Background:Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation.Methods:A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg–1) and escalating doses of MK-2206 (90–200 mg) or escalating doses of dalotuzumab (7.5–10 mg kg–1) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752.Results:A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles.Conclusions:Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.
GYNECOL ONCOL 1989,35/3 (349-351) Ovarian management at the time of radical hysterectomy for cervical cancer was reviewed retrospectively over a 7-year period. All patients had early-stage cancer except three who had stage IIB disease. Approximately 80% of patients had squamous cancer and 20% adenocarcinoma or adenosquamous carcinoma. The mean age was 44, and 24% of patients were 35 or younger. Ninety-nine patients had their ovaries removed. None of the ovaries contained metastatic disease including 22 patients with adenocarcinoma or adenosquamous carcinoma. Of the 17 patients with retained ovaries 14 had transposition into the paracolic gutters. Only one of the 14 patients with transposed ovaries developed symptoms of ovarian failure. No patients with retained ovaries developed metastatic disease or required reoperation secondary to new ovarian pathology. It is our opinion that normal ovaries can be preserved in young women at the time of radical hysterectomy for early cervical cancer regardless of histologic type.Use of CA 125 monoclonal antibody to monitor patients GYNECOL ONCOL 1989,35/3 (323-329) The monoclonal antibody (mAb) OC 125 reacts with an antigen on human ovarian carcinama (OVCA) cells that is also shed into the body fluids and can be detected in patients' sera and/or ascites with a radioimmunometric assay. For the present study, serum CA 125 levels of patients (n = 36) with different stages of OVCA were investigated. Serum levels seem to correlate with tumor burden. In stages I and II (n = 12), 33qo of patients were CA 125 positive, whereas 70% of stage III and IV patients (n = 24) were CA 125 positive. Mean serum levels were in 93 U/ml (stages I, II) and 279 U/ml (stages III, IV). CA 125 levels in ascites and in pleural effusions were manyfold higher than serum levels of the same patients (P < 0.0001). Immunohistochemical investigations of CA 125 in different ovarian tumors (n = 91) revealed that 85% of malignant and 75% of borderline serous cystadenocarcinomas had detectable CA 125 surface expression. Furthermore, 71% of benign tumors showed the CA 125 epitope, whereas mutinous tumors were negative for this marker. One of six ovarian cancer cell lines was CA 125 positive, whereas in 6 of 11 patients, ascitesderived ovarian cancer cells (fresh and gradient isolated) were positive for this marker. The proportion of positive cells ranged from 10 to 90% in these samples. Intraperitoneal recombinant interferon-gamma (rIFN-gamma) therapy resulted in an increase in the number of cells reacting with CA 125. The results of monitoring in patients receiving different therapeutic regimens and/or agents demonstrate the usefulness of this marker. lead-212 and bismuth-212 to low-LET X-rays on ovarian carcinoma GYNECOL ONCOL 1989,35/3 (297-300) We are investigating the potential use of short-lived a-emitting radionuclides for the treatment of ovarian carcinoma. These radionuclides transfer dense high ionizing linear energy (high LET) over a short path length without dependence upon cellular oxygen. The o-...
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