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Biomedical subjects

M G Hanna

Publications and source records attributed to M G Hanna.

At least 19 recordsLinked to original sources
PubMed1997

A multicenter trial evaluation of the fibrin/fibrinogen degradation products test for detection and monitoring of bladder cancer.

PURPOSE: Presently there is a lack of effective, noninvasive tests for the detection and monitoring of bladder cancer. Measurement of fibrin/fibrinogen degradation products in urine has been shown to be a useful indicator of bladder carcinoma. The objective of this study was to evaluate the AuraTek FDP rapid immunoassay device for the detection of urinary fibrin/ fibrinogen degradation products associated with bladder cancer. MATERIALS AND METHODS: A prospective multicenter study was conducted to compare AuraTek FDP with urinary cytology and hemoglobin dipstick for the detection of bladder cancer in 192 patients with a history of bladder cancer. RESULTS: AuraTek FDP was significantly more sensitive (68%) than conventional urinary cytology (34%, p < 0.001) or hemoglobin dipstick (41%, p < 0.001) in the detection of bladder tumors, particularly for low stage low grade disease. In subjects with invasive disease (T2-T4) the AuraTek FDP test had a sensitivity of 100%. Specificity of AuraTek FDP was 96% for healthy subjects, 86% in patients with urological disease other than bladder cancer and 80% for patients under surveillance for bladder cancer but with a negative cystoscopic finding at the time of assay. CONCLUSIONS: This simple, rapid (less than 7 minutes) point of care test is superior to conventional urine cytology and hemoglobin dipstick as an aid in the detection of bladder cancer.

Aged↗
PubMed1997

Movement disorders and mitochondrial dysfunction.

Primary defects of mitochondrial DNA leading to respiratory chain dysfunction have been described in association with dystonia, chorea and parkinsonism. Myoclonus remains the commonest movement disorder associated with such defects. The genetic basis of Leigh's syndrome, which is frequently associated with movement disorders, may be mitochondrial or nuclear. Respiratory chain dysfunction has been identified in Huntington's disease in addition to Parkinson's disease, but the cause and relationship of this dysfunction to the pathogenesis of these common disorders is not yet determined.

Chorea↗
PubMed1997

Preclinical studies of indium-111-labeled IgM: a human monoclonal antibody for infection imaging.

UNLABELLED: Indium-111-labeled plasma proteins, such as albumin, transferrin and IgG, have been proven useful to image infection. We reported previously that 111In-labeled human monoclonal antibody, IgM 16.88 (In-IgM) also would localize at the site of infection. However, the kinetics of blood clearance, distribution and infection uptake have not been investigated. We compared the kinetics of distribution and infection uptake of In-IgM 16.88 with that of in-polyclonal IgG in rats with focal infection. METHODS: Both IgM 16.88 and polyclonal IgG were labeled with 111In using a bifunctional chelating agent, LiLo. The labeling efficiency was > 95%. Focal infection was induced in rats by an intramuscular injection of E. Coli in the right thigh. In-IgM (30-40 microCi) was injected into five groups of rats (five rats/group). The rats were killed at 4, 8, 16, 24 and 36 hr. The percent injected dose (%ID) in blood, infection muscle, control muscle, liver, spleen and kidney were determined. Similar studies were performed with In-IgG. RESULTS: The In-IgM activity in blood at 4 hr postinjection was 27% which decreased to 2% by 36 hr. In contrast, the In-IgG blood activity was 40% at 4 hr and 20% at 36 hr. The infection/ muscle (I/M) ratios are higher with In-IgM at all time points postinjection compared to that of In-IgG. At 24 hr, the I/M ratio was 22 compared to 9 with In-IgG. At the same time point, the infection/ blood (I/B) ratio with In-IgM was 2.7 compared to only 0.8 with that of In-IgG. In-IgM was taken up mostly by the liver compared to diffuse abdominal uptake of IgG. CONCLUSION: These result indicate that In-IgM produces higher lesion to background ratio when compared to In-IgG and, therefore, is potentially useful to image infection in patients.

Animals↗
PubMed1996

A phase I randomized study of subcutaneous adjuvant IL-2 in combination with an autologous tumor vaccine in patients with advanced renal cell carcinoma.

We performed a prospective, randomized study to determine whether subcutaneous administration of interleukin-2 (IL-2) in combination with an autologous renal cell vaccine is feasible and can potentiate antitumor immunity. Seventeen patients with metastatic renal cell carcinoma underwent surgical resection with preparation of an autologous tumor cell vaccine. Patients were vaccinated intradermally twice at weakly intervals with 10(7) irradiated tumor cells plus bacillus Calmette-Guérin, and once with 10(7) tumor cells alone. Patients were randomized to one of three groups: no adjuvant IL-2, low-dose IL-2 (1.2 x 10(6) IU/m2), or high-dose IL-2 (1.2 x 10(7) IU/m2). IL-2 was administered subcutaneously on the day of vaccination and the subsequent 4 days. Immune response was monitored by delayed-type hypersensitivity (DTH) response to tumor cells as compared with normal autologous renal cells. Sixteen of 17 patients received vaccine therapy. Four patients developed cellular immunity specific for autologous tumor cells as measured by DTH responses; two had received no IL-2 and two had received high-dose IL-2. There were two partial responses (PR) noted, both in patients who received high-dose IL-2. One responding patient was DTH(+) and one was negative. A third patient who was DTH(+) after vaccination with no IL-2 had a dramatic PR after receiving IL-2 subcutaneously in a subsequent protocol. Prospective testing of response to recall antigens indicated that only 5 of 12 tested patients were positive, including both clinical responders. These data suggest that subcutaneously administered adjuvant IL-2 does not dramatically augment the immunologic response to autologous renal cell vaccines as determined by the development of tumor-specific DTH response.

Adjuvants, Immunologic↗
PubMed1995

A new mitochondrial DNA mutation associated with progressive dementia and chorea: a clinical, pathological, and molecular genetic study.

A novel mitochondrial DNA transfer RNA mutation at position 5549 was identified in a patient with dementia, chorea, cerebellar ataxia, deafness, and peripheral neuropathy in the absence of clinical myopathy. Muscle biopsy specimens showed ragged red and cytochrome oxidase-negative fibers, and reduced complex I activity on polarography. There was diffuse neuronal loss and gliosis throughout the brain on postmortem examination. The heteroplasmic mutation had a widespread distribution in autopsy tissues.

Adult↗
PubMed1995

Impaired mitochondrial translation in human myoblasts harbouring the mitochondrial DNA tRNA lysine 8344 A-->G (MERRF) mutation: relationship to proportion of mutant mitochondrial DNA.

The mitochondrial DNA transfer RNA lysine A8344G mutation is commonly associated with the MERRF (myoclonus epilepsy with ragged red fibre) phenotype. The molecular pathogenesis of disease associated with this mutation is unclear. Theoretically, a mitochondrial tRNA mutation might affect transcription or translation, or both. We therefore studied these processes in cloned primary human myoblast cultures containing different proportions of mutant mtDNA. No abnormality of transcription was observed. However, there was a progressive decrease in mitochondrially encoded protein synthesis as the proportion of mutant mtDNA increased. Furthermore, there was evidence that subunits were differentially affected, based on selective reduction of cytochrome c oxidase subunits with relatively low proportions of mutant mtDNA.

Autoradiography↗
PubMed1995

The mitochondrial DNA transfer RNALeu(UUR) A-->G(3243) mutation. A clinical and genetic study.

The mitochondrial tRNALeu(UUR) A-->G(3243) mutation was identified in 22 unrelated patients. The probands and their relatives were assessed clinically and by quantitative mitochondrial DNA (mtDNA) analysis. While 10 probands had clinical features consistent with the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), usually associated with this mutation, 12 probands had other phenotypes including other encephalopathies, chronic progressive external ophthalmoplegia (CPEO), myoclonic epilepsy and ragged red fibres (MERRF), myopathy alone and diabetes and deafness. Histochemical analyses of muscle biopsies showed a higher proportion of cytochrome oxidase (COX) negative fibres, but fewer strongly COX reactive fibres, in patients with CPEO compared with those with MELAS. The proportion of mutant mtDNA present in blood was significantly greater in symptomatic than asymptomatic subjects, and was correlated with age in both. This correlation was not observed in patients with the tRNALys A-->G(8344) mutation. The proportion of mutant mtDNA A-->G(3243) in muscle was always greater than that in blood. Significant correlations between proportion of mutant mtDNA in blood and both age of onset of disease and a clinical severity score were observed. However, the proportion of mutant mtDNA in blood in affected and unaffected cases overlapped, preventing use of the genetic-clinical correlation for prognostic or predictive purposes. The presence of intrafamilial clustering of phenotypes and the imperfect relationship between proportion of mutant mtDNA and the presence or absence of disease suggests that other factors may determine the phenotype. To investigate this possibility further, the tRNALeu(UUR) gene was sequenced in 23 probands and six relatives. In 28 patients the sequence was normal apart from the 3243 mutation, but in members of one family there was a homoplasmic T-->C transition at position 3290 which was not found in 140 controls or 50 other patients with mitochondrial myopathy. The family with this transition had high levels of mutant mtDNA A-->G(3243), with a unique phenotype of predominant skeletal myopathy, suggesting that this second base change in tRNALeu(UUR) may influence the clinical phenotype.

Adult↗
PubMed1995

Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation.

We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardation and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adult-onset diabetes mellitus alone. Ragged-red and cytochrome c oxidase (COX)-negative fibers were present in muscle biopsies. Biochemical studies of muscle mitochondria showed reduced complex I and IV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matrilineal relatives analyzed. Primary myoblast, but not fibroblast, cultures containing high proportions of mutant mtDNA exhibited impaired mitochondrial translation. These observations indicate that mtDNA tRNA point mutations should be considered in the differential diagnosis of congenital myopathy. In addition they illustrate the diversity of phenotypes associated with this mutation in the same family and further highlight the association between mtDNA mutations and diabetes mellitus.

Adult↗
PubMed1994

Time-dependent aggregation of reconstituted BCG vaccine.

The procedures for the reconstitution, dilution and storage of BCG for intravesical use in superficial bladder cancer have not been previously analyzed. Package inserts in the FDA-approved BCG vaccines suggest instillation immediately after reconstitution but allow storage of diluted vaccines for as long as 2 hours prior to treatment. In this report, we examined the effect of storage of diluted BCG vaccines on the quality and antitumor activity of various BCG vaccine preparations. The data show a time-dependent aggregation of BCG after reconstitution. All vaccine preparations tested, including Connaught, Institute Armand Frappier, Japanese, Pasteur, RIVM, and Tice, aggregated after reconstitution and dilution. Visible aggregation was reduced by elimination of the liquid/gas interface. Aggregation appeared to have no effect on colony forming unit counts but adversely affected antitumor activity. We conclude that for optimal results, BCG vaccines should be reconstituted and diluted immediately prior to instillation.

BCG Vaccine↗
PubMed1993

Identification of colon-tumor-associated antigens by T-cell lines derived from tumor-infiltrating lymphocytes and peripheral-blood lymphocytes from patients immunized with an autologous tumor-cell/bacillus Calmette-Guérin vaccine.

Tumor immunity developing as a response to an autologous colon-tumor/bacillus Calmette-Guérin (BCG) vaccine appears to be associated with induction of CD4+ helper T cells, implied by the observation that vaccine efficacy is associated with major histocompatibility complex class-II molecule expression on the vaccine tumor cells. Therefore, in an attempt to identify colon-tumor-associated antigens responsible for conferring immunity, we examined and compared the proliferative responses of peripheral-blood lymphocytes (PBL) from patients immunized with the autologous tumor/BCG vaccine to T-cell lines cloned expanded from colon-tumor-infiltrating lymphocytes to 5 antigens isolated on the basis of their reactivity by colon-tumor-reactive human monoclonal antibodies. Enzymatically dissociated colon tumors provided a source for establishment of cloned T-cell lines, tumor cell lines propagated in vitro or in vivo as nude-mouse xenografts and EBV-transformed B-cell lines used as antigen-presenting cells. Of 104 different T-cell lines tested, only 3 proliferated in response to CTAA 28A32-46K, and I to the CTAA28A32-32K antigen. In contrast, PBL from 64% of patients immunized with the autologous colon-tumor/BCG vaccine responded to the CTAA 28A32-32K antigen. This antigen is related to a family of calcium- and phospholipid-binding placental proteins termed annexins. Since proliferative responses developed to this antigen after vaccination in 64% of individuals, this antigen may be an important common colon-tumor-associated rejection antigen.

Animals↗
PubMed1993

Delivery of radionuclides to pretargeted monoclonal antibodies using dihydrofolate reductase and methotrexate in an affinity system.

A novel affinity system for a two-phase delivery of radionuclides to tumor cells has been developed. In the first phase, a nontoxic bivalent monoclonal antibody conjugated to an enzyme is targeted to the tumor cells. In the second phase, a radionuclide-derivatized enzyme inhibitor, specific for the enzyme conjugated to the antibody, is administered. The model system selected for this study is the recombinant human enzyme dihydrofolate reductase (rhDHFR) and its high-affinity competitive inhibitor methotrexate (MTX). MTX was labeled with a radionuclide by covalent attachment of diethylenetriaminepentaacetic acid (DTPA) complexed with 111In. Using the gamma-carboxyl residue of MTX for the attachment of DTPA, binding of the inhibitor to rhDHFR was not affected. The inhibitory activities of nonderivatized MTX and DTPA-MTX were indistinguishable. Human K562 erythroleukemia cells were used to evaluate under in vitro conditions the DHFR-MTX affinity system for the delivery of 111In-labeled DTPA-MTX to pretargeted alpha-transferrin receptor antibody-rhDHFR conjugates (alpha-TFR-DHFR). The data demonstrate that the delivery of 111In is dose dependent and highly specific. Under saturating conditions, binding of 111In-DTPA-MTX to alpha-TFR-DHFR-treated cells was 14-fold higher than to cells treated with nonconjugated alpha-TFR antibody. Further experiments indicated that the low level of nonspecific binding of 111In-DTPA-MTX was comparable to that of 111In-DTPA, known for its complete extracellular distribution and rapid clearance through the kidneys. Based on the data of this study, antibody-conjugated rhDHFR and radionuclide-labeled DTPA-MTX complexes provide components for an alternative radioimmunotherapeutic approach that can be expected to result in improved tumor tissue ratios of both the targeting moiety and the radionuclide-labeled derivative as compared to current approaches.

Antibodies, Monoclonal↗
PubMed1993

Delayed-type hypersensitivity reactions to tumor-associated antigens in colon carcinoma patients immunized with an autologous tumor cell/Bacillus Calmette-Guérin vaccine.

Five different colon tumor-associated antigens (CTAA) were tested for their ability to induce an immune response in vivo and in vitro in ten colon carcinoma patients immunized with an irradiated autologous tumor cell/Bacillus Calmette-Guérin vaccine (active specific immunization) after resection of the primary tumor. The CTAA were defined by two different human monoclonal antibodies (MCA 1688 and MCA 28A32) derived by immortalization of peripheral blood B-lymphocytes from an active specific immunization patient. Delayed-type cutaneous hypersensitivity responses against a mixture of CTAA 28A32-50K and -32K were positive in seven of ten patients tested. In vitro T-cell responses upon stimulation with CTAA 28A32-32K were found to be positive in seven of ten patients and correlated with delayed-type cutaneous hypersensitivity responses to the antigen mixture. These data suggest that CTAA 28A32-32K might contain an important tumor-related T-cell epitope. Moreover, this method is suitable to define potential future candidates for antitumor vaccine development.

Animals↗
PubMed1993

Current status of cancer immunodetection with radiolabeled human monoclonal antibodies.

The use of radiolabeled murine monoclonal antibodies (MoAbs) for cancer immunodetection has been limited by the development of human antimouse antibodies (HAMA). Human monoclonal antibodies do not elicit a significant human antihuman (HAHA) response. The generation and production of human monoclonal antibodies met with technical difficulties that resulted in delaying their clinical testing. Human monoclonal antibodies of all isotypes have been obtained. Most were immunoglobulin (Ig) M directed against intracellular antigens. Two antibodies, 16.88 (IgM) and 88BV59 (IgG3k), recognize different epitopes on a tumor-associated antigen, CTA 16.88, homologous to cytokeratins 8, 18, and 19. CTA 16.88 is expressed by most epithelial-derived tumors including carcinomas of the colon, pancreas, breast, ovary, and lung. The in vivo targeting by these antibodies is related to their localization in nonnecrotic areas of tumors. Repeated administration of 16.88 over 5 weeks to a cumulative dose of 1,000 mg did not elicit a HAHA response. Two of 53 patients developed a low titer of HAHA 1 to 3 months after a single administration of 88BV59. Planar imaging of colorectal cancer with Iodine-131 (131I)-16.88 was positive in two studies in 9 of 12 and 16 of 20 patients preselected by immunohistochemistry. Tumors less than 2 cm in diameter are usually not detected. The lack of immunogenicity and long tumor residence time (average = 17 days) makes 16.88 a good candidate for therapy. Radioimmunlymphoscintigraphy with indium-111 (111In)-LiLo-16.88 administered by an intramammary route was used in the presurgical staging of primary breast cancer. The negative predictive value of lymph node metastases for tumors less than 3 cm was 90.5%. Planar and single photon emission computed tomography imaging of colorectal carcinoma with technetium-99m (99mTc) 88BV59 was compared with computed tomography (CT) scan in 36 surgical patients. The antibody scan was more sensitive than the CT scan in detecting abdominal and pelvic tumors: 68% versus 40% (P < .05). The combination of antibody scan and CT scan was superior to CT scan alone: 80% versus 40% (P < .01). Lesions as small as 0.5 cm in diameter were detected by antibody scan. The CT scan appears superior to the antibody scan for liver metastases. Patients with a high serum titer of HAMA from previous exposure to murine antibodies were successfully imaged. Antibody scans obtained with 99mTc-88BV59 have imaging characteristics similar to murine antibody scans obtained with radiolabeled IgGs. The absence or weak immunogenicity of the human monoclonal antibodies makes them good candidates for radioimmunodetection and radioimmunotherapy.

Breast Neoplasms↗
PubMed1993

Adjuvant active specific immunotherapy for human colorectal cancer: 6.5-year median follow-up of a phase III prospectively randomized trial.

PURPOSE: Patients with colon or rectal cancer were entered onto a prospectively randomized, controlled clinical trial of active specific immunotherapy (ASI) with an autologous tumor cell-bacillus Calmette-Guérin (BCG) vaccine. We investigated whether ASI could improve disease-free status and survival. PATIENTS AND METHODS: Ninety-eight patients with Dukes' stage B2-C3 colon or rectal cancer were randomized into groups treated by resection alone or resection plus ASI. Eighty patients met all eligibility criteria. All patients with rectal cancer were to receive 50 Gy of pelvic irradiation. Analysis of distribution of survival and disease-free survival was made on all eligible patients until December 31, 1990. RESULTS: As a single study, no statistically significant differences were detected in survival or disease-free survival for all 80 eligible patients. However, since it was recognized at the outset that there were treatment differences, in that rectal cancer patients were to receive postimmunotherapy radiation, it was considered that a cohort analysis of the colon and rectal cancer patients might be informative. With a median follow-up of 93 months, there is a significant improvement in survival (two-sided P = .02; hazards ratio, 3.97) and disease-free survival (two-sided P = .039; hazards ratio, 2.67) in all eligible colon cancer patients who received ASI. With a median follow-up of 58 months, no benefits were seen in patients with rectal cancer who received ASI. CONCLUSION: This study suggests that ASI may be beneficial to patients with colon cancer.

Adult↗
PubMed1992

Expression of class II major histocompatibility complex molecules correlates with human colon tumor vaccine efficacy.

Vaccination of colon cancer patients with X-irradiated autologous tumor cells and Bacillus Calmette-Guérin results in a significant reduction in tumor recurrence. A study was undertaken to determine whether the expression of tumor-associated antigens, expression of major histocompatibility complex molecules, or the cellular composition of the vaccine cells correlates with vaccine efficacy. A significant increase in the percentage of histocompatibility leukocyte antigen (HLA) class II molecule-expressing tumor cells was the only marker with a positive correlation. Because HLA class II molecule expression is not a prognostic marker in control patients, it was hypothesized that HLA class II molecules are involved in the induction of tumor immunity in patients treated with the autologous colon tumor vaccine. Enhancement of HLA class II molecule-expressing cells could be induced in X-irradiated colon tumor cells injected into the skin of mice when the cells were mixed with gamma-interferon. Therefore, addition of gamma-interferon to the colon tumor vaccine, resulting in increased numbers of HLA class II molecule-expressing cells, could potentiate the generation of tumor immunity.

Antigens, Neoplasm↗