Phase I study of epirubicin given on a weekly schedule

Epirubicin was studied in a phase I setting to find the maximum tolerated dose when given weekly for 3 of 4 weeks. Forty-one evaluable patients were treated in groups at doses increasing from 20 to 45 mg/m2. The highest dose level produced the maximum degree of myelosuppression (lowest neutrophil count, 1.9 X 10(9)/L; range, 0-3.7) recorded on Day 22. This was well-tolerated in this group of mainly pretreated patients. Nonhematologic side effects were minimal. This dose schedule allows a greater dose per unit time to be administered than other recommended schedules for epirubicin.     

Trends in cancer mortality sex ratios in Europe, 1950-1989.

A study was carried out to analyse trends in cancer mortality sex differentials. This study compared age-standardized sex ratio values for mortality from 18 cancers (or groups of cancers), and total cancer mortality over the period 1950-1989 in 24 European countries, for 4 age groups (all ages, 20-44 years, 45-64 years, and 65 years and over). For lung cancer and other tobacco-related neoplasms, appreciable rises in sex ratio values were observed until the late 1970s, particularly in Southern and Eastern Europe, before levelling off in recent years, particularly among the younger age groups. In the late 1980s, the range of variation in overall age-standardized sex ratios for lung cancer was between 2 and 3 in the United Kingdom and in Nordic countries, and around or over 10 in Southern Europe. In young adults, the decline in sex ratio values observed in Denmark and Sweden (unity), and in other Nordic countries and in the United Kingdom (around or below 2) reflects a levelling of lung cancer in young males and an increase in young females. This clearly indicates that young women are a priority target group for smoking control interventions in Europe. Appreciable cohort effects were also observed for stomach cancer: rises in sex ratio values were greater in, or restricted to, middle- and older age groups, whereas in the young there was some tendency towards a levelling in sex differentials. The overall sex ratio values for stomach cancer were around 2 in most areas of Europe in the late 1980s. For intestinal cancer, sex ratio values showed some tendency to rise, reaching a level of 1.3-1.7 in the late 1980s; steady rises were also registered in sex ratio values for melanoma (skin cancer), reaching 1.5-1.8 in the late 1980s in most countries. These upward trends which were minor or inconsistent at younger ages in several countries became progressively stronger with advancing age. Sex ratio values were below unity for cancers of the gallbladder and the thyroid. Sex ratio values tended to rise also for leukaemia (from 1.2-1.5 to 1.5-1.7), but showed no noticeable trend for lymphomas or myeloma. The overall sex ratio values for total cancer mortality in the 1950s were between 1.2 and 1.4 in most European countries. Thereafter, they rose appreciably in several countries, reaching 1.9 in Czechoslovakia, Italy and Poland, and 2.3 in France.(ABSTRACT TRUNCATED AT 400 WORDS)     

Chronology of cellular events leading to derangements in function of pancreatic islets in chronic renal failure.

In chronic renal failure (CRF), a multitude of metabolic derangements occur in the pancreatic islets, resulting in impaired glucose-induced insulin secretion. These abnormalities include a rise in the basal level of cytosolic calcium ([Ca2+]i) in the islet, a decrease in their basal and stimulated ATP and ATP/ADP ratio, a reduction in the Vmax of Ca2+ATPase and Na(+)-K+ATPase, and an impaired glucose-induced calcium signal. The sequence of events that lead to these derangements and to the impairment in insulin secretion during the evolution of CRF are not defined. The study presented here examined this issue by measuring the metabolic profile of pancreatic islets weekly during the evolution of CRF over a period of 6 wk. The results show that serum levels of parathyroid hormone (PTH) begin to rise during the first week of CRF. The Vmax of Ca2+ATPase and Na(+)-K+ATPase increased during weeks 1 to 3 of CRF but fell to low levels thereafter. At week 3 of CRF, the basal level of [Ca2+]i began to rise, whereas basal and the stimulated ATP content and ATP/ADP ratio started to fall. Glucose-induced calcium signal, delta[Ca2+]i/basal [Ca2+]i, and insulin secretion became abnormally low between weeks 3 and 6 of CRF. The data allow the following formulation: as serum levels of PTH begins to rise, calcium entry into islets is augmented; this in turn will stimulate the activity of Ca2+ATPase and the Na(+)-Ca2+ exchanger, and hence, calcium extrusion out of the islets is increased. As a result, [Ca2+] remains normal during the first 2 wk of CRF.(ABSTRACT TRUNCATED AT 250 WORDS)     

A monoclonal antibody (IID510g52) for the determination of functional domains within integrin cell surface receptors.

Monoclonal antibodies against cell surface receptors can be useful for the study of structural and biochemical features involved in protein interactions underlying platelet adhesion and aggregation. We report here the characterization of a monoclonal antibody, IID510g52 (hereafter referred to as IID5), which has been selected based on its specific binding properties against the platelet membrane glycoprotein IIIa. Characterization of the reactive epitope, including evolutionary conservation and identification of related IID5 target antigens in tumor cells, suggest that the IID5 epitope is implicated in the ligand-binding function of integrin receptors. Indeed, we show that this MoAb acts as a potent inhibitor of platelet aggregation and cell adhesion. Taken together, these results indicate that such a monoclonal may be a strategic tool for better understanding multiple integrin-mediated adhesive reactions, as well as the determination of interacting recognition sites.     

The Role of Donor Bone Marrow Infusions in Withdrawal of Immunosuppression in Adult Liver Allotransplantation

We investigated the role of donor bone marrow cell (DBMC) infusions in immunosuppression withdrawal in adult liver transplantation. Patients enrolled were at least 3 years post-transplantation, with stable graft function. Forty-five (study group: G1) received DBMC, and 59 (control group: G2) did not. Immunosuppression was reduced by one third upon enrollment, by another third the second year of the study and was completely withdrawn the third year. Patient and graft survival were similar between the two groups. Although rejection episodes were significantly less in G1 the first 2 years of the study (35% vs. 57%, p = 0.016), there was no significant difference overall (74% vs. 81%, p = 0.14). Until February 2004, 20 patients, 10 in each group, were immunosuppression free for 1-3 years. Approximately 20% of long-term survivors of liver transplantation can successfully discontinue their immunosuppression. DBMC infusions, do not increase this likelihood.     

Experimental investigation on histocompatibility of bovine collagen in rat tongue.

Authors injected a 1.5-2 cc Gax-Collagen into the tongue of 13 rats in order to examine the reactivity of the tissues around the graft and its attitude and duration. The research had practical purposes as the material is mainly used in E.N.T. for reconstructing the vocal cords. The animals have been sacrificed from 1 day to 9 months and the tongue subjected to the ordinary histologic methods. Our conclusions are as follows: a) a moderate inflammatory reaction following the introduction of the foreign body, then it attenuates and disappears at the third month; b) the implant is well tolerated, does not cause structural alterations in the surrounding tissues, in particular in the musculature where it is placed; c) a neovascularization appears, it lessens over the time, keeping itself only at the edge of the graft; d) in the formed fissures, fibroblasts, traces of collagen and neocollagen are present. All these conditions allow for taking root and the persistence of the implant. It is remarkable that the spherical form of the Gax-Collagen does not modify even if it has been implanted into a muscular organ and therefore subjected to severe and continuous mechanical stress.     

Inhibition of angiotensin converting enzyme by ramipril in serum and tissue of man.

Studies in animal models have indicated that ramipril is a potent inhibitor of angiotensin converting enzyme (ACE) in serum and tissue. In our study, the normal range of ACE activity and the inhibitory effect of short-term oral administration of ramipril on ACE activity in human serum and tissue samples of renal cortex, heart and blood vessels were determined. ACE activity in the renal cortex (125.2 +/- 11.5 nmol/mg per min) was greater than 600 times that of the heart (0.20 +/- 0.01 nmol/mg per min), greater than 500 times that of the veins (0.23 +/- 0.09 nmol/mg per min) and greater than 150 times that of the arteries (0.80 +/- 0.23 nmol/mg per min). ACE activity in the renal cortex and arteries 2 h after last dosing was almost completely inhibited by ramipril whereas ACE activity in the veins and heart was inhibited to a lesser extent. Our results demonstrate in man, for the first time, an inhibition of tissue ACE following short-term oral treatment with an ACE inhibitor.     

The imprecision of stereopsis

In comparison to lateral judgments of distance, stereoscopic judgments are not precise. Although stereoacuity thresholds for targets presented in the fixation plane can equal the best thresholds for the monocular hyperacuities, i.e. a few sec arc, the increment thresholds for disparity are substantially larger than the increment thresholds for lateral separation (width). We measured the minimum detectable change in the three-dimensional distance separating two features, one presented in the fixation plane, and the other some distance in front of it, i.e. with a significant standing disparity between the two features. For briefly-presented targets (150 msec), the Weber fraction for disparity was 10-20% over the range from 1 to 20 min arc, while the Weber fraction for width was only 2-3% under comparable conditions. The disparity thresholds were substantially improved for a longer duration target (1000 msec), but they were still a factor of two worse than the monocular width thresholds. In a related experiment, the vernier acuity for a standard vernier target was profoundly degraded by pairing the offset upper line presented to one eye with a disparate line in the other eye; the vernier threshold was elevated for disparities ranging from 3 to 30 min arc. This finding shows that the more precise monocular signals are actively suppressed in fused or partially-fused stereoscopic images.     

Corticosteroids reduce regenerative repair of epithelium in experimental gastric ulcers.

The association between corticosteroid treatment and gastric ulcer healing is controversial. The effects of corticosteroids on experimental ulcer healing in the rat were studied and the effect of coadministration of a prostaglandin E1 analogue was determined. Forty male adult rats were divided into five groups and pretreated for 10 days as follows: (a) control, (b) prednisolone (10 mg/kg), (c) prednisolone and misoprostol (300 micrograms/kg), (d) misoprostol, and (e) indomethacin (2 mg/kg) Gastric ulcer was induced by applying a cryoprobe to the serosal surface of the stomach. Healing was assessed by determining the ulcer size at three and six days. Mucosal regenerative activity at the ulcer edge was assessed by quantitating DNA synthesis in cells by immunohistochemical techniques using monoclonal antibodies to detect expression of proliferating cell nuclear antigen (PCNA) and incorporated 5-bromo-5-iododeoxyuridine (BrdU). Compared with control rats, the rate of healing and the mucosal regenerative activity were significantly reduced in rats treated with prednisolone and indomethacin (p < 0.05). Coadministration of misoprostol and corticosteroids reversed the delay in healing and the reduction in mucosal regeneration induced by corticosteroids alone. With misoprostol alone, the ulcer size and the number of epithelial cells that actively synthesised DNA did not differ from control animals. A comparison between the two immunohistochemical markers of cell proliferation showed a highly significant correlation between the two techniques (r = 0.64, p < 0.005), indicating that the simpler PCNA technique should prove valuable in assessing regeneration in experimental ulcer disease.     

Surveillance for stage I non-seminomatous germ cell tumours of the testis: the optimal protocol has not yet been defined

Forty-six patients with clinical stage I testicular non-seminomatous germ cell tumours were followed up according to a protocol of active surveillance between 1979 and 1987. The median follow-up time was 40+ months. Thirteen patients (28%) relapsed, predominantly in retroperitoneum and/or lung. Ten of these relapses (76%) occurred within 8 months of orchiectomy. Relapses occurred in 7/35 T1 tumours and 5/10 T2 to T4 tumours. No correlation was detected between the histological type and relapse rate. Three late relapses were diagnosed at 23, 29 and 36 months. Eleven of the relapsed patients remain in prolonged complete remission after PVB chemotherapy +/- surgery; one patient, who initially refused treatment at the time of relapse, has died. Another relapsed with predominant elements of rhabdomyosarcoma intermingled with malignant teratoma in a bone metastasis. He had a partial response to PVB chemotherapy but subsequently died. Thirty-four patients (74%) did not undergo lymphography (LG) and had a higher relapse rate (11/34) than those who had LG (2/12); this was not a statistically significant difference in this small series. The policy of active surveillance is not yet the "state of the art" and should be under constant scrutiny with respect to safety and practice.