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From November 1st 1977 to August 31st 1978, 842 consecutive patients with operable breast cancer were observed at the National Cancer Institute of Milan. Characteristics of the primary tumor and the status of regional lymph nodes were evaluated at clinical and postsurgical examination: it was found that qualitative characteristics of the primary were properly defined by clinicians, who usually overestimated maximum diameter of the primary. The status of regional lymph nodes is not reliable at clinical examination: 34.5% of clinically uninvolved nodes were found to contain metastatic growth at histologic examination. Age of patients, maximum diameter of the primary, histologic type and quadrant of origin of the primary tumor were significantly related to the frequency of regional node metastases. Multifactorial analysis showed that the last three factors were independent variables, while age, which is significant by itself, loses importance when adjusted by at least one of the other three factors. Frequently of extension of node metastases beyond the lymph node capsule was found to be related to the number of involved nodes: maximum diameter, histologic type and site of origin are significantly related to the frequency of extracapsular invasion. This study confirms that the evaluation of the status of regional lymph nodes is not reliable at clinical examination and indicates that characteristics of the primary may be useful in predicting regional lymph node involvement. The direct correlation between the number of involved nodes and the frequency of infiltration beyond the capsule suggests that prognosis of patients with positive nodes depends more on this factor than on the number of involved nodes.

The results obtained with isolation perfusions in stage IIIA-IIIAB melanoma patients, performed at 42.5-43 degrees C for 2.5 h, are reported. These temperatures and perfusion times were chosen on the basis of experimental data in animal models and in vitro. The clinical results were impressive, but the high percentage of complications and the high cost from a social and human point of view make this experience negative with regard to its clinical applicability, at least with such a high temperature and long perfusion time.

The authors studied the prognosis of patients with so called local recurrences, satellites and in-transit metastases from cutaneous melanoma on the basis of 291 patients. These are the 19.3% of the 1503 patients with stage I and II melanoma originally submitted to surgical treatment at the National Cancer Institute of Milano (Italy). The majority of patients were males (M/F = 0.7): 102 had local recurrence, 99 in-transit metastases, 24 satellites and 66 both local and in-transit metastases. Regional non-nodal metastases were not related with the site of origin, and inadequate treatment of primary. These metastases were more frequently observed in patients who were submitted to regional node dissection no matter whether in discontinuity or in continuity with primary tumor. The frequency of regional non-nodal metastases was found to increase with increasing thickness of primary melanoma or, in stage II patients, with the number of involved nodes. Local and in-transit metastases were related with prognostic criteria in the same way. The overall survival was very close between in-transit and local metastases. Similar survival rates were observed comparing regional non-nodes and disseminated cutaneous and subcutaneous metastases. The authors conclude that the distinction between local recurrences, satellites and in-transit metastases is artificial and that these metastatic events are not prognostically dissimilar from metastases in distant skin areas.

Two patients with extensive squamous cell carcinoma of the lower extremities, candidate for demolitive surgery, were treated by hyperthermic antiblastic perfusion in extracorporeal circulation. The temperature reached was 41 degrees C and the drug used was methotrexate at the dosage of 500 mg. Radical excision of the ulcer was possible in the 2 patients. Both tumors underwent extensive necrosis, and histology done 1 month after perfusion on surgical specimens showed limited areas of residual malignancy. These 2 patients suggest that hyperthermic antiblastic perfusion may be a limb salvage procedure in the multimodal management of extended squamous cell carcinoma of the extremities.

American eels, Anguilla rostrata, were exposed to crude oil by ingestion of a 10, 100, or 500 microliters/kg fish dose per day for five days. Depuration was followed for an additional twelve days. All oil doses caused an induction of hepatic microsomal enzymes, maximally by three days of exposure. Benzo(a)pyrene hydroxylase (BaPH) showed a dose related response, with greater induction at 100 microliters/kg than at the other doses. The highest dose was hepatotoxic. Cytochrome P-450 induction was dose independent, and remained induced maximally for the entire experimental period, in contrast to BaPH which declined in activity. Reaction optimum for BaPH was at pH 7.5 and 27 degrees C. A study of tissue distribution showed the liver to account for nearly all BaPH activity. A significant increase in the protein content of the hepatic postmitochondrial fraction of oil-exposed fish was also observed.

Twelve patients with disseminated breast cancer were injected with monoclonal antibody MBr1 at the National Cancer Institute of Milan, Italy, from January 1983 to March 1985. The first seven patients had advanced disease and the remaining five operable breast cancer. In the first seven patients the initial dosage of MBr1 was 0.5 mg and was doubled in the next patient up to 16 mg. The last five women received 10 mg of MBr1. No general side effects such as bronchospasm, hypotension, immediate or delayed allergic reactions were observed. Four patients who were injected with 10 mg or more experienced fever, shudder and vague abdominal and articular pain. The following tests were monitored: R.B.C., W.B.C., percentage of lymphocytes, blood glucose, urea nitrogen and creatinine, serum levels of Na+, K+, Cl-, total proteins levels, albumins and globulins, bilirubin, GOT, GPT, alkaline phosphatase, LDH, amylase, gamma GT and CPK. No major modifications were observed: a limited increase of the transaminases, LDH and gamma GT was evident at the last check. An early temporary alteration of CPK was observed in the four patients who had symptoms. Serum levels of MBr1 are detectable immediately after injection starting from 4 mg, and all sera were negative 48 hours later. It is concluded that the scanty toxicity allows to continue clinical investigations to verify the linkage between MBr1 and Ca-MBr1 "in vivo" after a single injection of no more than 16 mg of the MoAb. The increase of this dosage as well as multiple injections do not seem safe at present.

Lp[a] is a lipoprotein whose plasma concentration is highly correlated with cardiovascular disease. Its protein moiety, apoLp[a], consists of two large polypeptides, apo[a] and apo B. The possible contribution of Lp[a] to atherosclerosis in saphenous vein aortocoronary bypass grafts was studied in a population of patients undergoing coronary re-bypass surgery. The vein graft tissue levels of apoLp[a] were compared with graft duration, gross and light microscopic pathology, as well as plasma levels of apoLp[a]. The localization pattern of apo[a] and apo B in vein graft tissue was determined. In addition, the plasma levels of cholesterol, triglycerides, apoproteins (apo) A-I, A-II, and E were measured. In a representative subpopulation of 17 patients with a mean age of 63 years from whom grafts with a mean duration of 112 months were resected, the mean total plasma cholesterol level was 221 mg/dl, the mean high density lipoprotein cholesterol level was 31 mg/dl, and the mean plasma triglyceride level was 228 mg/dl. In normal saphenous veins, the level of apoLp[a] was below measurable limits (less than 2 ng/mg), and the level of apo B was very low (3.3 ng/mg). In resected grafts, the mean tissue level of apoLp[a] was 32 ng/mg, and that of apo B was 70 ng/mg, demonstrating the net accumulation of these apoproteins in veins from the time of their grafting into the arterial bed. The apoLp[a]/apo B ratio was determined in 77 tissue segments from 59 grafts (28 patients) and was found to be 0.313. This tissue ratio was significantly higher (p = 0.02) than the plasma apoLp[a]/apo B ratio from these patients, which was 0.132. Immunostaining showed co-localization of apo[a] and apo B in the neointima of grafts. The most abundant pathologic features observed in resected grafts were proliferated intima (43/52), thrombus (28/52), and atherosclerotic core regions (21/52). The level of tissue apo B correlated well with the abundance of core regions (r = 0.501), whereas the level of tissue apoLp[a] did not correlate as well with this feature (r = 0.233). Although apo[a] and apo B are almost absent from normal saphenous vein, these apoproteins (and presumably the lipoproteins Lp[a] and low density lipoprotein) accumulate in bypass vein grafts. The data support the view that these lipoproteins play a significant role in vein graft atherosclerosis.

Scanning electron microscopy has shown a typical cell surface morphology in hairy cell leukemia. Scanning immunoelectron microscope techniques, utilizing monoclonal antibodies and colloidal gold particles, have recently become available. Eight patients with hairy cell leukemia have been studied with a panel of monoclonal antibodies of which B1, BA1, OKM1, anti-TAC and LeuM5 were shown to be suitable for scanning immunoelectron microscopy and reactive with hairy cells. The combination of typical cell surface features with reactivity for the B1 and LeuM5 monoclonal antibodies permits accurate diagnosis of hairy cell leukemia, particularly when low percentages of hairy cells are present as in hypocellular or in interferon-treated patients.

The phagocytosis (in the absence of serum factors) of zymosan particles by peripheral leukocytes isolated from ten patients with acute leukemia (AMbL, AMoL, AMML, AUL, ALL and CML-BC) was studied at the electron microscope. An evident phagocytic activity was observed only in the cells in which cytochemical and ultrastructural features suggested that the blast elements belonged to the monocytic series. However, no phagocytosis by unclassifiable leukemic blasts was observed, even though they had some submicroscopic characteristics of the monocytic series. These findings suggest that phagocytic capacity develops during the course of cell differentiation, becoming striking only when the blast cell acquires the ultrastructural features of the pro-monocytic stage. Using the myeloperoxidase reaction, this study also demonstrates a morphological alteration in the degranulation process after the ingestion of zymosan particles in both the blasts and the mature PMN cells of leukemic patients. This defect could be related to the susceptibility to severe infections usually found in subjects with hematological malignancies.

From February 1982 to December 1983, 42 patients affected by neoplasms of the limbs were treated at the Istituto Nazionale Tumori of Milan by hyperthermic antiblastic perfusion in extracorporeal circulation at the temperature of 40-41 degrees C for 1 h. Thirty-two were affected by melanoma, 4 by osteogenic sarcoma, 2 by squamous-cell carcinoma, 1 by liposarcoma, 1 by hemangiopericytoma, 1 by clear-cell sarcoma and 1 by Kaposis's sarcoma. As regards the immediate response, a complete plus partial remission rate of 88% without any major complication was obtained. The follow-up period is too short for any considerations about overall survival. However, because of these good clinical results we consider this method able to locally control the evolution of neoplasms of the extremities, allowing in many cases a limb salvage.

To evaluate the effect of adjuvant chemotherapy in patients with local-regional nasopharyngeal carcinoma (NPC) (squamous or undifferentiated) in complete remission at the end of curative radiotherapy (RT) 229 patients were randomized from 1979 to 1983 in a multicenter study to no further therapy (116 patients) or a combination of vincristine, cyclophosphamide, and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) (VCA) for six monthly cycles (113 patients). The RT and RT + VCA groups were well balanced for median age (50 v 49 years), histology (undifferentiated carcinoma, 73% v 70%), tumor extent (tumor limited to nasopharynx, 57% v 57%), and nodal extent (negative nodes 26% v 24%, nodes in the lower cervical levels, 17% v 16%). RT was delivered to the nasopharynx, the base of the skull, and bilateral cervical nodes using a split course technique over 10 weeks up to the dose of 60 to 70 Gy in involved sites and 50 Gy to negative nodes. Response to RT was evaluated within 65 days post-RT treatment. Analysis at 48 months did not show significant difference between the two treatment groups in terms of relapse-free survival (RT, 55.8%, RT + VCA, 57.7%, P = .45) and overall survival (RT, 67.3%, RT + VCA, 58.5%, P = .13). The pattern of relapse was similar in the two treatment arms. Distant metastases were the cause of treatment failure in about 50% of relapsing patients. Although the results of the present study did not show any benefit from VCA administered after curative RT, combined systemic chemotherapy should be further explored due to the high incidence of local and distant failure after intensive RT.

We have studied the effect of chronic noise stress (St) and ACTH administration (Ac) affecting blood pressure and plasma corticosterone levels in male Wistar rats. Both chronic treatments elicited an increase in plasma corticosterone and blood pressure levels. The blood pressure increased from the first week of treatment period in St and Ac rats and remained high 4 weeks after the end of the stress period. However, blood pressure elevation decrease progressively during the first three weeks of post-treatment in ACTH administrated rats. The rise of blood pressure levels was due to the effect of chronic treatment. This was demonstrated by the absence of differences between the two values of blood pressure measurement with and without daily treatment in both St and Ac groups. Increased corticosterone levels decreased rapidly during the post-treatment period in St and Ac rats. The results suggest a possible relationship between the development of hypertension and the Hypothalamus-Hypophysis-adrenal (HHA) axis stimulation in rats.

Human Lp[a] was isolated in preparative amounts from two donors; the native lipoprotein and its constituent apoproteins, apo[a] and apoB, were characterized extensively. Based on differences in apparent molecular weight, four different isoforms of apo[a], a1-a4, were observed between the two donors. The number and relative distribution of these isoforms varied between donors but were constant for each donor. Each apo[a] isoform was shown to be derived from a discrete apo[a]-B100 disulfide-linked complex present before reduction. Complete delipidation of Lp[a] was followed by solubilization, reduction, and carboxamidomethylation of the constituent apoproteins. These apoproteins were then separated by immunoaffinity chromatography using anti-apo[a]- or anti-apoB-Sepharose; their purity and structural integrity were demonstrated by Western blot analysis. ApoB isolated by this procedure was essentially identical to apoB from autologous LDL with respect to molecular weight, secondary structure, amino acid composition, and sialic acid content. However, apo[a] differed from apoB in that it exhibited: a much less alpha-helical, less beta, but much more disordered structure; a lower proportion of aspartate, isoleucine, leucine, phenylalanine, and lysine, but a higher proportion of proline, glycine, and threonine; and a much higher content of sialic acid. These results indicate that apo[a] is not a superglycosylated form of apoB but is distinctly different in its composition and structure.

Thirty-seven consecutive patients with disseminated malignant melanoma and previously untreated with chemotherapy were randomly allocated to receive vindesine, cis-platinum, and etoposide (Regimen A) or vindesine, cis-platinum, and lomustine (Regimen B). In 31 evaluable patients, Regimen A induced an overall response rate of 31% and a complete response rate of 6%; with Regimen B the corresponding findings were 20% and 20%, respectively. The median duration of complete response was 12 months with both regimens and the comparative median total survivals were 8 and 6 months, respectively. In no case was toxicity so severe to require treatment discontinuation, and the major dose-limiting side effect was myelosuppression, especially in the patients treated with Regimen B. Present results confirm once more the limited activity of drugs and regimens presently utilized in the treatment of advanced malignant melanoma.

The mechanism of the rise in plasma low density lipoprotein (LDL) levels following intravenous administration of a triglyceride-phospholipid emulsion (Intralipid) has been investigated by measuring LDL turnover in eight healthy subjects. The plasma half-life, and the absolute and fractional catabolic rates of LDL protein (apo-LDL) were unaffected by intragastric Intralipid, whereas apo-LDL half-life was prolonged and its fractional catabolic rate was decreased by intravenous Intralipid. Similar changes were observed after intravenous administration of the egg phospholipid constituent of Intralipid. Accompanying increases in the oleate: linoleate ratio of both high and low density lipoprotein cholesterol esters were secondary to phospholipid exchange between infused and endogenous lecithin. These results suggest that the increased concentration of LDL in plasma following intravenous administration of egg phospholipid-containing emulsions was due, at least in part, to a decrease in the fractional catabolic rate of apo-LDL. The data further suggest a possible relationship between apo-LDL catabolism and the fatty acid composition of LDL.

The Backscattered Electron Imaging (BEI) mode of Scanning Electron Microscopy (SEM) has been applied to the study of cells stained with various heavy metals in cytochemical reactions. Improvements or modifications of some of these methods and their application to the study of normal and leukemic leukocytes have been evaluated in this report. The results obtained after staining peroxidase-positive granules with osmium, copper, cobalt-nickel and gold-cobalt are compared. Granules containing non-specific esterase activity were demonstrated in the BEI mode after incubation of the cells in Hanker medium and staining with osmium. While sites of acid phosphatase activity were easily localized with a conventional lead method, alkaline phosphatase activity was demonstrated only in the phagocytic vacuoles of cells previously incubated with latex particles and subsequently stained with lead. Cell nuclei were identified in the BEI mode after silver methenamine or bismuth staining. Combining their cell surface and cytochemical characteristics a more accurate identification of the different blood cell types with the SEM becomes possible.

The aim of the study was to investigate the centralized impulsive dynamics of 21 obese women in comparison with 21 normal ones, with particular reference to the unconscious bodily experiences and sexuality. Two tests comparing areas of unconscious experience and body organs and classes of feelings, and emotional self-assessment questionnaire and a colour choice test, were given. The statistical analysis of the results showed significant differences between the two groups studied, the obese women being immature, dependent, hypersensitive and introverted with great oral requirements and low autonomous control and with some confusion between food and affection. Their sexuality is pervaded with great aggressiveness and has little connection with its maternal and relational function. Finally, some psychotherapeutic strategies are mentioned.

The kinetics of oxidation of horse cytochrome c and the trifluoromethylphenylcarbamylated lysine-13 derivative by cytochrome c oxidase (ferrocytochrome c: oxygen oxidoreductase, EC 1.9.3.1) were compared using both spectrophotometric and polarographic methods under different experimental conditions. The rate constants measured spectrophotometrically in 0.025 M tris-cacodylate buffers were similar with the two cytochrome at pH 7.8, but those with the derivative were slightly higher at pH 6. Rates measured with polarographic assays in these buffers were the same with the horse and the derivative cytochromes c at pH 6, but at pH 7.8 the rates with the derivative were less at cytochrome c concentrations between 0.05 and 0.5 micro M and were greater at higher concentrations. The pH optima in the polarographic assays of the derivative and the native pigments were different in 0.025 M Tris-cacodylate buffers; in spectrophotometric assays at pH 7.8 the trifluoromethylphenylcarbamylated lysine-13 cytochrome c showed a greater sensitivity to changes in ionic strength than did the native cytochrome. The variations in apparent Km and V values calculated from spectrophotometric and polarographic assays with the two cytochromes cannot be explained as due to changes in binding of cytochrome c to cytochrome oxidase. The large excess of O2 uptake seen in polarographic assays with horse cytochrome c over that expected from spectrophotometric measurements was not apparent with the trifluoromethylphenylcarbamylated lysine-13 derivative. Thus, the derivative seems to have decreased ability to form the combination of cytochrome c with the oxidase giving high turnover rates.