The predictive impact of body mass index on the efficacy of extended adjuvant endocrine treatment with anastrozole in postmenopausal patients with breast cancer: an analysis of the randomised ABCSG-6a trial.

BACKGROUND: We investigated whether body mass index (BMI) can be used as a predictive parameter indicating patients who benefit from extended aromatase inhibitor (AI) treatment. METHODS: The ABCSG-6a trial re-randomised event-free postmenopausal hormone receptor-positive patients from the ABCSG-6 trial to receive either 3 additional years of endocrine therapy using anastrozole vs nil. In this retrospective analysis, we investigated the prognostic and predictive impact of BMI on disease outcome and safety. RESULTS: In all, 634 patients (177 normal weight, 307 overweight, and 150 obese) patients were included in this analysis. Normal weight patients with additional 3 years of anastrozole halved their risk of disease recurrence (disease-free survival (DFS) HR 0.48; P=0.02) and death (HR 0.45; P=0.06) and had only a fifth of the risk of distant metastases (HR 0.22; P=0.05) compared with normal weight patients without any further treatment. In contrast, overweight+obese patients derived no benefit from additional 3 years of anastrozole (DFS HR 0.93; P=0.68; distant recurrence-free survival HR 0.91; P=0.78; and OS HR 0.9; P=0.68). The possible predictive impact of BMI on extended endocrine treatment could be strengthened by a Cox regression interaction model between BMI and treatment (P=0.07). CONCLUSION: Body mass index may be used to predict outcome benefit of extended AI treatment in patients with receptor-positive breast cancer.

Randomized trial of low-dose chemotherapy added to tamoxifen in patients with receptor-positive and lymph node-positive breast cancer.

PURPOSE: To evaluate the outcome in patients with stage II hormone receptor-positive breast cancer treated or not treated with low-dose, short-term chemotherapy in addition to tamoxifen in terms of disease-free and overall survival. PATIENTS AND METHODS: A total of 613 patients were randomized to receive either low-dose chemotherapy (doxorubicin 20 mg/m(2) and vincristine 1 mg/m(2) on day 1; cyclophosphamide 300 mg/m(2); methotrexate 25 mg/m(2); and fluorouracil 600 mg/m(2) on days 29 and 36 intravenously) or no chemotherapy in addition to 20 mg of tamoxifen orally for 2 years. A third group without any treatment (postmenopausal patients only) was terminated after the accrual of 79 patients due to ethical reasons. RESULTS: After a median follow-up period of 7.5 years, the addition of chemotherapy did not improve the outcome in patients as compared with those treated with tamoxifen alone, neither with respect to disease-free nor overall survival. Multivariate analysis of prognostic factors for disease-free survival revealed menopausal status, in addition to nodal status, progesterone receptor, and histologic grade as significant. Both untreated postmenopausal and tamoxifen-treated premenopausal patients showed identical prognoses significantly inferior to the tamoxifen-treated postmenopausal cohort. Prognostic factors for overall survival in the multivariate analysis showed nodal and tumor stage, tumor grade, and hormone receptor level as significant. CONCLUSION: Low-dose chemotherapy in addition to tamoxifen does not improve the prognosis of stage II breast cancer patients with hormone-responsive tumors. Tamoxifen-treated postmenopausal patients show a significantly better prognosis than premenopausal patients, favoring the hypothesis of a more pronounced effect of tamoxifen in the older age groups.

Very low-dose adjuvant chemotherapy in steroid receptor negative stage I breast cancer patients. Austrian Breast Cancer Study Group.

A randomised clinical trial was performed to test whether or not low-dose chemotherapy lasting only 35 days improves the outcome of breast cancer patients with stage I disease and negative oestrogen and progesterone receptors (ER-, PgR-). Between 1984 and 1990, 277 stage I breast cancer patients with tumours negative for both oestrogen and progesterone receptors were randomised to receive either low-dose short-term chemotherapy or no chemotherapy. Chemotherapy consisted of one cycle of doxorubicin, vincristin (AV) and one cycle of cyclophosphamide, methotrexate, fluorouracil (CMF). Patients were stratified for tumour stage, type of surgery, menopausal status and participating centre. Results were analysed both by univariate and multivariate statistical. After a median length of follow-up of 84 months, disease-free (DFS) and overall survival (OS) did not differ significantly between patients having received adjuvant chemotherapy and the control group. Uni- and multivariate analysis did not show any significant prognostic or therapy related factor. A low-dose short-term adjuvant chemotherapy is insufficient to improve the prognosis of patients with breast cancer stage I with ER-, PgR-tumours.

Dose intensification of epidoxorubicin and cyclophosphamide in metastatic breast cancer: a randomised study with two schedules of granulocyte-macrophage colony stimulating factor.

A randomised phase II/III study was conducted in patients with advanced breast cancer to determine the dose intensity achievable through an acceleration of administration of chemotherapy with epidoxorubicin and cyclophosphamide (EC) alone, as compared with the combination of this regimen with two different schedules of granulocyte-macrophage colony stimulating factor (GM-CSF). 73 patients received EC intravenous (i.v.) (epidoxorubicin 100 mg/m2, cyclophosphamide 600 mg/m2) on day 1 (group A), or the same chemotherapy plus sub-cutaneous (s.c.) GM-CSF (5 micrograms/kg/day) either from days 3 to 12 (group B) or from days -6 to -3 (group C). The primary objective of the study was the investigation of dose intensity delivered in the three treatment arms, whereas the secondary objective was response rate. A significant increase (P = 0.006) in dose intensity of 21% was observed for treatment group B, whereas the increase in dose intensity achieved in group C (7%) was not significant (P = 0.086). Response rates (complete response (CR) + partial response (PR)) of 56% were observed in group A, 65% in group B, and 57% in group C, respectively. This difference in response rates did not reach statistical significance (P = 0.271). We thus conclude that an acceleration of the EC regimen over the standard schedule could be accomplished with postchemotherapeutic GM-CSF support, leading to an increase in dose intensity, whereas pretherapeutic short-term GM-CSF administration did not reach this goal.

Monoclonal antibody CM-H-9 detects circulating placental isoferritin in the serum of patients with visceral metastases of breast cancer.

The aim of the current pilot study was to determine whether placental isoferritin (PLF) can be detected in the serum of patients with metastatic breast cancer. Sera were obtained from breast cancer patients with metastatic disease (n = 100), from breast cancer with no evidence of disease (n = 70) and from healthy female controls (n = 34). PLF and total serum ferritin levels were independently measured using specific monoclonal antibody ELISAs in a double-blind study. It was found that the mean serum PLF levels were significantly elevated only in patients with visceral metastases (lung, liver, brain) compared with the levels of patients with non-visceral metastases (bone, skin) or with healthy controls. Contrary to this, analysis of total serum ferritin levels did not reveal significant differences between these groups. Considering 0-10 units/ml as a PLF negative result, it was found that PLF was negative in 87.5% of healthy controls and in 96% of breast cancer patients with no evidence of disease. In contrast, PLF was positive in 73% of the patients with visceral metastases and in 29.7% of those with non-visceral metastases. The striking difference between visceral and non-visceral metastases is not yet understood. It could result from a difference in the degree of vascularisation or, alternatively, a difference in the cell types and genes expressed by cells metastasizing to visceral or non-visceral organs.

Expression of p43 in breast cancer tissue, correlation with prognostic parameters.

Placental isoferritin (PLF) and its unique superheavy chain p43 have been recently described as being synthesized by breast cancer cell lines but not by normal breast epithelial cells. Since previous reports have demonstrated a correlation between the content of 'normal' ferritin in breast cancer tissue and the degree of differentiation and prognosis, we have determined p43 in the cytosol of 122 breast cancer samples by use of the new monoclonal antibody CM-H-9. The synthesis of p43 showed a significantly negative correlation with tumor size (P = 0.0001), histologic grading (P = 0.0038), nuclear pleomorphism (P = 0.0019), rate of mitosis (P = 0.0002), lymphocytic reaction (P = 0.0001) and a significantly direct correlation with estrogen receptor status (P = 0.0009). Although patients with a higher p43 content showed a trend for a better outcome (median follow-up: 61.4 months), an independent influence of the cytosolic p43 content on survival could not be confirmed by a multiple Cox model. Therefore it seems that p43's prognostic impact is linked to the highly significant correlation with features of differentiation although a statistical bias in the Cox model due to the limited number of patients must also be taken into account. On the other hand, the significant correlation of p43 expression with factors for good prognosis was striking and consistent and warrants further research of this tumor product.

Local gentamicin application for perineal wound healing following abdominoperineal rectum excision.

A major complication of abdominoperineal rectum excision for rectal or anal carcinoma is local wound infection. The main reason for this infection is that systemically administered antibiotic prophylaxis does not reach sufficiently high concentrations of antibiotic in the tissue of the sacroperineal wound. Since gentamicin-polymethylmethacrylate (PMMA) in the form of chains of beads has been confirmed as a useful tool in the treatment of local infection in bone and soft tissue surgery, we have evaluated its effect on the abdominoperineal rectum excision in a prospective, randomized trial. Forty-four patients with rectal or anal carcinoma entered the study. Only patients with stage Dukes D were excluded from the trial. Following randomized selection, the patients were treated either with local gentamicin and drainage (Group A) or drainage alone (Group B), using the Lloyd-Davies procedure. The two groups were comparable regarding age, sex, tumor stage and level, and risk factors predisposing for an infectious complication (anemia, nutritional status, blood transfusion). The postoperative mortality rate was 0% in both series. Analysis of local perineal wound healing revealed a statistically significant higher percentage of primary wound healing in Group A than in Group B (87% versus 46%; p less than 0.01). This led to a significantly shorter hospitalization period for patients in Group A (p less than 0.01). Gentamicin-PMMA chains have been demonstrated to exert a favorable effect on local wound healing and the postoperative outcome of patients with abdominoperineal rectum excision.

Determination of placental ferritin-positive peripheral lymphocytes in early stages of breast cancer.

"Ferritin-blocked lymphocytes" or placental ferritin (PLF) -positive T cells have repeatedly been described in the circulation of patients with female breast cancer. Since a monoclonal antibody directed against PLF became available, a study was performed to evaluate its usefulness in an easily reproducible system. One hundred patients with controversial or highly suspicious findings on mammography who subsequently underwent operation entered this trial. Sixty-one healthy blood donors served as controls. Patients with early (lymph-node negative) stages of breast cancer (in situ and T1N0 tumors) revealed significantly higher numbers of PLF-positive cells (9.00% +/- 4.5% and 6.21% +/- 3.4%) as compared with controls or patients with benign lumps (p < 0.001). Patients with negative lymph nodes differed significantly from node-positive patients (9.79% versus 2.55%; p < 0.001), whereas no difference as related to menopausal and estrogen-receptor status was observed. In order to define the sensitivity and specificity of this test, we analyzed four different cutoff levels (3%, 4%, 5%, and 6% of PLF-positive T cells). At a level of PLF-positive lymphocyte cells of 4%, 94% of cancer patients with stage T1N0 disease or ductal carcinoma in situ, 5% of patients with benign lumps, and 7% of healthy controls were identified. Furthermore, 88% of all lymph node-negative cancer patients had more than 4% positive cells, compared with only 25% in patients with axillary node involvement. The fact that more than 90% of all patients with in situ carcinomas and patients with stage T1N0 cancer had values above 4% offers promising aspects for this method to be used to complement mammography in the early detection of breast cancer.

Expression of p43 associated placental isoferritin (PLF) correlates inversely with cell growth in breast cancer cell lines MCF-7 and T47-D.

We have previously demonstrated that the expression of the recently described immunosuppressive antigen p43 in breast cancer patients correlates with early stages of the disease and a low degree of proliferation of the tumors. Attempts were made to evaluate the expression of p43 in two breast cancer cell lines (MCF-7 and T47-D) stimulated to proliferation by 17-beta estradiol and fetal bovine serum (FBS). p43 expression was determined by RIA technique using the new monoclonal antibody CM-H-9, the rate of proliferation was assessed by [3H]thymidine incorporation during 72 hours of incubation. Induction of proliferation by addition of 17-beta estradiol and FBS to serum-free tissue culture medium correlated with a decrease of p43 synthesis in both cell lines. The level of p43 expression in nonstimulated cells was low in comparison to that in cells cultivated routinely (15% FBS, no estrogen). However, the drop of p43 synthesis was significantly stronger in cell lines with estrogen stimulated proliferation. Our in vitro results confirmed previous clinical observations describing an inverse correlation between p43 synthesis and degree of proliferation and differentiation in breast cancer for the first time. However, the pathologic mechanisms leading to this phenomenon need to be elucidated.

[Effect of early diagnosis on the prognosis of metastatic breast cancer]. / Einfluss der Frühdiagnose auf die Prognose des metastasierenden Mammakarzinoms.

Between 1980 and 1986 676 patients with primary breast cancer were operated on with curative intent at the Department of Surgery of the Hanusch Hospital in Vienna. Of these 133 developed recurrences. The patients were closely followed up at our outpatient clinic. We have retrospectively analysed this patient collective to evaluate the impact of routine technical and chemical-pathological follow-up programmes on the detection rate of subclinical distant metastases and on improvement of prognosis. There was no difference in the outcome with respect to survival after recurrence and to overall survival between patients with early detection of recurrence at an asymptomatic stage, who received general antitumor therapy immediately and a second group where therapy was initiated only upon clinical manifestation of metastasis. The results are discussed in relationship to screening costs. We would like to emphasize the importance of follow-up programmes in the timely detection of local recurrence and also of cancer of the contralateral breast, as well as benefitting the psychological aspect of the doctor-patient relationship.

[2 years of experience with balanced oral feeding in abdominal surgery]. / Zwei Jahre Erfahrung mit bilanzierter oraler Ernährung in der Abdominal-Chirurgie

Together with the progress of surgical technique there is the continued development of pre- and postoperative care of patients. There are two fields for the use of BSD (balanced synthetic diet): I. Preoperative: a) Full caloric nutrition b) Intestines free from waste matter and lowering of bacterial content. II. Postoperative: Interruption of the vicious circle of diminished offer of nutrition, postoperative katabolism, which increases the need for amino-acids and so interferes with the process of wound-healing and the protection against infection.

[Early experience with the advanced breast biopsy instrumentation system in a multicentre study]. / Zwischenbericht über die Anwendung des 'Advanced Breast Biopsy Instrumentation'- Systems im Rahmen einer Multizenterstudie.

Early Experience with the Advanced Breast Biopsy Instrumentation System in a Multicentre Study In an Austrian multicentre trial between September 1998 and December 2001, 474 procedures were performed with the Advanced Breast Biopsy Instrumentation (ABBI), and 389 were entered in the protocol. For reasons of patient comfort, radiological accuracy and low complication rate, the stereotactic excision biopsy with the ABBI system is a useful alternative to 'open' biopsy of non-palpable breast lesions, although there are technical limitations. The question of the therapeutic option in breast cancer cannot be answered yet.

Nuclear pleomorphism, a strong prognostic factor in axillary node-negative small invasive breast cancer.

We have evaluated established risk factors (tumor size, menopausal status, receptor status, tumor histology, and grading according to Bloom & Richardson including subfactor analysis) as well as local therapeutic procedures in a series of 121 patients with axillary node-negative (ANN) breast cancer stage T1a and T1b. The patients were operated on at a single institution (Department of Surgery, Hanuschkrankenhaus, Vienna) from 1969 to 1989. After a median observation time of 185 months, a total of 16 patients (13%) had a recurrence; of these, 6 had died of the primary disease by the control date (Dec 1, 1990). Grading (distant recurrence-free survival (DRFS) p = 0.01, overall survival (OS) p = 0.006, mitosis rate (DRFS p = 0.006, OS p = 0.02), and particularly nuclear pleomorphism (DRFS p = 0.0002, OS p = 0.00001) proved to have prognostic impact on distant recurrence-free survival and/or overall survival (Mantel-Cox log rank test; level of significance: p = 0.006 after adjustment for multiple testing by Bonferroni correction). Therapeutic procedures had a borderline-significant impact on local recurrence (p = 0.09). No other parameters had statistically significant impact. Thus, our long-term analysis confirms the superior prognostic relevance of histologic grading and nuclear pleomorphism in patients with ANN breast cancer stage T1a and T1b.

Partial pancreaticoduodenectomy (Whipple procedure) for pancreatic malignancy: occlusion of a non-anastomosed pancreatic stump with fibrin sealant.

Following partial pancreaticoduodenectomy for periampullary and pancreatic cancer, the complication and mortality rates are particularly high. Various approaches have aimed at improving the postoperative result, with less than complete success. The discouraging results of others, and our own dissatisfaction, led us to evaluate an atraumatic, sutureless method for management of the residual gland. Following head resection, the remaining pancreas is occluded with a fibrin sealant (Tisseel c, Immuno AG, Vienna) via injection into the pancreatic duct, which is then ligated and left free in the peritoneal cavity. Among 44 patients treated with this method, there were no perioperative deaths. Three patients developed local complications (2 fistulae, 1 pancreatitis) due to technical errors that presumably resulted in incomplete occlusion. Evaluation of patients after two to three years indicates that the endocrine function of the pancreas has been largely conserved despite ductal occlusion.

[Breast saving therapy in the small breast cancer]. / Brusterhaltende Therapie beim kleinen Mammacarcinom.

According to the satisfying results reported by Fisher, Veronesi and other authors who used a breast-conserving operation modality in the treatment of breast cancer since 1980 109 patients with a carcinoma up to 2.5 cm underwent this kind of operation at the surgical department of the Hanusch-Hospital, Vienna. Although the median follow-up-time (29 months) is too short for conclusive statements, results of recurrence and survival compared to 162 cases of modified radical mastectomy were satisfying. Therefore--following certain indications--breast conserving operation is offered to our patients as a possible method.

Influence of early diagnosis on prognosis of recurrent breast cancer.

Between 1980 and 1986 676 patients with primary breast cancer were operated on with curative intention at the Department of Surgery, Hanusch Medical Center, Vienna, Austria. Of these, 133 had recurrences. The patients were closely followed at the Outpatient Clinic. The authors have retrospectively analyzed this patient collective to evaluate the impact of routine technical and laboratory-chemical follow-up programs on the detection rate of subclinical distant metastases and improvement of prognosis. There was no difference in outcome in terms of survival after recurrence and overall survival between patients with detection or recurrence in the asymptomatic stage who received general antitumoral therapy immediately, and a second group whose therapy was initiated upon clinical manifestation. The authors discuss the results in view of the screening costs. They emphasize the potential of follow-up programs due to timely detection of local recurrence, and observation of the contralateral breast, as well as the psychological aspect of a stable doctor-patient relationship.

Placental isoferritin (PLF) in comparison with MCA and CEA in advanced breast cancer--first data from a pilot study.

The development of new and effective marker substances has optimized tumor-marker-guided follow-up programs to monitor generalization of disease and to assess the therapeutic outcome. Isoferritins of placental origin were first determined in the serum of patients with lymphoproliferative disease by way of the recently developed monoclonal antibody CMH-9. We have set up an Austro-Israeli working group and analysed 64 patients in terms of the sensitivity of placental ferritin (PLF) compared with the standard markers carcinoembryonic antigen (CEA) and mucinous-like cancer-associated antigen (MCA) in patients with metastatic breast cancer. We have additionally evaluated the importance of combined marker determination. Analysis of the data in view of site of metastatic spread yielded satisfying results both for PLF (sensitivity 70.4%) as well as MCA (sensitivity 76.9%) for visceral metastases; a combination of these two markers revealed a striking sensitivity of 88.4%, which, however, could not be improved by adding the third marker (CEA). With regard to non-visceral metastases, CEA and MCA were clearly superior.

[Mastopathy in partial testicular feminization]. / Mastopathie bei partieller testikulärer Feminisierung.

We report on a patient with synchrony of mastopathic alterations and incomplete testicular feminization. In the 54-year old patient, typical climacteric complaints as well as mastopathy-associated symptoms occurred. After orchiectomy and subsequent oestrogen substitution, clinical symptoms disappeared.

Rapid detection of polyamines in the sera of patients with colorectal carcinoma by liquid ion-exchange chromatography.

The polyamines spermidine and spermine and the diamines putrescine and cadaverine have been determined in their free and unbound state in the sera of patients with colorectal carcinoma. The obtained values were compared with normal control levels. Elevated levels of putrescine and spermidine were found in untreated patients and declined to the control range after surgical and chemotherapeutic treatment. Spermine levels remained unchanged throughout the observation at normal control levels.