Phase I and pharmacologic evaluation of intraperitoneal 5-fluoro-2′-deoxyuridine

Summary Intraperitoneal (i.p.) 5-fluoro-2-deoxyuridine (Floxuridine, FUdR, FdUrd) was evaluated in a phase I study at a starting level of 500 mg given on 1 day in 2 I 1.5% dialysate. Escalations within patients were allowed every other cycle. A total of 23 patients (age, 32–78 years) received 108 treatment courses. Local tolerance at all dose levels was excellent, with no cases of drug-related peritonitis being observed. Nausea and vomiting increased in severity in relation to dose and was universal at >3,000 mg ×3 days. One patient each developed grade 1 mucositis as well as diarrhea at a dose of 3,000 mg×3 days and leukopenia and thrombocytopenia at 5,000 mg×3 days. Peritoneal fluid (PF) and plasma (PL) FdUrd profiles were monitored by an HPLC method in 13 subjects, with 7 being studied serially at 2–4 increment doses for up to 6 h. Profiles that exhibited apparent linear pharmacokinetics gave PF drug levels 2–4 logs higher than the PL counterparts, with the latter essentially declining in parallel to the former, indicating that the disposition of FdUrd from the peritoneal compartment is rate-determining. The mean terminal half-life for PF FdUrd was found to be 115 min and mean peritoneal clearance was 25 ml/min. The vast differences in drug levels and AUC found between the PF and the PL profiles suggests a high systemic clearance of FdUrd, which was confirmed in two patients receiving 2 g FdUrd by short i.v. infusion. A disproportionate increase in the plasma FdUrd levels and the corresponding AUC values was found with increasing dose, suggesting a disproportionate increase in the systemic partitioning of FdUrd when doses were escalated within a patient. Substantial levels of peritoneal 5-fluorouracil (FUra) were also detected in most of the subjects. Thus, FdUrd was found to have several desirable properties for i.p. administration: (1) a 2- to 4-log pharmacologic advantage, (2) the absence of local toxicities, and (3) a favorable antitumor spectrum and some evidence of antitumor effects in this phase I and pharmacology study. A 3,000-mg dose given in 2 l 1.5% dialysate for 3 consecutive days exhibited antitumor activity and produced no systemic toxicity except nausea and vomiting, which was controlled by antiemetics. This dose schedule is therefore recommended for phase II trials directed against small-volume disease in the peritoneal cavity, such as may be found in some stages of ovarian and gastrointestinal cancers. In addition, it is suitable for further exploration as a part of regimens including systemic therapy or drugs that modulate the action of fluoropyrimidines.Supported in part by Cancer Center Core Grant CA 14089, by ROI CA 50 412, by an ACS Institutional Grant (IN21Z, to C. R.) and by the Italian-American Foundation award (to N. C.)Deceased     

Identification of novel prognosticators of outcome in squamous cell carcinoma of the head and neck.

PURPOSE: The goal of this study was to identify chromosomal aberrations associated with poor outcome in patients with head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: We assessed the global genomic composition of 82 HNSCCs from previously untreated patients with comparative genomic hybridization (CGH). The CGH data were subcategorized into individual cytogenetic bands. Only genomic aberrations occurring in more than 5% of cases were analyzed, and redundancies were eliminated. Each aberration was submitted to univariate analysis to assess its relationship with disease-specific survival (DSS). We used Monte Carlo simulations (MCS) to adjust P values for the log-rank approximate chi(2) statistics for each abnormality and further applied the Hochberg-Benjamini procedure to adjust the P values for multiple testing of the large number of abnormalities. We then submitted abnormalities whose univariate tests resulted in an adjusted P value of less than.15 together with significant demographic/clinical variables to stepwise Cox proportional hazards regression. We again verified and adjusted P values for the chi(2) approximation of the final model by MCS. RESULTS: CGH analysis revealed a recurrent pattern of chromosomal aberrations typical for HNSCC. Univariate analysis revealed 38 abnormalities that were correlated with DSS. After controlling for multiple comparisons and confounding effects of stage, five chromosomal aberrations were significantly associated with outcome, including amplification at 11q13, gain of 12q24, and losses at 5q11, 6q14, and 21q11 (MCS adjusted P =.0009 to P =.01). CONCLUSION: HNSCC contains a complex pattern of chromosomal aberrations. A sequential approach to control for multiple comparisons and effect of confounding variables allows the identification of clinically relevant aberrations. The significance of each individual abnormality merits further consideration.     

Compromised kidney graft rejection response in Vervet monkeys after withdrawal of immunosuppressants tacrolimus and sirolimus

BACKGROUND: In nonprimates, organ allografts are often not rejected after withdrawal of immunosuppression. In this study, we examined whether such a phenomenon also occurs in primates. METHODS: Vervet monkeys were transplanted with renal allografts and treated for 60 days with tacrolimus, or tacrolimus plus sirolimus. The drugs were totally withdrawn on day 61. The survival of the monkeys was monitored, and their response to donor- or third party-derived alloantigens was examined in vivo and in vitro. RESULTS: The majority (80-100%) of the grafts survived for at least additional 30 days with no signs of acute rejection. The compromised rejection is donor-specific, because recipient monkeys failed to reject a donor-derived skin graft, but a third-party skin graft was rejected. In vitro mixed lymphocyte reaction and interleukin-2 production in the mixed lymphocyte reaction between the recipients and their donors or between the recipients and a third party had no discernable patterns, and thus did not reflect the in vivo status of the immune system. Although the recipients could not reject the graft acutely after drug withdrawal, the kidney grafts and the donor-derived skin grafts had pathological findings of chronic rejection. CONCLUSIONS: The rejection response of the monkeys to an established graft after withdrawal of immunosuppression is compromised. The compromised rejection is specific and is not due to a permanent alteration of the immune system by the initial drug treatment. The allografts are not inert but have low levels of interaction with the recipient immune system.     

Isothermal titration calorimetry method for determination of cyclodextrin complexation thermodynamics between artemisinin and naproxen under varying environmental conditions.

A novel isothermal titration calorimetry method was used to determine the complexation thermodynamics for hydroxypropyl-beta-cyclodextrin with artemisinin and naproxen at varying temperature and pH. The new method is very useful for studying complexation reactions between cyclodextrin and drugs with poor solubility and all the thermodynamic parameters of the cyclodextrin complexation were determined. The analysis of the thermodynamic data reveals involvement of hydrophobic bonding in the cyclodextrin complexes studied. The data also reveals the presence of enthalpy-entropy compensation in the system and provide information as to the orientation of the drug molecule inside the cyclodextrin cavity. From the thermodynamic parameters for dissociation of HPBCD complexes of artemisinin and naproxen at pH 2 it is concluded that the complexation is primarily driven by enthalpy with entropic assistance at all temperatures studied. From the dissociation studies of HPBCD complexes of naproxen at pH 10 it is concluded that the complexation is predominantly driven by entropy and moderately by enthalpy at lower temperatures and by enthalpy with entropic assistance at higher temperatures.     

Survival patterns in treated cases of carcinoma larynx in north india - a 10 years followup study

Conclusion  Patients with stage I and II tumors had the best results with radical radiotherapy alone 5 years survival for patients with stage I and stage II tumors was 90-95% and 75-85% respectively Patients with advanced stage III & IV disease were treated Unoperable stage IV cancer patients had poor outcome and received only palliative treatment     

Mifepristone versus the Yuzpe regimen (PC4) for emergency contraception.

OBJECTIVE: To compare side effects, women's acceptance and satisfaction with mifepristone (100 mg) versus the Yuzpe regimen for emergency contraception (EC). METHODS: A total of 1000 women requesting EC within 72 h of unprotected intercourse were randomized to receive mifepristone 100 mg or the standard Yuzpe regimen. Outcome measures included patient acceptability and satisfaction. RESULTS: A total of 620 (62%) questionnaires were returned, 64% in the mifepristone group and 60% in the Yuzpe group. Mifepristone was better tolerated than the Yuzpe regimen. The rates of nausea (P<0.0001), abdominal pain (P=0.001), tiredness (P<0.0001), lethargy (P=0.001), hot flushes (P<0.0001) and dizziness (P<0.0001) were all significantly higher in women given the Yuzpe regimen compared to those who received mifepristone. Of these 94% and 80% in the mifepristone and Yuzpe groups, respectively, were satisfied with treatment (P<0.0001). Of women in the mifepristone group, 56% (181/321) had used the Yuzpe regimen of EC in the past and of these, 93.6% (161/172) indicated they would use mifepristone in the future. A total of four women in the Yuzpe group had mifepristone in the past and all four said they would use mifepristone in the future. CONCLUSION: Mifepristone has high patient acceptability and few side effects compared to the standard Yuzpe regimen for EC.     

Complement, fetal antigen, and shaking rigors in parturients.

OBJECTIVES: To assess the relationship, if any, between complement, fetal antigen, and shaking rigors during labor and delivery. METHODS: We recruited 13 volunteers for serial blood sampling during labor and childbirth. RESULTS: Complement levels had a small but significant drop (11-15%) immediately following childbirth but had no association with fetal antigen levels or shaking rigors. Fetal antigen levels failed to show any consistent relationship with shaking rigors or the labor and delivery process. CONCLUSION: Shaking rigors do not appear to be associated with changes in either complement or fetal antigen levels. Complement levels remain stable during labor but drop immediately following birth.     

Noninvasive monitoring of murine tumor blood flow during and after photodynamic therapy provides early assessment of therapeutic efficacy.

PURPOSE: To monitor tumor blood flow noninvasively during photodynamic therapy (PDT) and to correlate flow responses with therapeutic efficacy. EXPERIMENTAL DESIGN: Diffuse correlation spectroscopy (DCS) was used to measure blood flow continuously in radiation-induced fibrosarcoma murine tumors during Photofrin (5 mg/kg)/PDT (75 mW/cm2, 135 J/cm2). Relative blood flow (rBF; i.e., normalized to preillumination values) was compared with tumor perfusion as determined by power Doppler ultrasound and was correlated with treatment durability, defined as the time of tumor growth to a volume of 400 mm3. Broadband diffuse reflectance spectroscopy concurrently quantified tumor hemoglobin oxygen saturation (SO2). RESULTS: DCS and power Doppler ultrasound measured similar flow decreases in animals treated with identical protocols. DCS measurement of rBF during PDT revealed a series of PDT-induced peaks and declines dominated by an initial steep increase (average +/- SE: 168.1 +/- 39.5%) and subsequent decrease (59.2 +/- 29.1%). The duration (interval time; range, 2.2-15.6 minutes) and slope (flow reduction rate; range, 4.4 -45.8% minute(-1)) of the decrease correlated significantly (P = 0.0001 and 0.0002, r2= 0.79 and 0.67, respectively) with treatment durability. A positive, significant (P = 0.016, r2= 0.50) association between interval time and time-to-400 mm3 was also detected in animals with depressed pre-PDT blood flow due to hydralazine administration. At 3 hours after PDT, rBF and SO2 were predictive (P < or = 0.015) of treatment durability. CONCLUSION: These data suggest a role for DCS in real-time monitoring of PDT vascular response as an indicator of treatment efficacy.