Preoperative FLAC/Granulocyte-Colony-Stimulating Factor Chemotherapy for Stage II Breast Cancer: A Prospective Randomized Trial

Background: Preoperative chemotherapy for stage II breast cancer may reduce locoregional tumors and provides initial treatment for systemic micrometastases. We conducted a prospective, randomized trial to evaluate the ability of intensive preoperative chemotherapy to enhance the outcome of this approach.Methods: Patients with clinical stage II breast cancer (T2N0, T1N1, and T2N1) were prospectively randomized to receive either preoperative or postoperative chemotherapy with five 21-day cycles of fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamide (FLAC)/granulocyte-colony-stimulating factor. Local therapy consisted of modified radical mastectomy or segmentectomy/axillary dissection/breast radiotherapy, according to patient preference.Results: Fifty-three women were randomized (26 preoperative chemotherapy and 27 postoperative chemotherapy). The objective clinical response rate of the primary tumor to preoperative chemotherapy was 80%, and the pathologic complete response rate was 20%. Preoperative chemotherapy reduced the overall incidence and number of axillary lymph node metastases. There was no difference in the use of breast-conserving local therapy between the two treatment arms. There were 20 local/regional or distant recurrences (9 preoperative and 11 postoperative). There was no difference in the overall or disease-free survival between the preoperative and postoperative chemotherapy arms.Conclusions: Preoperative FLAC/granulocyte-colony-stimulating factor chemotherapy was effective against local/regional tumors in stage II breast cancer but was otherwise comparable to postoperative chemotherapy.     

Lens epithelium-derived growth factor promotes photoreceptor survival in light-damaged and RCS rats

PURPOSE: To investigate possible protective effects of lens epithelium-derived growth factor (LEDGF) against photoreceptor death in light-damaged, Royal College of Surgeons (RCS) and P23H rhodopsin transgenic rats. METHODS: Twelve-week-old Sprague-Dawley (SD), 6-week-old RCS, and 10-day-old P23H (line 1, heterozygote) rats received an intravitreal injection of LEDGF fused with glutathione-S-transferase (GST-LEDGF). Fellow eyes received vehicle and served as control specimens. Two days after the injections, the SD rats were exposed to light of 2000 lux for 48 hours. Corneal Ganzfeld ERGs were recorded 10 days after light damage, at 10 weeks of age in RCS rats, and at 4 weeks of age in P23H rats. The eyes were then processed for histologic analysis. Heat shock protein (hsp) content in the sensory retina was analyzed quantitatively by protein immunoblot. RESULTS: In light-damaged rats, the ERG indicated retinal protection in GST-LEDGF-injected eyes, with b-wave and STR thresholds being 1.14 +/- 0.50 (mean +/- SD) and 0.60 +/- 0.26 log candela (cd)/m2 lower, respectively, than in vehicle-injected eyes (P < 0.01). The GST-LEDGF-treated eyes had maximum b-wave amplitudes that were significantly larger (P < 0.0005), had more than twice as many remaining photoreceptors, and had better organized outer segments than the control eyes. In RCS rats, the treated eyes had 2.76 +/- 0.73 and 0.83 +/- 0.09 log cd/m(2) lower thresholds for the b-wave and STR, respectively (P < 0.005), and had significantly larger maximum b-wave amplitude (P < 0.0005). GST-LEDGF-treated eyes of RCS rats also had more photoreceptors remaining (P < 0.005) and a thinner debris layer than control eyes. In P23H rats, GST-LEDGF treatment did not protect either retinal function or structure. The retinas from GST-LEDGF-treated eyes of SD and RCS rats had higher levels of hsp25 and alphaB-crystallin than vehicle-injected eyes. CONCLUSIONS: GST-LEDGF protects photoreceptor structure and function in both light-damaged and RCS rats. The increased expression of hsp25 and alphaB-crystallin may play a role in this protection. The absence of rescue in P23H raises the possibility that some forms of inherited retinal degeneration may not be amenable to treatment by intraocular injection of LEDGF.     

Rapid cycling bipolar disorder

Rapid cycling bipolar disorder (RCBD) is defined in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) as a type of manic-depressive illness in which the patient experiences four or more episodes of mania and/or major depression per year. It was first reported as a consequence of the reduced effectiveness of lithium carbonate in the treatment and prophylaxis of this form of bipolar disorder (BD) in contrast to those with less frequent cycling. Among the anticonvulsants, there have been reports with different degrees of controlled data concerning carbamazepine, valproate, lamotrigine, topiramate, gabapentin and primidone. There is a paucity of double-blind studies, but what is available supports the use of lamotrigine. There is open data supporting the use of carbamazepine, valproate and topiramate. Regarding other classes, nimodipine may have specific utility in ultradian- (ultra-ultra-) or ultra-RCBD and there is double-blind data regarding the specific utility of olanzapine in RCBD. Low thyroid function may be a factor in development of RCBD; therapies aimed at elevating thyroid levels, even beyond the usual range, have frequently produced benefits in open trials. More research is needed into the possible therapeutic benefits of verapamil, bupropion, choline, light therapy and electroconvulsive therapy (ECT).     

Bioterrorism: a threat for which we are ill prepared

Of the weapons of mass destruction, the biological ones are the most feared and bioterrorism has become one of the most vicious threats to civilized society in recent times. Biological weapons have been sporadically used for centuries. Despite international regulations, there has been a global re-emergence of the threat of biological warfare. As many as 17 countries are suspected of either including or developing biological agents in their weapons programmes. In the past decade, a number of terrorist organizations with access to bioweapons technology have emerged. Current surveillance systems may be inadequate to detect biological attacks. The onset of illness is often delayed, thus the timing and location of such an event may be extremely difficult to identify. We are unfamiliar with most of the agents of biological warfare and are ill-equipped to handle the consequences of such an attack. In addition, there is no apparent coherent policy to handle a biological terrorist incident. Given the enormity of what is possible in the event of a biological attack, we must be prepared to detect, diagnose, epidemiologically characterize and respond appropriately to biological weapons. Of the potential biological weapons, smallpox and anthrax pose the greatest threats.     

Boneloc bone-cement: experience in hip arthroplasty during a 3-year period

Polymethyl methacrylate (PMMA) bone-cement was introduced in the 1960s for fixation of total hip arthroplasty replacement components. Long-term results of cement fixation for hip and knee arthroplasty have been extremely good. Although the use of PMMA bone-cement has enabled long-term survival of joint arthroplasty implants, there has been concern about aseptic loosening. This concern led to the introduction of Boneloc bone-cement (Biomet, Warsaw, IN) in the early 1990s. It was hoped that with the improved physical and chemical characteristics of Boneloc, there would be less aseptic loosening in the long-term. A clinical trial was conducted to evaluate Boneloc bone-cement in cementing the femoral component of the Bimetric total hip arthroplasty prosthesis in 33 hips in 32 patients. On follow-up, 7 stems (24%) developed definite loosening, and 3 stems (10%) were possibly loose. Of the 7 definite loose stems, 5 (17%) were revised because of increasing pain or progressive loosening. Despite the biologic advantages of Boneloc, this study suggests that the chemicals substituted in Boneloc bone-cement led to an alteration in its mechanical properties. These properties proved to be inferior to conventional PMMA bone-cement. There is possible time-dependent deterioration of mechanical properties leading to early aseptic loosening. The conventional PMMA bone-cement has stood the test of time. Research and experimental studies should continue to improve the mechanical properties of Boneloc before further human trials.     

The role of the allograft in the induction of donor-specific T cell hyporesponsiveness

BACKGROUND: With adequate immunosuppression the majority of renal allografts are accepted, despite the exceptional vigour of the T cell alloimmune response. Previous work from this laboratory has demonstrated that this is accompanied by significant reductions in the precursor frequencies of anti-donor T cells. We have also shown that parenchymal cells are tolerogenic in vitro. We propose that the reduction in T cell frequencies may be due to the interaction between circulating T cells and potentially tolerogenic graft parenchymal cells. Primed/memory T cells (CD45RO+) are the only subset capable of reaching the allograft and therefore we would predict that T cell hyporesponsiveness would develop predominantly in the CD45RO+ subset due to their trafficking properties. METHODS: Frequencies of IL-2 secreting CD45RA+ and CD45RO+ CD4+ T cells in response to donor and third party stimulator cells were estimated in a series of renal transplant recipients, both before and after transplantation. RESULTS: There were highly significant reductions in the frequencies of donor-specific CD4+CD45RO+ T cells, when adjusted to control for the generalised effects of immunosuppression. There were no significant alterations in the frequencies of donor-specific CD4+CD45RA+ T cells. CONCLUSIONS: In renal transplant recipients, donor-specific CD4+ T cell hyporesponsiveness occurs predominantly in CD4+ CD45RO+ T cells which is the subset capable of trafficking through the graft.     

Adolescent nutrition in a rural community in Bangladesh

The objective of this study was to assess the nutritional status of adolescent boys and girls in a rural community in Bangladesh. Between December 1996 and January 1997, a cross-sectional survey was carried out in 803 households, each containing at least one adolescent, sampled consecutively from four purposely-selected villages in Rupganj Thana, Narayanganj district. Initially, the guardians of 1483 healthy and unmarried 10–17 year old adolescents (51% boys and 49% giris) were interviewed about family structure and socio-economic status. Out of these children, 906 (47% boys and 53% girls) from 597 households were weighed, had their height and MUAC measured and were clinically examined. Blood was then collected from 861 adolescents for haemoglobin estimation. The median monthly income per person in these 597 families was approximately Taka 554 (US $12). Twenty seven per cent of the household heads were labourers, 21% were solvent farmers, 14% ran small scale businesses and 6% were unemployed. Sixty seven per cent of adolescents were thin (defined as BMI < 5th centile of WHO recommended reference) with 75% boys and 59% girls being affected. The percentage of thin adolescents fell from 95% at age 10 years to 12 % at age 17 years. The prevalence of stunting (height for age < 3rd centile NCHS/WHO) was 48% for both boys and girls and rose from 34% at age 10 to 65% at age 17. On clinical examination angular stomatitis was present in 46%, 27% nad glossitis, 38% had pallor, 11% ha’d dental caries, 3.2% had an conspicuously enlarged thyroid and 2.1% had eye changes of vitamin A deficiency. According to INACG (International Nutritional Anaemia Consultative Group, 1985) cut-off values, 94% of the boys and 98% of the girls were anaemic. We conclude that rural Bangladesh adolescents suffer from high rates of malnutrition and almost universal anaemia. Nutritional interventions to target this population are urgently required.     

Phase I and imaging trial of a monoclonal antibody directed against gastrin-releasing peptide in patients with lung cancer.

Small cell lung cancer (SCLC) cells express and secrete bombesin-like peptides (BLP) that can activate specific receptors that stimulate the growth of these cells. A murine monoclonal antibody, 2A11, which binds to the BLP, gastrin-releasing peptide with high affinity, has been reported to decrease the growth of SCLC cells in vitro and in athymic nude mice. A Phase I trial in lung cancer patients was performed using multiple doses of 2A11. Thirteen patients with lung cancer received 12 doses of 2A11 antibody three times a week for 4 weeks at one of four dose levels. Serum samples were obtained prior to initiation and before each dose of 2A11 antibody therapy for measurement of 2A11 antibody levels and determination of serum human anti-mouse antibody levels. A pilot imaging evaluation using 111In conjugated 2A11 monoclonal antibody was also performed in the same patients to aid in the study of pharmacokinetics and biodistribution. No toxic reactions were observed, and none of the patients developed detectable human antimouse antibody; however, no objective antitumor responses were observed. The mean trough serum 2A11 levels in patients increased with increasing dose level: 0.26+/-0.2 microg/ml, 6.7+/-6 microg/ml, 71.5+/-60 microg/ml, 248+/-184 microg/ml for dose levels 1 mg/m2, 10 mg/m2, 100 mg/m2, and 250 mg/m2, respectively. At each dose level, sustained detectable serum levels of the monoclonal antibody were achieved. Tumor uptake was noted in 11 of 12 patients who were injected with 111In conjugated 2A11. Because no dose-limiting clinical toxicity was observed, a mathematical model was used to define the recommended Phase II dose of 250 mg/m2. This trial established that repeated doses of monoclonal antibody 2A11 could be given safely to patients, and sustained levels could be achieved for a 4-week schedule. Further evaluation of the antitumor effects of 2A11 is warranted.