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There is general agreement as to the definition and subclassification of Hodgkin lymphomas, which is acceptable for practical reasons. However, the nature of the different types of Hodgkin lymphomas needs further consideration. On the other hand, today we are as far from agreement on non-Hodgkin lymphomas as ever before. Earlier European and American classifications have now to be reconsidered in the light of modern concepts of experimental immunology. It has become necessary to apply immunochemical and immunomorphological methods in addition to histological, histochemical, cytological, and ultrastructural techniques. Only such a complex approach has been able to provide new insight into the functional properties of the tumor cells. The result was a new lymphoma classification, which conforms to LUKES' concept in many respects. It was fundamentally accepted by a group of European lymphoma experts and has been condensed and modified in order to be applicable by as many lymphoma centers as possible. It has received the name "Kiel Classification" 1974. The main principles of the classification are as follows: 1. A distinction is made between malignant lymphomas of low-grade and those of high-grade malignancy; "-cytic", "-blastic" m.l. 2. The terms "sarcoma" and "leukemia" are avoided. All types of malignant lymphoma can be leukemic, however with differnt frequencies. All B-cell lymphomas can also show a monoclonal immunoglobulin increase ("paraproteinemia") in the blood, mostly of IgM. So-called macroglobulinemia of Waldenström is therefore not itself an etity, but instead a clinical syndrome. It has been shown that so-called reticulosarcoma is derived from immunoblasts, not from reticulum cells or histiocytes. The group of reticuloses also needs reconsideration. The term "reticulosis" is cytologically incorrect in most cases. Otherwise it refers to a group of diseases which we do not yet understand.
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Several studies have suggested that forestry workers are at increased risk for certain types of cancer including soft-tissue sarcoma (STS) and non-Hodgkin's lymphoma (NHL). We now report a series of national case-control studies based on the New Zealand Cancer Registry (NZCR). These involved 19,904 male patients with cancer for the period 1980-1984 who were aged 20 years or more at the time of registration. For each cancer site, the registrations for the remaining sites formed the control group. Current or most recent occupational titles were coded. There was an increased risk for STS (OR = 3.24) in forestry workers which was confined to men under 60 years of age at registration. An elevation in risk for NHL (OR = 1.84) was due to an increase in risk for lymphosarcoma and reticulosarcoma (ICD 200) (OR = 3.18). Acute myeloid leukemia was also associated with forestry work, although the estimate of risk was imprecise (OR = 2.24). Among other cancer sites, an increase in risk of neoplasia of the upper gastro-intestinal tract (ICD 150, 151, 152) was demonstrated. Odds ratios were elevated for cancer of the esophagus (OR = 1.77), stomach (OR = 2.22), small intestine (OR = 5.22), gall-bladder (OR = 4.13) and pancreas (OR = 1.79), as well as for nasopharyngeal cancer (OR = 5.56). These increases in cancer risk were not present in sawmill workers in New Zealand during the same period. The factors responsible for the increased cancer risks in forestry workers remain unclear and require further study.
A cohort of 1971 chemical workers licensed to handle ethylene oxide was followed up retrospectively from 1940 to 1984 and the vital status of each subject was ascertained. No quantitative information on exposure was available and therefore cohort members were considered as presumably exposed to ethylene oxide. The cohort comprised 637 subjects allowed to handle only ethylene oxide and 1334 subjects who obtained a licence valid for ethylene oxide as well as other toxic gases. Potential confounding arising from the exposure to these other chemical agents was taken into consideration. Causes of death were found from death certificates and comparisons of mortality were made with the general population of the region where cohort members were resident. Seventy six deaths were reported whereas 98.8 were expected; the difference was statistically significant. The number of malignancies for any site exceeded the expected number (standardised mortality ratio (SMR) = 130; 43 observed deaths; 95% confidence interval (95% CI) 94-175) and approached statistical significance. For all considered cancer sites the SMRs were higher than 100 but the excess was only significant (p < 0.05, two sided test) for lymphosarcoma and reticulosarcoma (International Classification of Diseases--9th revision (ICD-9) = 200; SMR = 682; four observed deaths; 95% CI 186-1745). The excess of cases for all cancers of haematopoietic tissue (ICD-9 = 200-208) also approached statistical significance (SMR = 250; six observed deaths; 95% CI 91-544). Focusing the analysis on the subcohort of the ethylene oxide only licensed workers, who are likely to have experienced a more severe exposure to this gas, it became evident that all but one of the observed cases of haematopoietic tissue cancers in the cohort were confined to this subgroup, enhancing the relevant SMR to 700 (95% CI 237-1637) and the SMR of lymphosarcoma and reticulosarcoma to 1693 (95% CI 349-4953).
Macrophage chemotactic activity was studied as a marker of the anti-inflammatory effect accompanying tumour growth. An inhibiting effect of the tumour on the macrophage mobility was observed by comparing the macrophages collected from normal rats and those from animals bearing the IRE reticulosarcoma. To explain these results, it is postulated that a MIF, or a similar inhibiting factor is released by the tumour. Both the the nature and function of such a factor(s) remain to be clarified.
Three patients who had idiopathic steatorrhoea associated with reticulosarcoma of either the jejunum or the ileum are described. Previously reported cases with these features are reviewed and the suggestion is made that the reticulosis may arise as a complication of idiopathic steatorrhoea.
Previously, we reported that a novel styryl diphenylamine derivative, RX-465, reverts the transformed phenotype of human fibrosarcoma HT1080 cells in vitro. To determine whether agents inducing such phenotypic reversion show antitumor and/or antimetastatic effects in vivo, we assessed tumor growth and metastasis in mice inoculated with either murine B16-, B16BL6 melanoma or M5076 reticulosarcoma. These mice received orally our new derivatives of RX-465, namely RX-512 and RX-549. We found that these-derivatives inhibited B16 melanoma and M5076 reticulosarcoma growth by greater than 80% in vivo. RX-512 also inhibited the metastatic dissemination of B16BL6 melanoma into the lung and that of M5076 reticulosarcoma into the liver by 98% and 100% at doses of 60 and 40 mg/kg/day, respectively. These treatments did not cause significant decreases in body weight. Our data strongly demonstrate that styryl diphenylamine derivatives that revert transformed phenotype in vitro potentially inhibit tumor growth and metastasis in mice with negligible toxicity at effective doses.
The toxicity and anti-tumor activity of a lipophilic diaminocyclohexane (DACH) platinum complex entrapped in liposomes (liposomal-cis-bis-neodecanoato-trans-R, R-1, 2-DACH platinum II-L-NDDP) were compared with those of the liposomal preparation of the same compound without the DACH group (liposomal-cis-bis-neodecanoato-(diammine) platinum II-L-CNDP). Both liposomal preparations had the same liposome size distribution, drug entrapment efficiency (greater than 95%), and liposome stability (greater than 95%). Although no differences were observed in the mouse LD50 (60.2 mg/kg for L-NDDP vs 67.8 mg/kg for L-CNDP), the liposome entrapped non-DACH compound (L-CNDP) was more nephrotoxic than the liposome entrapped DACH compound (L-NDDP), but much less than cisplatin (CDDP) (mean BUN elevation 4 days after the administration of the LD50 dose 67 mg% for L-CNDP vs 30 mg% for L-NDDP vs 255 mg% for CDDP). L-NDDP was not cross-resistant with CDDP against L1210/CDDP leukemia while L-CNDP was cross-resistant (%T/C 200 for L-NDDP, 112 for CDDP, and 100 for L-CNDP). In addition, L-NDDP was slightly more active than L-CNDP against i.p. L1210/0 leukemia and i.v. M5076 reticulosarcoma. These studies suggest that the attachment of a cyclohexane group to the amino functions of lipophilic platinum complexes results in a decrease of the nephrotoxicity and a lack of cross-resistance with CDDP. The lack of cross-resistance is preserved when the compounds are entrapped and delivered in a liposomal carrier but not when they are delivered in a micellar suspension.
The role of lymphatic obstruction in the formation of ascites in reticulosarcoma type A bearing mice was studied. The egress of 51Cr-labeled red blood cells (injected i.p.) from the peritoneal cavity into the peripheral blood was significantly impaired. Discovery of tumor cells in the lymphatics and on the surface of the diaphragm suggested that lymphatic obstruction by tumor cells was probably one of the factors which took, part in the formation of ascites.
New methods helpful in the classification of lymphoid and monocytoid leukaemias and haematosarcomas have recently become available. Among the most valuable procedures have been those detecting immunological markers and the ultrastructural analysis permitted by convention and scanning electron microscopy. The results of these studies, taken together with a meticulous morphologic examination on Giemsa smears allow a more subtle classification on these neoplasias. Among the most interesting points, one can list: a) The description of macroglobulinemic proplasmocytic leukaemia; b) The observation that all the prognostic parameters in the four types of common acute lymphoid leukaemia (ALL) (prolymphocytic, microlymphocytic, macrolymphocytic, prolymphoblastic) such as age, tumour mass (or leucocytosis are related to the cytological type); T marker may be found in all these types, except for the prolymphoblastic one; c) T or B immunoblastic acute lymphoid leukaemias have been described as a fifth type of ALL; d) The lymphosarcomas which can be histologically nodular (composed of B cells) or diffuse (composed of cells presenting B, T or no markers) can be cytologically prolymphocytic or lymphoblastic (or lymphoblastoid) if they are nodular, prolymphocytic, lymphoblastic, or immunoblastic if they are diffuse; true (African) Burkitt's lymphosarcomas (BLS) must be distinguished from all the pseudo (non-African) Burkitt's lymphosarcomas which have been described elsewhere and which are either immunoblastic or lymphoblastic (oid) lymphosarcomas with a few macrophages; e) The diagnosis of reticulosarcoma which was in the past abusively carried out (because of confusion with immunoblastic lymphosarcoma) is based on the presence of many reticluins fibers at histological examination and on the cytological aspect of the cells on smears (the distinction of those cells with immunoblasts is easy).
In a collection of 11 cases, the benign lymphoepithelial lesion presented clinically in every case as a tumour of a salivary gland. In eight cases the parotid was affected, in two a palatal salivary gland, and in one the submandibular gland was affected. Microscopically the lesion consisted of a mixture of lymphoid and epithelial components and, although the appearances in several cases suggested lymphosarcoma or reticulosarcoma, the arrangement of the epithelial component in characteristic islands (epi-myoepithelial islands) indicated the benign nature of the lesion. In one case incomplete excision of a lesion of the palate was followed by a recurrence that was cured by a radium mould. The microscopical appearances of the benign lymphoepithelial lesion were identical with those of the salivary lesions of Sjögren's syndrome but in all the cases the lesion was an isolated one and the sicca syndrome was absent.
The response of murine lymphoreticular tissues to transplantation of a syngenic reticulosarcoma with mild transplantation antigenicity was studied by recording weight changes and histology. The results were compared with those obtained in normal mice and mice challenged with syngenic spleen cells. The tumor induced vigorous histological response in regional lymph nodes and mild response in nonregional lymph nodes and spleen. Mesenteric lymph nodes and thymus did not respond to the tumor. Observed morphological and gravimetrical changes indicated that both regional and nonregional lymph nodes and spleen take part in host immune response to tumor. A possible contamination of tumor tissue by viruses has been excluded.
We evaluated the entrapment of 21 different water-insoluble aglycones or anthracycline antibiotics in multilamellar liposomes composed of dimyristoyl phosphatidyl choline and dimyristoyl phosphatidyl glycerol at a 7:3 molar ratio. The drug:lipid weight ratio was 1:15 to 1:50. The different analogues tested were modified at position 4 in the aglycone portion (4-demethoxy) and/or positions 2' (halo), 3' (hydroxy, acetoxy), or 4' (epi, acetoxy) in the sugar portion. The entrapment efficiency was assessed by measuring the amount of free drug remaining in the supernatant after centrifugation of the liposomes and by direct examination of the pellets by fluorescent microscopy. Optimal entrapment (greater than 98%) was observed with only four compounds: 4-demethoxyadriamycinone; 2'-iododaunorubicin; 4-demethoxydaunorubicin; and 2'-iodo-3'-hydroxy-4'-epi-4-demethoxydoxorubicin (Compound 22). All other compounds showed significant drug precipitation outside the multilamellar vesicles when observed by fluorescent microscopy. Compound 22, entrapped in liposomes, was evaluated in vivo against i.p. L-1210 leukemia by the i.p. route, and liver metastases of M5076 reticulosarcoma by the i.v. route. In both models, liposome-entrapped Compound 22 was more active than doxorubicin at the optimal dose [median survival (given in percentage) of treated to control animals was for L-1210, greater than 600 versus 212; for M5076, 200 versus 133]. 4-Demethoxy and 2'-iodo are structural modifications that markedly enhance the affinity of anthracycline antibiotics for lipid bilayers without compromising biological activity. These findings will serve as a guideline to obtain liposome-anthracycline preparations, with optimal formulation characteristics, enhanced tumor-targeting properties, and non-cross-resistance with doxorubicin.
The authors relate 15 cases of bone tumors located on the ribs. In 5 cases the tumors were benign, 10 were malignant with 6 reticulosarcoma and 2 chondrosarcoma. This histologic type very rare in childhood has been confirmed after reexamination of the slides. Uncommon but not exceptional ribs tumors are characterized by few clinics signs 4 cases having been detected by systematic radiography whereas 2 correspond to malignant tumors. Biologics signs to, can be totally missing. Radiological analysis is misleading and rib origin of the tumor is sometime very difficult to state, usual sign of malignancy being often missing in spite of advanced lesions. Treatment, easy in benign lesion by sub or extraperiosteal bone resection, is difficult in malignant one demanding large resection of chest wall requiring delicat parietal reconstruction.
The antitumor efficacy of the conjugate of doxorubicin (DXR) and carboxymethylpullulan (CMPul) with Phe-Gly spacer (CMPul-FG-DXR) was evaluated using murine tumor models and compared with that of DXR. The conjugate exhibited higher antitumor efficacy against Lewis lung carcinoma than DXR. Complete tumor regression followed by long-term tumor-free survival was frequently observed when CMPul-FG-DXR was administered i.v. three times at a dose equivalent to 10 mg / kg of DXR. The superior survival as well as anti-metastatic effect of CMPul-FG-DXR in comparison with DXR was also demonstrated with the M5076 murine reticulosarcoma model. Body weight loss in mice treated with the conjugate was less than that in the DXR-treated group, indicating lower systemic toxicity of CMPul-FG-DXR. Simply mixing CMPul with DXR did not enhance the antitumor activity of DXR, showing that the conjugation of DXR with CMPul is necessary for improved antitumor activity. However, no enhanced antitumor efficacy of the conjugates was observed against a non-solid tumor model such as P388 leukemia. In summary, improved antitumor efficacy with reduced systemic toxicity of CMPul-FG-DXR was demonstrated in the present study. CMPul-FG-DXR may be useful as a cancer chemotherapy agent against solid tumors and metastases.
Primary growth of AMC 60 fibrosarcoma inoculated into the hind leg of ACI/N rats resulted in occasional generation of concomitant resistance to growth of a second graft of the same tumor cells in the peritoneal or pleural cavity. Using this syngeneic tumor-host system, experiments were carried out to elucidate the effect of intratumoral injections of an immunomodulator, Nocardia rubra cell wall skeleton (N-CWS), on concomitant immunity. Rats bearing a solid tumor into which N-CWS was repeatedly injected showed a significant inhibitory effect on the proliferation of the tumor cells inoculated secondarily into the peritoneal cavity, i.e., concomitant immunity, as compared to control groups of normal, N-CWS-treated and solid tumor-bearing rats. Peritoneal macrophages, when harvested after i.p. tumor inoculation into the N-CWS treated solid tumor-bearing rats, were found to be significantly potentiated for tumoricidal activity against [5-125I]iodo-2'-deoxyuridine-labeled AMC tumor cells. These potentiated macrophages were induced tumor specifically by i.p. inoculation of AMC tumor cells but not by unrelated syngeneic reticulosarcoma SL 1 tumor cells; nevertheless their tumoricidal activity was observed tumor nonspecifically for the SL 1 tumor cells. Additional experiments revealed that nonadherent peritoneal cells were only weakly tumoricidal and that the macrophage tumoricidal activity was completely abolished in the presence of carrageenan. Thus in the model presented here, it is possible to conclude that the augmentation of concomitant immunity by injection of N-CWS into a primary solid tumor is mainly due to potentiation of the tumoricidal activity of tumor-associated macrophages in the peritoneal cavity. Although the underlying mechanism by which concomitant resistance can be augmented by intratumoral injection of N-CWS remains undetermined, the existence of a tumor-specific trigger for induction of potentiated tumoricidal macrophages may indicate that N-CWS when injected repeatedly into the tumor tissue plays an important role in augmenting a pre-existing, weak, tumor-specific cell-mediated immune response leading to activation of macrophages.