[Tetracyclines in cancer].
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Biomedical subjects
Publications and source records attributed to G B Snow.
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A total of 130 human head and neck cancers was transplanted subcutaneously in athymic nude mice in order to obtain a series of xenografts. All tumours were derived from previously untreated patients. Initial growth, which was histopathologically confirmed, was observed in 34 cases (26.1%). Serial passages were successful in 12 of 23 cases (52.1%). Of 117 squamous cell carcinomas, 30 (25.9%) showed initial take in the mice. Poorly differentiated squamous cell carcinomas tend to grow more readily than moderately differentiated and well-differentiated ones. Material from metastatic lymph nodes tends to show a higher take than material from primary tumours. In general the tumour-volume doubling time decreased to 4-6 days when the number of passages increased. Histology of the xenografted tumours showed that transplantation had caused no major changes. No macro-, or microscopic signs of metastasis were observed in any of the mice. The implications of this model for fundamental and applied research are discussed.
In experimental models cis-diamminedichloroplatinum(II) (cis-platinum) showed to have a radioenhancing effect. The feasibility of daily administration of cis-platinum in combination with radiotherapy was studied in 21 patients with locally advanced inoperable cancers (head and neck 7, esophagus 5, bronchus 3 and others 6). The tumours were squamous cell (15), or adenocarcinoma (6). Radiotherapy was delivered in one (180 cGy; 5 patients) or two (each of 125 cGy; 16 patients) fractions per day to a cumulative dose of 3000-6800 cGy, while cis-platinum was administered at a total daily dose of 8 mg/m2 (14 patients) or 6 mg/m2 (7 patients), in one single or two divided injections (total dose 168-352 mg cis-platinum). Fourteen patients received a total daily cis-platinum dose of 8 mg/m2 with 4 l of i.v. hydration. Severe myelosuppression occurred in 10/14 patients (range white blood cell count nadirs 0.6-2.1 X 10(9)/l) after 3-5 weeks of treatment, while seven developed severe thrombocytopenia (less than 75 X 10(9)/l). All patients became anaemic. Due to this myelosuppression, radiation treatment had to be postponed in four patients for 18-35 days. Eight patients developed bronchopneumonia, two of them had a septicaemia and one died. One patient with a bronchial carcinoma developed necrotizing pneumonitis with a cavity outside the tumour area and subsequent severe pulmonary fibrosis within the radiation field. Seven patients received cis-platinum at 6 mg/m2 per day without i.v. hydration. A moderate leukopenia (white blood cell count nadirs 1.8-2.1 X 10(9)/l) was observed in three patients requiring postponement of treatment in one of them.(ABSTRACT TRUNCATED AT 250 WORDS)
In earlier experiments chemotactic responsiveness of peripheral blood monocytes obtained from patients with head and neck cancers was found to be markedly depressed. In an attempt to attribute this defect in migration to an influence excited by low molecular weight factors of less than 25,000 daltons, derived from the tumor, Amicon filtrates of head and neck cancer cells were administered subcutaneously to C3H mice 24 hrs. before the intraperitoneal injection of concanavalin A. Subsequent macrophage accumulation into the peritoneal cavity was quantified. A clear inhibition of macrophage infiltration was found, particularly when filtrates of poorly differentiated tumors were used. Injection of filtrates from healthy oral mucosa were negative, whereas mouse mammary carcinoma filtrates strongly inhibited accumulation.
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Data from 150 patients with laryngeal carcinoma, consecutively treated primarily by radiotherapy from 1965 through 1974 was analyzed to assess the quality of voice. The voice appears to improve in majority of the successfully irradiated patients. In 76% of the evaluable patients in this group, the quality of voice appears to have attained normalcy or near normalcy. Smoking appears to have a negative influence. High incidence of bronchogenic carcinoma along with the negative influence of smoking on the quality of voice in this series of patients indicate that the patients should be advised against smoking in day-to-day clinical practice.
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To otolaryngologists involved in ablative surgery for tumours, restoration of function and appearance after extirpation has always been a matter of concern. This is particularly important for two reasons. In the first place, the function of the pharynx as a pathway for deglutition and respiration makes reconstruction of this area of vital importance. Secondly, while scars, defects and prosthetics in other parts of the body can be easily hidden and camouflaged, this is difficult in the head and neck area. For almost a century skin grafts, free, pedicled or as rotation flaps, have been used for reconstruction. In recent years the development of myocutaneous flaps has considerably altered this picture and this field is rapidly advancing. The purpose of this paper is to acquaint ourselves with this advance and to present our own experience.
Human head and neck tumours were successfully transplanted in athymic nude mice. In 14 xenograft lines the effect of 1 to 3 clinically active agents could be tested. Maximum tolerated doses were given daily for 3-7 days. Growth delay was estimated in terms of the number of volume doubling times gained by the treatment. Cis-platinum and bleomycin appeared to be effective agents. In all 6 lines in which cis-platinum was examined, growth delay sometimes followed by complete regression was achieved. In 6/7 lines a response to bleomycin was observed. There was wide variation in sensitivity to cis-platinum and bleomycin among the different lines. Methotrexate, effective in 40-60% of patients with head and neck cancer, essentially showed no activity. Methotrexate produced a minimal growth delay in 1/11 lines treated. Two of the patients from whom xenografts were obtained responded to methotrexate treatment. The observed lack of activity of methotrexate against these tumour xenografts indicates that this model has limitations in the screening of new anticancer agents.
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A retrospective clinico-pathological study has been carried out in a series of 405 patients with squamous cell carcinoma of the head and neck who underwent a total of 484 radical neck dissections. The recurrence rate in the neck in 327 patients who had histological positive nodes was 21.1%. Recurrence in the neck after a standard radical neck dissection almost invariably proved fatal. A statistical analysis has been carried out to evaluate the clinical and pathological factors which are of importance in regards to recurrence in the neck. Histological factors such as extra-nodal spread and the number of histological positive nodes have been shown to be of much more prognostic importance than clinical parameters. When corrections are made for interdependencies between variables, histological extra-nodal spread proved to be the most important single prognostic factor (P less than 10(-7)).
The number of blood monocytes, their ability to mature into macrophages, their NBT-dye reduction capacity and their migration towards casein were studied in 29 patients with squamous cell carcinoma of the larynx, 12 patients with squamous cell carcinoma at other sites within the head and neck and two groups of male controls, one of 29.7 yrs. +/- 7.2 (SD) and the other of 71.4 yrs +/- 6.8 (SD). An age dependency of monocyte function in healthy individuals was established. Increased numbers of monocytes per ml blood were found in the older men. These cells showed an enhanced migration toward casein. Their maturation capacity was decreased. A clear impairment of migration toward casein was found in the two groups of carcinoma patients. The number of monocytes was only marginally affected. The maturation was found to be enhanced. An impaired recruitment of mononuclear phagocytes at the site of malignant growth due to diminished migratory capacities might be important for failing immune surveillance.
Among several methods of surgical restoration of voice which were introduced in the last two decades, the one of Staffieri has so far been most successful, though perfection with this technique still remains to be achieved. Question has always been raised as to the nature of function of the neoglottis in the production of voice in these patients. An attempt has been made to study this function with the aid of electroglottography. Results show that the neoglottis functions in some ways similar to the normal human glottis, and as the source of vibrations in these laryngectomized subjects.
An animal model was constructed using retrograde cannulation of a branch of the external carotid artery of rats in order to study the intraarterial (IA) and systemic effects of bleomycine, methotrexate, and 5-fluorouracil on a squamous cell carcinoma implanted in both ears. Continuous seven-day IA infusion of bleomycine and 5-fluorouracil proved to be superior to the systemic way by about a factor of 3. Unfortunately, the tumor did not respond to methotrexate and therefore, for this drug, no conclusion could be made as to the relative benefits of IA administration. Comparing simultaneous, sequential, and intermittent multiple-drug regimens, the last one showed an antitumor effect which was superior to either of the other schedules. It is concluded that IA administration of effective cytotoxic drugs is a superior treatment modality and that in this model IA intermittent multiple-drug therapy is the most successful schedule yet studied.
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