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Biomedical subjects

D C Dahlin

Publications and source records attributed to D C Dahlin.

At least 37 records · Page 2Linked to original sources
PubMed1985

Trends and variability in survival among patients with osteosarcoma: a 7-year update.

This report is an update of a 1978 article on osteosarcoma in Mayo Clinic patients. It includes additional follow-up on previously reported cases and incorporates new cases treated since the time of that original study. From 1963 through 1981, 336 patients with classic, previously untreated osteosarcoma received their first definitive treatment at our institution. Survival of these patients was studied in detail. The most significant result was that survival in the 1960s was much worse than that in the 1970s. The first evidence of improvement in survival was noted in 1969; subsequently, further improvement occurred but was not consistent. This finding prevailed with respect to duration of survival to death, survival to detection of metastasis, and survival from occurrence of metastasis to death. On the basis of detailed regression analysis, several variables had independent prognostic value. From these findings, a prognostic score was developed, which was based on the number of the following unfavorable characteristics: age younger than 10 years, male sex, tumor diameter more than 15 cm, cell type osteoblastic or chondroblastic, duration of symptoms 2 months or less, and involvement of the femur or humerus. Patients with five or six of these unfavorable characteristics had a very poor survival; in contrast, patients with only one or two characteristics had a good outcome. Even when these scores were fairly constant, however, the calendar period had a strong influence on survival. Likewise, when treatment was considered and adjustments by score were made, no significant differences could be found between those patients treated by amputation only and those treated by amputation supplemented with chemotherapy or radiotherapy.

Adolescent↗
PubMed1985

Caldwell Lecture. Giant cell tumor of bone: highlights of 407 cases.

This retrospective study of 407 cases of giant cell tumor indicated that most tumors were in the expected locations, usually in the end of a major tubular bone. Female patients accounted for a definite, but slight, majority. Five patients had metaphyseal tumors, and three patients had multifocal tumors. Only one tumor occurred in a lesion of Paget disease. Local soft-tissue implantation, ordinarily with the implant having a mineralized shell, was observed in 10 of the cases. Eight patients had tumors that produced benign metastatic lesions, and two of them have died. Histologically, malignant change developed in 28 of the cases; in 21 of these, radiation had been included in the treatment of the primary lesion.

Adult↗
PubMed1984

Enzymatic and non-enzymatic reduction of N-acetyl-p-benzoquinone imine and some properties of the N-acetyl-p-benzosemiquinone imine radical.

N-Acetyl-p-benzoquinone imine (NAPQI) is the postulated hepatotoxic intermediate in acetaminophen overdosage. NAPQI was rapidly metabolized by NADPH-cytochrome P-450 reductase, with an apparent Km of 1.8 to 4.0 microM and an apparent Vmax of 29.4 mumoles per min per mg, and exhibited substrate inhibition of metabolism at NAPQI concentrations above 10 microM. NADPH was oxidized by NAPQI at a slower rate in the absence of enzyme. NAPQI did not appear to undergo redox cycling at an appreciable rate to form superoxide, and it did not stimulate oxygen utilization or superoxide release by rat isolated hepatocytes. Electron spin resonance studies failed to show formation of a free radical by chemical or enzymatic reduction of NAPQI under anaerobic conditions in aqueous media.

Animals↗
PubMed1984

Cytotoxic effects of N-acetyl-p-benzoquinone imine, a common arylating intermediate of paracetamol and N-hydroxyparacetamol.

The cytotoxic effects of N-acetyl-p-benzoquinone imine (NAPQI), a postulated ultimate reactive metabolite of paracetamol (pHAA), was studied in suspensions of isolated rat hepatocytes. Incubation of cells for 10-300 min with 0.1-0.5 mM NAPQI led to concentration dependent cell damage, as determined by increased trypan blue exclusion, lactate dehydrogenase release and glutathione (GSH) depletion. NAPQI and N-hydroxyparacetamol (N-OH-pHAA), a postulated proximate metabolite of pHAA, caused cytotoxic effects in the same concentration range. In contrast, no toxic effects of pHAA (less than or equal to 20 mM) could be demonstrated. With the short half-life of NAPQI, less than 0.5% of the NAPQI added is expected to be left in the incubation medium after a 2 min incubated period. Nevertheless, 10-120 min (depending on the concentration of NAPQI) elapsed before the cells responded with increased membrane permeability. Clearly, the initial damage caused by NAPQI must be followed by subsequent cellular steps before toxicity becomes apparent. The addition of N-acetylcysteine, GSH or ascorbate during the NAPQI exposure period fully protected the hepatocytes from NAPQI damage. Lesser effects were demonstrated when these agents were added after the 5 min NAPQI exposure period. The results presented in this study further support the hypothesis that NAPQI is the ultimate reactive formed from pHAA.

Acetaminophen↗
PubMed1984

Fibrocartilaginous mesenchymoma with low-grade malignancy.

In a review of cases of fibrous cartilaginous dysplasia of bone, five of fibrocartilaginous lesions were found to be different in clinical behavior and radiographic and morphologic features from the others. We have named these previously undescribed tumors "fibrocartilaginous mesenchymomas with low-grade malignancy in the fibrous elements."

Adolescent↗
PubMed1984

The covalent binding of acetaminophen to protein. Evidence for cysteine residues as major sites of arylation in vitro.

Covalent binding of the reactive metabolite of acetaminophen has been investigated in hepatic microsomal preparations from phenobarbital-pretreated mice. Low molecular weight thiols (cysteine and glutathione) were found to inhibit this binding, whereas several other amino acids which were tested did not. Bovine serum albumin (BSA), which contains a single free sulfhydryl group per molecule and which thus represents a macromolecular thiol compound, inhibited covalent binding of the reactive acetaminophen metabolite to microsomal protein in a concentration-dependent manner. The acetaminophen metabolite also became irreversibly bound to BSA in these experiments, although this binding was reduced by approx. 47% when the thiol function of BSA was selectively blocked prior to incubation. Covalent binding of the acetaminophen metabolite to bovine alpha s1-casein, a soluble protein which does not contain any cysteine residues, was found to occur to an extent of 37% of that which became bound to native BSA. These results were taken to indicate that protein thiol groups are major sites of covalent binding of the reactive metabolite of acetaminophen in vitro. The covalent binding characteristics of synthetic N-acetyl-p-benzoquinoneimine (NAPQI), the putative electrophilic intermediate produced during oxidative metabolism of acetaminophen, paralleled closely those of the reactive species generated metabolically. These findings support the contention that NAPQI is indeed the reactive arylating metabolite of acetaminophen which binds irreversibly to protein.

Acetaminophen↗
PubMed1984

Genotoxicity studies with paracetamol.

Paracetamol and its major ultimate reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI) were studied for their genotoxic potential. Neither paracetamol nor NAPQI were found to cause mutations in Salmonella typhimurium, whereas NAPQI was severely cytotoxic to the bacteria. Radiolabelled paracetamol was found to bind covalently to DNA added to mouse-liver microsomal incubations at a rate of 2.6 pmoles/mg DNA/min. Paracetamol also bound covalently to hepatic DNA at a level of 15 pmoles/mg DNA after a hepatotoxic dose of paracetamol to mice. NAPQI caused extensive DNA single-strand breaks as evidenced by alkaline elution of DNA from treated Reuber hepatoma cells. This effect occurred at concentrations which later resulted in cytotoxicity. Paracetamol was shown to induce increased DNA-repair synthesis in isolated mouse-liver cells in monolayer culture, at concentrations where also cytotoxicity was evident. Increased DNA-repair synthesis occurred at lower paracetamol concentrations in cells isolated from mice pretreated with phenobarbital. Taken together, these data show that paracetamol can cause DNA interaction leading to damage at levels which are cytotoxic.

Acetaminophen↗
PubMed1984

N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen.

N-acetyl-p-benzoquinone imine (NAPQI) has been proposed as the toxic metabolite of acetaminophen for the past 10 years, although it has never been detected as an enzymatic oxidation product of acetaminophen. We report (i) direct detection of NAPQI formed as an oxidation product of acetaminophen by cytochrome P-450 and cumene hydroperoxide and (ii) indirect evidence that is compelling for NAPQI formation from acetaminophen by cytochrome P-450, NADPH, and NADPH-cytochrome P-450 reductase. Evidence is provided for the rapid reduction of NAPQI back to acetaminophen by NADPH and NADPH-cytochrome P-450 reductase such that steady-state levels of NAPQI were below our detection limits of 6.7 X 10(-8) M. In mouse liver microsomal incubations, radiolabeled analogs of both NAPQI and acetaminophen bound covalently to microsomal protein with the loss of approximately equal to 20% of the acetyl group as acetamide. The binding in each case was decreased by glutathione with concomitant formation of 3-S-glutathionylacetaminophen. The binding also was decreased by L-ascorbic acid, NADPH, and NADH with reduction of NAPQI to acetaminophen. Results of partitioning experiments indicate that NAPQI is a major metabolite of acetaminophen, a considerable fraction of which is rapidly reduced back to acetaminophen.

Acetaminophen↗
PubMed1984

Clear cell chondrosarcoma of bone. Observations in 47 cases.

Clear cell chondrosarcoma of bone, a low-grade malignant tumor, frequently presents diagnostic difficulties. Its clinical, roentgenographic, and pathologic characteristics separate it from conventional chondrosarcoma and, more importantly, from several benign bone tumors with which it is often confused. This report analyzes 47 cases seen at the Mayo Clinic and in consultation. The lesion is more common in males than females (2.6:1) and has a predilection for the end of long bones, particularly the proximal femur. The age range is wide; most patients are in the third and fourth decades of life. Roentgenographically, the lesion most often is purely lytic and slightly expansile, with a sharp margin between the tumor and the adjacent normal bone. Pathologically, clear cells arranged in an indistinct lobular pattern characterize the tumor. Frequently, areas mimicking other primary bone tumors, benign and malignant, are present, often to such an extent as to obscure the true identity of the process. The overall mortality in the present series was 15%. En bloc resection, including a margin of normal bone and soft tissue, appears to be the treatment of choice.

Adolescent↗
PubMed1984

Giant cell tumor: ossification in soft-tissue implants.

Benign giant cell tumor of bone may be implanted into the surrounding soft tissues at the time of surgery or pathologic fracture. These soft-tissue implants may produce ossification that is radiographically visible. A review of the available radiographs of 400 cases of giant cell tumor from the Mayo Clinic and 700 cases seen in consultation yielded 17 examples of this phenomenon. In all but one case, the ossification was found at the periphery of the implant. The radiographic appearance of these implants is characteristic. Recognition of this appearance is necessary so that the tumor may be totally eradicated.

Adolescent↗
PubMed1984

A controlled pilot study of high-dose methotrexate as postsurgical adjuvant treatment for primary osteosarcoma.

Thirty-eight patients whose primary extremity or limb girdle osteosarcomas had been completely excised (37 amputations, one limb sparing procedure) were allocated at random to two treatment groups receiving respectively regular follow-up examinations plus a high-dose methotrexate (HDMTX) regimen or regular follow-up without primary adjuvant chemotherapy. Although the vincristine, HDMTX, leucovorin regimen was generally quite tolerable when given at three-week intervals for one year and most of the chemotherapy patients followed the planned HDMTX dose escalations from 3 to 6 to 7.5 g/m2, delayed methotrexate excretion limited dosage escalations in 25%. An estimated 52% of the 38 patients were surviving five years after randomization and an estimated 42% remained continuously relapse-free after five years. No significant differences between the outcomes of the 20 treated and the 18 untreated patients were apparent; however, power to detect differences was low. Furthermore, no significant differences in postmetastasis survival were apparent between the 12 treated and 10 untreated patients who relapsed. Approximately 20% of these failing patients appear to have been salvaged for long-term survival. This pilot study of HDMTX confirms the continuing need for controlled clinical trials in determining the therapeutic value of adjuvant chemotherapy programs for patients with primary osteosarcoma.

Adult↗
PubMed1984

Reduction and glutathione conjugation reactions of N-acetyl-p-benzoquinone imine and two dimethylated analogues.

N-Acetyl-3,5-dimethyl-p-benzoquinone imine, N-acetyl-2,6-dimethyl-p-benzoquinone imine, and N-acetyl-p-benzoquinone imine were synthesized via the oxidation of 3,5-dimethylacetaminophen, 2,6-dimethylacetaminophen, and acetaminophen, respectively. All three quinone imines were rapidly reduced to their corresponding semiquinone imines by NADPH-cytochrome P-450 reductase. All three benzoquinone imines underwent comproportionation with their respective phenols to yield the corresponding semiquinone imines, which in the presence of oxygen gave superoxide. Identification of this latter free radical was based on spin-trapping techniques. Reduced GSH was found to be an excellent nucleophile toward N-acetyl-2,6-dimethyl-p-benzoquinone imine, whereas this thiol behaved as a one-electron reductant toward N-acetyl-3,5-dimethyl-p-benzoquinone imine. Finally, GSH was determined to act as both a nucleophile and a reductant toward N-acetyl-p-benzoquinone imine.

Animals↗
PubMed1984

Grading of bone tumors.

Malignant tumors are graded based on the resemblance of the tumor cells to their "normal" counterparts. Tumors with cells that least resemble normal cells are of the highest grade. Grading may be applied to any tumor in which cytologic variation occurs from tumor to tumor. Most small cell tumors are uniformly undifferentiated and, hence, do not lend themselves to grading. Most bone sarcomas may be graded. Grading is most useful in chondrosarcomas and angiosarcomas for predicting prognosis.

Bone Neoplasms↗
PubMed1984

Dedifferentiated parosteal osteosarcoma.

Parosteal osteosarcoma is an uncommon malignant tumor of bone, and in a review of Mayo Clinic records we identified eleven cases of so-called dedifferentiated parosteal osteosarcoma. Ten of the eleven patients had had a long history of treatment for multiple recurrences of the tumor as a low-grade parosteal osteosarcoma and then for a definite recurrence as a high-grade undifferentiated osteosarcoma. The prognosis in this group of patients was similar to that in patients with conventional osteosarcoma.

Adolescent↗
PubMed1983

Melanotic neuroectodermal tumor of infancy. A review of seven cases.

The melanotic neuroectodermal tumor of infancy (MNTI) is a rare, usually benign, pigmented neuroectodermal tumor which most often involves the maxilla. The authors reviewed seven cases of MNTI, with patient ages of our patients ranged from nine weeks to 18 months; six of the seven were less than six months old at initial diagnosis. Four patients were males, and all were white. One tumor each was located in the femur, the temporal bone, and the epididymis; the remaining lesions occurred in the maxilla. Three of the four maxillary tumors recurred locally; the epididymal and femoral tumors metastasized. Two of these cases had unique clinical or pathologic features. The case of the femoral tumor is remarkable in that it is the first reported one of MNTI presenting in a long bone. This tumor was aggressively malignant; within two months after its discovery, a large mass of similar tumor was formed in the pelvis, and the tumor resulted in the patient's death. To the authors' knowledge, the case of the temporal bone tumor is the first one of MNTI in which neuronal differentiation of the neuroblastic cells is convincingly demonstrated. This finding provides additional evidence in support of the neuroectodermal theory of origin of these neoplasms.

Female↗
PubMed1983

Osteosarcoma of the jaw.

The records of 66 patients with osteosarcoma of the jaw were reviewed. The ages of the 42 males and 24 females ranged from 12 to 79 years (mean, 34.2 years). Swelling and pain, the most frequent presenting complaints, were noted an average of three months before the patient was seen by a physician. Fifty-one percent of the lesions involved the maxilla and 49% involved the mandible. The most common sites of involvement were the body of the mandible and the alveolar ridge of the maxilla. Radiologically, most of the lesions in the maxilla were osteoblastic (50%), whereas most of those in the mandible were osteolytic (43%). Chondroblastic osteosarcoma was the most frequent histologic type (48%) and was associated with the best survival rate (47%). Treatment included radical and local surgery with radiotherapy, chemotherapy, or various combinations. The recurrence rate for all treatment modalities was 70%. Patients treated by initial radical surgery had the best survival (80%). Survival decreased to 27% with local surgery. Of the 43 (65%) patients who died, most died with uncontrolled local disease; only four patients had documented distant metastasis, which involved lung, cervical lymph nodes, spinal column, and brain.

Adolescent↗
PubMed1983

Adenocarcinoma of the rectum arising in a hamartomatous polyp in a patient with Peutz-Jeghers syndrome.

The malignant potential of the hamartomatous polyps in Peutz-Jeghers syndrome has been debated. Although this is a very rare event, these polyps can undergo carcinomatous transformation, as demonstrated by this report of a 37-year-old man with well-documented Peutz-Jeghers syndrome who developed an invasive grade 2 adenocarcinoma on the surface of a hamartomatous polyp in the rectum.

Adenocarcinoma↗