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Patients with synchronous metastastic breast cancer and intact primary tumor traditionally undergo systemic treatment. Surgical intervention at the primary site is typically reserved for palliation and often replaceable by radiation. Nevertheless, local surgery in metastatic breast cancer has become an issue of great controversy since retrospective studies published during the recent years suggested a slight benefit from an operative procedure. We evaluated the effect of surgery on long-term survival and progression-free survival in synchronous stage IV breast cancer.We retrospectively reviewed the records of all breast cancer patients treated at our institution between 1986 and 2007. Information recorded for each patient included age, tumor characteristics, metastasis characteristics, therapy, progression-free survival, and overall survival. Survival data were compared between surgical and nonsurgical patients.61 patients with synchronous metastastic breast cancer and intact primary tumor were analyzed. 26 patients (43%) received no primary site surgery and 35 (57%) patients had surgery. Overall survival and progression-free survival determined via the Kaplan-Meier method showed no significant difference between the surgery and the non-surgery group.In patients with metastatic breast cancer, the operation of the primary tumor did not influence overall survival or progression-free survival.

International audience; The estrogen receptor (ER) pathway and the epidermal growth factor receptor (EGFR) pathway play pivotal roles in breast cancer progression. Targeted therapies able to intercept ER or signaling downstream to EGFR and its kin, HER2, are routinely used to treat distinct groups of breast cancer patients. However, patient responses are limited by resistance to endocrine therapy, which may be due to compensatory HER2/EGFR signaling. This raises the possibility that simultaneous interception of HER2 and ER may enhance therapeutic efficacy. To address the question, we treated breast cancer cells with both fulvestrant (ICI 182780), an ER antagonist with no agonist effects, and lapatinib, an orally available tyrosine kinase inhibitor specific to EGFR and HER2. Our results indicate that the combination of drugs is especially effective when applied to HER2-overexpressing, ER-positive cancer cells. Interestingly, fulvestrant activated the mitogen-activated protein kinase (MAPK) pathway of these cells, but complete inhibition of MAPK signaling was observed on cotreatment with lapatinib. Taken together, our observations reinforce the possibility that the effectiveness of combining anti-ER and anti-HER2/EGFR drugs may be especially effective on a relatively small subtype of HER2-overexpressing, ER-positive tumors of the breast.

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B(AKT)/mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in many types of cancer, including breast cancer. It is recognized that breast cancer cells develop resistance to a variety of standard therapies through the activation of this pathway. We hypothesized that targeting this signaling by the mTOR inhibitor RAD001 may potentiate the cytotoxicity of a conventional chemotherapeutic drug, carboplatin, and enhance the treatment efficacy for breast cancer.Cell proliferation was measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; cell apoptosis with enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used for the analysis of cell cycle distribution and mitochondrial membrane function. Gene expression at the protein level was determined by Western blot.MTOR inhibitor RAD001 enhanced the sensitivity of breast cancer cells to carboplatin. RAD001 in combination with carboplatin resulted in synergistic inhibition of cell proliferation and caspase-independent apoptosis in these cells. Moreover, in MCF-7 and BT-474 cells, synergistic effects of this combination on G₂/M cell cycle arrest and regulation of different molecules responsible for cell cycle transition and apoptosis were observed. The p53 pathway was involved in the synergism of RAD001 and carboplatin on breast cancer cell proliferation and apoptosis, since the synergistic effect was demonstrated in all tested breast cancer cell lines with wild-type p53 and the use of p53 inhibitor partially antagonized the effect of RAD001 and carboplatin on p53 and p21 expression, as well as their inhibitory effect on cell proliferation. However, a synergistic effect of the combination of the two drugs on cell proliferation was observed in two p53-mutated cell lines with high AKT expression, suggesting that an alternative mechanism underlying the observed synergism exists.Our results suggest that the combination of RAD001 and carboplatin is a promising treatment approach for breast cancer. On the basis of these results, we have initiated a phase I/II clinical trial with the combination of carboplatin and RAD001 in patients with metastatic breast cancer.

BACKGROUND: Leptomeningeal metastasis (LM) is a devastating complication of advanced cancer. Despite aggressive therapy survival is very poor. METHODS: Data of all breast cancer patients with LM were retrospectively analyzed (n = 27). RESULTS: Median survival was 9 weeks. Patients with contrast-enhancing meningeal lesions (n = 11) detected by MRI had a median survival of 33 weeks versus 8 weeks for patients without contrast-enhancing lesions (n = 9; p = 0.0407). Patients who received systemic chemotherapy (n = 18) had a median survival of 15 weeks versus 7 weeks (n = 9; p = 0.0106). Patients undergoing radiotherapy (n = 8) had a median survival of 17 weeks as compared to 5 weeks for patients without radiotherapy (n = 18; p = 0.0188). In a multiple Cox regression analysis, lack of systemic therapy (hazard ratio, HR 89.5; p = 0.002) and negative hormone receptor status (HR 4.2; p = 0.027) emerged as significant main risk factors, together with contrast-enhancing lesion as effect modifier for systemic therapy (p = 0.03). CONCLUSION: Contrast-enhancing meningeal lesions, systemic therapy, and radiotherapy were significantly associated with longer survival. Patients with contrast-enhancing lesions who were treated systemically had the longest survival. Evidence is increasing that systemic therapy plays an important role and should be applied in breast cancer patients with LM.

Aim of the study Clinical practice guidelines (CPG) are an appropriate method to optimise routine clinical care. Numerous CPGs for the diagnosis and treatment of breast cancer have been developed by national health institutions or medical societies. While a comparison of methodological criteria has been undertaken before, it is unknown whether these CPGs differ in their actual treatment recommendations. Methods We included national breast cancer CPGs from the USA, Canada, Australia, the UK, and Germany that satisfy internationally recognised methodological criteria and are in widespread use in daily clinical care. Treatment recommendations for adjuvant invasive breast cancer including surgery, radiation, endocrine therapy, chemotherapy and anti-HER2-therapy were compared. Results Recommendations for endocrine therapy show discordances regarding optimal usage of ovarian function suppression for premenopausal patients and aromatase inhibitors for postmenopausal patients. However, most other treatment recommendations exhibit a large degree of congruency. This reflects the fact that they rest on the same evidence base, and that many national guidelines are adopted from other guidelines so that well accepted guidelines are cited within other guidelines. Concluding statement Considering that the development of guidelines is a very expensive and resource-intensive task the question arises whether the development of national guidelines in numerous countries is worth the effort since the recommendations differ only marginally.

International audience; One of the most controversial questions in early breast cancer treatment is the need of chemotherapy in patients with estrogen receptor positive disease. Therefore, we analyzed a group of patients with high estrogen receptor (ER) expression to scrutinize the role of chemotherapy in this situation. To gauge the effect of chemotherapy on recurrence free survival (RFS) three treatment modalities were compared: endocrine treatment only, chemoendocrine treatment, and chemotherapy. 3,971 breast cancer patients whose treatment modalities as well as ER level were known, were included in this retrospective analysis. Their level of ER expression was documented as immunoreactive score (IRS). A high ER group was defined as ER IRS ≥9; primary endpoint was RFS. RFS was associated with ER, with the best outcome for strong and the worst result for negative expression. Adjusted to Nottingham prognostic index (NPI), RFS did not differ between the treatment cohorts of endocrine treatment and chemoendocrine treatment ( = 0.828) in the high ER group. Patients with chemotherapy alone fared significantly worse ( = 0.003). Even in high risk patients (according to NPI) the chemoendocrine and the endocrine treatment only groups did not differ significantly (HR = 1.15; 95% CI (0.56-2.34), = 0.709). Omission of endocrine treatment led to significantly worse outcome ( = 0.013). In conclusion, RFS was significantly longer in patients with high ER expression than with weak or no ER expression. In the high expression group, there was no significant difference in RFS between endocrine treatment only and chemoendocrine therapy--even in high risk patients, for whom chemoendocrine treatment is routinely indicated. It seems insufficient for high ER patients to only consider tumor size, nodal status, and grading in order to decide which patient will benefit from adding chemotherapy to endocrine treatment.

Background: A clinical phase II study with a topical formulation of hexadecylphosphocholine (Miltefosine solution 6%) was performed in patients with skin-metas-tasized or locally re

Nach den Empfehlungen der Konsensuskonferenz von St. Gallen 1998 [5] ist bei der weit uberwiegenden Mehrzahl der Patientinnen mit Mammakarzinom eine adjuvante Chemotherapie indiziert. Literaturdaten und neue Studien lassen zudem auf einen hohen Stellenwert der adjuvanten Hormontherapie beim rezeptorpositiven Mammakarzinom schliesen. Die moglicherweise beste Option besteht in der sequenziellen Behandlung mit Chemo- und Hormontherapie. Die Integration neuer Substanzen wie Paclitaxel ist wahrscheinlich ein effektiverer Ansatz, die Chemotherapie zu verbessern, als die alleinige Dosissteigerung von Anthrazyklinen oder Cyclophosphamid. Der Nutzen der Hochdosistherapie ist nach wie vor ungeklart. Vor einer endgultigen Beurteilung sollten die Ergebnisse der noch laufenden Studien abgewartet werden. In den vergangenen Jahren hat die adjuvante Chemotherapie eine Aufwertung erfahren, die Hormontherapie hingegen an Bedeutung verloren. Dies trifft insbesondere auf die Behandlung pramenopausaler Frauen zu, bei denen nach Empfehlung der Konsensuskonferenz von St. Gallen 1998 [5] eine Chemotherapie klar indiziert ist. Die stiefmutterliche Behandlung der Hormontherapie lasst sich jedoch nicht mit Literaturdaten begrunden.

Treatment options for patients with metastatic breast cancer (MBC) include a rapidly expanding repertoire of medical, surgical and supportive care measures.To provide timely and evidence-based recommendations for the diagnostic workup and treatment of patients with MBC, an international expert panel reviewed and discussed the evidence available from clinical trials regarding diagnostic, therapeutic and supportive measures with emphasis on their impact on the quality of life and overall survival of patients with MBC.Evidence-based recommendations for the diagnostic workup, endocrine therapy, chemotherapy, use of targeted therapies and bisphosphonates, surgical treatment and supportive care measures in the management of patients with MBC were formulated.The present consensus manuscript updates evidence-based recommendations for state-of-the-art treatment of MBC depending on disease-associated and biological variables.

Background: BIBW 2992 (Tovok™*) is a novel, oral, irreversible inhibitor of the epidermal growth factor receptor (EGFR)/ human epidermal growth factor receptor (HER)1 and HER2 inhibitor. It has promising preclinical activity in HER2-negative MDA-MB-453 and triple-negative SUM 149-PT cell lines, and showed clinical Phase I activity. First results of a Phase II study of BIBW 2992 in patients with HER2-negative, hormone receptor (HR)-positive or triple-negative breast cancer who have progressed following no more than two prior lines of chemotherapy are presented. The trial was conducted as a multi-institutional, open-label study in Germany and Belgium.Methods: Eligible patients had stage IIIB or IV HER2-negative metastatic breast cancer (MBC), with progression following no more than two prior lines of chemotherapy. No prior EGFR-targeted therapy was allowed and measurable disease, Eastern Cooperative Oncology Group performance status of 0–2 and an adequate organ function were required. Patients received 50 mg BIBW 2992 once-daily until disease progression. Tumor assessment was performed every other treatment course (one course is 28 days). The primary endpoint was objective response rate by Response Evaluation Criteria In Solid Tumors criteria in patients with HR-positive and triple-negative MBC. The latter was changed to clinical benefit, i.e. objective response (OR) or stable disease (SD) on treatment for at least four cycles for patients with triple-negative disease. Safety data were collected and analyses are still ongoing.Results: A total of 56 patients were enrolled with 50 actually starting treatment on the trial, including 29 patients with triple-negative and 21 patients with HER2-negative and HR-positive MBC. No ORs were observed in either cohort. Three patients in the triple-negative cohort had SD for at least 4 treatment cycles, one of them for 12 cycles. The most frequently observed side-effects at snapshot date (on 49 patients) are diarrhea (Common Terminology Criteria for Adverse Events Grade 3 in 18 patients [36.7%]) and Grade 3 skin rash in two patients [4.1%]). These were managed by symptomatic treatments and dose reductions.Conclusion: Long-term oral administration of BIBW 2992 was safe in HER2-negative MBC patients. Side effects mainly affected the skin and gastrointestinal tract, and were manageable. Clinical benefit was achieved in a fraction of triple-negative MBC patients.*Trade name not FDA approved. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5062.

Although eosinophilia has been reported as a side effect of purine analogues, there is no report on fludarabine-induced eosinophilia in chronic lymphocytic leukemia (CLL). During chemotherapy with fludarabine and cyclophosphamide, we observed two cases of significant eosinophilia. A 67-year-old patient with CLL developed bone marrow and peripheral blood eosinophilia up to 7.9x10(9)/l, the highest eosinophil count ever reported during treatment with a purine analogue. The eosinophilia persisted for 33 days. Another patient developed bone marrow eosinophilia without eosinophilia in the peripheral blood. These are the first documented cases of fludarabine-induced eosinophilia in CLL, and this side effect may conceivably be more common than previously recognized.

In a patient with nephrotic syndrome, renal biopsy revealed AL amyloid deposits. Monoclonal lambda light chains were identified in serum and urine. A low percentage of monoclonal plasma cells was detected in the bone marrow. The patient received four cycles of VAD and subsequent high-dose chemotherapy (HDCT) with melphalan (200 mg/m2) followed by autologous peripheral blood stem cell transplantation. Proteinuria rapidly diminished during chemotherapy. Three months after HDCT, the patient has no edema, and no signs of plasma cell dyscrasia are currently detectable. Using VAD before starting HDCT may improve the condition of patients with amyloidosis and reduce transplantation-related morbidity and mortality.

SummaryUm Leitlinien fur die adjuvante Therapie bei Kolon- und Rektumkarzinom zu erstellen, haben Vertreter der CAO, der AIO und der ARO am 11. 03.1994 einen Konsens erarbeitet; dieser wu

Purpose The third-generation nonsteroidal aromatase inhibitors (AIs) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal, hormone receptor–positive (HR+) breast cancer. Because many patients subsequently experience progression or relapse, it is important to identify agents with efficacy after AI failure. Materials and Methods Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) is a randomized, double-blind, placebo controlled, multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR+ advanced breast cancer (ABC) progressing or recurring after nonsteroidal AI. The primary end point was time to progression (TTP). A fulvestrant loading-dose (LD) regimen was used: 500 mg intramuscularly on day 0, 250 mg on days 14, 28, and 250 mg every 28 days thereafter. Exemestane 25 mg orally was administered once daily. Results A total of 693 women were randomly assigned to fulvestrant (n = 351) or exemestane (n = 342). Approximately 60% of patients had received at least two prior endocrine therapies. Median TTP was 3.7 months in both groups (hazard ratio = 0.963; 95% CI, 0.819 to 1.133; P = .6531). The overall response rate (7.4% v 6.7%; P = .736) and clinical benefit rate (32.2% v 31.5%; P = .853) were similar between fulvestrant and exemestane respectively. Median duration of clinical benefit was 9.3 and 8.3 months, respectively. Both treatments were well tolerated, with no significant differences in the incidence of adverse events or quality of life. Pharmacokinetic data confirm that steady-state was reached within 1 month with the LD schedule of fulvestrant. Conclusion Fulvestrant LD and exemestane are equally active and well-tolerated in a meaningful proportion of postmenopausal women with ABC who have experienced progression or recurrence during treatment with a nonsteroidal AI.

Investigation of high-dose chemotherapy (HD-CT) compared with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and >/=10 axillary lymph nodes. From November 1993 to September 2000, 307 patients were randomized to receive after four cycles of epirubicin (90 mg/m(2)), cyclophosphamide (600 mg/m(2)) i.v. (every 21 days) and either HD-CT of cyclophosphamide (1500 mg/m(2)), thiotepa (150 mg/m(2)) and mitoxantrone (10 mg/m(2)) i.v. for four consecutive days followed by stem cell transplantation or a SD-CT of three cycles CMF (cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), 5-fluorouracil 600 mg/m(2), i.v. on day 1 and 8, respectively, every 28 days). After a median follow-up of 6.1 years, 166 events with respect to event-free survival (EFS) (SD-CT: 91, HD-CT: 75) have been observed. The hazard ratio of HD-CT versus SD-CT is estimated as 0.80 [95% confidence interval (0.59, 1.08)], P = 0.15. The trend to a superiority of HD-CT as compared with SD-CT with respect to EFS seems to be more pronounced in premenopausal patients as compared with postmenopausal patients and in patients with tumor grade 3 as compared with patients with tumor grade 1/2. With a follow-up of 6 years, there was a trend in favor of HD-CT with respect to EFS not being significant. A proper meta-analysis needs to be undertaken for an evaluation of subgroups of patients who might benefit from HD-CT.

BACKGROUND Proteasome inhibitors are a novel class of compounds entering clinical trials as a method to increase tumour sensitivity to standard chemotherapy. This phase I/II trial was carried out to evaluate the combination of capecitabine and the proteasome inhibitor bortezomib in anthracycline and/or taxane-pretreated patients with metastatic breast cancer. PATIENTS AND METHODS A total of 35 patients were treated with bortezomib (1.0-1.3 mg/m(2) on days 1, 4, 8 and 11) and capecitabine (1500-2500 mg/m(2) on days 1-14) in 3-week intervals for up to eight cycles. RESULTS The maximum tolerated doses (MTDs) were bortezomib 1.3 mg/m(2) and capecitabine 2500 mg/m(2). The treatment was generally well tolerated and associated with toxic effects that were consistent with the known side-effects of the individual agents. The intent-to-treat overall response rate was 15% and an additional 27% of patients had stable disease (SD). In the 20 patients treated at the MTD, the response rate was 15% and 40% had SD. Median time to progression and overall survival were 3.5 months [95% confidence interval (CI) 1.9-4.4] and 7.5 months (95% CI 5.6-14.6), respectively. Median duration of response was 4.4 months. CONCLUSION The combination of bortezomib and capecitabine is well tolerated and has moderate antitumour activity in heavily pretreated patients.

Compound 48 (C48) is a novel dual ligand for peroxisome proliferator-activated receptor alpha and gamma (PPAR alpha/gamma). Culture of imatinib-sensitive and -resistant CML cell lines with C48 resulted in a strong growth inhibition which associated with G0/G1 cell cycle arrest. However, it showed no obvious toxicity to normal CD34(+) hematopoietic stem cells. Decrease of pSTATs and pAKT were noticed suggesting that interference of AKT and STATs signaling may be the mechanisms for the effects of PPAR alpha/gamma ligands. Of more clinical importance, this ligand strongly enhanced the anticancer-effects of imatinib. Overall, our data suggest that the PPAR alpha/gamma ligands may have potentials in the treatment of CML in an adjuvant setting either before or after the development of imatinib resistance.

Estrogen deprivation by aromatase inhibition is an effective treatment in breast cancer. Between October 1986 and March 1988, 91 postmenopausal patients with advanced breast cancer entered a phase II study performed jointly in three center to investigate the new aromatase inhibitor 4-hydroxyandrostenedione. Patients received 500 mg 4-hydroxyandrostenedione intramuscularly (IM) every 2 weeks for 6 weeks, and 250 mg every 2 weeks thereafter. There were two complete (CRs) and 19 partial remissions (PRs) (response rate, 23%). Disease stabilization (no change; NC) was seen in 26 patients, and in 44 patients (48%), disease progression occurred. Duration of the CRs is 20+ months, median durations of PR and NC are 13+ and 8 months, respectively. Receptor status, relapse-free interval, and sites of metastatic lesions did not appear to influence treatment results. However, efficacy of previous tamoxifen treatment favorably predicted response to 4-hydroxyandrostenedione. Serum estradiol levels decreased significantly in patients after 2 weeks of treatment. Side effects were mostly nonspecific and of low degree, requiring discontinuation of treatment in only 3% of the patients. We conclude that aromatase inhibition with 4-hydroxyandrostenedione is efficacious in the treatment of postmenopausal breast cancer.

Therapeutical hyperthermia has been considered for cancer therapy since William Coley observed tumour remission after induction of fever by bacterial toxins at the end of the 19th century. Because fever is associated with a variety of immunological reactions, it has been suspected, that therapeutical hyperthermia might also activate the immune system in a reproducible manner and thereby positively influence the course of the disease. During the last decade, new insight has been gained regarding the immunological changes taking place during therapeutic hyperthermia. In this chapter, we review the most relevant data known about the effect of hyperthermia on the immune system with special focus on alterations induced by therapeutical whole-body hyperthermia (WBH) in cancer patients.

Therapeutical hyperthermia has been considered for cancer therapy since William Coley observed tumour remission after induction of fever by bacterial toxins at the end of the 19th century. Because fever is associated with a variety of immunological reactions, it has been suspected, that therapeutical hyperthermia might also activate the immune system in a reproducible manner and thereby positively influence the course of the disease. During the last decade, new insight has been gained regarding the immunological changes taking place during therapeutic hyperthermia. In this chapter, we review the most relevant data known about the effect of hyperthermia on the immune system with special focus on alterations induced by therapeutical whole-body hyperthermia (WBH) in cancer patients.

BACKGROUND. Inflammation and perturbation of the hypothalamic-pituitary-adrenal (HPA) axis function appears to play a putative role in the etiology of depression. Patients with metastatic cancer demonstrate elevated prevalence rates for depression. The objective of the current study was to illustrate the efficacy of interleukin-6 (IL-6) and HPA axis function as adjuncts to support the diagnosis of depression in cancer patients. METHODS. Plasma concentrations of IL-6 and cortisol were measured in 114 cancer patients with and without depression. The relative diurnal variation of cortisol (cortisol VAR), expressed as a percentage, was calculated. Receiver operating characteristics analysis was performed. RESULTS. Depression was associated with increased plasma concentrations of IL-6 (18.7 pg/mL vs. 2.7 pg/mL; P < .001) and higher cortisol concentrations at 8 AM and 8 PM. The relative cortisol VAR (11.7% vs. 60.6%, respectively; P < .001) was found to be decreased in cancer patients with depression, indicating a disturbed circadian function of the HPA axis. As a biomarker of depression, IL-6 yielded at a cutoff value of 10.6 pg/mL, a sensitivity of 79%, and a specificity of 87% (area under the curve [AUC] = 0.86; 95% confidence interval [95% CI], 0.78–0.94), whereas cortisol VAR demonstrated a sensitivity of 81% and a specificity of 88% (AUC = 0.85; 95% CI, 0.74–0.97) at a cutoff value of 33.5%. CONCLUSIONS. Depression is associated with increased plasma IL-6 concentrations in patients with cancer. These patients demonstrate a dysfunction of the HPA-axis, characterized by a decreased diurnal variation of cortisol. The high sensitivity and specificity of these parameters biomarkers of depression make IL-6 and cortisol VAR helpful tools in the diagnosis of depression in patients with cancer. Cancer 2006. © 2006 American Cancer Society.

Treatment of adult Philadelphia chromosome-positive lymphocytic leukemia is rarely successful. We report here the effects of TZD18, a novel dual ligand specific for peroxisome proliferator-activated receptor alpha and gamma (PPARalpha/gamma) on Ph(+) lymphocytic leukemia cell lines BV173, SD1, and SupB-15. Exposure of these cells to TZD18 resulted in growth inhibition in a dose- and time-dependent manner that was associated with G(1) cell cycle arrest. This effect was much stronger than that mediated by the PPARgamma ligand pioglitazone (PGZ), which also belongs to the thiazolidinediones (TZD) class of ligands. However, it may not be mediated through PPARgamma or PPARalpha activation because antagonists of PPARgamma and PPARalpha cannot reverse it. Study of the key regulators of cell cycle progression by Western blot analysis showed that the expression of the cyclin-dependent kinase inhibitor (CDKI) p27(kip1), but not that of p21(cip1), was enhanced, whereas that of c-Myc, cyclin E, cyclin D2, and cyclin-dependent kinases 2 and 4 (CDK-2 and CDK-4) was decreased when these cells were treated with TZD18 (10 or 20 microM). Therefore, the up-regulation of p27(kip1) and the down-regulation of CDK-2 and CDK-4 may, at least in part, account for the G(1) cell cycle arrest. Furthermore, a remarkable induction of apoptosis was observed in the cells treated with this dual ligand. No obvious alteration of bcl-2 protein level occurred, but bax was up-regulated in these TZD18-treated cells. Activation of caspase 8 and caspase 9 by TZD18 was also observed. Importantly, NF-kappaB DNA-binding activity was markedly decreased by the TZD18 treatment. In addition, TZD18 enhanced the growth inhibitory effect of imatinib, a specific tyrosine kinase inhibitor therapeutically used in the treatment of Ph(+) leukemia. Overall, our findings strongly suggest that TZD18 may offer a new therapeutic approach to aid in the treatment of Ph(+) lymphocytic leukemia.

Haufigkeit: Das Mammakarzinom stellt mit etwa 23% aller malignen Erkrankungen den haufigsten Tumor der Frau dar. In der westlichenWelt erkrankt derzeit jede 8-10. Frau an diesem Tumor. Die kumulative Wahrscheinlichkeit, im Verlauf des Lebens an Brustkrebs zu erkranken, betragt fur Frauen in den westlichen Landern 5-12%.

The prescription practice of adjuvant therapy with aromatase inhibitors (AI) in Germany is not known, also considering that approval is still limited or awaited. We conducted a survey among breast specialists of the German Society of Senology.A standardized questionnaire and the latest abstracts of the 3 trials were sent out to 1,223 members, responses were anonymized. All questions were to be answered with respect to the patients' national health insurance (NHS) or private health insurance (PHS) status.Questionnaire were predominantly completed by gynecologists (82.4%). In all,16,000 breast cancer patients had been treated in 2003. A total of 69.4% of physicians initiated adjuvant AI in up to 25% of NHS patients, 5.6% treated50% of patients. However, 10.3% of physicians treated50% of their PHS patients with an AI. Under the hypothesis of an unrestricted label for AI, 44.5% of physicians would treat50% patients. The switch to an AI after 2-3 years of tamoxifen was chosen in 22% for NHS patients and in 36% of PHS patients. Continuing an AI after 5 years of tamoxifen was favored. in 26% of NHS and 35% of PHS patients.Tamoxifen as the previous gold standard is being replaced by AI; a dramatic change in treatment pattern is expected with less restricted approval.

Background: Combinations of anthracyclines, taxanes and gemcitabine have shown high activity in breast cancer. This trial was designed to evaluate a modified combination regimen as primary chemotherapy. Non-pegylated liposomal doxorubicin (NPLD) was used instead of conventional doxorubicin to improve cardiac safety. Gemcitabine was given 72 h after NPLD and docetaxel as a prolonged infusion over 4 h in order to optimize synergistic effects and accumulation of active metabolites. Patients and methods: Forty-four patients with histologically confirmed stage II or III breast cancer were treated with NPLD (60 mg/m 2 ) and docetaxel (75 mg/m 2 ) on day 1 and gemcitabine as 4-h infusion (350 mg/m 2 ) on day 4. Treatment was repeated every 3 weeks for a maximum of six cycles. All patients received prophylactically recombinant granulocyte colony-stimulating factor. Patients with axillary lymph node involvement after primary chemotherapy received adjuvant treatment with cyclophosphamide, methotrexate and fluorouracil. Results: The clinical response rate was 80%, and complete remissions of the primary tumor occurred in 10 patients (25%). Breast conservation surgery was performed in 19 out of 20 patients (95%) with an initial tumor size of less than 3 cm and in 14 patients (70%) with a tumor size £3 cm. Seven patients had histologically confirmed complete responses accounting for a pCR rate of 17.5%. Expression of Ki-67 was the most important predictive parameter for response with high 38.9% breast pCR rate in patients with elevated Ki-67 expression. Although the predominant toxicity was myelosuppression with grade 3/4 neutropenia in 61% of patients few neutropenic complications resulted. Non-hematological toxicity was generally moderate with grade 3 or 4 toxicity in 10.0% of cycles. Most common non-hematologic toxicities were nausea, vomiting, alopecia, mucositis, asthenia and elevation of liver enzymes. Conclusion: The evaluated schedule provides a safe and highly effective combination treatment for patients with early breast cancer, which is suitable for phase III studies.

Cancer-induced bone disease results in bone destruction, pathological fractures, and pain. We hypothesized that the inhibition of the proteasome-ubiquitin system in osteoclasts could abolish the receptor activator of NF-kappaB ligand (RANKL) mediated osteoclast differentiation and function, since RANKL-mediated downstream signaling plays a crucial role in osteoclast life cycle. In this study, we examined the effects of the proteasome inhibitors MG-132 and MG-262 on RANKL-induced osteoclast differentiation and function. Osteoclast precursors from peripheral blood mononuclear cells were cultured in the presence of RANKL and M-CSF. Osteoclasts were identified as multi-nucleated TRAP-positive cells. Osteoclast function was quantified with the extent of dentine resorption and TRAP activity in culture supernatants. For the evaluation of the effects of proteasome inhibitors towards osteoclastogenesis, sub-apoptotic concentrations of MG-132 and MG-262 were used. Effects on NF-kappaB were obtained in treated and untreated osteoclasts. MG-132 and MG-262 inhibit both osteoclast differentiation and osteoclast function. 0.01 microM MG-132 induced a 3.2-fold (P = 0.004) and 0.001 microM MG-262 a 3.3-fold (P = 0.004) reduction of osteoclast differentiation, respectively. The resorption capacity was decreased 2.6- and 11.1-fold (P = 0.003) by treatment with 0.01 and 0.1 microM MG-132, and 14.2- and 16.6-fold (P = 0.003) by 0.001 and 0.01 microM MG-262, respectively. This decrease correlated with the extent of NF-kappaB binding capacity. In conclusion, this study shows for the first time that proteasome inhibitors act on osteoclast development and function at low concentrations and should be considered as potential drugs for the treatment of cancer-induced osteolytic bone disease.

Proteasome inhibitors represent novel anti-cancer drugs which interact with the proteasome-ubiquitin pathway. The 26S proteasome is a multicatalytic threonine protease with three distinct catalytic activities. It is responsible for intracellular protein turnover in eukaryotic cells, including the processing and degradation of short- and some long-living proteins required for regulation of various cellular functions. Subsequently, the inhibition of the proteasomal function results in stabilization and accumulation of its substrates, which notably include cyclins, cyclin-dependent kinase inhibitors, transcriptional factors, tumor suppressor proteins and proto-oncogenes. This results in confounding signals in the cell inducing cell cycle arrest and activation of apoptotic programs. Acting on transcriptional factor NF-kappaB, which is upregulated in some tumors undergoing chemotherapy or irradiation and downregulated by proteasome inhibition, a significant chemosensitization and consequently synergistic effects concerning the anti-tumor activity could be achieved. Bortezomib is the first proteasome inhibitor that has entered clinical trials. In multiple myeloma, both the US Food and Drug Administration and European Medicine Evaluation Agency granted approval for the use of bortezomib (Velcade) for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. At present, other trials examine the activity in a variety of solid tumors and hematological malignancies. This paper reviews preclinical and clinical results.

Item does not contain fulltext For many years, tamoxifen has been the 'gold standard' amongst anti-oestrogen therapies for breast cancer. However, the selective aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, have demonstrated advantages over tamoxifen as first-line treatments for advanced disease. Anastrozole is also more effective as an adjuvant treatment in early, operable breast cancer and is being increasingly used in the adjuvant setting. Generally, the selective oestrogen receptor modulators (SERMs), such as toremifene, droloxifene, idoxifene, raloxifene, and arzoxifene, show minimal activity in tamoxifen-resistant disease and show no superiority over tamoxifen as first-line treatments. In addition to these agents, other treatment options for advanced disease include high-dose oestrogens and progestins. Response rates for high-dose oestrogens and tamoxifen are similar, but the use of oestrogens is limited by their toxicity profile. Consequently, there is a need for new endocrine treatment options for breast cancer, particularly for use in disease that is resistant to tamoxifen or AIs. Fulvestrant ('Faslodex') is a new type of steroidal oestrogen receptor (ER) antagonist that downregulates cellular levels of the ER and progesterone receptor and has no agonist activity. This paper reviews the key efficacy and tolerability data for fulvestrant in postmenopausal women in the context of other endocrine therapies and explores the potential role of fulvestrant within the sequencing of endocrine therapies for advanced breast cancer.

Approximately 75% of breast tumours in postmenopausal women are positive for the oestrogen receptor (ER) and/or the progesterone receptor (PgR) and are, therefore, potential candidates for endocrine treatment. Fulvestrant is a new type of ER antagonist with no agonist effects and a novel mode of action; it binds, blocks and degrades the ER, leading to a reduction in cellular ER and, consequently, in PgR levels. This novel mode of action results in a lack of cross-resistance with other commonly used endocrine treatments. In Phase III trials in postmenopausal women with advanced breast cancer progressing on prior anti-oestrogen therapy, fulvestrant was at least as effective as the third-generation aromatase inhibitor, anastrozole, in terms of time to progression and objective response, and was associated with similar overall survival. In the first-line setting, fulvestrant showed similar efficacy to tamoxifen in patients with ER-positive and/or PgR-positive disease. Efficacy in more heavily pretreated patients has also been demonstrated in the fulvestrant compassionate use programme. Fulvestrant is well tolerated, being associated with a significantly lower incidence of joint disorders compared with anastrozole, and a lower incidence of hot flushes compared with tamoxifen. Fulvestrant, therefore, provides clinicians with a useful additional treatment for hormone-sensitive advanced breast cancer in postmenopausal women. Ongoing trials will help to clarify the optimal position of fulvestrant in the endocrine treatment sequence for these patients.

The HER-2/neu oncogene is overexpressed in many types of cancer and especially in 25% to 30% of breast cancers. Single reports mention HER-2/neu positivity in hematological malignancies like Hodgkins's disease and even diffuse large-cell lymphoma.To test for HER-2/neu overexpression in patients with non-Hodgkin's lymphoma and the possible role of the recombinant monoclonal anti-HER-2/neu antibody trastuzumab (Herceptin) in the treatment of non-Hodgkin's lymphoma.Serum samples from 87 consecutive unselected patients with non-Hodgkin's lymphoma were retrospectively retrieved from a serum bank and tested for the shed antigen of HER-2/neu using the Oncogene Sciences ELISA assay (Cambridge, MA, USA). From those lymphoma patients, the paraffin-embedded lymph-node specimens of 25 cases with diffuse large-cell lymphoma were stained with the HER-2/neu DAKO HercepTest.In 87 lymphoma patients, the serum level of HER-2/neu ranged from 3.6 to 244.1 ng/ml (median 8.0 ng/ml). Only 2 patients showed a marginal or increased HER-2/neu level with 15 ng/ml (which is the upper limit of normal) and 244.1 ng/ml, respectively. No patient with diffuse large-cell lymphoma showed HER-2/neu overexpression by immunhistochemistry of the lymph node. The paraffin block of the one patient with a very high HER-2/neu serum level was also stained for HER-2/neu overexpression. In this patient, suffering from a high-grade T-cell non-Hodgkin's lymphoma, no staining could be found.HER-2/neu is not overexpressed in non-Hodgkin's lymphoma and especially not in diffuse large-cell lymphoma, using a standardized immunochemistry technique with complementary serum testing. Thus, specific anti-HER-2/neu-targeted therapy should play no role in the treatment of non-Hodgkin's lymphoma.

To examine the effect of a novel peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonist TZD18 on cell proliferation and apoptosis in human glioblastoma T98G cells and its possible mechanism.RT-PCR, MTT, TUNEL, Flow cytometry, and Western blot analysis were employed.TZD18 inhibited the growth of T98G cells in a concentration-dependent manner, which was associated with a G1 to S cell cycle arrest. Besides, significant apoptosis was induced after treatment with a non-toxic dose of TZD18. During the process, the expression of Bcl-2 protein was down-regulated, while that of Bax and p27kip proteins was up-regulated, and the activity of caspase-3 was elevated. However, this effect appeared to be PPARalpha and PPARgamma independent since their antagonists could not reverse this effect.TZD18, a novel PPARalpha/gamma dual agonist, inhibited cell growth and induce apoptosis in human glioblastoma T98G cells in vitro, indicating a therapeutic potential for TZD18 in the treatment of glioblastoma.

Elevated levels of the extracellular domain of HER-2/neu in serum (sHER-2/neu) have been shown to be of prognostic importance. In this phase II study with weekly paclitaxel in metastatic breast cancer, we investigated the predictive quality of this serum oncoprotein by correlating the outcome of therapy to sHER-2/neu levels. Paclitaxel (90 mg/m2 weekly x6, q9w) was administered to 35 patients with complete outcome assessment and biochemical follow-up. sHER-2/neu was measured using standardized enzyme-linked immunoassays. We found that 62.9% (22/35) of the patients had elevated levels (or = 15 ng/ml) of sHER-2/neu. The overall response rate (RR) to weekly paclitaxel was 40.0% (14/35). There was no difference in RR between sHER-2/neu-positive patients (40.9%) and sHER-2/neu-negative patients (38.5%; p = 0.4). The progression-free interval was longer for sHER-2/neu-negative patients (53.2 weeks) in comparison to sHER-2/neu-positive patients (31.2 weeks; p = 0.098). Responses were significantly more durable in sHER-2/neu-negative patients (65.2 weeks) than in the sHER-2/neu-positive subgroup (25.7 weeks; p = 0.042). Introducing hypothetical cut-offs into the sHER-2/neu-positive subset, we found that in patients with a sHER-2/neu level of greater than 22 ng/ml, the progression-free survival decreased significantly with increasing sHER-2/neu levels (por = 0.022). Considering the high impact of progression-free survival and duration of response as outcome parameters, the sHER-2/neu status is a predictive indicator for benefit from paclitaxel chemotherapy.

Objectives Acute cytostatic drug induced nausea and vomiting is provoked by a release of endogenous serotonin that mediates its effect by binding to the 5-hydroxytryptamine type 3 (5-HT 3 ) receptors. The most effective antiemetic drugs are the 5-HT 3 receptor antagonists. Nevertheless about 30% of the patients do not respond satisfactorily. Five 5-HT 3 receptor genes (5-HT 3A-E ) with high sequence homology have been identified. Two subunits, the 5-HT 3A and 5-HT 3B are expressed in anatomical structures known to'be involved in the mechanism of acute cytostatic drug induced emesis. Methods We included 242 cancer patients at their first day of chemotherapy to investigate the influence of genetic polymorphisms of the 5-HT 3A receptor gene on the intensity of nausea and vomiting which was documented using standardized interviews and visual analog scales. Results Sequencing of the entire 5-HT 3A receptor gene of all patients revealed 21 polymorphisms, two of them were amino acid substitutions (Ala33Thr, Met257IIe). Linkage disequilibrium analysis revealed that 15 polymorphisms of the 5-HT 3A receptor gene are partially linked to each other. However, none of the haplotypes was significantly associated with the intensity of cytostatic induced nausea and vomiting. Conclusion Polymorphisms and haplotype analysis of the 5-HT 3A receptor gene may not serve as a pharmacogenetic predictor of the antiemetic treatment with 5-HT 3 receptor antagonists in cancer patients.

To assess the efficacy and safety of primary systemic treatment with doxorubicin and paclitaxel in patients with early breast cancer. Forty patients with newly diagnosed, histologically confirmed breast cancer (T2, N0–1, M0) received primary chemotherapy with doxorubicin (60 mg/m2) and paclitaxel (200 mg/m2) in 3-week intervals for up to four courses. A total of 151 cycles were administered. The clinical response rate as assessed by sonographic measurement was 70%, and complete remissions of the primary tumor occurred in two patients. Eight patients (20%) had histologically confirmed complete responses. Predominant toxicity was myelosuppression with grade 3/4 neutropenia in 70% of patients. Non-hematological toxicity was generally moderate. Grade 4 non-hematological toxicities were not observed and grade 3 toxicity was reported with alopecia (98%) and stomatitis (10%). The combination of doxorubicin and paclitaxel is safe and highly active in patients with early breast cancer. The evaluated schedule is suitable for phase III studies.

Campath-1H, a monoclonal antibody against human CD52, is used for the therapy of refractory or relapsed chronic lymphocytic leukemia (CLL). Treatment with campath is associated with an increased incidence of infections and also fatal reactivation of viral infections. Reactivation of hepatitis B virus (HBV) in HBsAg-positive patients is a well-documented complication of cytotoxic or immunosuppressive therapy and has also been observed after treatment with rituximab. To date, there are no reports on campath treatment in HBsAg carriers. Here, we present the case of a patient with heavily pretreated CLL who was HBsAg-positive with a high virus load (2 billion copies/mL). He required treatment because of progressive CLL with massive bone marrow infiltration, severe anemia and thrombocytopenia. Campath was initiated and lamivudine, an inhibitor of reverse transcriptase, was simultaneously given to prevent HBV proliferation. During the treatment, no deterioration of liver parameters was observed, and the virus load decreased. After therapy with campath, hemoglobin and platelet counts increased markedly. This report shows that lamivudine is highly effective in inhibiting HBV proliferation and can be used to prevent HBV flare-up during campath treatment in patients tested positive for HBs antigen.

For molecular diagnosis of fungal disease using DNA amplification procedures in the routine laboratory, choice of appropriate target structures and rapid and inexpensive identification of amplification products are important prerequisites. Most diagnostic procedures described thus far are characterized by limited applicability, considerable cost for laboratory equipment or low power of discrimination between species. This study aimed at identification of a PCR target appropriate for diagnosis of clinically relevant yeasts and an affordable procedure for characterization of the PCR products to the species level. Here, we describe a PCR-based system using amplification of intergenic spacers ITS1 and ITS2 and restriction length polymorphism of PCR products after sequence-specific enzymatic cleavage. We show the evaluation of the system for clinically relevant Candida species. The simple and inexpensive procedure should be instrumental for rapid identification of medically important yeasts.