Influence of zoledronic acid on disseminated tumor cells in bone marrow and survival: results of a prospective clinical trial

BACKGROUND: The presence of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients is associated with reduced clinical outcome. Bisphosphonate treatment was shown to eradicate DTC from BM in several studies. This controlled randomized open-label multi-center study aimed to investigate the influence of zoledronic acid (ZOL) on DTC and survival of breast cancer patients (Clinical Trial Registration Number: NCT00172068). METHODS: Patients with primary breast cancer and DTC-positive bone marrow were randomized to treatment with ZOL plus adjuvant systemic therapy (n = 40) or adjuvant systemic therapy alone (n = 46) between 03/2002 and 12/2004. DTC were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3 and by cytomorphology. The change in DTC numbers at 12 months and 24 months versus baseline, as well as patient outcomes were evaluated. RESULTS: 86 patients could be included into survival analysis (median follow-up: 88 months, range: 8–108 mths). Patients in the control group were more likely to die during follow-up than those in the ZOL-group (11% vs. 2%, p = 0.106). 15% of patients in the control group presented with relapse whereas only 8% of ZOL group patients developed metastatic or recurrent disease during follow-up (p = 0.205). At 24 months, 16% of patients from the control group were still DTC positive, whereas all patients treated with ZOL became DTC negative (p = 0.032). Patients presenting with persistent DTC 12 months after diagnosis had significantly shorter overall survival (p = 0.011). CONCLUSIONS: Bisphosphonate therapy contributes to eradication of disseminated tumor cells. The positive influence of bisphosphonates on survival in the adjuvant setting may be due to their effects on DTC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00172068 [Zoledronic Acid in the Treatment of Breast Cancer With Minimal Residual Disease in the Bone Marrow (MRD-1)]

Neoadjuvant letrozole in postmenopausal estrogen and/or progesterone receptor positive breast cancer: A phase IIb/III trial to investigate optimal duration of preoperative endocrine therapy

<p>Abstract</p> <p>Background</p> <p>In recent years, preoperative volume reduction of locally advanced breast cancers, resulting in higher rates of breast-conserving surgery (BCS), has become increasingly important also in postmenopausal women. Clinical interest has come to center on the third-generation nonsteroidal aromatase inhibitors (AIs), including letrozole, for such neoadjuvant endocrine treatment. This usually lasts 3–4 months and has been extended to up to 12 months, but optimal treatment duration has not been fully established.</p> <p>Methods</p> <p>This study was designed as a multicenter, open-label, single-arm, exploratory phase IIb/III clinical trial of letrozole 2.5 mg, one tablet daily, for 4–8 months. The primary objective was to investigate the effect of neoadjuvant treatment duration on tumor regression and BCS eligibility to identify optimal treatment duration. Tumor regression (by clinical examination, mammography, and ultrasound), shift towards BCS eligibility, and safety assessments were the main outcome measures. Standard parametric and nonparametric descriptive statistics were performed.</p> <p>Results</p> <p>Letrozole treatment was received by 32 of the enrolled 33 postmenopausal women (median (range): 67.0 (56–85) years) with unilateral, initially BCS-ineligible primary breast cancer (clinical stage ≥ T2, N0, M0). Letrozole treatment duration in the modified intent-to-treat (ITT; required 4 months' letrozole treatment) analysis population (29 patients) was 4 months in 14 patients and > 4 months in 15 patients. The respective per-protocol (PP) subgroup sizes were 14 and 11. The majority of partial or complete responses were observed at 4 months, though some beneficial responses occurred during prolonged letrozole treatment. Compared with baseline, median tumor size in the ITT population was reduced by 62.5% at Month 4 and by 70.0% at final study visit (Individual End). Similarly, in the PP population, respective reductions were 64.0% and 67.0%. Whereas initially all patients were mastectomy candidates, letrozole treatment enabled BCS (lumpectomy) in 22 ITT (75.9%) and 18 PP (72.0%) patients.</p> <p>Conclusion</p> <p>Over half of patients become BCS-eligible within 4 months of preoperative letrozole treatment. While prolonged treatment for up to 8 months can result in further tumor volume reduction in some patients, there is no clear optimum for treatment duration. Letrozole has a favorable overall safety and tolerability profile.</p> <p>Trial registration</p> <p>ClinicalTrials.gov identifier NCT00535418.</p

Proteomic Analysis of Neisseria gonorrhoeae Biofilms Shows Shift to Anaerobic Respiration and Changes in Nutrient Transport and Outermembrane Proteins

Neisseria gonorrhoeae, the causative agent of gonorrhea, can form biofilms in vitro and in vivo. In biofilms, the organism is more resistant to antibiotic treatment and can serve as a reservoir for chronic infection. We have used stable isotope labeling by amino acids in cell culture (SILAC) to compare protein expression in biofilm and planktonic organisms. Two parallel populations of N. gonorrhoeae strain 1291, which is an arginine auxotroph, were grown for 48 h in continuous-flow chambers over glass, one supplemented with 13C6-arginine for planktonic organisms and the other with unlabeled arginine for biofilm growth. The biofilm and planktonic cells were harvested and lysed separately, and fractionated into three sequential protein extracts. Corresponding heavy (H) planktonic and light (L) biofilm protein extracts were mixed and separated by 1D SDS-PAGE gels, and samples were extensively analyzed by liquid chromatography-mass spectrometry. Overall, 757 proteins were identified, and 152 unique proteins met a 1.5-fold cutoff threshold for differential expression with p-values <0.05. Comparing biofilm to planktonic organisms, this set included 73 upregulated and 54 downregulated proteins. Nearly a third of the upregulated proteins were involved in energy metabolism, with cell envelope proteins making up the next largest group. Of the downregulated proteins, the largest groups were involved in protein synthesis and energy metabolism. These proteomics results were compared with our previously reported results from transcriptional profiling of gonococcal biofilms using microarrays. Nitrite reductase and cytochrome c peroxidase, key enzymes required for anaerobic growth, were detected as highly upregulated in both the proteomic and transcriptomic datasets. These and other protein expression changes observed in the present study were consistent with a shift to anaerobic respiration in gonococcal biofilms, although changes in membrane proteins not explicitly related to this shift may have other functions

Investigación - COMPOSICIÓN BOTÁNICA DE LA DIETA DE ALPACAS (Lama pacos L.) Y LLAMAS (Lama glama L.) EN DOS ESTACIONES DEL AÑO, EN PRADERAS ALTIPLÁNICAS DE UN SECTOR DE LA PROVINCIA DE PARINACOTA, CHILE (Botanical composition of alpaca (Lama pacos L.) and llama (Lama glama L.) diets in two seasons of the year on highland ranges of Parinacota province, Chile.)

The botanical composition of alpaca (Lama pacos   L.) and llama (Lama glama   L.) diets was determined, grazing on a highland range of Parinacota, Chile (18°12' S lat; 69°16' W long; 4390 m.o.s.l.), using microhistological analysis of feces. The evaluations were carried out in dry-winter and rainy-summer seasons. The availability of dry matter (MS) and botanical composition (BC) of the main grassland, the "bofedal," was measured. The availability of DM varied between 1860 and 2940 kg ha-1, and the BC was dominated by Oxychloe andina   (Cyperaceae) and Festuca nardifolia   (Poaceae). Diets were dominated by species of the bofedal, especially by the grasses (F. nardifolia, Deschampsia caespitosa   and Agrostis tolucensis   ) and grass-like plants (O. andina), also being prominent, the "pajonal" and "tholar" species, Festuca orthophylla and Parastrephia lucida   , respectively, especially in winter and in llama diets. Diets differed in their composition and diversity, there being an interaction between the type of herbivore and the season of the year, with a significant overlapping between 61.4% in summer and 73.6%, in winter, that suggests a differentiated grazing management of these camelids to avoid eventual competition. The Ivlev's selectivity index, highlighted the grass species A. tolucensis, D. caespitosa and the ranunculaceae Ranunculus uniflorus   , which obtained positive values close to one, indicating a high preference by the herbivores. Whereas, the dominant species of bofedal, O. andina, obtained a negative value (rejection), and consequently, tended to dominate in the BC of grassland, having a negative effect on the grassland's condition

Composici\uf3n bot\ue1nica de la dieta de alpacas ( Lama pacos L.) y llamas ( Lama glama L.) en dos estaciones del a\uf1o, en praderas altipl\ue1nicas de un sector de la provincia de Parinacota, Chile

The botanical composition of alpaca ( Lama pacos L.) and llama ( Lama glama L.) diets was determined, grazing on a highland range of Parinacota, Chile (18\ub012' S lat; 69\ub016' W long; 4390 m.o.s.l.), using microhistological analysis of feces. The evaluations were carried out in dry-winter and rainy-summer seasons. The availability of dry matter (MS) and botanical composition (BC) of the main grassland, the "bofedal," was measured. The availability of DM varied between 1860 and 2940 kg ha-1, and the BC was dominated by Oxychloe andina (Cyperaceae) and Festuca nardifolia (Poaceae). Diets were dominated by species of the bofedal, especially by the grasses (F. nardifolia, Deschampsia caespitosa and Agrostis tolucensis ) and grass-like plants (O. andina), also being prominent, the "pajonal" and "tholar" species, Festuca orthophylla and Parastrephia lucida , respectively, especially in winter and in llama diets. Diets differed in their composition and diversity, there being an interaction between the type of herbivore and the season of the year, with a significant overlapping between 61.4% in summer and 73.6%, in winter, that suggests a differentiated grazing management of these camelids to avoid eventual competition. The Ivlev's selectivity index, highlighted the grass species A. tolucensis, D. caespitosa and the ranunculaceae Ranunculus uniflorus , which obtained positive values close to one, indicating a high preference by the herbivores. Whereas, the dominant species of bofedal, O. andina, obtained a negative value (rejection), and consequently, tended to dominate in the BC of grassland, having a negative effect on the grassland's condition.Se determin\uf3 la composici\uf3n de las dietas de alpacas ( Lama pacos L.) y llamas ( Lama glama L.) que pastorearon praderas altipl\ue1nicas de Parinacota, Chile (18\ub012' lat. Sur; 69\ub016' long. Oeste; 4390 m.s.n.m.) utilizando microhistolog\ueda fecal. Las evaluaciones se realizaron en la \ue9poca seca-invernal y la lluviosa-estival. Se midi\uf3 la disponibilidad de materia seca (MS) y composici\uf3n bot\ue1nica (CB) de la principal pradera, el "bofedal". La disponibilidad de MS vari\uf3 entre 1860 y 2940 kg ha-1, y la CB fue dominada por Oxychloe andina (Cyperaceae) y Festuca nardifolia (Poaceae). En las dietas dominaron especies del bofedal, especialmente gram\uedneas (F. nardifolia, Deschampsia caespitosa y Agrostis tolucensis ) y graminoides (O. andina), destacando tambi\ue9n, especies del "pajonal" y el "tolar", Festuca orthophylla y Parastrephia lucida , respectivamente, especialmente en invierno y en las dietas de llamas. Las dietas difirieron en composici\uf3n y diversidad, existiendo una interacci\uf3n entre el tipo de herb\uedvoro y la \ue9poca del a\uf1o, con una significativa superposici\uf3n de 61,4% en verano y de 73,6%, en invierno, lo que sugiere un manejo del pastoreo diferenciado de estos cam\ue9lidos para evitar una eventual competencia. El \uedndice de selectividad de Ivlev, destaca a las gram\uedneas A. tolucensis y D. caespitosa y la ranuncul\ue1cea Ranunculus uniflorus , las que obtuvieron valore positivos y cercanos a uno, indicando una alta preferencia por parte de los herb\uedvoros. Contrariamente, la especie dominante del bofedal, O. andina, obtuvo un valor negativo (rechazo) y, en consecuencia, tender\ue1 a dominar en la CB de la pradera, teniendo un efecto negativo en la tendencia de la condici\uf3n de la misma

Investigación - COMPOSICIÓN BOTÁNICA DE LA DIETA DE ALPACAS (Lama pacos L.) Y LLAMAS (Lama glama L.) EN DOS ESTACIONES DEL AÑO, EN PRADERAS ALTIPLÁNICAS DE UN SECTOR DE LA PROVINCIA DE PARINACOTA, CHILE (Botanical composition of alpaca (Lama pacos L.) and llama (Lama glama L.) diets in two seasons of the year on highland ranges of Parinacota province, Chile.)

The botanical composition of alpaca (Lama pacos   L.) and llama (Lama glama   L.) diets was determined, grazing on a highland range of Parinacota, Chile (18°12' S lat; 69°16' W long; 4390 m.o.s.l.), using microhistological analysis of feces. The evaluations were carried out in dry-winter and rainy-summer seasons. The availability of dry matter (MS) and botanical composition (BC) of the main grassland, the "bofedal," was measured. The availability of DM varied between 1860 and 2940 kg ha-1, and the BC was dominated by Oxychloe andina   (Cyperaceae) and Festuca nardifolia   (Poaceae). Diets were dominated by species of the bofedal, especially by the grasses (F. nardifolia, Deschampsia caespitosa   and Agrostis tolucensis   ) and grass-like plants (O. andina), also being prominent, the "pajonal" and "tholar" species, Festuca orthophylla and Parastrephia lucida   , respectively, especially in winter and in llama diets. Diets differed in their composition and diversity, there being an interaction between the type of herbivore and the season of the year, with a significant overlapping between 61.4% in summer and 73.6%, in winter, that suggests a differentiated grazing management of these camelids to avoid eventual competition. The Ivlev's selectivity index, highlighted the grass species A. tolucensis, D. caespitosa and the ranunculaceae Ranunculus uniflorus   , which obtained positive values close to one, indicating a high preference by the herbivores. Whereas, the dominant species of bofedal, O. andina, obtained a negative value (rejection), and consequently, tended to dominate in the BC of grassland, having a negative effect on the grassland's condition

FemZone trial: a randomized phase II trial comparing neoadjuvant letrozole and zoledronic acid with letrozole in primary breast cancer patients

Background: The objective of this prospectively randomized phase II trial (Trial registration: EUCTR2004-004007-37-DE) was to compare the clinical response of primary breast cancer patients to neoadjuvant therapy with letrozole alone (LET) or letrozole and zoledronic acid (LET + ZOL). Methods: Patients were randomly assigned to receive either LET 2.5 mg/day (n = 79) or the combination of LET 2.5 mg/day and a total of seven infusions of ZOL 4 mg every 4 weeks (n = 89) for 6 months. Primary endpoint was clinical response rate as assessed by mammogram readings. The study was terminated prematurely due to insufficient recruitment. We report here on an exploratory analysis of this data. Results: Central assessment of tumor sizes during the treatment period was available for 131 patients (66 LET, 65 LET + ZOL). Clinical responses (complete or partial) were seen in 54.5% (95% CI: 41.8-66.9) of the patients in the LET arm and 69.2% (95% CI: 56.6-80.1) of those in the LET + ZOL arm (P = 0.106). A multivariate model showed an OR of 1.72 (95% CI: 0.83-3.59) for the experimental arm. Conclusion: No increase in the clinical response rate was observed with the addition of ZOL to a neoadjuvant treatment regimen with LET. However a trend towards a better reponse in the LET + ZOL arm could be observed. This trend is consistent with previous studies that have investigated the addition of ZOL to chemotherapy, and it may support the evidence for a direct antitumor action of zoledronic acid