In this study (GI 6384), regimens are compared which, in phase II investigations, produced 2-fold increases in the historical rates of objective and minor responses. These regimens were associated with overall survival exceeding 1 year. In arm 1, 5-fluorouracil (FUra) alone, 500 mg/m2 on days 1 through 5 was escalated in 25-mg/m2 increments in monthly courses to produce mild to moderate toxicity. This allows an examination of dose-response relationships and comparisons of therapeutic index. In arm 2, leucovorin (LV), was escalated from 25 to 250 to 500 mg/m2 beginning 1 hour before a bolus FUra (30 mg/kg) every 3 weeks. Arm 3 (not previously tested) employed LV (25 mg/m2) 1 hour before FUra (600 mg/m2) given weekly for 6 weeks. It tested the efficacy of low-dose LV. Arm 4 tested high-dose LV (500 mg/m2) as a 2-hour infusion beginning 1 hour before a bolus FUra (600 mg/m2) weekly for 6 weeks. In a preliminary analysis of this study, findings are statistically consistent with the anticipated high frequencies of objective response. It also finds evidence of biological activity across the wide range of LV dosages and that LV produces an apparent favorable change in FUra side effects from hematological to gastrointestinal toxicities. One or more regimens may favorably change the anticipated prognosis of patients with measurable cancer of the colon and rectum.
Small bowel adenocarcinoma is a rare but well-known complication of Crohn’s disease. The diagnosis of small bowel adenocarcinoma remains difficult since its presentation is highly variable and mimics active or obstructive Crohn’s disease. The diagnosis is often delayed and typically detected only at surgery in an advanced stage with a poor prognosis. We report a case of metastatic ileal adenocarcinoma in a patient with Crohn’s disease with prolonged survival. Our case describes serial promising treatment options of these advanced malignancies and raises a possible role for checkpoint immunotherapy.
e16160 Background: Advanced (Adv) intrahepatic IH Cholangiocarcinoma BD trials found multi-drug, sequences (GFLIO) safely expand eligibility (El) for patients (pts) of all ages -/+ resistant Ca (R). Two series had response/survival (S) of 80% / > 2 years (yr) (Bruckner et al Anti Ca Res 16). Therapy reverses R to key drugs, improves the pts' many immune functions and exposure to neoantigens, (Caraglia RT et al Front Oncol 19.) A.L.A.N.(AS) blood tests (Ts) predict chances of S (Salati et al EuJCa 18). Methods: Kaplan-Meier analyses examine prognostic Ts as El criteria for real-world pts. El included poor risk pts: any adult age, +/- R (-/+ prior test drugs). El: Intent to treat; consent; adv measurable IHBD; active progression (pg); Performance 0-2 and expected 6 wks S. The inE have 2ary CNS, require IVs; are unable to reach office, or have gr3-4 toxicity. GFLIO every 2 wks in mg/M2: Gemcitabine 500; 5-Fluorouracil 1200 over 24 hrs; Leucovovorin 180 Irinotecan 80 and day (D)2, Oxaliplatin 40. On pg, drugs are added, none are discontinued: D2 docetaxel 20-25, -/+ Mitomycin C 4-6; on 2nd pg, D1 Cetuximab is added (KRAS wild), wkly, and replaced on 3rd pg with D1 bevacizumab 10 mg/kg every 2 wks. Baseline A.L.A.N. assays (AS) are in Salati ibid. Results: Survival of the 35 pts, 19 R, is: 84% at 1 yr and 64% (CI 50-78%) at 2 yrs, median S CI 22.5 - > 24 mos; S at 12, 18 and 24 mos: with no unfavorable (UF) AS0 Ts (12 pts), is 100, 100, and 90%; with 1-2 UF Ts (15pts), is 76, 66 and 66% (CI > 56%). With 3-4 UF Ts (8 pts) S is 67, 34, and 13%. The old, 14 > 70, and young S similarly (̃); 4/4 > 75 S in remission for > 2 yr. p. 0.36, HR 1.68. Pts, 19R/16 - prior therapy, S similarlỹ, p 0.96, HR 1.03; both groups have similar ̃ Ts AS. Females, 17, and males, in spite of a cluster with UF AS 3-4, have similar ̃ S, p 0.6, HR 1.4. GFLIO induction produced neither hospitalizations, neutropenic fevers nor severe neuropathy and no initial need for prophylactic or high dose granulocyte factors. Favorable (Fav) Ts include: low < 3.1 neutrophile-lymphocyte ratio, 57%of pts, 81% S 2yr, p 0.005 HR 9.4; 2-4/4 fav ALAN Ts, 77% of pts,78% S 2 yr, p 0.007, hr 6.3; low < 300,000 platelets 71%, 80% S 2 yr, p 0.01, HR 1.7, and high > 3.5 albumin,74% of pts,72% S 2yr, p 0.03, HR 3.9. Groups defined by single UF Ts (except low albumin, 33% S 2 yr) S > ̃ 50% at 2 yr. Conclusions: A real world, safe, survival of > 2yr, is confirmed in this 3rd series. This meets NCI criteria for: selective use, and development of GFLIO's elements (lowest effective dosages and sequential regimens), and prognostic tests (criteria and models). Therapy can, in theory, correct UF T's - pathology. When matched for AScore, GFLIO is ̃ effective, -/+, R and at all ages. Tests and GFLIO can change practice, improve El and survival for under treated pts, some half of all pts, the aged and the Resistant, told they have "only 6 or 12 mos to live." Clinical trial information: NCT01905150.
Introduction: Zonisamide is admitted in Japan since 17 and in the United States since 6 years. In different studies a favourable effect could be shown in refractory epilepsies. Zonisamide was introduced in Germany in June 2005. The use is limited to adults in the moment.
Methotrexate, tetracycline, gentamicin, streptomycin, and penicillin inhibited the growth of L5178Y murine leukemia cells in culture with I 50 (concentration of drug that caused a 50% inhibition of growth at 72 h) values of 0.0028 μg/ml (6.2 × 10 −9 M), 7.9 μg/ml, 200 μg/ml, 1,700 μg/ml, and 3,000 μg/ml (5,000 U/ml), respectively. At concentrations achieved clinically or utilized in the laboratory, the antibiotics did not alter the I 50 of methotrexate.
Introduction Routine blood tests are prognostic tests for patients with cholangiocarcinoma. New drug regimens may produce a median overall survival of 2 years or more. Methods This single practice, IRB-approved, phase II trial examines prognostic tests, Kaplan-Meier survival, and univariate Cox regression analyses. Eligibility requires: intent-to-treat; signed consent; advanced measurable intrahepatic cholangiocarcinoma, with or without resistance to the test drugs; any adult age; performance status 0–2; and expected survival of ≥ 6 weeks. Biweekly treatment, with 1/3 of standard dosages in mg/M 2 , includes: Gemcitabine 500; 5-Fluorouracil 1200 over 24 hours; Leucovorin 180; Irinotecan 80; and on day 2, Oxaliplatin 40. On progression, drugs are added on day 2: first, Docetaxel 25 precedes Oxaliplatin, with or without Mitomycin C 6 after Oxaliplatin. The next sequential additions are day 1, Cetuximab 400 total mg, then 200 mg weekly, and then Bevacizumab 10 mg/kg is substituted for Cetuximab (FDA IND# 119005). Results For 35 patients, 19 with 1–2 lines of prior therapy, resistant tumors, and 16 no prior therapy, survival at 24-months is ≥ 72 and ≥ 58%, respectively. For 14 patients aged ≥ 70 years, ≥ 63% survive 24 months, P = 0.28. Validated tests that predict ≤ 6-month survivals find median survival times of 17-months through > 2-years when compared to patients with favorable tests: Neutrophils lymphocyte ratio > 3.0, HR = 6.54, P < 6.4x10–3; absolute neutrophil count > 8000/μl, HR = 4.95, P < 6.5x10–3; serum albumin < 3.5 g/dl, HR = 4.10, P < 0.03; and lymphocyte monocyte ratio< 2.1, HR = 1.6, P = 0.50. Overall, the 76 (60–90)% of patients with 0–2 out of 4 high risk tests survive ≥ 24 months, (P = 7.1x10–3). Treatments produce neither hospitalization, neutropenic fever, severe enteritis, nor severe neuropathies. Conclusion Two-year survival is replicable and predictable. Findings warrant phase III validation tests of sequential regimens, re-challenge with recombination, low dosages, and blood tests that are associated with lethal mechanisms that impair response and survival.
Objectives: Surgery represents an additional therapeutic option for drug resistant focal epilepsies in childhood. The results of surgical procedures for epilepsy performed on 100 children are presented.
