Tumori Journal

Twenty-four incidental cases of mesothelioma, diagnosed in the province of Padova during the period 1965–1976, were analyzed according to age characteristics. The results show that the incidence rate increases in the general population under study at the same rate as in other populations occupationally and non-occupationally exposed to carcinogenic fibers according to the time since first exposure. This finding suggests a similar neoplastic process independent of age, in different environmental situations.

Metronidazole, which is widely used in the treatment of «Trichomonas vaginalis», «Entamoeba histolytica» and «Giardia lamblia» infections, was administered to BALB/c mice by stomach tube in an aqueous solution at a dose rate of 2 mg/day for 100 days (total 200 mg) to test its carcinogenicity. The treatment induced a significant increase in lung tumors in male mice (p < 0.001) and provoked the appearance of lymphomas in females (p < 0.001). Although there is insufficient evidence to pass judgement on the potential carcinogenicity of metronidazole in man, the results of this and other investigations reported in the literature have demonstrated that metronidazole develops carcinogenic activity in rats and mice.

Continuous administration of 500 ppm hexachlorocyclohexane (HCH) in the diet induced 100 % liver tumors in mice, but none were observed in rats and hamsters treated with the same dose of HCH. In Swiss male mice, tumor incidence at earlier ages was greater than that observed in corresponding age groups of Swiss female mice. It was further observed that in Swiss females, sex hormones retarded the tumorigenic effect of HCH; in BALB/c mice a similar phenomenon was not observed.

The urethan-induced clastogenic effect in BALB/Mo mice carrying the Moloney murine leukemia virus (M-MuLV) as an endogenous retrovirus was evaluated by short-term micronucleus assay on bone marrow polychromatic erythrocytes (PCE). A single urethan injection in 3 dose levels brought the incidence of micronucleated PCE far above baseline values when scoring was performed 24 h after treatment; this increase was higher in BALB/Mo than in M-MuLV-free BALB/c mice. In a second experiment, micronucleated PCE incidence was determined as a function of the time interval after a single injection of 1 mg urethan/g of body weight. Higher values of micronucleated PCE were scored in BALB/Mo than in BALB/c mice; statistically significant differences were found at 24 and 48 h after treatment.

The level of cAMP was investigated in the following three types of hamster malignant melanomas: amelanotic, depigmented and melanotic. The amelanotic and depigmented tumors were undifferentiated, with high proliferative activity, and lacked tyrosinase. The melanotic one was slow growing, highly differentiated, and expressed tyrosinase activity. Among the melanomas investigated, the higher concentration of cAMP was found in undifferentiated tumors. The single treatment of the tumor-bearing animals with theophyllin or isoproterenol did not change the cAMP level in melanotic tumors, but significantly enhanced the cAMP content in amelanotic and especially depigmented melanomas. Multiple theophyllin treatment of tumor-bearing animals caused elevation of cAMP content in all tumors, but this effect was accompanied by enhancement of tyrosinase activity only in melanotic melanoma.

Differential pulse Polarographic assay of the antineoplastic agent cis-dichlorodiamineplatinum II and its analogues was performed after acid oxidative hydrolysis (HCIO₄, HNO₃, HCI) of biological samples (plasma, tissue homogenates, urine) and reaction with ethylenediamine. Platinum levels and kinetics were determined in blood and urine of patients with non-oat-cell lung carcinoma. Detection limit of the polarographic assay was 0.5 ng platinum; analytical error was ± 3%. Levels of free cis-dichlorodiamineplatinum (II) in plasma fell in samples stored at –20 °C; the half-life of free drug was 38 h.

The resistance of normal BALB/c mice (H-2^d) against the L1210 Ha leukemia of DBA/2 mouse (H-2^d) origin is due to the T-lymphocyte-dependent reaction towards DBA/2 multiple minor histocompatibility antigens (Mhas). These Mhas are displayed by the leukemic cells, though in a poorly immunogenic manner. The simultaneous presence of mitomycin C-inactivated DBA/2 leukocytes induces a significantly stronger T-lymphocyte-dependent reaction. This efficient presentation of target Mhas is restricted to Ia⁺ leukocytes. Their presence significantly increases BALB/c resistance, even when they are injected 3 days after the L1210 Ha challenge.

A study of some aspects of granulocyte function was carried out before, during, and after cyclic chemotherapy in 9 patients surgically treated for carcinoma and in 6 patients with very advanced and inoperable cancer. In most patients, total leukocyte mobilization, Candida-stimulated nitroblue tetrazolium dye reduction, and phagocytosis increased after chemotherapy. Furthermore, delayed hypersensitivity skin reactions to PPD and above all to Varidase increased in the same cases. A significant correlation between accumulation of polymorphonuclear leukocytes into skin chambers and skin tests was found in both groups of patients (p < 0.001). In some instances, fluctuations in the levels of circulating immune complexes without a distinct correlation between these complexes and granulocyte function were found. The data support the hypothesis that depressed granulocyte function may contribute to an increased susceptibility to infections and may be considered an additional factor that favors tumor dissemination. Chemotherapy seems to restore polymorphonuclear function and delayed hypersensitivity skin reactions.

Seventy-nine cases of parotid masses were punctured by fine needle for cytologic examination and subsequently operated on. Of the material obtained, conventional smears, as well as formalin-fixed, paraffin-embedded histologic sections were prepared. The two procedures detected 16 malignant tumors and 63 nonmalignant lesions, with a high sensitivity (86%) and absolute specificity (100%). These data confirm the validity of this combined method and favor the complementary use of the two procedures, which improves the accuracy (80%) of preoperative diagnosis and histologic typing of parotid tumors.

The authors report the results obtained from the application of electron microscopy techniques to the cytology of fine-needle-aspirated samples of neoplastic lesions from various body sites. These results show that the tissue structure, which is usually lost during the squashing necessary for light microscopy cytology, is preserved when the samples are processed for ultrastructural analysis. Electron microscopy also allows a highly detailed study of the cell's inner structures. Thus, when this technique is applied, fine needle-aspirated samples can be regarded as actual microbiopsies. However, because of the high cost of ultrastructural techniques, we suggest that actual analysis be performed only in selected cases, whereas fixation and inclusion for electron microscopy could be done routinely.

The classification of bronchogenic carcinoma as a function of the prognosis is still an open field. The evaluation of stage, by use of the TNM system, and histologic cell type is not sufficient to guarantee a correct prognosis. The growth rate of the neoplasm is another important parameter. We propose a classification that takes into account the stage (S), histologic cell type (M), immune status (I) and the growth rate of the primary tumor (G): S.M.I.G. We studied 90 lung cancer patients according to the S.M.I.G. classification and we observed that their prognoses were directly correlated with their S.M.I.G. scores (the higher the score, the higher the 10-month mortality rate). The mortality rates within the first 10 months of follow-up were respectively 0%, 0%, 36.36%, 68%, 90.9% for the 5 groups obtained by S.M.I.G. The difference is statistically significant (P < 0.0075) and there is a linear correlation between the mortality rate and the score assigned to each group (R = 0.943; P < 0.05). The S.M.I.G. classification can predict the prognosis more efficiently than the usual classification (TNM) and histological cell type.

From 1965 to 1981, 43 cases of metastatic tumors were examined without localizing the initial primary site. All the cases were subjected to intensive studies to detect the primary, and most cases received multidisciplinary treatment. In 19 cases it was not possible to discover the primary tumor, and 6 of them are alive 2 to 9 years after the diagnosis. In 24 cases the primary tumor was subsequently located, but 23 of them died 1 to 5 years after diagnosis of the primary. One case is alive after 9 years. The actual point of view vis-a-vis this pathology and the rationale and active plan to obtain worthwhile results are discussed.

1164 patients with stage I melanoma of the skin who were submitted to wide excision only of the primary tumor were studied to evaluate the rates of regional lymph node and distant metastases. Of these, 516 (44.3%) had a recurrence of the disease which was at regional lymph nodes in 264 (22.7%), at distant sites in 91 (7.8%), and simultaneously at regional lymph nodes and distant sites in 161 (13.8%). Most of the patients had a relapse within 5 years: regional node metastases were most frequently observed during the first 3 years, and distant metastases appeared later. The ratio regional:distant metastases was not different (P > 0.05) when subgroups of patients were considered according to prognostic criteria (sex, site of origin, levels, thickness, ulceration). Sex, levels, thickness and ulceration were found to be significantly related with the frequency of recurrences (regional and distant). It is concluded that the prognostic criteria considered do not predict whether the tumor will metastasize to regional nodes or to distant sites.

Eighty-four consecutive, previously untreated patients with stage I, II A-B and IIIA Hodgkin's disease were treated with combined modality therapy including subtotal or total nodal irradiation, followed by three cycles of MOPP. MOPP was administered before radiotherapy in patients with systemic symptoms or with bulky disease. Seventy-six of 84 patients (90.5%) achieved complete remission, and 8 died from disease progression after a variable period of incomplete remission. Three of 76 (3.9%) relapsed, and 2 of them have been subsequently salvaged. Up to the present time, 70 patients are alive, without evidence of disease; 9 have died from Hodgkin's disease, 2 from acute non-lymphoblastic leukemia, and 3 from inter-current causes. No death occurred from acute toxicity due to chemotherapy. Actuarial overall survival is 82.3% and freedom from relapse is 81.8% after 48 months’ median observation (range: 12–111 months). No significant difference in survival and freedom from relapse has been observed with respect to age, sex, stage, presence or absence of unfavorable prognostic factors. The role of adjuvant chemotherapy and its use in a reduced number of cycles in early stage Hodgkin's disease are discussed.

Forty-nine patients with previously untreated advanced Hodgkin's disease were treated in our Institution between 1973 and 1981. Treatment modalities of these patients were reviewed, and they were divided into 3 groups according to the treatment employed: 13 patients received MOPP only, 22 patients received MOPP plus involved field radiotherapy, and 14 received alternating MOPP/ABVD chemotherapy. The response rates for the 3 groups were respectively 38.5%, 63.6% and 78.6%. A longer follow-up is needed to assess a significant difference in survival curves. The advantages of adjuvant radiotherapy and alternating non-cross-resistant drugs in advanced Hodgkin's disease are discussed.

Fourteen patients with Hodgkin's disease resistant to ABVD were treated with MOPP chemotherapy (nitrogen mustard, vincristine, procarbazine, prednisone). Complete remission was obtained in 6 patients (43%). Four of the 6 complete responders are disease free after 5, 20, 23, 35 months. The actuarial median survival after MOPP of all patients is 20 months. These data confirm that there is no «cross-resistance» among the drugs included in the two schedules.

Prolonged follow-up of large series of patients treated for Hodgkin's disease with an intensive therapeutic approach has demonstrated an incidence of second tumors of around 5–10%. Acute leukemia is the most frequent second neoplasia, and treatments including alkylating agents and radiotherapy seem to be correlated with a higher risk of this fatal complication. Bone and soft tissue sarcomas have rarely been observed after treatment of Hodgkin's disease, and only a few cases are described in the literature. Four cases observed at the Istituto Nazionale Tumori of Milano in a large series of nearly 800 patients treated over the last two decades with different modalities are presented. One case of chondrosarcoma and 3 cases of soft tissue sarcomas were diagnosed after a median and mean interval of 50 and 70 months, respectively (range 49–96). Three patients had been treated with radiotherapy plus chemotherapy (MOPP, 2 cases; ABVD, 1 case), and one with radiotherapy alone. The site of the second tumor was always within an irradiated area, which had received a dose ranging from 10 to 43 Gy. Prognosis of secondary bone and soft tissue sarcomas is very poor. Three of our cases died 14, 15 and 19 months after diagnosis; only one patient is alive, 3 months after diagnosis of a chondrosarcoma. The problem of second tumors in patients treated for Hodgkin's disease requires a careful evaluation of aggressive treatment modalities to minimize the risks of this severe complication.

A series of 743 consecutive cases of operable breast cancer, admitted and treated at the Istituto Nazionale Tumori of Milan from 1969 to 1970, was analized by a multivariate statistical method to evaluate a) the variables of the host and the primary tumor associated with the frequency of nodal metastases, b) the variables that significantly affect survival, and c) the identification of homogeneous risk groups. As regards the frequency of regional node metastases, they were more frequently observed in young than in old patients with large tumors (P values 10^–5 and 3×10^–5, respectively). Tumors that originated in the axillary tail, upper, outer and central quadrants were significantly associated with a higher rate of node metastases (P = 0.002). Each of these variables maintained its significant value when adjusted by the other two. Survival was affected at a statistically significant level by the age of the patients (P = 2×10^–4), the pathologic diameter of the primary tumor (P < 10^–6), and the number of metastatic regional nodes (P < 10 ^–6). The number of involved nodes appears to be the most relevant factor in the assessment of prognosis of patients with positive nodes, Age of the patients, size of the primary tumor, and number of involved nodes maintain their own statistical significance when each is adjusted by the remaining two. The site of origin of the primary tumor, even if associated with the frequency of regional node metastases, did not affect survival. Three groups with a significantly different risk of death were identified in patients with negative lymph nodes and three groups in patients with positive nodes. It is concluded that age, size of the primary, and number of involved lymph nodes are important pieces of information that clinicians should have at hand following radical surgery, not only to make a prognosis, but also to identify groups of patients with high risk of death on which the role of adjuvant treatment should be evaluated.

Twenty consecutive patients who had biopsy proven metastatic colorectal cancer were treated with combination chemotherapy. The drug regimen (FVH), in a 4 week cycle, consisted of 5-fluorouracil (600 mg/m² i.v. on days 1, 8, 15 and 22), vincristine (1.4 mg/m² i.v. on day 4), and hydroxyurea (2400 mg/m² p.o. on days 3, 10, 17 and 24). Three of the 18 evaluable patients achieved an objective tumor remission (2 CR and 1 PR) and 15 patients had stable disease. The overall response rate to FVH was therefore not superior to that achieved in patients who received 5-fluorouracil alone, and the overall survival in this study was comparable to that of other studies involving patients with metastatic colorectal cancer.