Refractory Ulcerative Colitis Improved by Scheduled Combination Therapy of Vedolizumab and Granulocyte and Monocyte Adsorptive Apheresis.

Granulocyte and monocyte adsorptive apheresis (GMA) is occasionally introduced as an alternative combination therapy after loss of response to biologics in ulcerative colitis (UC) patients. However, there have been no reports of the concomitant use of vedolizumab (VDZ) and GMA for the initial induction of UC. A 20-year-old man with refractory UC was admitted for recrudescence. VDZ monotherapy had previously been introduced but was ineffective. Therefore, he received scheduled combination of VDZ and GMA and achieved clinical remission. The combination of two different approaches to inhibit the migration of leukocytes into the inflamed tissue led to satisfactory clinical outcomes.

Granulocyte function during prophylaxis with doxycycline.

The influence of doxycycline on granulocyte migration was investigated on patients undergoing fracture surgery. The granulocyte migration of the patients was depressed when doxycycline was administered. Scanning electron microscopy demonstrated a decreased granulocyte adherence to glass as well as a decrease in number of filopods per cell in the presence of doxycycline.

Treatment of chronic myelogenous leukemia with 3,3'-iminodi-1-propanol, dimethanesulfonate (ester), p-toluenesulfonate (NSC-140117) given orally.

A methanesulfonic acid ester of the aminoglycols, 3,3'-iminodi-1-propanol, dimethanesulfonate (ester), p-toluenesulfonate (NSC-140117) has been found to be very effective in inducing and maintaining complete remissions in early cases of chronic myelogenous leukemia. The drug was given in daily doses of 1-2 mg/kg for remission induction and 0.5-1.0 mg/kg for remission maintenance, with dose adjustment according to blood cell counts. It induced complete remissions (normal white blood cell count and complete disappearance of splenomegaly) in all nine patients treated and has been maintaining these remissions (as well as a complete remission which was originally induced by NSC-84641 in an additional patient) for a period of 2 1/3 + to 15 1/3 + months. The only toxic effect observed occurred in two patients who had mild discomfort in the upper abdomen associated with soft stools. We need further observations, however, regarding the chronic toxic effects of this drug. The myelosuppressive effect of NSC-140117, within the dose range used, is granulocyte specific and appears less long lasting than that of busulfan.

Treatment of metastatic malignant melanoma with a combination of 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (NSC-45388), cyclophosphamide (NSC-26271), and vincristine (NSC-67574).

Courses of treatment with a combination of 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (NSC-45388) (850 mg/m2), cyclophosphamide (750 mg/m2), and vincristine (2.0 mg/m2) were given intravenously in single doses to patients with metastatic malignant melanoma. Treatment was repeated at 4-week intervals. Objective responses were observed in five of 20 patients (25%), indicating that treatment with this drug combination is at least as effective as treatment with NSC-45388 alone in either 5-day courses or intermittent, high-dose, single injections. The toxicity resulting from the combined treatment, although somewhat greater than that reported with the 5-day courses of NSC-45388, is acceptable and much less severe than that found with the single, high-dose schedule. Although the combination does not appear to increase the tumor response rate, it does maintain the advantage of a brief hospitalization for the patient.

Phase I clinical study of didemnin B. A National Cancer Institute of Canada Clinical Trials Group study.

Didemnin B (NSC-325319), a new depsipeptide isolated from a Caribbean tunicate, has been evaluated in a clinical phase I study. The drug was administered in a schedule of a 4 weekly intravenous injection in a six-weeks cycle. Fifty-three patients received 71 evaluable cycles in an escalated dose ranging from 0.4 mg/m2/week to 2.5 mg/m2/week. No hematological toxicity was demonstrated at any dose level. Without prophylactic antiemetics nausea and vomiting was dose limiting at 1.2 mg/m2/week. Due to the use of Cremophor EL as a solvent, hypersensitivity reactions occurred in 9 patients. These reactions occurred following prior exposure to the drug and were commonly seen at the 3rd dose. They were not dose related but became more frequent at 1.5 mg/m2/week necessitating prophylactic treatment with H and H2 receptor blocking agents. Non-hematological toxicities included mild diarrhea, mucositis, anorexia, headaches, and local phlebitis. The dose- limiting toxicity was generalized weakness which became severe and disabling in 3 of 6 patients treated at 2.5 mg/m2/week. No objective responses were documented in 39 patients with evaluable disease. The recommended dose for phase II studies was 2.3 mg/m2/week x 4 in a 6-weeks cycle given with prophylactic antiemetics and H1 and H2 receptor blocking agents.

Effect of methylprednisolone on the oxidative burst activity, adhesion molecules and clinical outcome following open heart surgery.

Following cardiac surgery with cardiopulmonary bypass (CPB), activated granulocytes may be involved with ischaemia/ reperfusion injury. The purpose of this study was to investigate whether steroids could reduce the oxidative burst activity of granulocytes, the expression of adhesion molecules on granulocytes and improve clinical outcome. Sixteen patients undergoing open heart surgery participated in the study. Eight were randomized to receive methylprednisolone (30 mg/kg intravenously) at the start of anaesthesia while eight patients served as a control group. The oxidative burst was measured flow cytometrically using 123-dihydrorhodamine. A panel of adhesion molecules was measured using monoclonal antibodies. Following CPB the oxidative burst activity and the expression of the adhesion molecule L-selectin more than doubled compared to initial values. There was no difference between the steroid group and the control group regarding the expression of adhesion molecules or the oxidative burst activity. In the steroid group the fluid gain during extracorporeal circulation (ECC) was 683 ml (median) compared to 1488 ml in the control group. Steroids prevented hyperthermia in the postoperative period but did not improve the weaning from the ventilator or reduce the stay in the intensive-care unit. In conclusion, treatment with steroids prevented hyperthermia following open heart surgery with CPB and reduced capillary leak during ECC. Methylprednisolone, however, did not reduce the oxidative burst activity or the expression of adhesion molecules on granulocytes following CPB.

Macrophage colony-stimulating factor prevents febrile neutropenia induced by chemotherapy.

There are very few studies describing the preventive effect of macrophage colony-stimulating factor (M-CSF/CSF-1) on chemotherapy-induced infection. In this study, we evaluated the changes in superoxide anion production by granulocytes before and after chemotherapy in ovarian cancer patients and investigated the preventive effect of M-CSF on chemotherapy-induced febrile neutropenia. Three courses of chemotherapy [paclitaxel 180 mg/m(2) and carboplatin (area under the curve; AUC 5)] were administered to 32 ovarian cancer patients, and seven patients presented febrile neutropenia. In the 25 afebrile patients, the percentage of superoxide anion production by granulocytes was significantly decreased from 86.5 +/- 7.7 (%) to 75.1 +/- 8.8 (%) at day 7 and 71.0 +/- 6.3 (%) at day 14 without administration of CSF. However, in the patients who presented febrile neutropenia, it was more severely decreased from 86.8 +/- 6.8 (%) to 60.0 +/- 9.9 (%) at day 7 and 56.8 +/- 5.0 (%) at day 14 without administration of CSF. When M-CSF was administered to all patients in the next course with the same dose of chemotherapy, the incidence of febrile neutropenia was significantly decreased (P = 0.0195), and the duration of fever (>or= 38.0 degrees C) and high serum C-reactive protein (CRP) (>or= 2.0 mg/dl) were also significantly shortened (P = 0.0023, P = 0.0051). Moreover, in these M-CSF-treated patients, the percentage of superoxide anion production by granulocytes was maintained at the level before chemotherapy. These findings indicate that severe impairment of granulocyte function leads to febrile neutropenia, and that M-CSF reduces the incidence of febrile neutropenia by maintaining or improving granulocyte function.

Phase I trial of subcutaneous interleukin-1 alpha in children with malignant solid tumors.

Interleukin-1 alpha (IL-1 alpha) is myeloprotective in a variety of animal models of cancer chemotherapy and is similarly beneficial in adults treated with carboplatin, 5-fluorouracil, and after autologous bone marrow transplantation. There are no trials of this agent in children. Our purpose was to determine the toxicity and maximum tolerated dose (MTD) of recombinant human interleukin-1 alpha (rhuIL-1 alpha) in children with solid tumors receiving intensive cancer chemotherapy and to evaluate its myelo-protective effects. Cohorts of patients received rhuIL-1 alpha in doses of 0.1-10 micrograms/m2 for 4 days by subcutaneous injection prior to ICF chemotherapy (ifosfamide, 2 g/m2/day x 3, carboplatin targeted to an area under the curve of 8 mg/ml x min on day 1, and etoposide, 100 mg/m2 daily for 3 days). Patients were randomized to receive rhuIL-1 alpha before either the first or second course of therapy. After the MTD of rhuIL-1 alpha was determined an additional group of patients received rhuIL-1 alpha at the dose immediately following ICE chemotherapy. The dose-limiting toxicities of rhuIL-1 alpha in the 27 children tested comprised systemic symptoms of fever, chills, headache, and hypotension. The MTD was 3 micrograms/m2/day. There were no differences in chemotherapy-induced hematologic toxicity with increasing doses of rhuIL-1 alpha or in comparisons before or after ICE chemotherapy. Although rhuIL-1 alpha can be given safely to children receiving myelosuppressive chemotherapy, clinical usefulness would mandate a significant hematopoietic benefit in view of the trouble some side effects identified. We saw no evidence of a hematoprotective effect.