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D R Vlock

Publications and source records attributed to D R Vlock.

12 recordsLinked to original sources
PubMed1992

Homozygous deletions within human chromosome band 9p21 in melanoma.

Genetic studies have implicated the early involvement of a gene on chromosome arm 9p in the development of cutaneous melanoma. We have performed loss-of-heterozygosity studies to confirm these original findings and identify the most frequently rearranged or deleted region of 9p. Eight markers were analyzed, including (from 9pter to proximal 9q) D9S33, the beta-interferon (IFNB1) locus, the alpha-interferon (IFNA) gene cluster, D9S126, D9S3, D9S19, the glycoprotein 4 beta-galactosyltransferase (GGTB2) gene, and the argininosuccinate synthetase pseudogene 3 (ASSP3). Two or more of these loci were found to be hemizygously reduced in 12 of 14 (86%) informative metastatic melanoma tumor and cell line DNAs, and homozygous deletions of the marker D9S126 were observed in 2 of 20 (10%) melanoma cell lines. These findings have resulted in the identification of a small critical region of 2-3 megabases on 9p21 in which a putative melanoma tumor-suppressor gene appears likely to reside. Several 9p candidate genes, including IFNB1, the IFNA gene cluster, GGTB2, and the tyrosinase-related protein (TYRP) locus, have all been eliminated as potential targets because they are located outside of the homozygously deleted regions.

Base Sequence↗
PubMed1992

Serial studies of autologous antibody reactivity to squamous cell carcinoma of the head and neck.

In previous studies we evaluated the incidence and specificity of autologous antibody reactivity against squamous cell carcinoma of the head and neck (SCCHN). We were able to demonstrate that autologous antibody reactivity is present in native sera but was usually of too low a titer to allow further analysis. Dissociation of immune complexes by acidification and ultrafiltration of serum augmented autologous antibody reactivity in nine out of nine autologous systems tested. Native antibody and antibody derived from immune complexes produced by the host and reactive with autologous tumor cells may be directed against physiologically relevant antigens. Therefore, correlations of antibody titers with clinical course may provide insight into the nature of the host response to cancer. In the present analysis, serological studies of six patients with SCCHN were performed with serum samples obtained over many months. Results of serial serological assays were correlated to tumor progression and clinical course. Fluctuations in autologous antibody reactivity were noted over time. In four cases, rises in autologous antibody titers preceded the clinical diagnosis of recurrence by several months. Drops in autologous antibody reactivity were noted in two cases following surgery or radiation therapy. In two cases of long-term survivors, no correlation between antibody reactivity and clinical course was noted. Specificity analysis of the six autologous systems demonstrated reactivity against autologous and allogeneic SCCHN as well as melanoma cell lines. These sera did not react with glioma, neuroblastoma, renal cell, breast, bladder and colon carcinoma cell lines nor with fetal calf serum, pooled lymphocytes, red blood cells and platelets. Autologous serial serological studies may provide a means by which to evaluate the host/tumor relationship in patients with SCCHN.

Aged↗
PubMed1992

Modulation by interferon alpha and gamma of the expression of a melanoma-associated antigen detected by autologous antibody.

Interferons (IFN) are known to alter the expression of histocompatibility and tumour-associated antigens. We have reported the isolation and purification of a 66-kD melanoma-associated antigen (MAA) that is recognized by the host. Competitive binding with MAA reduced autologous antibody binding to five melanoma cell lines, suggesting that a similar antigen is detected by other patients with melanoma. Nine melanoma cell lines were incubated for 3 days with 0.01-100 units/ml of interferon alpha (IFN-alpha) or interferon gamma (IFN-gamma) and the maximum titre of autologous antibody reactivity was determined by protein A haemadsorption. Incubation with IFN-alpha or IFN-gamma resulted in a decrease in maximum titre of autologous antibody reactivity directed against all melanoma cell lines. A 3-day incubation of three melanoma cell lines with IFN-gamma augmented the expression of HLA-DR, as has been reported by others. Incubation with spent media from autologous melanoma cells exposed to IFN-alpha inhibited autologous antibody binding less than control media from melanoma cells to which no IFN was added, indicative of decreased production or internalization of MAA. Conversely, incubation with spent media obtained after exposure to IFN-gamma inhibited autologous antibody binding to a greater degree than control spent media, consistent with increased shedding of antigen. These results suggest that IFN-alpha and IFN-gamma down-regulate the expression of MAA detected by autologous antibody by different mechanisms of action.

Antigenic Modulation↗
PubMed1991

Purification and partial characterization of a shed 66 kDa melanoma-associated antigen identified by autologous antibody.

We have previously reported the isolation of a 66 kDa melanoma-associated antigen, identified by autologous antibody, in serum and unfractionated spent tissue culture media by Western blot analysis. The antigen, detected by autologous serum S150, was found to be broadly represented on melanoma, glioma, renal cell carcinoma, neuroblastoma and head and neck carcinoma cell lines. S150 did not react with bladder or colon carcinoma, fetal fibroblasts, pooled platelets, lymphocytes and red blood cells, autologous cultured lymphocytes or fetal calf serum. To further characterize the antigen, spent tissue culture media, obtained from autologous melanoma cell line, Y-Mel 84:420, was separated by an isoelectric focusing column. Unabsorbed control serum S150 was noted to have a maximum titer of 1:2040 against autologous melanoma cells as measured by protein A hemadsorption. Following isoelectric focusing the greatest decrease in autologous antibody titer (30-fold) occurred with fractions having a pI between 2 and 3. Further resolution of the antigen was accomplished with high-pressure ion-exchange chromatography. One of these fractions showed a significantly higher concentration of antigen and was distinctly resolved from bulk serum albumin. Subsequent Western blot analysis, with autologous antibody, of the isolated antigen-containing fraction, confirmed the presence of a single 66 kDa band. Exposure of the antigen, purified by high-pressure ion-exchange chromatography, to neuraminidase ablated recognition by autologous antibody and suggests that sialic acid is present on the protein and may be part of the antigenic epitope. Binding of antigen, obtained following DEAE anion exchange chromatography, was noted to lectins derived from Triticum vulgaris, Dolichos biflorus and Lycopersicon esculentum. Preparative purification of the antigen was accomplished by anion exchange followed by lectin affinity chromatography with a Dolichos biflorus column. Antigen obtained following lectin affinity chromatography subjected to SDS-PAGE and silver stain revealed a single band at 66 kDa. We conclude that a melanoma-associated antigen detected by autologous antibody in spent tissue culture media is an unusually acidic glycoprotein (pI 2-3).

Antigens, Neoplasm↗
PubMed1991

Immunobiologic aspects of head and neck cancer. Clinical and laboratory correlates.

The role of the immune system in the pathogenesis and treatment of cancer remains to be determined. Impairment of humoral and cellular immunity has been associated with various factors implicated in head and neck cancer--tobacco, alcohol, and malnutrition. Whether these immune dysfunctions are causative or a secondary effect is not known. Patients with head and neck cancer have well-documented defects in immune function. In general, depression in cellular immunity has been noted, which can be correlated with stage of disease and prognosis. Conversely, increased humoral immune responses are seen, especially salivary IgA and circulating immune complexes. It may be that IgA or immune complexes are capable of suppressing the cellular immune response. Clinical trials utilizing biologic response modifiers in head and neck cancer have begun. Preliminary studies with heavily pretreated patients have demonstrated antitumor activity, suggesting that immunotherapy may provide a treatment alternative. In conclusion, the weight of evidence suggests that the immune response to head and neck cancer does play a role in the pathogenesis of the disease. A better understanding of the host-tumor interaction will allow for improved utilization of biologic response modifiers in the treatment of head and neck cancer.

Antibody Formation↗
PubMed1989

Incidence of serum antibody reactivity to autologous head and neck cancer cell lines and augmentation of antibody reactivity following acid dissociation and ultrafiltration.

Serum antibody reactivity to squamous cell carcinoma of the head and neck (SCCHN) was evaluated in 41 autologous serum-tumor cell line combinations using the protein A hemadsorption assay. Autologous antibody reactivity (median titer of 1:4) was detected in sera from 24 of the patients tested. In 10 cases autologous antibody reactivity could be detected only in undiluted serum precluding further analysis. Analysis of higher titer sera from one patient revealed antibodies that define an antigen expressed on autologous tumor cells cultured from both the primary tumor (UM-SCC-17A) and from a metastasis (UM-SCC-17B). Absorption analysis showed that this antigen was also expressed on 6 of 10 allogeneic SCCHN cell lines but not on autologous fibroblasts or on allogeneic melanoma cell lines. Due to the low titer of autologous antibody reactivity in most sera, we sought to determine if dissociation of immune complexes through acidification and ultrafiltration of serum might enhance detectable antibody reactivity as has been done in previous studies in melanoma. Twelve serum samples from eight patients were subjected to acid dissociation and ultrafiltration (AD-U). Only six of the untreated sera had detectable antibody reactivity against the autologous SCCHN cell line whereas following AD-U all 12 sera had enhanced IgG reactivity against autologous SCCHN. Specificity analysis of one serum sample after dissociation revealed that the antibody detected an antigen common to SCCHN cell lines as well as melanoma, glioma, renal, and colon carcinoma cell lines. Circulating immune complexes may provide a reservoir of antibody with potential diagnostic and therapeutic applications.

Antibodies, Neoplasm↗
PubMed1988

Isolation and partial characterization of melanoma-associated antigens identified by autologous antibody.

The study of the autologous immune response to cancer avoids the difficulties encountered in the use of xenoantisera and may identify antigens of physiological relevance. However, the low titer and incidence of autologous antibody to melanoma have hampered further evaluation. By utilizing acid dissociation and ultrafiltration of serum, we have been able to augment the detectable autologous immune response to melanoma in the majority of patients studied. In autologous system Y-Mel 84:420, serum S150 demonstrated a rise in titer from 1:32 in native sera to 1:262,044 after dissociation. The antigen detected by S150 was found to be broadly represented on melanoma, glioma, renal cell carcinoma, neuroblastoma, and head and neck carcinoma cell lines. It did not react with bladder or colon carcinoma, fetal fibroblasts, pooled platelets, lymphocytes and red blood cells, or autologous cultured lymphocytes. Using polyacrylamide gel electrophoresis, S150 detects a 66,000-mol wt antigen in spent tissue culture media and serum ultrafiltrate. In cell lysate two bands between 20,000 and 30,000 mol wt are detected by S150. The 66,000-mol wt antigen is sensitive to trypsin digestion and but is resistant to pepsin and heat inactivation. Exposure of spent media to trypsin results in the development of a 24,000-mol wt band that appears to correspond to the antigen detected in the cell lysate. The difference between the antigens detected in the cell lysate as compared with spent media and serum ultrafiltrate may be due to degradation during cell lysis. We conclude that melanoma-associated antigens are present in the serum of patients with melanoma and are shed or secreted by their tumor cells.

Antibodies, Neoplasm↗
PubMed1986

Prognostic role of antibody reactivity to melanoma.

Antibody reactivity against cultured allogeneic melanoma Y-Mel 81:180 was studied in 43 patients who participated in an adjuvant trial for stage I and II melanoma. Serum samples were obtained at trial entry within 2 mo of definitive surgery. At the time of serum acquisition, all patients were free of disease by physical examination and routine radiologic and laboratory parameters. Serum antibody reactivity was tested for by protein A hemadsorption before and after acid dissociation and ultrafiltration of serum. We have previously shown that this technique for immune complex dissociation augments autologous antibody reactivity. Results of serum antibody reactivity were scored by an investigator blinded to the patient's clinical status. Of the 43 patients studied, 15 relapsed and 28 remained disease-free. At study entry, there were 25 stage I patients and 18 stage II patients. Breslow depth was 3.25 +/- 2.5 mm in relapse patients and 1.67 +/- 1.1 mm in disease-free patients. The presence and titer of antibody directed against melanoma in either native serum or serum dissociated from immune complexes was found to be associated with eventual relapse (P = 0.0001). When results were subgrouped by stage of disease, Breslow depth, and hypopigmentation, antibody reactivity was still correlated with eventual relapse. The incidence and titer of antibody reactivity against melanoma appears to be a new prognostic factor in predicting eventual disease recurrence.

Adult↗
PubMed1985

Serial studies of autologous antibody reactivity to melanoma. Relationship to clinical course and circulating immune complexes.

The low titer and incidence of autologous antibody to melanoma has hampered its evaluation. Through acid dissociation and ultrafiltration of serum, we have been able to augment the autologous immune response in 9 of 10 patients studied. This result suggests that autologous antibody is present in most patients with melanoma, but is obscured by circulating antigen and the formation of immune complexes. Because native antibody and antibody derived from circulating immune complexes are produced by the host against physiologically relevant antigens, correlations can be made to clinical course. Serological studies of three patients with melanoma were performed with serum samples obtained over many months; these studies demonstrated correlations with tumor progression and clinical course. Serial serologic studies may yet provide one of the better ways to evaluate these relationships. They have the advantage of detecting transient events that may occur with the inception of metastatic disease or autoimmune phenomena, and of avoiding the difficulties encountered in comparing antibody responses between different individuals.

Animals↗
PubMedDate not supplied

Preliminary trial of nonrecombinant interferon alpha in recurrent squamous cell carcinoma of the head and neck.

Fourteen patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) were treated with 10 x 10(6) U of nonrecombinant interferon alpha (IFN) intramuscularly (IM) daily for 3 days every 28 days. There were 11 men and 3 women, with ages ranging from 48 to 74 years. Patients had previously been treated with surgery (9 patients), radiotherapy (13 patients), or chemotherapy (8 patients). All patients had measurable disease by physical exam and radiologic evaluation and a performance status of less than or equal to 2 (ECOG). Patients were treated for a minimum of 3 months and continued on therapy until disease progression. The dose and treatment schedule of IFN was well-tolerated. Toxicities included low-grade fever, mild anorexia, and malaise. Treatment was stopped in 1 patient due to the development of atrial fibrillation. One death occurred as a complication of aspiration pneumonia 2 weeks following the onset of therapy and was not felt to be related to IFN therapy. Of the 14 patients treated, there was 1 complete response (30+ months) of a base of tongue primary. Two patients had stabilization of disease (SD, 8 and 12 months). One patient had a mixed response with resolution of subcutaneous nodules. The remaining 10 patients died of progressive disease. Immunological assessment was performed on 8 patients. The 1 patient who had a complete response was noted to have markedly low pretreatment natural killer (NK) cell activity and a subsequent sharp rise in activity after initial treatment. We conclude that low-dose cyclic IFN is well-tolerated in patients with recurrent SCCHN and has potential antitumor activity.

Aged↗