Robert Taylor

Abstract 1. Combinations of effective agents produce at least an additive increase in complete remission rates over that which can be achieved when the agents are used individually. 2. Patients who do not achieve complete remission with initial treatment have a significantly shorter survival. 3. Alternating MTX and 6-MP at 28-day intervals during remission does not prolong the duration of remission over that of combined concurrent 6-MP and MTX. 4. The administration of folic acid antagonists intrathecally at 28-day intervals during antimetabolite maintained remission did not prolong the duration of remission. Meningeal leukemia, however, occurred significantly less frequently in these patients. 5. The duration of combined 6-MP and MTX maintained remission is not greater than that of 6-MP maintained remission. 6. The toxicity of 6-MP and MTX in combination in patients in remission is additive. The above conclusions were drawn from this comparative study of combinations of chemotherapeutic agents in children with acute lymphocytic leukemia.

Abstract The efficacy of three therapeutic programs for acute leukemia were compared. These programs included (1) Methotrexate (Phase I) followed by 6-mercaptopurine (Phase II); (2) 6-mercaptopurine (Phase I) followed by Methotrexate (Phase II); and (3) Combination Therapy, i.e., 6-mercaptopurine given in combination with Methotrexate. In children with acute lymphocytic leukemia the remission rate was 59 per cent for combination therapy, 47 per cent for 6-mercaptopurine, and 29 per cent for Methotrexate. The better remission rate for combination therapy is consistent with that predicted if it is assumed that 6-mercaptopurine and Methotrexate act independently. The median duration of complete remissions for the three treatments was not different (4 to 5 months). However, long lasting remissions were more frequent in patients receiving combination therapy. The median survival from the onset of therapy to death was 9 months. There were no differences between the three treatment programs as regards survival. In adults the remission rate was 15 per cent for combination therapy, 21 per cent for 6-mercaptopurine and 7 per cent for Methotrexate. As regards survival in adults, early deaths were more common in patients who received MTX as initial therapy, whereas after 5 months survival was somewhat better in those patients receiving combination therapy. In both children and adults there was no evidence that prior treatment with one of the antimetabolites altered response to the other antimetabolite. This result differs from those in animal models, and its effect on our concept of the mechanism of resistance is discussed. Responsiveness to the second course of antimetabolite therapy (Phase II) was as good as that to the first course of treatment. This was true for the remission rate, remission duration, and even for survival when appropriate corrections were made. Thus, responsiveness to drug therapy is maintained as the disease progresses temporally. It may be concluded therefore that new agents can be effectively studied in patients with "late" disease. Responsiveness to Phase II therapy was independent of responsiveness to Phase I. The most common and severe toxic manifestations related to the bone marrow and gastrointestinal tract. There were no major differences quantitatively in the toxicity for the three treatment programs in children in spite of the fact that the drugs were given in full dosage in the combination program. Oral ulcers and a generalized erythematous rash occurred significantly more frequently in patients receiving Methotrexate. Jaundice was significantly more frequent in adults and in patients receiving 6-MP.

OBJECTIVES/HYPOTHESIS: Endoscopic endonasal skull base surgery defects require effective reconstruction. Although the nasoseptal flap (NSF) has become our institution's workhorse for large skull base defects with cerebrospinal fluid (CSF) leaks, situations where it is unavailable require secondary flaps. Clinical outcomes, pearls and pitfalls, and an algorithm will be presented for these secondary flaps. STUDY DESIGN: Clinical case series. METHODS: Medical records of all endoscopic endonasal skull base surgeries at a tertiary care academic medical center were reviewed for skull base defect type, reconstruction method, CSF leak rate, and flap necrosis rate. RESULTS: Of 330 flaps for reconstructing endoscopic endonasal skull base defects, secondary flaps were used in 34 cases (10%). These included 16 endoscopic-assisted pericranial flaps, seven tunneled temporoparietal fascia flaps, three inferior turbinate flaps, two middle turbinate flaps, two anterior lateral nasal wall flaps, two palatal flaps, one occipital flap, and one facial artery buccinator flap. There were 19 anterior cranial fossa defects, 10 clival defects, three sellar defects, and one frontal and one lateral orbit/middle fossa defect. Twenty-five of the 34 cases (73.5%) had either prior or postoperative radiation therapy. The most common pathology was sinonasal cancer, with 16 cases (47.1%). The postoperative CSF leak rate was 3.6% due to one middle turbinate flap necrosis. CONCLUSIONS: Secondary flaps for skull base reconstruction can be harvested with minimally invasive techniques and demonstrate excellent success rates (97%) that are comparable to that of the NSF (>95%). Multiple flaps for complex skull base defects should be in the armamentarium of comprehensive skull base surgery centers. LEVEL OF EVIDENCE: 4.

NovaSil clay (NS) provides significant protection from the adverse effects of aflatoxins (AFs) in multiple animal species by decreasing bioavailability from the gastrointestinal tract. It is postulated that NS clay can be safely added to human diets to diminish exposure and health risks from AF contaminated food. To determine the safety and tolerance of NS in humans and establish dosimetry protocols for long-term efficacy studies, a randomized and double-blinded phase I clinical trial was conducted. Volunteers (20-45 yr in age), were clinically screened for confirmation of their health status. Fifty subjects (23 males and 27 females) were randomly divided into two groups: The low-dose group received nine capsules containing 1.5 g/day, and the high-dose group received nine capsules containing 3.0 g/day for a period of 2?wk. NS capsules were manufactured in the same color and size and were distributed to each participant three times a day at designated sites where follow-up was taken to record any side effects and complaints. Blood and urine samples were collected before and after the study for laboratory analysis. All participants completed the trial and compliance was 99.1%. Mild GI effects were reported in some participants. Symptoms included abdominal pain (6%, 3/50), bloating (4%, 2/50), constipation (2%, 1/50), diarrhea (2%, 1/50), and flatulence (8%, 4/50). No statistical significance was found between the two groups for these adverse effects (p > 0.25). No significant differences were shown in hematology, liver and kidney function, electrolytes, vitamins A and E, and minerals in either group. These results demonstrate the relative safety of NS clay in human subjects and will serve as a basis for long-term human trials in populations at high risk for aflatoxicosis.