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.     

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.     

Viscerosomatic neurons in the lower thoracic spinal cord of the cat: excitations and inhibitions evoked by splanchnic and somatic nerve volleys and by stimulation of brain stem nuclei

Single-unit electrical activity has been recorded from 95 viscerosomatic neurons in the T9 and T11 segments of the cat's spinal cord. These neurons were excited by electrical and/or natural stimulation of visceral and somatic afferent fibers. The excitatory and inhibitory effects on these neurons of volleys in somatic and visceral afferent fibers and of electrical and chemical stimulation of the nucleus raphe magnus (NRM) and adjacent areas of the reticular formation (Ret. F.) have been studied. Electrical stimulation of the splanchnic nerve produced, after the initial excitation of the neurons, a period of inhibition lasting for up to 1 s. This inhibition reduced the responsiveness of the neurons to all inputs, somatic and visceral, and was still present after spinalization of the animals with cold block, which indicates a segmental organization of the inhibition. Electrical stimulation of afferent fibers within the somatic receptive field of the neurons produced, after the initial excitation, a period of inhibition similar to that induced by visceral afferent volleys. During this period of inhibition all inputs to the neurons were reduced. Reversible spinalization of the animals with cold block did not abolish this inhibition. On the basis of the effects of reversible spinalization on the visceral input to viscerosomatic neurons, two types of neurons were distinguished: 1) neurons whose visceral responses increased in the spinal state (neurons under tonic descending inhibition) and 2) neurons whose visceral responses were decreased or abolished in the spinal state (neurons subject to descending excitation). Neurons under tonic descending inhibition were inhibited by electrical stimulation of locations within the NRM and Ret. F. This inhibition lasted for less than 100 ms and could be evoked at intensities of stimulation of 100 microA or less. Neurons under descending excitation were also inhibited by electrical stimulation in the NRM and Ret. F. but, in addition, the inhibition was preceded by an excitation in 75% of these neurons. Chemical stimulation with DL-homocysteic acid (DLH) of locations within the NRM and Ret. F. was used to activate cell bodies, but not axons, located in these brain stem sites. The only effect observed following injections of DLH into the NRM and Ret. F. was inhibition of viscerosomatic neurons including those with descending excitation as well as those with descending inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pathogenesis of infection with a virulent allotropic variant of minute virus of mice and regulation by host genotype.

Neonates of various inbred strains of mice expressed three susceptibility phenotypes in response to infection with the lymphocyte-specific variant of minute virus of mice (MVMi). MVMi caused asymptomatic infections in C57BL/6 (B6) mice, lethal infections with intestinal hemorrhage in DBA/2 mice, and lethal infections with renal papillary hemorrhage in BALB/c, SWR, SJL, CBA, and C3H (H) mice. Sequential virus titration, histology, in situ hybridization with a full-length MVMi genomic probe, and immunohistochemistry for viral capsid antigen were used to compare the pathogenesis of MVMi infection in B6 and H mice. Peak infectious virus titers in heart, lung, liver, spleen, kidney and intestine did not differ between strains but brains of B6 mice, unlike H mice, were refractory to infection. Lesions in H mice consisted of renal papillary infarcts and accelerated involution of hepatic erythropoietic foci. No lesions were seen in B6 mice. In situ hybridization and immunohistochemistry indicated that three cell types were primary targets of MVMi; endothelium, lymphocytes, and hepatic erythropoietic precursors. Renal papillary infarcts in H mice were associated with virus replication in endothelial nuclei of the vasa recta. In contrast to the parity of infectious virus titers between strains, fewer cells in target organs of B6 mice were labeled with the MVMi probe then were labeled in H mice and fewer cells expressed viral capsid antigen. These results indicate (a) that the allotropic variants of minute virus of mice may be useful tools to dissect molecular mechanisms of parvovirus virulence, (b) that the virulence of MVMi for neonatal mice does not reside in its lymphotropism, and (c) that genetic susceptibility to lethal MVMi infection may result from overproduction of noninfectious virus products.     

Hemoglobin components in diabetes mellitus: studies in identical twins.

The minor components of hemoglobin which are increased in subjects with diabetes mellitus, hemoglobin Ala-c, were measured in identical twins concordant and discordant for diabetes to determine whether the observed increases represent a genetically determined abnormality. The mean values for the proportion of hemoglobins Ala-c in discordant twins differed markedly in the two members of the pair: 10.4 +/- 0.74 per cent for the diabetic twins and 6.85 +/- 0.33 for the nondiabetic twins (t = 4.3811, P less than 0.005). In concordant twins with juvenile onset diabetes, the mean proportion of Hb Ala-c was 11.4 per cent, and no marked differences were observed between members of twin pairs. Four pairs of identical twins concordant for maturity onset diabetes showed lower mean values for Hb Ala-c but did not show marked intra-pair differences. Thus, the abnormal proportions of hemoglobins Ala-c found in the presence of overt diabetes mellitus appear to be a manifestation of a metabolic abnormality of diabetes.     

Cell-death by apoptosis following anticancer drug-treatment in-vitro

The mechanism of cell death, apoptosis or necrosis, was determined morphologically and by DNA gel electrophoresis in 3 human leukaemic T-cell lines (CCRF-CEM.f2, CCRF-HSB and MOLT.4) after treatment with cytotoxic drugs. These include one hormone, dexamethasone (DXM); the DNA damaging agents, melphalan, cisplatin, bleomycin, mitomycin C and mithramycin; inhibitors of DNA synthesis, aphidicolin, cytosine arabinoside (Ara-C), methotrexate (MTX), 5-fluoro-2'-deoxyuridine (FUdR) and 5-fluorouracil (5-FU); and other metabolic inhibitors, bromo-2'-deoxy-2'-uridine (BUdR), actinomycin D, 5-azacytidine (5-AC), cycloheximide, vincristine, etoposide and adriamycin. When cell death was assessed morphologically apoptotic cell death was apparent in the three cell lines 48 hours after all drug treatments. However, a distinct pattern of DNA breakdown was observed for each cell line. A smear of DNA on agarose gels was seen for CCRF-CEM.f2 with 5-FU and mithramycin treatments whilst CCRF-HSB cells showed a similar DNA profile after 5-FU and MTX treatments. All drug treatments of MOLT.4 cells produced a necrotic pattern of DNA degradation. Cycloheximide, an inhibitor of protein synthesis reduced DNA fragmentation of CCRF-CEM.f2 cells treated with DXM, MTX and FUdR indicating that protein synthesis is required for cytotoxicity by apoptosis. However, the extent of DNA fragmentation caused by 5-FU was not significantly affected by cycloheximide. These results indicate that at least morphological and electrophoretic criteria should be used to avoid differing conclusions about modes of cell death.     

Cancer consultation preparation package: changing patients but not physicians is not enough.

PURPOSE: This study evaluated a cancer consultation preparation package (CCPP) designed to facilitate patient involvement in the oncology consultation. PATIENTS AND METHODS: A total of 164 cancer patients (67% response rate) were randomly assigned to receive the CCPP or a control booklet at least 48 hours before their first oncology appointment. The CCPP included a question prompt sheet, booklets on clinical decision making and patient rights, and an introduction to the clinic. The control booklet contained only the introduction to the clinic. Physicians were blinded to which intervention patients received. Patients completed questionnaires immediately after the consultation and 1 month later. Consultations were audiotaped, transcribed verbatim, and coded. RESULTS: All but one patient read the information. Before the consultation, intervention patients were significantly more anxious than were controls (mean, 42 v 38; P = .04); however anxiety was equivalent at follow-up. The CCPP was reported as being significantly more useful to family members than the control booklet (P = .004). Patients receiving the intervention asked significantly more questions (11 v seven questions; P = .005), tended to interrupt the physician more (1.01 v 0.71 interruptions; P = .08), and challenged information significantly more often (twice v once; P = .05). Patients receiving the CCPP were less likely to achieve their preferred decision making style (22%) than were controls (35%; P = .06). CONCLUSION: This CCPP influences patients' consultation behavior and does not increase anxiety in the long-term. However, this intervention, without physician endorsement, reduced the percentage of patients whose preferred involvement in decision making was achieved.