of the histological grade. A strong correlation was found between the magnitude of tumour volume reduction after 40 Gy and the long-term end results.

Analysis of immunodominance among minor histocompatibility antigens in allogeneic hematopoietic stem cell transplantation.

In major histocompatibility complex (MHC)-matched allogeneic hematopoietic stem cell transplantation (HSCT), donor responses are directed against multiple host minor histocompatibility antigens (mHAgs), producing graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) effects. We studied MHC-matched, mHAg-mismatched C3H.SW>C57BL/6 HSCT in which three mHAg are molecularly defined (B6dom1, H3, H13) to determine if there is a hierarchy of immunodominance among the mHAgs and to learn the contribution of each to GVHD. We found that B6dom1 was the immunodominant mHAg. B6dom1 did not block responses to the subdominant mHAgs H3 and H13. The mechanism of immunodominance was not mHAg avidity or affinity for class I. B6dom1 elicited a broader variety of Vbeta clonotypes than either H3 or H13. Severe GVHD could occur in the absence of a strong B6dom1 response. Alloreactivity to isolated B6dom1, H3 or H13 differences did not produce severe GVHD. We concluded that immunodominance is explained by both mHAg density on host cells and the repertoire of donor T cells capable of responding to the mHAgs. Clinically significant GVHD requires donor responses to multiple mHAgs. Modulation of responses to a single immunodominant mHAg is insufficient for the prevention of GVHD, while immunotherapies directed against isolated mHAgs may not provoke severe GVHD.

The use of misonidazole in association with a three-fractions per day regimen in advanced head and neck epidermoid cancer. A pilot study.

Twenty-one patients with Stage III or IV head and neck epidermoid cancer were treated by a three-fractions per day radiotherapy regime plus misonidazole (MIS). An initial course of 45 Gy was used, spread over 12 days and divided into 30 fractions 1.5 Gy each with a 3-hour interval between fractions. A daily MIS dose of 1 g/m2 was given 2 hours prior to the first fraction. A boost dose of 22.5 Gy/5 days was given to 10 patients, 4 weeks after the initial course, using the same fractionation scheme. The local acute and chronic reactions were acceptable. Eight patients suffered mild reversible peripheral neuropathy. The mean MIS blood level corresponded to an enhancement ratio of about 1.45. The 1-year disease-free survival rate was 9/21 and was significantly greater in patients receiving the boost irradiation. The control rate of nodal disease was encouraging. Based on this pilot study, a prospective trial is proposed aiming at testing the usefulness of MIS in MDF regimens in advanced head and neck cancer, either as the sole method of treatment or as a preoperative measure.

Non-albicans Candida is the most common cause of candidemia in pediatric cancer patients.

GOALS: Candidemia is a serious infection that can severely complicate the care of children with cancer. We sought to determine the spectrum of Candida species in children with cancer, since effective therapy may depend on the species involved. PATIENTS AND METHODS: A retrospective review of candidemia episodes in our pediatric oncology patients over a 9-year period was conducted. During this period azole prophylaxis was not routine in this group. RESULTS: 38 episodes of candidemia were identified: C. albicans 29%, C. tropicalis 26%, C. parapsilosis 24%, C. krusei 8%, C. glabrata 8%, and C. lusitaniae 5%. Non-albicans Candida was common in patients not receiving azole prophylaxis. Species typically susceptible to azoles were common among patients not using azoles. Death attributed to the fungal infection occurred in 21% of episodes, with nearly all the deaths occurring in patients with C. albicans and C. tropicalis. CONCLUSIONS: C. albicans is not the predominant species in pediatric oncology patients experiencing candidemia, even in azole-naive patients.

The topical use of misonidazole in bladder cancer.

Penetration studies of MIS after intravesical administration showed adequate concentrations with a gradient across the tumor. After instillation of 2.5 g in 50 ml water the concentration in the deep parts of the tumor amounted to about 100 microgram per ml. This corresponds to a SER for hypoxic cell of the order of 1.7. A more uniform tissue distribution of the drug was noted 3.5 hours after an oral dose of 3 g/meter square. The concentration in the deep parts of the tumor and perivesical tissue was of the order of 100 micrograms/g. The concentration in these regions are relevant to preoperative irradiation which aims at sterilizing the deep infiltrating margins. The intravesical use with or without oral augmentation is suitable for use in association with concentrated preoperative radiotherapy regimens. The topical use of MIS in such regimens markedly reduces the risk of neurotoxicity. The tissue concentration resulting from the two routes proved to be additive. The higher concentration in lymph nodes after the oral route the greater concentration and prolonged contact after combined administration may have therapeutic merits.