Biomedical subjects
Publications and source records attributed to M Campion.
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Our purpose was to determine the maximum tolerated dosage of rhIL-6 after high-dose cytotoxic chemotherapy and autologous BMT in patients with advanced breast cancer. Twenty patients (median age 43.5 years) received either CY and thiotepa (n = 3) or CY, thiotepa and carboplatin (n = 17) for 4 days. Unpurged autologous BM was reinfused 72 h later. Daily rhIL-6 therapy began the day of marrow infusion and continued until recovery of neutrophils (> or = 1.5 x 10(9)/l) and platelets (> or = 50 x 10(9)/l) or for a maximum of 28 days at a dosage of 0.3 microgram/kg/day (n = 7), 1 microgram/kg/day (n = 6) or 3 micrograms/kg/day (n = 7). Two of the initial 4 patients given rhIL-6 at 0.3 mu/kg i.v. experienced grade 4 hyperbilirubinemia, so subsequent patients received s.c. rhIL-6. Most toxicities attributable to rhIL-6 were reversible or mild constitutional symptoms, but dose-limiting grade 4 hyperbilirubinemia also occurred in 3 of the 7 patients receiving the 3 micrograms/kg dose. At the 0.3 and 1 microgram/kg/day doses, 8 of 13 patients completed the study vs. only 2 of 7 at the 3 micrograms/kg/day dose. During rhIL-6 treatment, neutrophil recovery (> or = 500 x 10(6)/l) occurred in 12 patients and platelet recovery (> or = 20 x 10(9)/l) occurred in 6 patients, 5 of whom received the 0.3 or 1 microgram/kg/day s.c. dose. The maximal tolerated dose of rhIL-6 after autologous BMT appeared to be 1 microgram/kg/day s.c., a dose appreciably lower than the maximal tolerated dose after conventional cytotoxic therapy.
Preclinical studies of recombinant human interleukin-3 (rhIL-3) and granulocyte-macrophage colony-stimulating factor (rhGM-CSF) have shown enhancement of multilineage hematopoiesis when administered sequentially. This study was designed to evaluate the safety, tolerability, and biologic effects of sequential administration of rhIL-3 and rhGM-CSF after marrow ablative cytotoxic therapy and autologous bone marrow transplantation (ABMT) for patients with malignant lymphoma. Thirty-seven patients (20 patients with non-Hodgkin's lymphoma and 17 patients with Hodgkin's disease) received one of four different treatment regimens before ABMT. Patients were entered in one of four study groups to receive rhIL-3 (2.5 or 5.0 micrograms/kg/day) administered by subcutaneous injection for either 5 or 10 days starting 4 hours after the marrow infusion. Twenty-four hours after the last dose of rhIL-3, rhGM-CSF (250 micrograms/m2/d as a 2-hour intravenous infusion) administration was initiated. rhGM-CSF was administered daily until the absolute neutrophil count (ANC) was > or = 1,500/microL for 3 consecutive days or until day 27 posttransplant. The most frequent adverse events in the trial included nausea, fever, diarrhea, mucositis, vomiting, rash, edema, chills, abdominal pain, and tachycardia. Three patients were removed from the study because of chest, skeletal, and abdominal pain felt to be probably related to study drug. Four patients died during the study period because of complications unrelated to either rhIL-3 or rhGM-CSF. The median time to recovery of neutrophils (ANC > or = 500/microL) and platelets (platelet count > or = 20,000/microL) was 14 and 15 days, respectively. There were fewer days of platelet transfusions than seen in historical control groups using rhGM-CSF, rhG-CSF, or rhIL-3 alone. In addition, there were fewer days of red blood cell transfusions compared with historical controls using no cytokines or rhGM-CSF. These data indicate that the sequential administration of rhIL-3 and rhGM-CSF after ABMT is safe and generally well-tolerated and results in rapid recovery of multilineage hematopoiesis.
There are about 20 types of human papillomaviruses (HPVs) which are generally believed to be confined to the anogenital tract. HPV 16 is the most common of these. Four squamous cell carcinomas of the finger from three individuals were analyzed for the presence of HPV DNA by Pst 1 restriction enzyme digest and Southern blotting. Under high stringency conditions, all were positive for HPV 16. The DNA from each patient was digested with a panel of restriction enzymes so that integration of HPV into the genome could be evaluated. Three of three samples contained high molecular weight oligomeric circular DNA arranged as catanates. None showed integration. To determine if the HPV was transcriptionally active, RNA was isolated, reverse transcribed, and amplified using primers that amplified the unspliced E6 transcript and the E6I and E6II spliced transcripts. All of the patient biopsies assayed expressed the unspliced E6 transcript and the spliced E6I transcript with the E6I transcript being the most abundant. The E6II transcript was not detected in any of the samples. These findings indicate that HPV plays a role in the development of squamous cell carcinoma of the finger and the role of the malignant genital HPV needs to be carefully looked at in areas outside the genital region. It also suggests that the natural history of HPV in areas outside the cervix may not be identical to that of HPV in the anogenital region.
Recombinant human interleukin-3 (rhIL-3) was administered to 30 patients undergoing autologous bone marrow transplant (ABMT) for treatment of lymphoma. In this phase I dose escalation study, rhIL-3 was administered from day 0 to 20 after ABMT by 2-hour intravenous infusion at dose levels of 1, 2, 5, and 10 micrograms/kg/d. Seventeen patients did not complete therapy with rhIL-3. Eleven requested early discontinuation for malaise, confusion, transplant complications, or rapid engraftment and were removed from the study, whereas six patients developed grade III toxicity, including fever (three patients), or headache (three patients) possibly attributable to rhIL3. Other common toxicities included diarrhea, rigors, mucositis, and rash. The maximum tolerated dose of rhIL-3 was 2 micrograms/kg/d. No evidence of earlier hematopoietic cell recovery was observed compared with similar historical patients treated with recombinant human granulocyte-macrophage colony-stimulating factor. Future trials will be needed to determine alternate schedules of administration of rhIL-3 or the use of rhIL-3 in combination or in sequence with other growth factors.
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We studied the effect at three months of four transverse astigmatic keratotomy incisions (TAK) performed prior to phacoemulsification in 61 eyes on corneal astigmatism. The optical zone was varied in each case depending upon the magnitude of preoperative astigmatism. The eyes were compared to 105 control eyes in which no astigmatic incisions were performed to assess the estimated effect of the TAK incisions. Keratometry readings were taken preoperatively and three months postoperatively. Surgically induced astigmatism was measured using vector corrected astigmatism. Improvement in astigmatism was reported in all three optical zone groups, but the astigmatism was undercorrected in each. No complications affecting vision were reported, indicating that TAK may be a safe way to reduce postoperative astigmatism when combined with phacoemulsification.
In a series of studies, recombinant interferon-alpha 2a (rIFN alpha 2a, Roferon-A) was administered alone (273 men) or combined with vinblastine (91 men) to patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS). Patients were treated with daily doses of rIFN alpha 2a ranging from 3 to 54 million international units (I.U.) administered intramuscularly. A dose of 36 million I.U. daily for approximately 10 weeks followed by a three times weekly maintenance schedule with the same dose resulted in the best overall therapeutic benefit. An escalating-dose regimen of 3, 9, and 18 million I.U. daily, each for 3 days, followed by 36 million I.U. daily, produced equivalent therapeutic benefit with amelioration of acute toxicity in some patients. Response was more likely in patients without a history of opportunistic infection or B symptoms (fever, night sweats, or weight loss). Response rate increased with increasing baseline CD4 lymphocyte count and was 45.5% in patients with a CD4 count of greater than 400/mm3. Responding patients with a CD4 count of greater than 200/mm3 had a distinct survival advantage over patients who had similar CD4 counts but whose tumors did not regress with therapy. The addition of vinblastine increased toxicity and did not improve the response rate or prolong survival. Side effects included fatigue, fever, chills, myalgias, headaches, anorexia, nausea, diarrhea, and dizziness. Mild abnormalities in hematologic and liver function tests occurred in some patients. Most adverse effects diminished or resolved with continued therapy. We conclude that rIFN alpha 2a offers important therapeutic benefit in a select group of patients with AIDS-related KS.
The integration of human papillomavirus (HPV) DNA into the human genome has been generally accepted as a characteristic of malignant lesions. To gain a better understanding of this phenomenon, genomic DNA from 181 cervical biopsy specimens was isolated and analyzed for HPV type and physical state of the HPV genome. These specimens represented the full spectrum of cervical disease, from condyloma to invasive carcinoma. Discrimination between integrated and episomal HPV DNA was accomplished by the detection of HPV-human DNA junction fragments on Southern blots. In most cases in which ambiguous Southern blot results were obtained, the specimens were reanalyzed by two-dimensional gel electrophoresis. Of the 100 biopsy specimens of cervical intraepithelial neoplasia analyzed, only 3 showed integrated HPV DNA, in contrast to 56 (81%) of 69 cervical carcinomas (P less than 0.001) showing integrated HPV DNA. Of the 40 carcinomas containing HPV 16 DNA, 29 (72%) had integrated HPV DNA, of which 8 (20%) also had episomal HPV DNA. In 11 (27%) cancers, only episomal HPV 16 DNA was detected. All 23 HPV 18-containing carcinomas had integrated HPV DNA, and 1 also had episomal HPV 18 DNA. The difference between HPV types 16 and 18 with respect to frequency of integration was statistically significant (P less than 0.01). The results of this study indicate that detectable integration of HPV DNA, regardless of type, occurs infrequently in cervical intraepithelial neoplasia. The absence of HPV 16 DNA integration in some carcinomas implies that integration is not always required for malignant progression. In contrast, the consistent integration of HPV 18 DNA in all cervical cancers examined may be related to its greater transforming efficiency in vitro and its reported clinical association with more aggressive cervical cancers.
Ninety-seven evaluable patients with measurable, advanced, malignant melanoma were treated with recombinant alpha interferon in a cooperative phase II efficacy trial, whose primary objective was to estimate the response rate. Interferon (rIFN alpha-2a, Roferon-A) was injected subcutaneously daily for 70 days. Dose was escalated in four steps from three million units to 36 million units over ten days. Eight patients responded objectively and six patients (6%) had a complete response. The median duration of complete response was 11 months. Patients achieving complete response had only cutaneous, nodal, or pulmonary disease; some had extensive prior therapy; some could tolerate no more than three million units per day. Few patients could tolerate the target dose of 36 million units daily for 70 days. Limiting toxicity was primarily fatigue. Interferon in tolerable doses is effective in a small subset of patients with melanoma. Comparison of published trials of dacarbazine and recombinant alpha interferon indicates the two drugs have similar activity.
I prospectively evaluated my own learning curve for radial keratotomy (RK) by comparing the results achieved in two groups: 20 consecutive eyes on which I performed RK without having had previous experience with the procedure (group 1); and 20 other eyes, matched for age, sex, and preoperative refractive error, on which I performed RK after I had performed the procedure 250 times (group 2). Although there were nine microperforations in group 1 and none in group 2, the postoperative refractions and uncorrected visual acuities were similar in both groups. Since the microperforations had no adverse effect on the visual results, it is reasonable to conclude that there was, in effect, no learning curve involved in my experience with RK.
In clinical trials with a range of doses of recombinant interferon-alpha 2a, we observed a 25% overall incidence of neutralizing antibody development. Careful data analysis did not reveal a relationship between antibody development and therapeutic response. Of 752 patients evaluable for antibody development and clinical response, 31% of the antibody-positive patients and 28% of the antibody-negative patients had therapeutic responses. Although the formation of anti-IFN antibodies seems to be associated with most IFN preparations, incidence and clinical significance have been difficult to determine for a number of reasons. Different assays with differing sensitivities for the detection of IFN antibodies have been utilized in different studies. Additionally, important clinical variables that affect antibody development have often not been carefully controlled or analyzed. The relationship between antibody development and multiple related factors, such as route of administration, dose regimen, cumulative dose, duration of treatment, and the underlying disease, requires clarification. Initial analyses suggest that the median time to antibody development may vary with the dose regime and cumulative dose, as well as the route of administration. Carefully designed prospective studies controlling for influential clinical variables and utilizing standardized assay techniques are required for a meaningful analysis of the antigenic potential of all therapeutic protein products.
We prospectively studied 100 consecutive deaths at St. Vincent's Hospital and Medical Center in New York City for possible eye donation. Fifty-two patients were unsuitable mainly because of medical contraindications and age at death. Of the 48 suitable candidates, 21 pairs (44%) of eyes were obtained. Sixteen of the 42 eyes (38%) were used for transplantation. Projection of the number of corneas obtainable for transplant in New York City were calculated. The figures indicated that the three-month waiting list of the New York Eye-Bank for Sight Restoration, Inc., could be eradicated if hospitals were able to get seven donors from every 100 deaths suitable for donation, a rate only 16% of that realized in this study.
Multiple markers were used to count Langerhans' cells in the cervix. In the normal cervix, thymocyte antigen (T6) and adenosine triphosphatase (ATPase) demonstrated the largest population of Langerhans' cells. MHC Class II positive cells were equivalent to 60%, and S100 positive cells were equivalent to 35% of T6 or ATPase positive cells. Whereas Langerhans' cells demonstrated by T6, ATPase, and MHC Class II antigen were evenly distributed throughout the epithelium, the S100 positive cells were seen predominantly near lymphocytic aggregates and capillaries. In human papillomavirus infection and cervical intraepithelial neoplasia the numbers of T6, ATPase, or MHC Class II positive Langerhans' cells were reduced by 60% but the S100 positive cells were almost completely depleted. These findings suggested that there were different subpopulations of Langerhans' cells in the cervical epithelium. The depletion of Langerhans' cells, particularly the selective depletion of the S100 positive subpopulation, might cause a localized immunodeficiency that impairs immune surveillance and the cell-mediated immune response to human papillomavirus infection and cervical intraepithelial neoplasia.
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