Tamoxifen in Advanced Breast Cancer; Response Rate, Effect on Pituitary Hormone Reserve and Binding Affinity to Estrogen Receptor

Patients with advanced breast cancer were treated with antiestrogen,tamoxifen, 20 mg orally, twice a day. Of the evaluable 23 patients,one achieved complete response with a duration of 16 months,and five achieved partial response lasting from two to eightmonths, indicating that the response rate was 26%. In the fiveperi-and postmenopausal patients, basal and LH-RH stimulatedplasma LH levels decreased but stayed within the postmenopausalrange in three patients during the tamoxifen therapy. Basaland LH-RH stimulated FSH levels decreased also but stayed withinthe postmenopausal range in all five patients. In a premenopausalpatient, basal and stimulated plasma LH and FSH levels did notchange significantly during the tamoxifen therapy. The plasmaTSH responses did not change significantly. In three of thesix patients, basal and TRH-stimulated prolactin levels decreasedslightly during the tamoxifen therapy. These relatively inconsistentand small changes in the pituitary hormone secretion observedduring the tamoxifen therapy suggest that the anti-tumor effectof tamoxifen was not due to alteration of the pituitary hormonesecretion. The binding of tamoxifen for the estrogen receptorwas examined in the estrogen receptor assay system. The doseresponse curve for tamoxifen was parallel to that for estradiol,indicating that tamoxifen competes with estradiol for the estrogenreceptor. The affinity constants of tamoxifen for the estrogenreceptor in eight cytosols of human breast cancer tissues were(139 ±79) X 10^–10M (mean±SD), indicatingthat the binding affinity of tamoxifen was about 0.7% that ofestradiol. The affinity constants for nuclear receptors weresimilar to those for cytosol receptors. These data suggest thattamoxifen is a useful drug for treatment of advanced breastcancer, and that the anti-tumor effect could be related to itsbinding to estrogen receptors in tumor tissues, and not causedby altering the secretion of pituitary hormones.     

Haemophagocytic lymphohistiocytosis in association with granular lymphocyte proliferative disorders in early childhood: characteristic bone marrow morphology

Five paediatric cases of haemophagocytic lymphohistiocytosis (HLH) which showed proliferation of granular atypical lymphocytoid cells in bone marrow are reported. All cases were girls aged 8 months to 4 years who had marked hepatosplenomegaly. Marker analysis on peripheral blood mononuclear cells revealed an increase in the CD3⁺HLADR⁺ subset in three cases and the CD³⁻CD56⁺ subset in one case. An Epstein-Barr virus genome was detected in three cases, and monoclonality was confirmed in two cases. A characteristic morphology of large granular lymphocytes (LGL) was identified, with elongated bizarre features that resembled horsetail-, tadpole-, cucumber- or shooting star-type configurations on the bone marrow smear. Serum concentrations of soluble interleukin-2 receptor and interferon-gamma were elevated in all cases. All five cases required multi-agent chemotherapy which resulted in two complete remissions, two partial remissions and one no response. Refinement of treatment is required for these paediatric GLPD cases which probably comprise a specific high-risk subgroup among secondary HLH patients which had previously escaped notice.     

Age-related profile of neuroblastoma: A comparison of tumors detected by mass-screening with those detected clinically

Infants with neuroblastoma are known to have a favorable prognosis compared to those over 1 year of age. However, there is little biological information about the age-related heterogeneity of neuroblastoma. We evaluated the biological profile comparing cases detected by mass screening with those detected clinically. A total of 238 patients with neuroblastoma were classified into four groups according to their age at diagnosis. Patients in group A were 0–5 months of age (n = 31). Patients in group B were detected clinically and were 6–11 months of age (n = 25). Patients in group C were 6–11 months of age and were detected by mass-screening (n = 97). Patients in group D were more than 12 months of age (n = 85). The age-related heterogeneity was evaluated by Kaplan-Meier survival analysis, several clinical markers (neuron specific enolase, ferritin, vanillylmandelic acid and homovanillic acid) at diagnosis, tumor Ha-ras p21 expression and tumor N-myc amplification. Infant neuroblastoma had unique features in comparison to neuroblastoma diagnosed over 12 months of age. Clinical outcome of the patients in groups A and C was quite favorable. Even patients with stage III or IV disease in group A had a favorable prognosis. However, stage IVs disease in group A was not necessarily associated with a good prognosis and the early death after diagnosis was also characteristic. The biological profile of tumors in group C was similar to that in group A but different from the profile in groups B and D. Tumors in group B had a biological profile intermediate between groups A and D. Cases detected by mass screening (group C) provided a new clinical entity with a good prognosis. The difference in biological profiles might affect their clinical outcome of respective age group. These analyses confirm the significance of prognostic markers and may help to direct an appropriate modality of treatment for the individual patient.     

Primary cutaneous T-cell lymphoma with an angiocentric growth pattern: association with Epstein-Barr virus

Summary We report a case of primary cutaneous T-cell lymphoma with an angiocentric growth pattern. The lesions had been confined for about 2.5 years to the skin, but there had been a gradual progression of the disease both clinically and histologically. We assessed the neoplastic clonality and the presence of Epstein-Barr (EB) virus genome in this case using immunohistochemistry. Southern blot analysis and RNA in situ hybridization. Clonal proliferation of a CD4⁺αβT-cell phenotype was demonstrated. In addition, the clonal population harboured the EB virus genome, which suggested that the virus was involved in the pathogenesis of the disease. The patient has remained in remission for 10 months, and has received treatment with cyclophosphamide and prednisone.     

Biochemical and histological features of hepatitis G virus infection

To assess the biochemical and histological characteristics of hepatitis G virus (HGV) infection, we examined four patients who were infected with HGV only (HGV group), and compared them with 16 patients infected with both HGV and hepatitis C virus (HCV; HGV + HCV group) and 18 patients infected with HCV only (HCV group). Biochemical examination showed a significantly low level of serum alanine aminotransferase (ALT) in the HGV group, and that the gamma-glutamyl transpeptidase (γ-GTP)/ALT ratio in the same group was significantly higher than in the other two groups. Although all three patient groups had a similar degree of liver fibrosis, both the degree of periportal inflammation and total histological activity index were significantly lower in the HGV group than in the other two groups. Fibrous enlargement of the portal tract without lymphoid infiltration and thin fibrous septa was characteristically observed in the HGV group. No significant difference was found between the HGV + HCV group and HCV group. Our results suggest that biochemical and histological changes in HGV infection are very mild and quite different from those of HCV infection.     

Assessment of autonomic nervous activity during gastrointestinal endoscopy: Analysis of blood pressure variability by tonometry

We continuously measured blood pressure by tonometry in 30 patients during endoscopy to determine the influence of upper gastrointestinal endoscopy on cardiac events. Patients were divided into two groups: one group treated with scopolamine butylbromide as premedication (SB group) and another group without premedication (C group). Time- and frequency domain analyses of beat-to-beat systolic blood pressure variability were performed for 128 consecutive beats. For time-domain analysis, we calculated the coefficient of variation of systolic blood pressure (CV_BP). For the frequency domain analysis, we determined the low-frequency (LF_BP; 0.04–0.15 Hz) and high-frequency (HF_BP; 0.15–0.40 Hz) powers of the variation in systolic blood pressure and the ratio of LF_BP to HF_BP (LF_BP/HF_BP) during endoscopy. The CV_BP and HF_BP, indicators of parasympathetic tone, increased in the early phase of endoscopy but decreased significantly in the middle and late phases compared with the pre-endoscopy value. The ratio of LF_BP/HF_BP, an indicator of indirect sympathetic tone, increased throughout the endoscopic procedure. Moreover, premedication with scopolamine butylbromide prevents the excessive parasympathetic nervous reflex when an endoscope passes through the upper digestive tract and also brings both decreased parasympathetic tone and increased sympathetic tone at the late phase of endoscopic procedure. Our results indicate that gastrointestinal endoscopy induced an autonomic nervous abnormality, which may contribute to the occurrence of cardiac events during endoscopic procedures.