Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial.

BACKGROUND: Aromatase inhibitors are considered standard adjuvant endocrine treatment of postmenopausal women with hormone receptor-positive breast cancer, but it remains uncertain whether aromatase inhibitors should be given upfront or sequentially with tamoxifen. Awaiting results from ongoing randomized trials, we examined prognostic factors of an early relapse among patients in the BIG 1-98 trial to aid in treatment choices. PATIENTS AND METHODS: Analyses included all 7707 eligible patients treated on BIG 1-98. The median follow-up was 2 years, and the primary end point was breast cancer relapse. Cox proportional hazards regression was used to identify prognostic factors. RESULTS: Two hundred and eighty-five patients (3.7%) had an early relapse (3.1% on letrozole, 4.4% on tamoxifen). Predictive factors for early relapse were node positivity (P < 0.001), absence of both receptors being positive (P < 0.001), high tumor grade (P < 0.001), HER-2 overexpression/amplification (P < 0.001), large tumor size (P = 0.001), treatment with tamoxifen (P = 0.002), and vascular invasion (P = 0.02). There were no significant interactions between treatment and the covariates, though letrozole appeared to provide a greater than average reduction in the risk of early relapse in patients with many involved lymph nodes, large tumors, and vascular invasion present. CONCLUSION: Upfront letrozole resulted in significantly fewer early relapses than tamoxifen, even after adjusting for significant prognostic factors.     

Do co-spray dried excipients offer better lysozyme stabilisation than single excipients?

The inherent instability of proteins when isolated from their native conditions creates the necessity of suitable stabilisation techniques. Because of the instability of proteins in solution it is often necessary to produce them as solid formulations. A method of producing relatively stable, solid protein pharmaceuticals is to incorporate them with a suitable excipient into an amorphous matrix by dehydration. The use of spray dried multiple excipient/single protein blends was compared to single excipient/protein systems using lysozyme as a model protein to establish the stabilising ability of such systems. Unprocessed controls and spray dried samples were characterised structurally by X-ray powder diffraction and Fourier transform Raman spectroscopy and also thermally by differential scanning calorimetry and thermogravimetric analysis. Retained lysozyme activity was assayed enzymatically. To assess long-term stability, samples were subjected to conditions of elevated temperature and relative humidity (RH) 40 degrees C/75% RH. Structural and thermal analysis of samples revealed that mannitol/trehalose spray dried excipient/lysozyme blends were completely amorphous upon production but partially recrystallised upon storage at elevated temperature and RH. Biological activity assays revealed that samples containing trehalose retained the highest percentage activity. Under the conditions employed mannitol/trehalose systems stabilise lysozyme more effectively than single excipient systems due to their ability to form amorphous products.     

Reproductive health of male Australian veterans of the 1991 Gulf War

Background  

Since the 1991 Gulf War concerns have been raised about the effects of deployment to the Gulf War on veterans' health. Studies of the reproductive health of Gulf War veterans have reported varied findings.     

Expression of Tumour Markers CA125, CASA and OSA in Minimal/Mild Endometriosis

Ovarian cancer associated antigens CA125, CASA and OSA were measured in serum from 23 patients with mild endometriosis before, during and after medical therapy. Pretreatment CA125 levels were elevated above 35 mu/ml in 4(17%), and above 25 mu/ml in 7 (30%) patients. Mean CA125 levels decreased during treatment, but in only 10 patients did levels reflect disease response. There was no correlation between CA125 levels and disease severity as measured by modified American Fertility Society Scoring. Neither CASA nor OSA were detected in these women.     

The International (Ludwig) Breast Cancer Study Group Trials I-IV: 15 years follow-up

BACKGROUND: Adjuvant systemic therapy prolongs disease-free and overallsurvival in both pre- and postmenopausal patients. Availabledata shown benefit from multi-agent chemotherapy, prolongedtamoxifen treatment, and ovarian ablation, and that the combinationof chemo- and endocrine therapy might be advantageous. In 1978the International (Ludwig) Breast Cancer Study Group (IBCSG)initiated four complementary randomized controlled clinicaltrials to evaluate the roles of chemo-endocrine combinationsor endocrine therapy alone in specific populations defined byrisk (for pre- and perimenopausal patients) or by age (for postmenopausalpatients). The results at 10 and 13 years' median follow-upfor these trials are summarized in this report and are comparedto those of the Overview meta-anal-ysis with regard to chemo-endocrineor endocrine therapy combinations. Furthermore, types of firstrelapses by sites and second malignant diseases are reported. PATIENTS AND METHODS: 1601 evaluable patients with node positive disease were includedinto the studies I–IV. In Trial I (491 premenopausal patientswith 1–3 positive axillary nodes) we studied the additionof low-dose continuous prednisone (p) to a cyclophosphamide-methotrexate-fluorouracil(CMF) combination. In Trial n 327 premenopausal patients withfour or more positive axillary nodes were randomized to oneyear CMFp or to a surgical oophorectomy followed by CMFp. InTrial III (463 postmenopausal patients 65 years old or younger),combined chemoendocrine therapy (one year of CMFp plus tamoxifen(T)) was compared to endocrine therapy (1 year of p + T) orto surgery alone. In Trial IV 320 postmenopausal patients 66to 80 years old were treated either by surgery alone or by surgeryfollowed by 1 year prednisone and tamoxifen. RESULTS: In Trial I the addition of prednisone allowed a higher doseof cytotoxics to be administered compared with CMF alone. Despitethis increased dose intensity, 13-year disease-free survival(DFS) and overall survival (OS) were similar for the two treatmentgroups (49% vs. 52% DFS, 59% vs. 65% OS for CMFp vs. CMF). InTrial II the addition of surgical oophorectomy to CMFp yieldedan improved outcome which approached statistical significancefor the subset of 107 patients known to have estrogen receptor-positivetumors (DFS, 23% vs. 15%, p     

Routine tests during follow-up of patients after primary treatment for operable breast cancer

Background: Follow-up tests for patients after diagnosis andprimary treatment of breast cancer are routinely performed.However, the usefulness of these follow-up parameters remainsunclear. We determined the yield of a variety of blood testsused to detect the presence of overt metastatic disease Methods: 4105 patients enrolled in International (Ludwig) BreastCancer Study Group (IBCSG) randomized clinical trials from 1978to 1985 were analyzed for abnormal or equivocal findings insix routine blood tests obtained every 3 months for the firsttwo years, every six months for years 3–5 and yearly thereafter.The relationship of test results to the occurrence of overtmetastatic disease was evaluated. The relapses were categorizedas follows in order to estimate the yield of the different testsfor relevant sites of metastases: any breast cancer relapse,bone ± other; liver ± other Results: Alkaline phosphatase alone was abnormal in a high proportionof patients with either bone metastases, liver metastases, orboth. SGOT and gamma-GT were also sensitive for patients withliver metastases. Bilirubin, serum calcium, and serum creatininewere relatively insensitive indicators of relapse. Abnormaltest results were reported sometime during a patient's disease-freeperiod for 3% to 6% of patients, depending on the test Conclusions: Alkaline phosphatase was the most effective bloodtest to distinguish patients with relapse from those withoutrelapse. It is inexpensive and its yield is relatively highfor predicting liver and bone metastases. The routine use ofthe other tests analyzed to detect metastases was not justified breast cancer, follow-up, evaluation, routine tests     

Review article: Immunosuppressants in distal ulcerative colitis

BACKGROUND: Distal ulcerative colitis may prove to be resistant to steroids and aminosalicylates, but total colectomy is more difficult to justify than in severe extensive colitis. Immunosuppression is of established benefit in generalized colitis, but there are no data available specific to distal disease. AIM: To determine whether the protocol-driven use of immunosuppressants in resistant distal ulcerative colitis is of similar efficacy and safety to that in extensive disease. METHODS: Two hundred and twenty-eight patients with distal ulcerative colitis seen in a 5-year period were identified from a prospective database. Details of 52 who had received immunosuppression were analysed. RESULTS: The 52 patients received 68 courses of therapy (53 azathioprine, five mercaptopurine, 10 ciclosporin). The thiopurines yielded clinically valuable responses in only 43% of courses, with failure of response in 16% and toxicity in 34%. Ciclosporin was helpful on only two of 10 occasions. Eight patients required total colectomy. Adverse events were typical of those normally associated with immunosuppressants, with potential risk to life in seven patients; treatment was discontinued because of toxicity on a total of 31% of occasions. CONCLUSIONS: Immunosuppression appears to be of lower efficacy and higher toxicity in resistant distal colitis than when used in more extensive colitis.     

Integrity of crystalline lysozyme exceeds that of a spray-dried form

The development of proteins as therapeutic agents is challenging partly due to their inherent instabilities. Consequently, crystallisation and spray drying techniques were assessed to determine their effects on protein integrity using lysozyme as a model protein. Unprocessed, crystallised and spray-dried lysozyme were characterised by: thermal analysis using hot stage microscopy (HSM), differential scanning calorimetry (DSC), high sensitivity differential scanning calorimetry (HSDSC) and thermogravimetry (TGA); and spectroscopic analysis employing Fourier transform Raman (FT-Raman). Moisture contents were determined by TGA and Karl Fisher titration (KFT). Enzymatic assay measured biological activity. HSM showed no changes in crystals until complete melting. TGA and KFT indicated that spray-dried lysozyme contained a lower moisture content than crystals, hence the higher apparent thermal stability was shown by DSC. HSDSC revealed that crystallisation and spray drying did not affect the denaturation temperature of lysozyme in solution when compared with unprocessed material. However, in the solid state, FT-Raman spectra showed perturbation of the conformational structure of spray-dried sample, whereas crystal conformation remained intact. Enzymatic assay revealed increased activity retention of crystals compared with spray-dried powder. Hence, crystals maintained the conformational integrity and activity of lysozyme in solution.