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Biomedical subjects

R M Hoffman

Publications and source records attributed to R M Hoffman.

At least 109 records · Page 6Linked to original sources
PubMed1996

"Decadose" effects of cisplatin on squamous cell carcinoma of the upper aerodigestive tract. I. Histoculture experiments.

There is substantial laboratory and clinical evidence that solid tumors rapidly acquire cellular resistance to cisplatin. Experiments with human carcinoma cell lines and clonogenic assays indicate that resistance is usually mild to moderate and can be circumvented with higher concentrations of drug. The purpose of this investigation was to test this hypothesis with a histoculture assay of human upper aerodigestive tract (UADT) carcinomas. Using a sponge-gel supported histoculture, 43 tumor specimens from patients with squamous cell carcinoma (SCC) of the UADT were grown and exposed to cisplatin. Growth inhibition by the drug, in concentrations equivalent to peak therapeutic doses (1.5 micrograms/mL) and concentrations 10 and 25 times greater (15 and 37.5 micrograms/mL), were measured in specimens from patients with previously untreated and recurrent lesions. In vitro, the overall rate of sensitivity of the tumor samples to cisplatin concentrations of 1.5, 15, and 37.5 micrograms/mL were 22%, 62%, and 83%, respectively. In patients with previously untreated disease, the respective rates were 25.9%, 63.3%, and 79.3%, as compared with 10.0%, 55.6%, and 85.6%, respectively, for patients with recurrent disease. The response difference between cisplatin concentrations of 1.5 and 15 micrograms/mL was statistically significant. The "decadose" effect of cisplatin on growth inhibition was 2.44-fold for untreated lesions and 5.56-fold for recurrent tumors. The results indicate that resistance to standard doses of cisplatin by SCC of the UADT can be substantially overcome with a decadose (standard dose x 10) increase and is more pronounced in tumors from patients with recurrent disease. Progress toward improving survival of patients may be possible by incorporating decadose cisplatin therapy into a multimodality treatment plan.

Antineoplastic Agents↗
PubMed1996

Calcium decreases and parathyroid hormone increases in serum of periparturient mares.

Changes in serum concentrations of Ca and parathyroid hormone (PTH) may develop in periparturient mares, may be influenced by dietary Ca, and may be associated with changes in Ca concentration of mammary secretion. Milk and blood samples were taken from eight mares on Farm A and eight on Farm B for 10 d before parturition and from four mares on each farm for 5 d postpartum. Milk Ca was measured by two commercial tests. Serum samples were analyzed for PTH and total Ca in 16 mares and for ionized Ca in six (Farm A). Parturition was induced in eight mares on Farm A and four on Farm B; no significant difference in serum Ca or PTH was found between mares with induced and spontaneous foaling. Mean serum total Ca decreased from 12.5 mg/dL to a nadir of 11 mg/dL on d 2 postpartum, and mean PTH increased from 46 pg/mL to a peak of 186 pg/mL on d 2 postpartum. Serum total Ca concentrations were lower and serum PTH concentrations were higher in Farm A mares than in Farm B mares, probably reflecting dietary Ca (.35% of DM on Farm A and .55% on Farm B). The serum PTH peak and Ca nadir occurred on d 2 postpartum, 1 d later than reported previously in dairy cows. Milk Ca concentration increased progressively from 7 d before parturition; this increase preceded, so was not dependent on, prepartal changes in serum Ca and PTH.

Animals↗
PubMed1995

Liver colonization competence governs colon cancer metastasis.

Tumors that metastasize do so to preferred target organs. To explain this apparent specificity, Paget, > 100 years ago, formulated his seed and soil hypothesis; i.e., the cells from a given tumor would "seed'' only favorable "soil'' offered by certain groups. The hypothesis implies that cancer cells must find a suitable "soil'' in a target organ--i.e., one that supports colonization--for metastasis to occur. We demonstrate in this report that ability of human colon cancer cells to colonize liver tissue governs whether a particular colon cancer is metastatic. In the model used in this study, human colon tumors are transplanted into the nude mouse colon as intact tissue blocks by surgical orthotopic implantation. These implanted tumors closely simulate the metastatic behavior of the original human patient tumor and are clearly metastatic or nonmetastatic to the liver. Both classes of tumors were equally invasive locally into tissues and blood vessels. However, the cells from each class of tumor behave very differently when directly injected into nude mouse livers. Only cells from metastasizing tumors are competent to colonize after direct intrahepatic injection. Also, tissue blocks from metastatic tumors af fixed directly to the liver resulted in colonization, whereas no colonization resulted from nonmetastatic tumor tissue blocks even though some growth occurred within the tissue block itself. Thus, local invasion (injection) and even adhesion to the metastatic target organ (blocks) are not sufficient for metastasis. The results suggest that the ability to colonize the liver is the governing step in the metastasis of human colon cancer.

Adenocarcinoma↗
PubMed1995

Plummer-Vinson syndrome. A case report and literature review.

The Plummer-Vinson syndrome is characterized by dysphagia, iron-deficiency anemia, and esophageal webs. The webs are best diagnosed by cineradiography. Iron repletion often improves the dysphagia, although some patients require esophageal dilatation or bougienage. The syndrome is associated with an increased incidence of postcricoid carcinoma, and surveillance endoscopy is recommended.

Aged↗
PubMed1995

Antioxidants and the prevention of coronary heart disease.

Oxygen-free radical reactions have been implicated in many chronic disease processes, including atherosclerotic cardiovascular disease. Recent studies of lipid metabolism have suggested that oxidative modification of low-density lipoprotein accelerates atherogenesis. Micronutrient antioxidants, including alpha-tocopherol and beta-carotene, however, can neutralize oxygen-free radicals and inhibit low-density lipoprotein oxidation. This review examines (1) the role of oxidized low-density lipoprotein in atherogenesis, (2) the association between nutritional antioxidant intake and atherosclerosis, and (3) observational and clinical trial data on the effect of antioxidants in reducing the risk of coronary heart disease. While evidence suggests that antioxidant supplements protect against coronary heart disease, definitive recommendations await results from ongoing randomized trials of primary and secondary prevention.

Antioxidants↗
PubMed1995

Host organ specifically determines cancer progression.

In order to further understand the role of the host organ in tumor progression, we have transplanted into nude mice histologically intact human colon cancer tissue on the serosal layers of the stomach (heterotopic site) and the serosal layers of the colon (orthotopic site). Xenograft lines Co-3, which is well differentiated, and poorly differentiated COL-3-JCK were used for transplantation. After orthotopic transplantation of the human colon tumors on the nude mouse colon, the growing colon tumor resulted in macroscopically extensive invasive local growth in 4 of 10 mice, serosal spreading in 9 of 10 mice, musclaris propria invasion in 1 of 10 mice, submucosal invasion in 3 of 10 mice, mucosal invasion in 3 of 10 mice, lymphatic duct invasion in 4 of 10 mice, regional lymph node metastasis in 4 of 10 mice, and liver metastasis in 1 of 10 mice. In striking contrast, after heterotopic transplantation of the human colon tumor on the nude mouse stomach, a large growing tumor resulted but with only limited invasive growth and without serosal spreading, lymphatic duct invasion, or regional lymph node metastasis. It has become clear from these studies that the orthotopic site, in particular the serosal and subserosal transplant surface, is critical to the growth, spread, and invasive and metastatic capability of the implanted colon tumor in nude mice. These studies suggest that the original host organ plays the same critical role in tumor progression.

Animals↗
PubMed1995

The feasibility of targeted selective gene therapy of the hair follicle.

Loss of hair and hair colour is associated with ageing, and when it involves the scalp hair, it can be distressing to both sexes. Hair loss resulting from cancer chemotherapy is particularly distressing. However, safe, effective therapies directed to hair have only just started to be developed. The hair follicle is a complex skin appendage composed of epidermal and dermal tissue, with specialized keratinocytes, the hair matrix cells, forming the hair shaft. Specific therapy of the hair follicle depends on selective targeting of specific cells of the hair follicle. We have developed the histoculture of intact hair-growing skin on sponge-gel matrices. We have recently found in histocultured skin that liposomes can selectively target hair follicles to deliver both small and large molecules. That liposomes can target the hair follicle for delivery has been confirmed independently. Two decades ago we introduced the technique of entrapping DNA in liposomes for use in gene therapy. In this report we describe the selective targeting of the lacZ reporter gene to the hair follicles in mice after topical application of the gene entrapped in liposomes. These results demonstrate that highly selective, safe gene therapy for the hair process is feasible.

Administration, Topical↗
PubMed1995

Resolution of obstructive sleep apnea after microvascular brainstem decompression.

Lesions of the brainstem have been associated with obstructive sleep apnea in previous reports. We now report a case in which retromastoid craniectomy with microvascular decompression of the medulla and ninth and tenth cranial nerves resulted in the complete resolution of severe obstructive sleep apnea. Possible mechanisms for this observation are discussed.

Brain Stem↗
PubMed1995

Preweaning diet and stall weaning method influences on stress response in foals.

The stress response of foals during weaning was examined in terms of a behavioral protocol and the responses of plasma ascorbate, serum cortisol, and the serum cortisol response to an ACTH challenge. The experimental plan was a 2 x 2 factorial of two preweaning diets and two stall weaning methods. Dietary groups included foals raised on pasture supplemented with hay and a pelleted concentrate (PHC) and foals raised on pasture supplemented with hay only (PH). Stall weaning methods included foals placed in stalls singly or in pairs. Sex influences were also examined. The foals exhibited characteristic behavioral and physiological responses to weaning stress. Behavior scores indicated fewer outward signs of stress in single than in paired foals (P = .008) and tended to indicate fewer signs of stress in PHC than in PH foals (P = .15). No differences in plasma ascorbate concentrations were found among treatments. Responses of serum cortisol to an ACTH challenge were lower (representing adrenal depletion arising from stress) in PH than in PHC foals (P = .001) and in paired than in single foals (P = .058). Behavior scores were positively correlated with the response of serum cortisol to ACTH. Both behavioral data and the ACTH response indicated that foals may cope better with weaning when supplemented with concentrate before weaning or when placed singly in stalls rather than in pairs.

Adrenocorticotropic Hormone↗
PubMed1995

[An experimental model of pleural adenocarcinoma constructed by the implantation of intact human neoplastic tissue in the nude mouse. The prognostic value of a lesion of the visceral pleura].

In certain cases pleural adenocarcinoma can behave like a primary tumour of the pleura. If the origin of this type of tumour is not clearly established, the macroscopic aspect of the pleura explored by thoracoscopy enables a distinction to be made between isolated disease of the parietal pleura and mixed disease of both the parietal and visceral pleura. The object of this study was to evaluate the prognosis of tumour disease of the visceral pleura. Using a murine model (the nude mouse) of cancer of both visceral and parietal pleura induced by implanting histologically intact human carcinoma, we have compared the symptoms of survival of the two groups of mice as well as the local and regional dissemination and metastases of the implanted tumour. The growth of the tumour was suspected by the appearance of weight loss, signs of respiratory difficulty and/or cachexia. Autopsy examination allowed a measure of the size of tumour dissemination. A pleural cancer, histologically identical to the initial human tumour with invasion of the neighbouring structures as one sees in man, was obtained in all the implants. Nevertheless, contralateral mediastinal lymph node metastases were only found in mice with implants on the visceral pleura. The median survival was 27.9 days and 31 days respectively for implanted mice on the visceral pleura and on the parietal pleura. Mice with implants on the visceral pleural lost more weight than those implanted on the parietal pleura (p < 0.001). The results of this study show that the models of parietal pleura and visceral pleura each correspond to an early stage disease and to a stage of advanced disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1995

Clinical applications of the histoculture drug response assay.

There is a need for a clinically useful drug-response assay for cancer patients to individualize their chemotherapy. Collagen sponge-gel-supported histoculture has been shown to maintain tissue architecture and function in vitro and has been utilized to develop the histoculture drug-response assay (HDRA) for individualizing chemotherapy. In order to evaluate the HDRA with the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide end point for clinical use, chemosensitivity to mitomycin C, doxorubicin, 5-fluorouracil, and cisplatin of 107 advanced gastric and 109 advanced colorectal cancers was determined in vitro in a correlative clinical trial. Two hundred eight (96.3%) of 216 of the patient specimens were evaluable in the HDRA. Thirty-eight patients with remaining measurable lesions after surgery were evaluable for comparison of the effects of chemotherapy in the HDRA with clinical outcome. Their overall response in the HDRA to all four drugs correlated to published historical data. Twenty-nine patients were treated with drugs shown to be ineffective in the HDRA, and all 29 cases showed clinical chemoresistance. In nine patients treated with drugs shown to be effective in the HDRA, six showed clinical chemoresponse and three showed arrest of disease progression. The correlation rate of the assay to clinical drug-sensitivity response was thus calculated to be 92.1% (35/38), with 100% (29/29) true-negative and 66.7% (6/9) true-positive rates, 100% (6/6) sensitivity, and 90.6% (29/32) specificity. Thirty-two patients with stage III and IV gastric cancer without remaining measurable tumor lesions after surgery were treated with mitomycin C and a fluoropyrimidine adjuvantly. The survival rate of 10 patients whose tumors were sensitive to either mitomycin C and/or 5-fluorouracil in the assay was significantly (P < 0.005) better than that of 22 patients whose tumors were shown to be insensitive to both drugs. Twenty-nine patients with stage III and IV colorectal cancer without remaining measurable tumor lesions after surgery were treated with fluoropyrimidines adjuvantly. The recurrence-free survival rate of 7 patients whose tumors were sensitive to 5-fluorouracil in the assay was significantly (P < 0.05) better than that of 22 patients whose tumors were insensitive. Thus the HDRA with the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide end point should be of clinical value to choose optimal chemotherapy for response as well as for survival.

Antineoplastic Agents↗
PubMed1994

Therapeutic trials for low back pain.

Little consensus exists regarding the indications for and effectiveness of many back pain treatments. This clinical uncertainty arises because most back pain research has been flawed by poor methodology. The authors discuss strategies for improving the quality of back pain research on treatment efficacy. Design features, including randomized treatment allocation, independent outcome assessors, comprehensive outcome measures, appropriate statistical analyses, and close patient follow-up can increase study validity. Complete descriptions of enrollment criteria, patient characteristics, and clinical interventions can increase the generalizability of results. Although large scale trials often involve university centers, community-based researchers can collaborate on randomized trials or conduct valuable cohort studies.

Clinical Trials as Topic↗
PubMed1994

Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice.

Matrix metalloproteinases have been implicated in the growth and spread of metastatic tumors. This role was investigated in an orthotopic transplant model of human colon cancer in nude mice using the matrix metalloproteinase inhibitor BB-94 (batimastat). Fragments of human colon carcinoma (1-1.5 mm) were surgically implanted orthotopically on the colon in 40 athymic nu/nu mice. Administration of BB-94 or vehicle (phosphate buffered saline, pH 7.4, containing 0.01% Tween 80) commenced 7 days after tumor implantation (20 animals/group). Animals received 30 mg/kg BB-94 i.p. once daily for the first 60 days and then 3 times weekly. Treatment with BB-94 caused a reduction in the median weight of the primary tumor from 293 mg in the control group to 144 mg in the BB-94 treated group (P < 0.001). BB-94 treatment also reduced the incidence of local and regional invasion, from 12 of 18 mice in the control group (67%) to 7 of 20 mice in the treated group (35%). Six mice in the control group were also found to have metastases in the liver, lung, peritoneum, abdominal wall, or local lymph nodes. Only two mice in the BB-94 group had evidence of metastatic disease, in both cases confined to the abdominal wall. The reduction in tumor progression observed in the BB-94-treated group translated into an improvement in the survival of this group, from a median survival time of 110 days in the control group to a median survival time of 140 days in the treated group (P < 0.01). Treatment with BB-94 was not associated with any obvious toxic effect, and these results suggest that such agents may be effective as adjunctive cancer therapies.

Adenocarcinoma, Mucinous↗
PubMed1994

Modifiable risk factors for incident heart failure in the coronary artery surgery study.

BACKGROUND: Even with aggressive treatment, heart failure is associated with a substantial morbidity and mortality. This poor prognosis has led to increasing interest in primary prevention, and the identification of modifiable risk factors. Our objective was to determine whether modifiable cardiovascular risk factors, including systolic and diastolic blood pressure, fasting glucose level, cholesterol level, weight, and smoking, were independent risk factors for heart failure in patients with anatomically confirmed coronary artery disease. METHODS: We studied all patients with documented coronary artery disease eligible for the multicenter, randomized-controlled Coronary Artery Surgery Study. After excluding 79 prevalent cases, we identified incident cases of heart failure using hospital discharge abstracts, mortality records, or self-reported follow-up questionnaires. Criteria for self-reported cases were treatment with digitalis and/or furosemide plus two or more heart failure symptoms, including dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, or edema. Cox regression analysis was used to estimate adjusted relative risks. RESULTS: At 12-year follow-up, the cumulative incidence of heart failure was 20.6%. Smoking (relative risk, 1.47) and weight (relative risk, 1.15/10 kg) were independently associated with incident heart failure. Myocardial infarction during follow-up, age, female sex, and baseline left ventricular dysfunction were also risk factors for heart failure. CONCLUSIONS: Patients with stable coronary artery disease are at high risk for developing heart failure, especially following myocardial infarction. However, interventions aimed at smoking cessation and weight reduction may prevent clinical heart failure in these patients.

Coronary Disease↗
PubMed1994

Sponge-gel-supported histoculture drug-response assay for head and neck cancer. Correlations with clinical response to cisplatin.

OBJECTIVE: Sponge-gel-supported histoculture drug-response assay (SSHDRA) represents a promising method to determine chemosensitivity of solid tumors. To determine whether the assay correlates clinically, we compared the in vivo and in vitro effects of cisplatin in 23 of 26 patients with head and neck cancers. DESIGN: The criterion for in vitro sensitivity to cisplatin was an 84% or greater inhibition by cisplatin of the number of tritiated thymidine-incorporating cells of the histocultured tumors compared with untreated control culture preparations, as measured by means of histologic autoradiography. Comparisons were made with clinical responses, ie, complete response, partial response, or no response. PATIENTS: The study was carried out in patients with head and neck cancers and comprised 21 patients with squamous-cell carcinoma, three patients with other carcinomas, and two patients with sarcoma. RESULTS: Ten of 12 patients with in vitro-sensitive tumors had either complete or partial response clinically. The overall accuracy of the SSHDRA was 74% in this correlative clinical trial; the predictive-positive value was 83%, the sensitivity was 71%, and the specificity was 78%. Seven of 11 patients with in vitro-resistant tumors demonstrated no response for a predictive-negative value of 64%. CONCLUSIONS: We conclude that the SSHDRA shows a high correlation for tumors that demonstrate both in vivo drug resistance and sensitivity. The in vitro-like maintenance of three-dimensional tissue architecture of the tumors in histoculture probably contributes to high clinical predictivity of drug response of the SSHDRA. The data support further comparisons to determine the clinical usefulness of the SSHDRA for identifying complete and partial responders to chemotherapy.

Adenocarcinoma↗