Tumor growth inhibition and potentiation of immunotherapy by indomethacin in mice.

Indomethacin was continuously administered in the drinking water of inbred C3H mice given grafts of syngeneic 3-methylcholanthrene-induced fibrosarcomas. A minor proportion of these animals died at the same time as the untreated controls, and others completely rejected their tumors; however, in most cases, the tumor growth rate was significantly slowed, and growth recommenced rapidly after drug withdrawal. This was the pattern for tumors either in their 10th to 14th transplant generation or only their third in vivo passage. Indomethacin exerted little prophylactic effect, in that it neither increased the minimal cell number required to initiate tumor growth nor significantly decreased the proportion of tumors established in drug-treated animals recieving tumor grafts. The injection of killed Corynebacterium parvum organisms into small, growing McC3-I tumors [intratumor (IT) route] caused the regression of most of these. In contrast, IT injection of BCG, ip injection of C. parvum, or IT injection of C. parvum into larger tumors had no effect. Oral administration of indomethacin enhanced BCG treatment and augmented the activity of C. parvum injected either systemically into animals with small tumors or IT into those with substantial tumor burdens. The duration of these effects was, however, often dependent on the continued administration of the drug.

Passive local anaphylaxis: demonstration of antitumor activity and complementation of intratumor BCG.

When an extracellular dye, Lissamine green, or 51Cr-labeled spleen cells were injected iv into C3H mice bearing small, partially necrotic 3-methylcholanthrene-induced transplantable fibrosarcomas (McC3), the tumor content of these circulating elements per unit weight was substantially lower than that of other selected organs. The level of these blood-borne materials was, however, significantly augmented by the intratumor induction of passive local anaphylaxis (PLA). The PLA-induced augmentation was inhibited by administration of the histamine and serotonin antagonist cyproheptadine; comparable increases were also induced by the intratumor injection of a histamine and serotonin mixture or BCG. The weekly intratumor induction of PLA in McC3 tumors resulted in the complete regression of a significant number of the tumors, and this therapeutic effect was eliminated by cyproheptadine treatment. The intratumor injection of BCG induced the regression of approximately 50% of injected tumors, and the combination of this immunostimulant treatment with the generation of PLA was more therapeutically effective than either treatment alone. PLA in the vicinity of solid tumors may, by increasing vascular permeability, potentiate antitumor effector mechanisms, particularly when these are BCG-stimulated. Despite this demonstration of a possible role of anaphylactic reactions in tumor immunity, no definitive evidence was found that active reagin-mediated local anaphylaxis occurred in C3H mice bearing the McC3 tumor, whether or not they were treated with immunostimulants.

The influence of intraperitoneal injections of histamine on tumour growth in fibrosarcoma-bearing mice.

Twenty C57BL/6 male and 20 C3H female mice carrying a methyl cholanthrene-induced fibrosarcoma received, daily, intraperitoneal injections of histamine dihydrochloride (1.8 mg or 6 mg histamine base/mouse). In all histamine-treated C57BL/6 mice, tumour growth was significantly slower than in control mice until day 18. Thereafter, the tumour growth rate of treated compared to control mice was accelerated. In 10 out of 20 C3H mice, tumour growth was significantly slower until day 25; in histamine responsive C3H mice, histological studies showed numerous and large loci of acute haemorrhagic necrosis in the tumours.

Ewing's sarcoma: transplantation in nude rat.

Eight Ewing's sarcoma, primary tumor or metastasis, have been transplanted in Nude Rats. These tumors grow slowly and only in female rats. One of them has been maintained for 13 months with 5 passages. It has conserved all the characteristics of the primary tumor, histologic and ultramicroscopic morphology, glycogen secretion and cytogenetic modification (11.22 translocation). The graft of Ewing's sarcoma to Nu/Nu rats is a valuable system to get more material in good condition to study the nature and the origin of Ewing's cells, to test the new chemotherapy trials and to prepare and test the monoclonal antibodies.

HIV induced neuroendocrine alterations in AIDS patients as a co-factor of immune deficiency.

HIV may induce subclinical neuroendocrine dysfunctions in some seropositive patients and these dysfunctions may be one of the co-factors that determine the pathogenesis of AIDS.

Paraneoplastic syndromes.

A given cancer is a disease which combines a paraneoplastic syndrome with an invasive tumour capable of giving rise to metastases. Surgeons, radiotherapists, medical oncologists and experimental scientists are primarily interested in the tumour. Tumours of tissues and organs which do not normally produce hormones might, during the neoplastic transformation, begin to secrete hormones or substances able to mimic hormones in their effects on other tissues in the organism. The number of known hormones has increased considerably in the last 20 years. It has been found that even in the absence of clinical signs there are often secretory abnormalities and changes in the hormone balance in cancer. The tumour-paraneoplastic syndrome interaction is bidirectional. That paraneoplastic syndromes are dependent upon the tumour, is universally accepted; the reverse, that the tumour might depend on the paraneoplastic syndrome is not part of the current way of thinking. To treat cancer patients, instead of debating the cause and effect in the tumour-paraneoplastic syndrome pair with the classical idea of acting as close to the cause as possible, it seems better, in all circumstances, to treat both the tumour and the paraneoplastic syndrome, even if only subclinical.

Elbow joint salvage with the transverse rectus island flap: a new application.

The transverse rectus island flap has gained wide acceptance in breast reconstruction. We introduce its use in reconstruction of extensive wounds of the elbow region. Three cases are presented. Its principal advantages over other methods are size, pedicle length, reliability, acceptable donor defect, and potential prevention of elbow and shoulder stiffness. Its disadvantages are bulk, weight, and required staged procedures.

Scapular free-flap dissection made easier.

An improved technique for the dissection of the scapular free flap is presented. It includes identification of the triangular space by palpation and delivery and deep dissection of the proximal flap pedicle by means of a counterincision in the axilla. This technique allows for a rapid, safe, and easy dissection of the transverse scapular flap.

[French oncology: a spatiotemporal general view from a special observation point, the Year Books of Cancer]. / La cancérologie francaise: vue d'ensemble spatiotemporelle d'un observatoire particulier, les Year Book of Cancer.

The Year Book(s) of Cancer were analyzed to count selected French articles within the 1965-1982 period. A comparison between two periods: 1966-1976 and 1978-1982 shows an increase in French production from 2.3 per cent to 4.6 per cent. Strong sectors are breast, female genital tract, leukemia and lymphoma, radiotherapy, immunology and immunotherapy. This increase in number of selected papers is mostly due to articles published in biomedical French journals in which French language is prevalent. The place of provincial institutions changed from 1/4 in 1965-1976 to 1/2 in 1978-1982. With the same method of analysis, cancerology seems more developed in France than cardiology or endocrinology. This statistic suggests the necessary endeavours to further regularly improve the situation.

Discrepancies in nude mice.

With the increasing number of publications in which nude mice are used, there is a growing list of apparent discrepencies. To avoid such problems, we propose the use of nude mouse populations with a large gene pool which will leave, if possible, the nude allele as the only homozygote. All phenotypic characters consistently different between nu/nu, nu/+ and +/+ mice could then, with more certainty, be linked with the nude mutation.

[Host-tumour relationships and immediate hypersensitivity reactions]. / Rapports hote-tumeurs et réactions d'hypersensibilité immédiate

When radiolabelled lymphoid cells and the extracellular dye Lissamine green were injected IV into C3H mice carrying non-necrotic methylcholanthrene-induced tumours, the tumour content of these agents was significantly lower than in other organs. The tumour content of these circulating blood components was significantly increased by the intratumoral (IT) induction of local passive anaphylactic reactions, and such reactions exerted an anti-tumour effect, and enhanced the therapeutic activity of IT BCG. No anti-tumour IgE antibody was detected in this model, but the tumour inhibited passive and active anaphylactic reactions in its host.

Therapeutic effect of intratumoral injection of bcg and other substances in rats and mice.

The experimental treatment of a rat sarcoma (McFiFi 2) by intratumoral injection of BCG2 is described. Tumors which have a mean diameter of less than 10 mm at the beginning of treatment are fully susceptible to BCG, although spontaneous regression is not observed at this stage. The effective dose of living BCG ranges from two injections of 0.1 mg to two injections of 1 mg, given IT at an interval of 7 days. The permanent cure of a proporation of the tumors may also be induced by IT injection of a similar dose of heat-killed BCG or of MER, or of 10(9) heat-killed C. parvum, according to the same schedule. Preimmunization of the rats with living BCG does not improve the efficiency of heat-killed BCG. Direct contact between the therapeutic material and the tumor cells is critical. If rats are grafted with two pieces of the same tumor in widely separated sites, the intratumoral treatment of only one of these tumors with living BCG is sufficient to induce regression of both tumors in 50% of the animals. The effect of BCG is counteracted by injection of silica or by ingestion of polaramine. The same intratumoral treatment with living BCG was applied to different rat and mouse tumors. Only McFiFi 2 tumors were cured by intralesional BCG. C3H mouse plasmocytoma 5563 was not cured by intratumoral BCG but its growth could be prevented by mixing BCG and tumor cells at the time of grafting; this tumor was considered to be of medium susceptibility. However, until there is definite proof that the two mechanisms are identical, one should consider the regression and cure of a growing tumor, and the prevention of tumor growth, as two different phenomena. The clinical treatment of human tumors resembles the first experimental procedure more closely than the second.

Immunotherapy of primary methylcholanthrene-induced mouse tumours by intratumoral BCG.

Tumours were induced s.c. in C3H/uip, SJL/uip, DBA/2 uip, C57BL/6 uip and BDF1 mice by different doses of methylcholanthrene (MCA) diluted in oil: 1 mg, 0.1 mg and 0.01 mg. In each mouse strain, tumour frequency showed a different decreasing pattern in relation to the decreasing dose of MCA. Tumour latent period (LP) increased between the 1mg and 0.1mg doses of MCA, but the 0.01mg dose induced tumours with a similar or shorter LP than those tumours induced by 1 mg. Half of the tumours were treated with two injections of intratumoral (IT) BCG. The strains of mice differed in their sensitivity to this treatment, but only tumours induced by 0.01 mg MCA were sensitive to IT BCG. The induction of tumours by MCA pellets gave similar results. After transplantation of the untreated tumours, very few were cured by BCG treatment. Analysis of the role of tumour LP, growth rate and immunogenicity favours a slow growth rate as the most important characteristic for BCG sensitivity of the primary tumour. The tumours induced by 0.01 mg MCA were less immunogenic than those induced by 1 mg MCA, but the difference was not significant. This finding permits us to exclude an important role for tumour immunogenicity in the sensitivity of the primary tumour to BCB.

Various modalities of local administration of bacterial immunostimulants in transplantable rat tumours and in primitive methylcholanthrene mouse tumours.

The frequent use of intra-lesional injection of bacterial immunostimulants is hampered by apparent rarity of susceptible tumours, absence of therapeutic effect on large tumours, lack of variety of experimental models, eventual traumatism which is feared in case of intra-lesional, and injection in visceral cancers. (1) Methylcholanthrene induced primitive tumours in mice are more frequently susceptible when the carcinogen induction dosage is low (0.01 mg). (2) Using transplantable rat tumours, one susceptible and one resistant to intra-tumoral BCG or Corynebacterium parvum therapy, we have shown that both are resistant to systemic administration of immunostimulants. For the susceptible tumour, subcutaneous peritumoral multiple injections have the same efficacy as intra-tumoral injection in curing small tumours and ipsilateral distant tumours, when the rats receive a double graft of the same tumour. Superficial multifocal intratumoral injections can cure more voluminous susceptible tumours. The association of peritumoral and intra-tumoral injections rendered susceptible the usually resistant tumours.

Tumour-associated inhibition of immediate hypersensitivity reactions in mice.

The intensity of anaphylactic shock was lower in C3H mice carrying a methylcholanthrene-induced tumour (McC3) than in their normal counterparts when immunized with ovalbumin and challenged i.v. after 14 days. This tumour-associated inhibitory effect on active systemic anaphylaxis was exerted mainly on events occurring after homocytotropic antibody synthesis because the serum titres of these antibodies were comparable in normal and tumour-bearing animals. In addition, passive systemic anaphylactic reactions were suppressed in animals carrying the tumour and the sensitivity of these animals to challenge with histamine and serotonin mixtures was also reduced. The presence of a growing McC3 tumour did not, however, diminish the amine-sensitizing effect of treatment with Bordetella pertussis vaccine. The McC3 tumour inhibited the generation of passive cutaneous anaphylactic reactions, an effect that was also exerted by a tumour extract, particularly when administered to the recipients shortly before antigen challenge. Thus immediate hypersensitivity reactions, like a variety of other immunological processes, can be inhibited by tumour products which by compromising the immune status of the host might permit tumour growth. The nature of the inhibiting factor is unknown, except that it is probably not the amine-degrading enzyme histaminase. In addition, which it is uncertain whether the inhibitory effect is exerted directly or indirectly, the possible importance of prostaglandins in the phenomenon is discussed.