Efficacy and toxicity of lower dose UFT without leucovorin in metastatic gastric cancer patients.

PURPOSE: Gastric cancer is the 4th most commonly diagnosed cancer and the 2nd leading cause of cancer death worldwide. In this study assessed were the efficacy and toxicity of the combination of epirubicin, cisplatin and UFT in patients with metastatic gastric cancer (MGC). PATIENTS AND METHODS: In this retrospective study 27 patients with MGC were treated with epirubicin 50 mg/m(2) and cisplatin 60 mg/m(2) i.v. on day 1 and subsequently UFT 250 mg/m(2)/day orally in divided doses for 21 days, followed by a 7/day rest (EP/UFT). RESULTS: Response and toxicity evaluation was possible for 25 patients. Three complete (12%) and 2 partial (8%) responses were observed. With a median follow-up 37 weeks (range 15-117), the median progression-free survival (PFS) and overall survival (OS) were 24 and 31 weeks, respectively. WHO grade 3 or 4 toxicity included neutropenia in 3 (12%) patients and nausea/vomiting in 1 (4%) patient. Neutropenic fever developed in only 1 (4%) patient. CONCLUSION: EP-UFT with lower UFT doses and without leucovorin support is a safe and effective regimen as first -line treatment of MGC.

Biological characteristics of breast cancer at the primary tumour and the involved lymph nodes.

Diminished oestrogen receptor (ER) expression in the involved axillary lymph nodes (ALN) in breast cancer compared with the primary tumour has been reported in previous studies. We have assessed a wider spectrum of tumour markers (ER, progesterone receptor (PgR), p53, Ki-67 and HER-2/neu) and compared extent and staining intensities at the primary tumour and the involved ALN on specimens of 22 cases with invasive ductal breast cancer. At the involved ALN, both the quantity of positive staining cells and the staining intensities for ER and PgR were decreased (p < 0.001 and p = 0.003, respectively). In contrast, the quantity of positive staining cells (p < 0.004) and the staining intensities for Ki-67 were increased. The differences for HER-2/neu and p53 staining at both sites were insignificant. The immunohistochemical staining properties of both the primary tumour and the ALN metastases showed no correlation with the number of involved ALN (p > 0.05). This study suggested that ALN metastasis might indicate a more unfavourable expression pattern of ER, PgR and Ki-67 in invasive ductal breast cancer.

Impact of regular attendance by infectious disease specialists on the management of hospitalised adults with community-acquired febrile syndromes.

The impact of attendance by infectious disease specialists (IDS) on hospitalised adults with community-acquired infection was assessed by studying 402 consecutive febrile adults who were admitted randomly to either of two internal medicine wards over a 4-month period and given intravenous antibiotics. In ward 1, patients were attended by IDS, whereas those in ward 2 were attended by physicians from other specialties. In total, 160 patients were treated in ward 1 and 242 in ward 2 (median age 66 years; 49% male). The case-mix was comparable. Only 39% of ward 2 patients underwent minimal fever diagnostic tests compared to 82% in ward 1 (p < 0.001). Ward 1 and 2 patients received 188 and 315 antibiotic courses, respectively, of which 32% and 20% required approval from IDS (p 0.003). Patients in ward 1 were more likely to receive ceftriaxone (7.5% vs. 2%; p 0.002), erythromycin (7% vs. 1.5%; p 0.002) and cefuroxime (48% vs. 26%; p < 0.0001), but were less likely to receive amoxycillin-clavulanate (8% vs. 28%; p < 0.0001). The mean durations of therapy were 3.6 and 3.2 days (not significant), and therapy was deemed to be completely appropriate in 55.5% and 43% of cases, respectively (p 0.012). The crude mortality rates were 6.3% and 7.9%, respectively (not significant), while the medication costs were US dollars 27.4 and US dollars 26.4/patient/antibiotic day, respectively. Regular attendance by IDS resulted in significantly higher rates of accurate diagnosis and appropriate therapy. IDS prescribed more restricted (and expensive) agents, but preferred less expensive agents among unrestricted drugs, thereby offsetting the overall medication costs.

Influence of high-dose leucovorin and 5-fluorouracil chemotherapy regimen on P wave duration and dispersion.

BACKGROUND: Although 5-fluorouracil (5-FU)-related cardiotoxicity is well known, atrial arrhythmia, as a potentially serious complication has not been studied in detail. The aim of this study was to determine the P max and Pd in the electrocardiograms (ECG) of patients receiving 5-FU treatment. METHODS: Twenty-five patients (mean age: 62 years) receiving a 5-FU bolus plus continuous infusion with calcium leucovorin over 48 h and with normal pre-treatment cardiac physical examinations, ECG and echocardiography were enrolled. P maximum (P max), P minimum (P min) and P dispersion (Pd) (maximum minus minimum P wave duration) were measured from the 12-lead ECG at the 0th and 48th hour of the first chemotherapy cycle. Echocardiography was also obtained in all patients at the same times. RESULTS: Clinical cardiotoxicity was observed in two patients. P max and Pd were both significantly longer after 5-FU treatment at the 48th hour (P < 0.001). P min did not change (P > 0.05). CONCLUSION: Treatment with 5-FU based regimens may increase Pd and prolong the P max in cancer patients. These alterations may be predictive of patients at risk of atrial arrhythmias during 5-FU treatment.

Two autoimmune diseases: Hashimoto's thyroiditis and vitiligo accompanying breast cancer; A coincidence?

Autoimmune diseases can accompany cancer either sporadically or as part of certain genetic abnormalities or syndromes. We report on a breast cancer case with both Hashimoto's thyroiditis and vitiligo. To the best of our knowledge, this case constitutes the first breast cancer patient in the literature with both of these two autoimmune diseases. The patient did not have significant genetic abnormalities, so this might be a simple coincidence. Evaluation of cancer cases for the existence of comorbid autoimmune diseases might yield more such cases, and their genetic analyses may be helpful for better understanding of the pathogenesis of cancer.

Impact of active monitoring of infection control practices on deep sternal infection after open-heart surgery.

BACKGROUND: Deep-sternal infection is a devastating complication after open-heart surgery. However, the association between infection control practices and deep-sternal infection rates is unclear. METHODS: To identify contributors to increased deep-sternal infection rates in our institution, consecutive open-heart surgery patients were prospectively studied during two periods (75 and 40 days), including 66 and 40 patients, respectively. Active monitoring including 149 infection control practices was performed in the operating room and intensive care unit. End-points were deep-sternal infection rates and their relation to infection control practices. RESULTS: Mean age was 62+/-11 years and 68% were males. Coronary bypass was performed in 82%. Clinical and surgical features were comparable, except that patients in period 2 were more likely to have heart failure (15% vs 1.5%, p = 0.01) and had a longer mean duration of surgery (277 vs 217 minutes, p < 0.005). Only 57 practices (38%) were adequately performed. The main categories showing inadequate practices were disinfection, traffic, hand-washing, and surgical attire of nonscrubbed personnel, anesthesiologists, and pump technicians. Many categories showed a statistically significant improvement between periods. Deep-sternal infection rates in prestudy and poststudy periods were 10% and 2.8%, respectively (p = 0.007). CONCLUSIONS: Active monitoring among personnel involved in open-heart surgery resulted in a significant and sustained decrease in deep-sternal infection rates, through modification of human behavior and improvement of performance standards, probably mediated by the Hawthorne effect. Periodic active monitoring may be a valuable tool to achieve and even sustain such a decrease with tremendous implications on morbidity, costs, and quality of care.

Phagocytic killing and antibody response during the first year after tetravalent meningococcal vaccine in complement-deficient and in normal individuals.

Seven individuals with late complement component (LCC) deficiency and seven control subjects were vaccinated with tetravalent meningococcal vaccine. The response to vaccination was evaluated by measuring the antibody titer and the phagocyte killing of the bacteria, before, 5-7 weeks, and 12-14 months after vaccination. Prior to vaccination, no phagocytic killing and a low titer of antibody was found in the LCC-deficient group and a low killing (mean of 40-58%, according to the serogroup) in normal controls. The phagocytic killing increased significantly 5-7 weeks after vaccination. However, while in normal controls the phagocytic killing was close to 100% after 5-7 weeks and decreased only slightly during the first year, the mean killing of the various meningococcal subgroups in LCC-deficient individuals was 70-89% and dropped to only 53-71% one year after vaccination. Six weeks after vaccination the mean antimeningococcal antibody titer increased similarly in the sera of LCC-deficient patients and controls. One year after vaccination the controls maintained the high concentration, while the LCC-deficient patients had tendency toward a decrease. In addition, the interpersonal variability of the antibody concentration, both in LCC-deficient individuals and in normal controls, was much higher than the phagocytic killing, with only a very mild increase in some individuals. Thus, it is possible that in spite of adequate increase of antimeningococcal antibody titer after vaccination of LCC-deficient individuals their immunity against the bacteria may not be optimal. Our data show also that phagocytic killing of meningococci is probably a more consistent assay than antibody titer levels for antimeningococcal immunity, especially in LCC-deficient patients.

Immune function in patients with beta thalassaemia receiving the orally active iron-chelating agent deferiprone.

Short-term deferiprone may reduce body iron in some patients with thalassaemia major. Concerns regarding potential immunosuppressive effects of deferiprone have been raised from results of animal studies and case reports in humans. We studied immune function in 57 thalassaemia patients: 36 treated with deferiprone (L1; CP020) and 21 treated with desferrioxamine (DFO). Circulating B lymphocytes were increased in all patient groups. No differences were detected between treatment groups in percentages of circulating lymphocytes, concentrations of IgG, IgM or IgA, specific antibody titres, complement levels, or in vitro lymphocyte proliferation. No clinically important infections were observed in any patient. These data suggest that no clinical or laboratory changes consistent with immuno-suppression or immunodeficiency are observed during deferiprone therapy.

Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor.

Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Despite the progress achieved in its treatment, 20% of cases relapse and no longer respond to chemotherapy. The most common phenotype of ALL cells share surface antigens with very early precursors of B cells and are therefore believed to originate from this lineage. Characterization of the growth requirement of ALL cells indicated that they were dependent on various cytokines, suggesting paracrine and/or autocrine growth regulation. Because many cytokines induce tyrosine phosphorylation in lymphoid progenitor cells, and constitutive tyrosine phosphorylation is commonly observed in B-lineage leukaemias, attempts have been made to develop protein tyrosine kinase (PTK) blockers of leukaemia cell growth. Here we show that leukaemic cells from patients in relapse have constitutively activated Jak-2 PTK. Inhibition of Jak-2 activity by a specific tyrosine kinase blocker, AG-490, selectively blocks leukaemic cell growth in vitro and in vivo by inducing programmed cell death, with no deleterious effect on normal haematopoiesis.

Functional platelet-derived growth factor-beta (PDGF-beta) receptor expressed on early B-lineage precursor cells.

Growth and maturation of B lymphocytes from stem cells require a series of complex processes that are dependent at least in part on growth factors. Uncontrolled expression of receptors from these early growth factors may contribute to a leukaemogenesis of such early B cell progenitors. We show here that early pre-pre-B cells, but not mature B cells, express the PDGF receptor-beta (PDGFR-beta). These receptors contain a protein tyrosine kinase domain which is activated upon ligation with PDGF in pre-pre-B cells. Further, pre-pre-B leukaemia cells seem to express more PDGFR-beta compared with their normal counterparts, suggesting a role for these receptors in growth promotion of leukaemia cells.

Three new adenosine deaminase mutations that define a splicing enhancer and cause severe and partial phenotypes: implications for evolution of a CpG hotspot and expression of a transduced ADA cDNA.

We report three novel adenosine deaminase (ADA) mutations with interesting implications. A Somali child with severe combined immunodeficiency disease (SCID) had reduced ADA mRNA in T cells and was homozygous for the nonsense mutation Q3X. Unexpectedly, her healthy father was a compound ADA heterozygote whose second allele carried a 'partial' mutation, R142Q, due to a G-->A transition of a CpG dinucleotide. A C-->T transition of the same CpG produced a nonsense mutation, R142X, in two homozygous Canadian Mennonite infants with SCID. The severe and healthy phenotypes associated with R142X and R142Q, the high frequency of 'partial' ADA mutations arising from CpGs in healthy individuals of African descent and the presence of CAA (glutamine) at codon 142 in murine ADA, suggest selection for replacement of this CpG hotspot by CpA during ADA evolution. R142X, located within a purine-rich segment at nt 62/116 of exon 5, caused skipping of the exon, possibly by disrupting a splicing enhancer. Absence of exon 5 in T cell ADA mRNA and low ADA activity in T cells and erythrocytes obtained at age 18-22 months from one of the Mennonite children, indicate limited expression of a normal ADA cDNA from retrovirally transduced CD34+ umbilical cord leukocytes infused shortly after birth in an attempt at stem cell gene therapy.

Enzymatic protein carboxyl methylation in rat posterior pituitary: neurophysins in rapid-turnover pool determine methyl accepting capacity.

In vitro stimulation of intact rat posterior pituitary by either veratridine or K+ depolarization results in the concomitant release of neurophysins and in a decrease (70-80%) in their carboxyl methylation as measured either with L-[methyl-3H]methionine in the intact lobes after stimulation or in their homogenates with [methyl-3H]S-adenosyl-L-methionine and purified protein carboxyl methyltransferase. A similar reduction in neurophysin methylation (60%) was observed when the arrival of newly synthesized neurophysins at the posterior pituitary was blocked by colchicine. Experimental data indicate that the reduction in neurophysin content of the lobes after 12 h of colchicine treatment (less than 7%) or after in vitro stimulation (about 10%) cannot account for the marked reduction in neurophysin methylation. The results suggest that the granule pool characterized by rapid turnover of neurophysins probably represents the major source of methyl acceptor proteins in the lobe. In spite of the marked reduction in neurophysin methyl accepting capacity observed after stimulation, there was no parallel increase in methyl accepting capacity of the released neurophysins. We propose that a neurophysin subfraction that might be associated with the membrane of releasable granules participates in the methylation reaction in situ.