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PubMed1968

Determining the extent of the cancer and clinical planning for cure.

The patient with presumed localized cancer should be carefully surveyed both for evidence of spread of the disease, and in order to obtain baseline data which may be relevant to interpret any later clinical changes. The procedures used--a careful medical history, complete physical examination, laboratory tests, biopsy and cytology preparations, radiographic procedures and radioactive isotope scans of selected organ system--are listed. The recommended procedures in the individual patient are related to the primary site and apparent local extent of the cancer, a knowledge of the natural history of the particular cancer, and the practicalities of the situation. Proper study will direct an attempt at optimal curative therapy or spare the patient with metastatic disease unrewarding and possibly disabling therapeutic efforts.

Humans↗
PubMed1983

Radioactive-induced tumors by phosphorus-32 as colloidal compound.

Chromic colloidal phosphate labeled with 32P, which has been proposed for the treatment of several articular diseases, was injected intra-articularly in the knee joint of adult Wistar rats. After a 270 days minimum latent period, tumors began to appear in the injected zone, to a 70% frequency. Ten lung metastases were detected. In five cases, squamous cell carcinomas were induced in the injected area. The relevance of a sound evaluation of the risk involved in treatments with radioactive isotopes, is discussed.

Animals↗
PubMed1984

Metabolic consequences of nutritional support of the cancer patient.

The year 1983-1984 has been a period of evaluation and examination of efficacy of nutritional support of the cancer patient. The early observation that individual patients, unable to ingest, digest, or absorb food could be nutritionally maintained by intravenous nutrition has been repeated in every cancer center. The premature application of parenteral nutrition as an adjunct to cancer care and the results of clinical trials with small numbers of patients have initiated a reevaluation of this therapy, as a routine. The most exciting advances have come from the opportunity to utilize nutritional support as a means of investigating the basic mechanisms by which the cancer patient disposes of exogenously delivered substrate. This opportunity had been initially under-appreciated and is only now receiving the full and intensive clinical and laboratory research necessary to delineate abnormalities of metabolism that occur in the cancer-bearing host. Studies have not been performed not only in intact man, but in specific organ systems in man during nutritional support. These studies, using stable and radioactive isotopes, have given us new insight into the way that the cancer patient handles glucose and amino acids. Whether these abnormalities of metabolism are due to the cancer or are due to treatment, complications of treatment, or inherent starvation accompanying progressive cancer cachexia is being examined. Such studies should indicate whether or not therapeutic interventions in limiting substrate availability for the tumor while preserving the host are possible.

Body Composition↗
PubMed1991

A review of californium-252 neutron brachytherapy for cervical cancer.

Since 1976 a clinical trial has been conducted to test the feasibility, the potential, and to develop methods for using the neutron-emitting radioactive isotope, californium-252 (Cf-252), for the treatment of cervical cancer. A total of 218 patients were treated in the initial study period from 1976 until 1983. The trials initially treated advanced (Stages III and IV) cervical cancer patients using different doses and schedules; they were extended to include unfavorable presentations of Stages I and II because of favorable results in the initial trials. The authors began to treat patients with Stage IB bulky or barrel-shaped tumors and the majority were treated with both radiation and hysterectomy. Actuarial survival was determined for Stage IB disease and was 87% at 5 years and 82% at 10 years. For those tested with preoperative radiation it was 92% at 5 and 87% at 10 years. For Stage II, it was 62% 5 years and 61% at 10. Survival 5 years after combined radiation and surgical therapy for Stage II disease was 68%. For Stage III, it was 33% at 5 years and 25% at 10. However, 5-year survival using the early neutron implant was 46% versus approximately 19% for delayed Cf-252 or cesium 137. Different schedules and sequences of neutrons and photons greatly altered outcome. Neutron treatment before external photon therapy was better for all stages of disease. Only about 5% of all patients developed complications after neutron therapy. No hematologic or mesenchymal second tumors were observed. Neutron brachytherapy was found to be very effective for producing rapid response and greatly improved local control of bulky, barrel, or advanced cervical cancers. The clinical trial identified and evolved schedules, doses, doses per session, and developed methods different from standard photon therapy but highly effective for local control and cure of cervical cancers of all stages. Clinical and radiobiologic understanding for the use of neutron therapy was greatly advanced by this trial. Future trials will focus on patients with advanced disease and will require evaluation of adjuvant chemotherapy studies and neutron-enhancing chemicals.

Adenocarcinoma↗
PubMed1993

Prostate cancer. Radiation therapy for localized disease.

BACKGROUND: Since 1910, a variety of radiation modalities, including radioactive isotopes, photons, and particle beams, have been used to treat prostatic cancer. METHODS: This report focuses on external beam x-irradiation produced by medium energy linear accelerators. Between 1956 and 1990, 1119 patients have been treated with curative intent at Stanford University. Tumor doses of 70 Gy delivered at 10 Gy/wk have been safe and effective. RESULTS: Fifteen-year survival rates ranging from 50%, equivalent to that of an age-matched cohort, for the least extensively localized tumors to 18% for the most extensive have been achieved. Survival is inversely proportional to clinical stage and histopathologic grade. CONCLUSION: Although external beam radiation therapy has been found to be safe and effective for the treatment of prostatic cancer, improvement in results of treatment of the more advanced tumors might be achieved by combining external beam and interstitial irradiation. This would achieve a higher radiation dose within the tumor. Alternatively, the treatment can be augmented with hyperthermia or other sensitizers in order to achieve a higher biological dose.

Adult↗
PubMed1994

Long term results of stereotactic brachytherapy used in the initial treatment of patients with glioblastomas.

BACKGROUND: Despite optimal therapy with surgery and radiotherapy, the prognosis of patients with glioblastomas remains poor. Stereotactic brachytherapy involves the accurate placement of radioactive isotopes within brain tumors, significantly increasing the dose of radiation that can be delivered to the tumor bed without substantial risk to surrounding normal tissue, potentially improving local tumor control and patient survival. METHODS: Between February 1987 and July 1993, the authors treated 56 patients with glioblastomas with stereotactic brachytherapy as part of their initial therapy. Patients underwent surgery, limited field external beam radiotherapy, and brachytherapy with temporary high-activity iodine 125 sources, giving an additional 50 Gy to the tumor bed. RESULTS: Median survival for patients undergoing brachytherapy was 18 months compared with 11 months for a matched brachytherapy control group with similar clinical and radiologic features (P < 0.0007). Survival rates at 1, 2, and 3 years after diagnosis of 83%, 34%, and 27%, respectively, for patients receiving brachytherapy were significantly increased compared with survival rates of 40%, 12.5%, and 9%, respectively, for control subjects. Thirty-six patients (64%) underwent reoperation for symptomatic radiation necrosis from 3 to 42 months (median, 11 months) after brachytherapy. The median survival of patients undergoing reoperation was 22 months compared with 13 months for those who did not have further surgery (P < 0.02). Thirty-five percent of patients relapsed locally within the brachytherapy target volume, whereas 65% had marginal or distant relapses. CONCLUSIONS: Brachytherapy may improve local tumor control and prolong survival when used in the initial treatment of selected patients with glioblastomas.

Adolescent↗
PubMed1994

Pediatric brachytherapy. The St. Jude Children's Research Hospital experience.

BACKGROUND: The use of interstitial, intracavitary, and permanent placement of radioactive isotopes has become a common practice in adult oncology patients based on numerous reports indicating improved local control and survival when used. These same irradiation techniques and treatments have been infrequently used for children with malignant disease despite known dose localization properties that allow for highly focal irradiation delivery with rapid reduction of the dose in nearby normal tissues. The noted benefit of decreased late complications noted in the adult series is also attractive, especially when considering the treatment of children. METHODS: Between May, 1981 and December 15, 1992, 46 children with non-CNS primary malignancy received 50 brachytherapy applications for primary therapy (n = 11 sites), as a boost in conjunction with external beam irradiation (n = 16 sites), or as treatment of recurrent disease or a second malignant neoplasm in a previously irradiated region that precluded further external irradiation or for metastatic disease (n = 23 sites). The most common tumor histologies were rhabdomyosarcoma (n = 14), soft tissue sarcoma (n = 10) and retinoblastoma (n = 10). Patient age at implantation ranged from 8 weeks to 24 years; follow-up maintained in all patients and has ranged from 2-115 months (median, 39 months). RESULTS: Forty-three of 50 sites receiving brachytherapy have maintained continuous disease free intervals, ranging from 2 to 115 months postimplantation (median, 41 months). The seven local failures occurred 2-20 months postimplant (median, 6 months). Severe complications occurred in 12 patients, two which were life threatening but resolved without further incident. CONCLUSIONS: Based on this ongoing clinical investigation, the authors recommend brachytherapy for selected pediatric malignancies and continue to evaluate the various factors associated with local control, local failures, and complications.

Adolescent↗
PubMed2002

A simple mathematical model to aid quantification of electrophoresis gels by image analysis.

In many scientific disciplines, measurements are taken from films that have been exposed to energetic sources. Examples include radiographs where the source is an X-ray tube, autoradiography where the source is a radioactive isotope and electrophoresis gels where the source is an enhanced chemiluminescence reaction. In these situations it is of interest to quantify the darkening of the film and compute the strength of the source which in the cases of autoradiography and electrophoresis can be used to compute unknown concentrations of biochemicals. We developed a simple mathematical model of the darkening of films in radiography, autoradiography and electrophoresis bands disclosed by enhanced chemiluminescence, and present formulae to calculate the strength of the source from measurement of film blackening by image analysis. A simple model is used in two examples to predict blackening of film exposed to electromagnetic radiation. This blackening is measured by image analysis. Results show reasonable agreement between predictions of the model and blackening of film for the examples chosen. This model is proposed as an aid to quantification of electrophoresis gels.

Autoradiography↗
PubMed1994

New intermediates in the B12 pathway.

Vitamin B12 has a complex structure which represents one of the most challenging biosynthetic problems in Nature. Exciting progress has been made by combining the techniques, approaches and strengths of chemistry, spectroscopy and biology. Most of the advances until recently came from experiments based either on labelling simpler precursors with radioactive isotopes followed by controlled degradation of the labelled products, or on the use of stable isotopes, 13C in particular, because it can be detected and its environment can be studied by NMR spectroscopy. These experiments imposed heavy demands on synthesis which provided the specifically labelled starting materials. More recently, the powerful methods of genetics and molecular biology have been added to the armoury, leading to another massive surge forward by allowing the preparation, through gene overexpression, of large quantities of the enzymes of the biosynthetic pathway. Equally important has been the generation of mutant forms of B12-producing organisms in which the biosynthetic pathway is blocked at specific points. Here I focus on the latest advances. The structures of the newly discovered intermediates are described and some of the chemistry involved is explored. In conclusion, the presently known pathway to vitamin B12 is reviewed.

Carbon Radioisotopes↗
PubMed2001

Occupational cancer genetics: infrequent ras oncogenes point mutations in lung cancer samples from chromate workers.

BACKGROUND: Chromium carcinogenicity and mutagenicity are no longer disputed. However, although chromium has various genetic effects that induce cancer, its mechanism of inducing lung cancer in humans is still not fully understood. p53, a tumor suppressor gene, was found to be infrequently mutated in samples of lung cancer in workers with long occupational exposure to chromium, suggesting other cancer-related genes to be targeted in such tumors. METHODS: To assess the contribution of the ras oncogenes in the pathogenesis of chromate-related lung cancer, we studied point mutations at the critical positions of codons 12, 13, and 61 of the Ha-ras and Ki-ras oncogenes in 38 lung cancer samples derived from Japanese patients who worked in the chromate industry for long periods. We used both radioactive isotope and non-radioisotope PCR-SSCP techniques. RESULTS: The results of this study demonstrated that activation of ras genes due to point mutations in chromate-related lung cancer is a rare event. CONCLUSIONS: Ras oncogenes activated by point mutations do not have a major role in the process of tumorigenesis of chromate-related lung cancer.

Adult↗
PubMed2003

Laparoscopic sentinel lymph node procedure using a combination of patent blue and radioisotope in women with cervical carcinoma.

BACKGROUND: The authors evaluated the feasibility of a laparoscopic sentinel lymph node (SN) procedure with combined radioisotopic and patent blue labeling in patients with cervical carcinoma. METHODS: Thirteen women (median age, 52.5 years) with cervical carcinoma (Stage Ia2 in 1 patient, Stage Ib1 in 10 patients, Stage Ib2 in 1 patient, and Stage IIa in 1 patient) underwent a laparoscopic SN procedure using an endoscopic gamma probe after both radioactive isotope and patent blue injections. After the procedure, all patients underwent complete laparoscopic pelvic lymphadenectomy and either laparoscopic radical hysterectomy (eight patients) or the Schauta-Amreich operation (five patients). RESULTS: SNs (mean, 1.7 SNs per patient; range, 1-3 SNs per patient) were identified in 12 of 13 patients. A median of 10.5 pelvic lymph nodes per patient (range, 4-17 pelvic lymph nodes per patient) were removed. No lymph node involvement was detected in SNs with hematoxylin and eosin staining. Immunohistochemical studies identified four metastatic SNs in two patients, with micrometastases in two SNs from the first patient and isolated tumor cells in two SNs from the second patient. No false-negative SN results were obtained. CONCLUSIONS: The results of this study suggest that SN detection with a combination of radiocolloid and patent blue is feasible in patients with cervical carcinoma. The combination of laparoscopy and the SN procedure permitted minimally invasive management of early-stage disease.

Adult↗
PubMed1992

Quantification of an in vitro cell-cell adhesion assay using interactive laser scanning cytometry.

We are interested in identifying cell-cell adhesion molecules on the surface of Sertoli cells that mediate Sertoli cell-spermatogenic cell adhesion. Numerous cell-cell adhesion assays employ microscopic observation, photomicroscopy or radioactive isotopes for quantification. Previously, we developed an in vitro assay for testicular cell interactions. This assay was, however, time consuming using photography for analysis. We have now modified this system using laser cytometry to quantify adherent cells. Rat testicular epithelial cells are cultured for approximately 6 days before labelling with fluorescein diactetate (FDA) to assess confluency by image scanning so that spermatogenic cell binding can be normalized to available epithelial cell surface area. Rat spermatogenic cells are labeled with FDA before addition to epithelial cell monolayers. In some studies, purified spermatogenic cell populations were isolated to determine average cell size. We found that spermatocyte area varied between 225-500 microns2, spermatids were 100-225 microns2 and residual bodies were less than 100 microns2. Using these parameters, scanning cytometry allows the differential analysis of adhesion by individual germ cell sub-classes from mixed cell suspensions, saving time, animals, and major expense. The scanning laser assisted assay is faster, more reproducible and less subjective than earlier cell-cell adhesion assays using light microscopy or isotopes. This experimental approach should facilitate any cell-cell adhesion assay in which one cell type is adherent to a substrate.

Animals↗
PubMed2006

A sensitive biochemical assay for the detection of uracil.

We have developed a sensitive new assay for the detection of uracil in DNA. The assay described here is an adaptation to the highly sensitive aldehydic slot blot (ASB) assay developed by Nakamura et al. (Nakamura et al. 1998: Cancer Res 58:222-225) in which aldehydic DNA lesions (ADLs) are detected through binding of a biotinylated aldehydic reactive probe to DNA. The uracil DNA glycosylase (UDG)-coupled ASB assay uses uracil-DNA glycosylase to generate an abasic site, which is subsequently detected by the ASB methodology. The ability to modify this technique for the detection of uracil has these advantages: small quantities of DNA are required (4 microg of DNA); the assay is adaptable to DNA from both cells and tissues; sensitivity is as good as that achieved by less accessible methodologies, like gas chromatography-mass spectroscopy (GC-MS); DNA strand breaks are not a confounding variable; preexisting aldehydic lesions are blocked through the use of methoxyamine; variation is very low (<3%); radioactive isotopes are not required; and the assay is easy to establish and involves only equipment and reagents that are inexpensive and readily available. This assay is conceivably adaptable to the detection of other DNA base lesions through the use of a variety of DNA glycosylases.

Aldehydes↗
PubMed1981

The dependence of tumor neutralization on bone-marrow-derived cells.

Radiosensitive host cells capable of potentiating tumor neutralization by immunocytes in normal recipients are present only in the bone marrow and not in the spleen or thymus. This was shown by selectively eliminating either the bone marrow, spleen or thymus of groups of mice and then subcutaneously injecting these animals with sensitized splenocytes and tumor cells. Bone marrow ablation was accomplished by the administration of the bone-seeking radioactive isotope 89Sr which did not reduce thymic or splenic cellularity. Sensitized splenocytes completely inhibited the growth of admixed tumor cells in normal, nude, splenectomized, or 88Sr-treated animals, but the sensitized cells were as ineffective in 89Sr-treated recipients as in 900-rad irradiated mice. Bone marrow cells of normal donors admixed with sensitized splenocytes and the sensitizing tumor cells caused a significant inhibition of tumor growth in 900-rad and 89Sr-treated mice. Therefore, the radiation-sensitive host cells that potentiate the tumor-inhibitory effect of sensitized splenocytes are unique to the marrow and, in the intact animal, apparently emigrate from this organ to interact with sensitized immunocytes at the site of tumor growth.

Animals↗
PubMed2003

In vivo imaging and tumor therapy with the sodium iodide symporter.

There has been great progress in the design of vectors for cancer gene therapy. However, it has been difficult to translate success in the laboratory into clinical practice. A major hurdle in understanding these failures has been the relative difficulty in monitoring repeatedly and non-invasively the biodistribution, gene expression and replication of these viral vector systems. With the advent of molecular imaging technology, this deficiency is being rapidly rectified. A number of reporter genes have been used to monitor gene expression. In this review, we discuss the role of the sodium iodide symporter (NIS) as a reporter and therapeutic gene for cancer gene therapy when combined with various radioactive isotopes.

Animals↗
PubMed2004

Synthesis and characterization of a sulfated and a non-sulfated cyclic CCK8 analogue functionalized with a chelating group for metal labelling.

Two cyclic peptides, cyclo29,34[Dpr29, Lys34(DTPA-Glu)]-CCK8 (1) and cyclo29,34[Tyr27(SO3H), Dpr29, Lys34(DTPA-Glu)]-CCK8 (2), bearing the chelating moiety DTPA-Glu covalently bound to the Lys side chain have been synthesized by solid-phase methodology. The presence in compound 2 of many acidic functions characteristic of the chelating agent increases the lability of the sulfate group on the Tyr side chain. This finding suggests that prolonged acid treatments should be avoided during the preparation of such peptides. Sulfation of cyclo29,34[Dpr29, Lys34(DTPA-Glu)]-CCK8 was performed using a pyridine-SO3 complex as reagent. This reaction has been found to be the most suitable synthetic strategy for obtaining compound 2 in good yield. Cyclo29,34[Tyr27(SO3H), Dpr29, Lys34(DTPA-Glu)]-CCK8 is a new promising CCK8 analogue, able to coordinate radioactive isotopes of metal ions such as 111In(III), and to bind, in a selective way, the CCKA-R receptor.

Chelating Agents↗
PubMed1993

A rapid method for the synthesis of methylmalonyl-coenzyme A and other CoA-esters.

A rapid and high-yield synthesis of methylmalonyl coenzyme A is reported. The two-step procedure involves preparation of the thiophenyl ester of methylmalonic acid using dicyclohexylcarbodiimide as a condensing agent, followed by transesterification with coenzyme A, to yield methylmalonyl coenzyme A in 80% overall yield. Inclusion of an additional step, methylation of malonic acid with iodomethane, affords the opportunity for introducing a stable or radioactive isotope into the product. This method should be applicable for the syntheses of other coenzyme A esters that are of biochemical interest such as succinyl coenzyme A.

Acyl Coenzyme A↗
PubMed2001

Negatively charged polymers protect antinuclear antibody against inactivation by acylating agents.

For many practical applications, monoclonal antibodies must be chemically modified without any significant loss in their immunoreactivity. In some situations, however, the amino acid residue crucial for antibody activity may be highly reactive toward the modifying agent, which results in antibody inactivation. The method to prevent inactivation of a modification-sensitive antinuclear monoclonal antibody by acylating agents was developed. The method is based on the hypothesis that a highly reactive amino group exists within, or in the vicinity of, the binding site of the antibody, providing crucial interaction with negatively charged moieties of DNA. It has been shown that negatively charged polymers, such as dextran sulfate or heparin, may provide temporary protection, presumably interacting noncovalently with this amino group and thus masking it. The protecting molecule can be removed later by chromatography on a protein A column, thus regenerating modified but not inactivated antibody in the free form for use in subsequent applications. In particular, we have modified antibody 2C5 with a chelating agent, diethylenetriaminepentaacetic acid (DTPA) without the loss of activity. Modified antibody was labeled with radioactive isotope, (111)In, via chelation by antibody-attached DTPA. The labeled antibody was shown to demonstrate the same specificity of binding to nucleosomes as the nonmodified antibody, so it may be used in immunoscintigraphy or biodistribution studies. The method might be useful for the modification of other modification-sensitive antibodies with other acylating chemicals, such as crosslinking agents or biotin derivatives.

Acylation↗