Reducing morbidity and mortality from oral and oropharyngeal cancer

There has been no reduction in the incidence of OOPCa, nor has the 5-year survival rate improved over the past 30 years. Most of these cancers are diagnosed in the later stages after they have grown to significant size, have become fixed to surrounding structures, hemorrhagic or painful or have caused noticeable impairment of speech or deglutition. To reduce the incidence of OOPCa and improve outcomes, the public must become more aware of the risk factors and seek regular oral cancer examination. More importantly, health professionals must incorporate a thorough oral soft tissue examination into their routine evaluation of all patients. Although an array of promising new technologies is becoming part of our diagnostic armamentarium, the most important factor is, as it has always been, an educated, astute and conscientious clinician.     

Dietary prevention of age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (ARMD) is the leading cause of blindness in people over the age of 65, and the prevalence of ARMD is expected to increase as the population ages. Although the incidence of ARMD increases sharply with age, recent studies indicate that prevention measures and dietary changes, implemented early in life, can reduce an individual's risk of ARMD. METHODS: Several dietary components have been proposed and studied with regard to their ability to protect against ARMD; these components include antioxidant vitamins and specific carotenoids. In particular, consumption of dark green, leafy vegetables has been shown in clinical studies to reduce the risk of ARMD. RESULTS: Biochemical studies of such vegetables have found that they contain several nutrients that may account for this effect, including high concentrations of the related carotenoids lutein and zeaxanthin. Structural and clinical studies have shown that these carotenoids are concentrated in the retinal macular pigment and that such accumulation is dependent on dietary intake. Further studies have indicated that the density of the macular pigment is related to preservation of visual sensitivity and (possibly) protection from ARMD. CONCLUSIONS: Large-scale clinical trials will be necessary to demonstrate that specific agents can reduce the incidence of ARMD. Nevertheless, specific dietary components--particularly, the carotenoids found in dark green, leafy vegetables--have shown great promise. While lifestyle modifications such as smoking cessation, reduction of alcohol consumption, and the wearing of sunglasses may reduce the risk of ARMD, it is likely that consumption of specific dietary components can reduce the risk further.     

Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children.

PURPOSE: In a preclinical model of neuroblastoma, administration of irinotecan daily 5 days per week for 2 consecutive weeks ([qd x 5] x 2) resulted in greater antitumor activity than did a single 5-day course with the same total dose. We evaluated this protracted schedule in children. PATIENTS AND METHODS: Twenty-three children with refractory solid tumors were enrolled onto a phase I study. Cohorts received irinotecan by 1-hour intravenous infusion at 20, 24, or 29 mg/m(2) (qd x 5) x 2 every 21 days. RESULTS: The 23 children (median age, 14.1 years; median prior regimens, two) received 84 courses. Predominant diagnoses were neuroblastoma (n = 5), osteosarcoma (n = 5), and rhabdomyosarcoma (n = 4). The dose-limiting toxicity was grade 3/4 diarrhea and/or abdominal cramps in six of 12 patients treated at 24 mg/m(2), despite aggressive use of loperamide. The maximum-tolerated dose (MTD) on this schedule was 20 mg/m(2)/d. Five patients had partial responses and 16 had disease stabilization. On day 1, the median systemic exposure to SN-38 (the active metabolite of irinotecan) at the MTD was 106 ng-h/mL (range, 41 to 421 ng-h/mL). CONCLUSION: This protracted schedule is well tolerated in children. The absence of significant myelosuppression and encouraging clinical responses suggest compellingly that irinotecan be further evaluated in children using the (qd x 5) x 2 schedule, beginning at a dose of 20 mg/m(2). These results imply that data obtained from xenograft models can be effectively integrated into the design of clinical trials.     

Chemotherapy dose-intensification for pediatric patients with Ewing's family of tumors and desmoplastic small round-cell tumors: a feasibility study at St. Jude Children's Research Hospital.

PURPOSE: To evaluate the feasibility of dose-intensification for patients with Ewing's family of tumors (EFT) and desmoplastic small round-cell tumors. PATIENTS AND METHODS: From February 1992 to June 1996, we treated 53 consecutive patients on our Ewing's protocol. Induction comprised three cycles of ifosfamide/etoposide on days 1 to 3 and cyclophosphamide (CTX)/doxorubicin on day 5, followed by granulocyte colony-stimulating factor. Local control using surgery and/or radiotherapy started at week 9 along with vincristine/dactinomycin. Maintenance included four alternating cycles of ifosfamide/etoposide and doxorubicin/CTX, with randomization to one of two CTX dose levels to determine the feasibility of dose-intensification during maintenance. RESULTS: Patients had a median age of 13.4 years (range, 4.5 to 24.9 years); 34 patients were male and 43 patients were white. Nineteen patients presented with metastatic disease, 29 had tumors greater than 8 cm in diameter, and 26 had primary bone tumors. These patients received 155 induction cycles, 91% of which resulted in grade 4 neutropenia, 68% in febrile neutropenia, and 68% in grade 3 to 4 thrombocytopenia. During maintenance, grade 4 neutropenia and grade 3 to 4 thrombocytopenia occurred in 81% and 85% of cycles, respectively. Thirty-five patients (66%) completed all therapy, only 13 without significant delays; three developed secondary myeloid malignancies. The toxicity and time to therapy completion were similar in both CTX arms. Estimated 3-year survival and event-free survival were 72%+/-8% and 60%+/-9%, respectively. CONCLUSION: Although intensifying therapy seems feasible for 25% of patients on this study, toxicity was considerable. Therefore, the noninvestigational use of dose-intensification in patients with EFT should await assessment of its impact on disease-free survival.     

Experience of discordant beta hCG results by different assays in the management of non-seminomatous germ cell tumours of the testis

Fifty-five patients with non-seminomatous germ cell tumours (NSGCT) who were referred to a regional clinical oncology centre over a 3-year period were assessed prospectively with assays of the serum tumour markers alpha-feto protein (AFP) and beta-human chorionic gonadotropin (beta hCG). Paired baseline beta hCG assays were undertaken using a polyclonal radioimmunoassay (RIA) and a monoclonal fluoroimmunoassay (FIA). Serial paired measurements were undertaken in patients showing discordance on baseline assays. Four patients (7%; 95% confidence interval 0-14) showed discordance between the paired beta hCG assays. Of these, two showed elevated beta hCG on RIA, with normal levels on FIA; two showed elevated beta hCG on FIA, with normal levels on RIA. No discordance was noted with AFP assays. Discordance persisted in two of the patients (50%) and disappeared on treatment in one (25%); one patient died during treatment. Discordant beta hCG assays present difficulties in interpretation and have therapeutic implications in patients with NSGCT. No single currently available assay is conclusive in all patients and commercial assay kits should be chosen with care.     

In vivo mutagenicity and hepatocarcinogenicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in bitransgenic c-myc/lambda lacZ mice.

2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is a mutagenic and carcinogenic heterocyclic amine found in cooked meat. Hepatic DNA adduct formation, in vivo mutagenicity, and hepatocarcinogenicity of MeIQx were examined in mice harboring the lacZ mutation reporter gene (Muta mice) and bitransgenic mice overexpressing the c-myc oncogene. C57Bl/lambda lacZ and bitransgenic c-myc (albumin promoter)/lambda lacZ mice were bred and weaned onto an American Institute of Nutrition-76-based diet containing 0.06% (w/w) MeIQx or onto control diet. After 30 weeks on diet, only male bitransgenic mice on MeIQx developed hepatocellular carcinoma (100% incidence). By 40 weeks, hepatic tumor incidence was 100%/75% (17%/0%) and 44%/17% (0%/0%) in male c-myc/lambda lacZ and C57Bl/lambda lacZ mice who were given MeIQx (or control) diet, respectively, supporting a synergism between MeIQx and c-myc overexpression in hepatocarcinogenesis. At either time point, mutant frequency in the lacZ gene was at least 40-fold higher in MeIQx-treated mice than in control mice of either strain. These findings suggest that MeIQx-induced hepatocarcinogenesis is associated with MeIQx-induced mutations. Elevated mutant frequency in MeIQx-treated mice also occurred concomitant with the formation of MeIQx-guanine adducts, as detected by the 32P-postlabeling assay. Irrespective of strain or diet, sequence analysis of the lacZ mutants from male mouse liver showed that the principal sequence alterations were base substitutions at guanine bases. Adenine mutations, however, were detected only in animals on control diet. MeIQx-fed mice harboring the c-myc oncogene showed a 1.4-2.6-fold higher mutant frequency in the lacZ gene than mice not carrying the transgene. Although there was a trend toward higher adduct levels in c-myc mice, MeIQx-DNA adduct levels were not significantly different between c-myc/lambda lacZ and C57Bl/lambda lacZ mice after 30 weeks on diet. Thus, it seemed that factors in addition to MeIQx-DNA adduct levels, such as the enhanced rate of proliferation associated with c-myc overexpression, may have accounted for a higher mutant frequency in c-myc mice. In the control diet groups, the lacZ mutant frequency was significantly higher in c-myc/lambda lacZ mice than in C57Bl/lambda lacZ mice. The findings are consistent with the notion that c-myc overexpression is associated with an increase in mutagenesis. The mechanism for the synergistic effects of c-myc overexpression on MeIQx hepatocarcinogenicity seems to involve an enhanced expression of MeIQx-induced mutations.     

Strength, flexibility, and maturity in adolescent athletes

The relationship between lower-extremity strength and flexibility and maturational status as measured by Tanner staging (TS) was assessed in 84 male high school athletes. The sum of one-repetition maximum lifts for knee extension and flexion was determined and flexibility was measured with the American Alliance of Health, Physical Education, Recreation, and Dance sit-and-reach test. Chronologic age, body weight, and percent fat were also recorded. Strength and flexibility were compared for each maturational and chronologic age category. Maturational age was better correlated with strength and flexibility than was chronologic age. All correlations were significant. Multiple regression analysis demonstrated significant correlations of TS and age with strength and flexibility. Tanner staging had greater predictive value than age for strength and flexibility. After adjusting for age, the relationship between TS and strength remained significant.     

The "breakfast tolerance test": screening for gestational diabetes with a standardized mixed nutrient meal

In a group of 50 presumed normal pregnant women and 20 known gestational diabetic women, all in the early third trimester, the function of a standard 50 gm, 1-hour screening test for gestational diabetes was compared with that of a plasma glucose level determined 1 hour after the ingestion of a standard 600 kcal mixed nutrient breakfast (breakfast tolerance test). The mean plus 2 SD for the breakfast tolerance test was 120 mg/dl. If this were used as the threshold for a screening test, 75% of cases of gestational diabetes would be identified (sensitivity), while 94% of normal pregnant women would be excluded (specificity). A threshold of 100 mg/dl yields a sensitivity of 96% and a specificity of 74%. These results are compared with those for the standard 50 gm glucose challenge.