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Biomedical subjects

D L Morton

Publications and source records attributed to D L Morton.

At least 217 records · Page 12Linked to original sources

Recurrence potential of thin primary melanomas.

Between April 1971 and January 1985, the University of California at Los Angeles (UCLA) Division of Surgical Oncology has seen 649 patients diagnosed with thin primary melanomas, as defined by a Clark level less than IV and Breslow depth less than 0.76 mm. Thirty-six patients, whose primary diagnosis was confirmed by UCLA pathologists, presented with or subsequently developed melanoma metastases. Twenty-four (67%) had Clark level II lesions, whereas the remaining 12 (33%) had Clark level III lesions. Metastases were noted more frequently in men than in women, with a man-to-woman ratio of 3 to 2. The site of the primary lesion in this group was most frequently on the trunk (16 of 36 cases, 44%), followed by the head and neck (9 of 36 cases, 25%) and arm and shoulder (7 of 36 cases, 19%). Metastasizing thin lesions were least likely to occur on the leg and hip (4 of 36 cases, 11%). Twenty of these lesions were recently reexamined, and 17 of 20 cases (85%) demonstrated evidence of regression. Twenty-eight patients (78%) had their first metastases to regional lymph nodes. Fifteen remained alive with no evidence of disease at a median follow-up of 99 months. Twenty patients died from systemic metastases, and one patient was alive with brain metastasis at the time of this article. Although infrequent, metastases from thin melanomas do occur, suggesting the need for careful long-term follow-up and immediate investigation of adenopathy even in low-risk patients.

Adult↗

Serial determinations of melanoma tumor-associated antigen and antibody in patients with stage I melanoma.

The correlation of circulating immune complexes (CICs) and the clinical course of malignant melanoma has not been consistent when using nonspecific assays for CIC. To improve predictability, serial serum samples from patients with pathologic stage I melanoma were analyzed for the presence of antimelanoma tumor-associated antigen (TAA) antibody by direct radioimmunoassay and for the presence of melanoma TAA in CIC by the antigen competition method. Immunochemically characterized TAA was isolated from the spent culture medium of a melanoma cell line. Seventy-five percent of patients with melanoma TAA-specific immune complex (IC) had recurrences, while 71% of patients without melanoma TAA-specific IC remained free of disease for prolonged periods (up to 14 years of follow-up). Anti-TAA antibody titers did not correlate with disease recurrence. Our results demonstrate a correlation with melanoma TAA-specific IC and disease recurrence. The absence of melanoma TAA-specific IC is associated with a low risk of recurrence. Fluctuations in melanoma TAA-specific IC levels indicate a dynamic tumor host immunobiology and the need for serial follow-up.

Antibodies, Neoplasm↗

Adjuvant chemo-immunotherapy in stage II carcinoma of the breast.

From July of 1974 to June of 1978, 131 patients with Stage II carcinoma of the breast were randomly assigned to one of three treatment arms in order to assess the efficacy of adding immunotherapy to adjuvant chemotherapy. All patients had metastases in the axillary lymph nodes, but no clinical evidence of systemic disease. Prognostic factors were relatively equally distributed among the three treatment arms. All patients received adjuvant chemotherapy consisting of cytoxan, methotrexate, and 5-fluorouracil (CMF). In addition, patients received adjuvant immunotherapy consisting of Bacille Calmette Guerin (BCG) or BCG plus a tumor cell vaccine. This vaccine was a mixture of allogeneic breast cancer cell lines grown in tissue culture. Fourteen patients receiving tumor cell vaccine developed hepatitis B, leading to the abandonment of this arm of the study. Side effects of chemotherapy were tolerable. No statistically significant difference could be demonstrated in recurrence rate or survival. However, the two groups receiving adjuvant chemo-immunotherapy had a slightly shorter time to recurrence and lower overall survival. The use of chemo-immunotherapy as administered in this study did not improve the clinical course of patients with Stage II breast cancer and was associated with significant morbidity.

Antineoplastic Combined Chemotherapy Protocols↗

Regression of cutaneous metastatic melanoma by intralesional injection with human monoclonal antibody to ganglioside GD2.

In this study we used human monoclonal antibody (Hu-mAb) L72 as an intratumoral injection of cutaneous metastasis of melanoma to study its anti-tumor effects in human patients. Hu-mAb L72 was developed by transforming peripheral blood lymphocytes from a melanoma patient in vitro with the Epstein-Barr virus, forming a human lymphoblastoid cell line that produces 2-5 micrograms of IgM per ml. This IgM Hu-mAb was shown to react specifically with ganglioside GD2 and have a strong cytotoxic effect on human melanoma cells in the presence of complement. Patients with cutaneous metastatic melanoma were given intralesional injections on a daily or weekly injection schedule. Regression was seen in all tumors except in those of two patients whose tumors were shown to have low antigenicity. Histopathological data showed tumor degeneration, fibrosis, free melanin, and some degree of lymphocyte or macrophage infiltration. One patient with melanoma satellitosis treated with Hu-mAb showed complete regression with no sign of recurrence 20 months after the initial treatment. With the exception of mild erythema, no side effects were observed in any patient.

Adult↗

Phase I trial of thermochemotherapy for brain malignancy.

High-grade primary and refractory brain tumors and metastases to the brain from other primary sites are associated with a grave prognosis. Treatment, usually palliative, consists of some combination of surgery, radiation, and chemotherapy. Recently, noninvasive hyperthermia by magnetic-loop induction has been safely used to treat patients with advanced cancer in extracranial sites. Both disease regression and disease stabilization have been observed. This technique was recently applied to brain tumors in an animal model, and its safety was again demonstrated. As a result, a Phase I trial of noninvasive localized hyperthermia in combination with intravenous chemotherapy has been carried out in ten patients whose primary or metastatic brain tumors failed to respond to standard therapy. Ten patients underwent 23 thermochemotherapy sessions using the magnetic-loop induction device. The median, maximum temperature of normal brain after 1 hour of hyperthermia was 41.1 degrees C (range, 38.6 degrees C-43.4 degrees C); the median, maximum temperature of brain tumor was 42.5 degrees C (range, 38.8 degrees C-46.3 degrees C) (P less than 0.01). The temperatures of both the normal brain and brain tumor were obtained during 18 treatments. The tumor temperature was greater than the normal brain temperature in 15 of 18 treatments. In 78% of the treatments, the measured tumor temperature reached at least 42 degrees C, whereas the normal brain reached 42 degrees C in only 13% of the treatments. These data demonstrate the "selective inability" of brain tumor tissue to dissipate heat. Vital signs, intracranial pressure, and neurologic status were monitored throughout the hyperthermia treatments. No mortality or increase in chemotherapeutic toxicity could be attributed to the thermochemotherapy. In addition, there were no local complications or permanent neurologic complications. Two patients with elevated intracranial pressure before therapy had transient neurologic deficits that may have been exacerbated by the hyperthermia. It is concluded that this new, noninvasive modality not only produced effective intracranial tumor heating, but could be performed safely with the proper precautions. Phase II trials are warranted.

Adult↗

Immunogenicity of melanoma-associated gangliosides in cancer patients.

The immunogenicity of gangliosides found on human melanoma cells was determined from sera of 26 melanoma patients who were immunized every 1-4 weeks for 4 months with tumor-cell vaccine (TCV) prepared from cultured melanoma cells. Total lipid-bound sialic acid in the gangliosides isolated from TCV was 0.38 mumol/10(8) cells, and was distributed as follows: 44.8% to GM3, 44.2% to GD3, 5.6% to GM2, and 4.6% to GD2. Sera were tested at monthly intervals for antibodies to each ganglioside by ELISA with purified gangliosides as the antigen source. The immunologic specificity of the antibody was confirmed by absorption tests. None of the 26 patients had detectable anti-GM3, anti-GD3, or anti-GD2 antibodies before immunization, although anti-GM2 antibody was detected in 3 patients. After immunization, 2 patients developed IgM anti-GD2, 10 developed IgM anti-GM2, and 2 developed IgG anti-GM2 antibodies. No patient developed detectable anti-GM3 or anti-GD3 antibodies. These results indicate that both GD2 and GM2 expressed on human melanoma cells are immunogenic in humans, although GM2 appears to be more immunogenic. The other two gangliosides, GM3 and GD3, are present in human sera and in human normal tissues, and thus immunologic tolerance may have been established against these gangliosides. Alternatively, circulating GM3 and GD3 may have neutralized anti-GM3 and anti-GD3 antibodies, if any were induced by TCV immunization.

Antibodies↗

Evolution and clinical application of a rapid chemosensitivity assay.

The clinical usefulness of the soft agar colony-formation assay of in vitro chemosensitivity developed by Hamburger and Salmon is limited by long turnaround time (2-3 weeks), low success rate for small specimens, and clumping artifacts that can lead to erroneous predictions of resistance (false-negative errors). An improved technique was developed for measuring in vitro growth by incorporation of tritiated thymidine that can be performed in 5 days. With this rapid assay, 819 tumors were processed, with an overall success rate of 59.3%. This result compared favorably to the overall success rate of 58.2% for 1591 colony-formation assays because more small specimens could be submitted for the rapid assay. Melanoma and ovarian cancer specimens grew particularly well (76% and 75% successful, respectfully). Sixty-five correlations of in vitro and in vivo responses are available to date. None of 30 tumors, predicted to be resistant in vitro responded to chemotherapy clinically. Patients whose tumors were predicted to be sensitive in vitro had a 43% clinical response rate. The assay appears to be particularly accurate for predicting clinical resistance to chemotherapy, possibly because clumping artifacts do not occur in this system and peak achievable plasma concentrations of chemotherapeutic agents can be used. Optimal in vitro drug concentrations and culture conditions are still being defined, and improved success rates are being seen with more recent specimens. The introduction of this technique underscores the fact that in vitro chemosensitivity tests must continuously evolve to maximize their clinical application.

Antineoplastic Agents↗

Variability of heating patterns in animals by magnetic induction hyperthermia.

In a test of electromagnetic induction hyperthermia to deep viscera of a live dog model, we found that heating was not uniform to any depth, but was quite variable. In general, there was a thermal gradient between peripheral and central portions of the transposed spleen of about 1 degree C. Though heat generation within the abdomen was not uniform, its temperature pattern in the alive animal resulted in significant heating of that part of the organ that had been surgically placed at the center of the animal. This heating could not be explained by perfusion with regionally heated core blood. Our results indicate that extensive investigations in living systems and complex dynamic phantoms will be necessary before individual patient response can be predicted.

Abdomen↗

Effects of intralymphatic immunotherapy on natural killer activity in malignant melanoma patients.

Adjuvant immunotherapy has the theoretical attraction of augmenting the host immune response at a time when the tumor burden is low. We have previously reported that intralymphatic immunotherapy (ILI) augments the cytolytic humoral immune responses in melanoma patients. This study was undertaken to assess the effects of ILI on cell-mediated immunity. As a model for the cellular effects of ILI, we investigated the natural killer (NK) cell activity in malignant melanoma patients. Fourteen patients were given an allogeneic cultured tumor cell vaccine (TCV) intralymphatically with concomitant administration of BCG. Natural killer cell activity was assessed sequentially using the single cell lysis and binding assay. Overall NK activity against the K562 target cell line showed a moderate increase over pretreatment levels as reflected by the increased number of target binding lymphocytes. However, the percentage of target binders mediating cell lysis remained unchanged during treatment. Assessment of NK activity against the NK-resistant M14 melanoma cell line reflected similar findings. These results suggest the activation of NK cells by tumor antigens, BCG, and/or alloimmunization with TCV. This increase appears to be manifested by increased target recognition rather than by alterations in effector cell function.

Antigens, Neoplasm↗

Value of therapeutic hyperthermic limb perfusion in advanced recurrent melanoma of the lower extremity.

Twenty-six patients with advanced melanoma metastases confined to the lower extremity underwent 28 therapeutic limb perfusions without a major complication or treatment-related death. A complete response to treatment occurred in 21 patients (81 percent). Of 16 patients, response persisted until death in 13 and was noted at 75, 87, and 96 months follow-up in 3. In five patients, response lasted a median of 5 months (range 3 to 14 months), and repeat perfusion in two of these patients was not beneficial. Unfortunately, despite locoregional disease control, most patients died from distant metastases at a median of 15 months after treatment. In fact, regardless of response to perfusion, the 3 year survival rate of patients with advanced metastatic melanoma of the extremity was only 25 percent or less. Thus, although limb perfusion can be a safe and highly effective means of achieving locoregional disease control, there appears to be little survival benefit. Therefore, perfusion should be reserved for palliative treatment of selected patients with locally advanced melanoma.

Adult↗

A comparison of deep-heating electrode concepts for hyperthermia.

There is mounting evidence that localized hyperthermia produced by electromagnetic waves may be useful in the treatment of cancer, and many innovative devices have been designed for this purpose. Most applicators employed for deep heating operate in the frequency region of 10-100MHz to provide greatest depth of penetration. Two basic categories of launching devices exist: E-field and H-field. The E-field applicators include conductive plates and fringing field devices; either may be used individually or in a multiple feed system. The H-field applicators include cylindrical and planar devices configured to produce specific heating patterns. We have analyzed and compared the performance of each of these devices, particularly in terms of engineering principles, design characteristics and their ability to transfer potentially therapeutic energy safely and at depth.

Electrodes↗

Characterization of antigenic components of immune complexes isolated from a melanoma patient.

Immune complexes (IC) from the serum of a melanoma patient were partially purified with DEAE Affigel Blue. The IC were radioiodinated and then immobilized with activated Sepharose 4B. Immunologically bound components in the IC were dissociated with 3M MgCl2 followed by gel filtration chromatography. A distinct antigen component of about 700,000 daltons was obtained by refractionation of a region of the chromatogram containing antigenic activity by Sephacryl S-300 column chromatography. Though the antigenic component behaved as a single entity in the gel filtration, it consisted of at least five polypeptide chains that were revealed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions. However, 92,000 and 41,000 dalton subunits were predominant. This procedure may be useful for isolating tumor antigens from circulating IC of cancer patients.

Antigen-Antibody Complex↗

A simple, inexpensive technique for clearing obstructed closed suction drainage catheters.

Closed suction drains are frequently used after a variety of surgical procedures. Occlusion of these drains by thrombus or debris is a common postoperative event. A simple, inexpensive technique for clearing occluded drains with the readily available polyvinylpropylene catheter used for central venous cannulation is described herein. This method represents an inexpensive alternative to a Fogarty balloon tipped thrombectomy catheter for the same purpose. Prompt recognition and clearance of an obstructed drain is essential to minimize postoperative wound complications.

Catheterization↗

Advances in the treatment of sarcomas of the extremity. Current status of limb salvage.

Nonamputative limb salvage is possible for many patients with malignant skeletal or soft tissue sarcomas. Significant advances in pathology, radiology, chemotherapy, radiation therapy, and surgical and biomechanical techniques have contributed to a better understanding of these diseases, and have provided the necessary techniques to achieve local tumor control without amputation. Integration of diagnostic and treatment modalities has reduced local recurrence and improved overall patient survival. Preoperative (neoadjuvant) therapy permits assessment of the treatment effect and appears to significantly improve selection of effective postoperative adjuvant therapy. As overall patient survival has improved, efforts to increase local tumor control and to evaluate long-term functional stability of the salvaged extremity are now possible.

Amputation, Surgical↗

Imaging of human tumor xenografts in nude mice with radiolabeled monoclonal antibodies. Limitations of specificity due to nonspecific uptake of antibody.

To determine if in vivo binding specificities of monoclonal antibodies to tumor nodules would reflect in vitro antibody specificities as determined by radioimmunoassay, two monoclonal antibodies were selected for imaging of human tumor xenografts in nude mice. By in vitro radioimmunoassay, antibody 436 binds to the M20 melanoma cell line, but not to the P3 carcinoma cell line; antibody 44 binds to P3 but not to M20. Both antibodies are IgG1 isotypes. Nude mice bearing an M20 melanoma in one flank and a P3 carcinoma in the other were injected intravenously with 5 to 25 micrograms of each antibody labeled with either I-125 or I-131; in separate animals the labels were reversed. Animals were imaged daily with a scintillation camera equipped with a pinhole collimator. On day 6 the animals were sacrificed, and binding of the antibodies to the tumors and normal tissue were compared. Antibody 436 had up to a two-fold binding advantage in vivo for the melanoma, whereas antibody 44 had up to a two-fold binding advantage for the carcinoma, thus confirming the in vitro specificities of each. However, imaging on day 4 and computer analysis of percent radioactivity in the tumors showed that tumor images were related directly to tumor size and relatively uninfluenced by antibody specificity. Thus, even though antibody specificity can be demonstrated by differential tissue counting, imaging of tumor deposits appears to involve a nonspecific phenomenon that is largely dependent upon tumor weight.

Animals↗