Analysis of trastuzumab and chemotherapy in advanced breast cancer after the failure of at least one earlier combination: An observational study

BACKGROUND: Combining trastuzumab and chemotherapy is standard in her2/neu overexpressing advanced breast cancer. It is not established however, whether trastuzumab treatment should continue after the failure of one earlier combination. In this trial, we report our experience with continued treatment beyond disease progression. METHODS: Fifty-four patients, median age 46 years, range 25–73 years, were included. We analysed for time to tumour progression (TTP) for first, second and beyond second line treatment, response rates and overall survival. RESULTS: Median time of observation was 24 months, range 7–51. Response rates for first line treatment were 7.4% complete remission (CR), 35.2% partial remissions (PR), 42.6% stable disease > 6 months (SD) and 14.8% of patients experienced disease progression despite treatment (PD). Corresponding numbers for second line were 3.7% CR, 22.2% PR, 42.6% SD and 31.5% PD; numbers for treatment beyond second line (60 therapies, 33 pts 3(rd )line, 18 pts 4(th )line, 6 pts 5(th )line, 2 pts 6(th )line and 1 patient 7(th )line) were 1.7% CR, 28.3% PR, 28.3% SD and 41.6% PD respectively. Median TTP was 6 months (m) in the first line setting, and also 6 m for second line and beyond second line. An asymptomatic drop of left ventricular ejection fraction below 50% was observed in one patient. No case of symptomatic congestive heart failure was observed. CONCLUSION: The data presented clearly strengthen evidence that patients do profit from continued trastuzumab treatment. The fact that TTP did not decrease significantly from first line to beyond second line treatment is especially noteworthy. Still, randomized trials are warranted

Defining and simulating open-ended novelty: requirements, guidelines, and challenges

The open-endedness of a system is often defined as a continual production of novelty. Here we pin down this concept more fully by defining several types of novelty that a system may exhibit, classified as variation, innovation, and emergence. We then provide a meta-model for including levels of structure in a system’s model. From there, we define an architecture suitable for building simulations of open-ended novelty-generating systems and discuss how previously proposed systems fit into this framework. We discuss the design principles applicable to those systems and close with some challenges for the community

Rifaximin preserves intestinal microbiota balance in patients undergoing allogeneic stem cell transplantation

Intestinal dysbiosis has been associated with acute gastrointestinal GvHD and poor outcome following allogeneic stem cell transplantation (ASCT). To assess the effect of a switch in 2012 from ciprofloxacin/metronidazole to rifaximin for gut decontamination on intestinal microbiota composition and ASCT outcome, we retrospectively analyzed 394 patients receiving ASCT from September 2008 through June 2015. In 131 and 90 patients, respectively, urinary 3-indoxyl sulfate levels and intestinal enterococcal load were measured before conditioning and weekly within the first 28 days after ASCT. The use of rifaximin correlated with lower enterococcal positivity (6.9 vs 21.9%, P = 0.05) and higher urinary 3-indoxyl sulfate concentrations (10.5 vs 4.6 mu moL/mmoL crea, P < 0.001) after ASCT. Patients on rifaximin showed lower 1-year transplant-related mortality (P = 0.04) and higher overall survival (P = 0.008). Treatment of infectious complications with systemic antibiotics did not abrogate the beneficial effects of rifaximin on intestinal microbiota composition in the early course of ASCT and outcome. The data underscore the importance of maintaining a diverse population of symbiotic and mutualistic bacteria in the gut on ASCT outcome

Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome

Urinary 3-IS levels predict outcome after ASCT and are associated with antibiotics and NOD2/CARD15 variants.Publisher’s Note: There is an Inside Blood Commentary on this article in this issue.Indole, which is produced from l-tryptophan by commensal bacteria expressing tryptophanase, not only is an important intercellular signal in microbial communities, but also modulates mucosal barrier function and expression of pro- and anti-inflammatory genes by intestinal epithelial cells. Here, we hypothesized that decreased urinary excretion of 3-indoxyl sulfate (3-IS), the major conjugate of indole found in humans, may be a marker of gut microbiota disruption and increased risk of developing gastrointestinal (GI) graft-versus-host-disease. Using liquid chromatography/tandem mass spectrometry, 3-IS was determined in urine specimens collected weekly within the first 28 days after allogeneic stem cell transplantation (ASCT) in 131 patients. Low 3-IS levels within the first 10 days after ASCT were associated with significantly higher transplant-related mortality (P = .017) and worse overall survival (P = .05) 1 year after ASCT. Least absolute shrinkage and selection operator regression models trained on log-normalized counts of 763 operational taxonomic units derived from next-generation sequencing of the hypervariable V3 region of the 16S ribosomal RNA gene showed members of the families of Lachnospiraceae and Ruminococcaceae of the class of Clostridia to be associated with high urinary 3-IS levels, whereas members of the class of Bacilli were associated with low 3-IS levels. Risk factors of early suppression of 3-IS levels were the type of GI decontamination (P = .01), early onset of antibiotic treatment (P = .001), and recipient NOD2/CARD15 genotype (P = .04). In conclusion, our findings underscore the relevance of microbiota-derived indole and metabolites thereof in mucosal integrity and protection from inflammation

Microbiota Disruption Induced by Early Use of Broad-Spectrum Antibiotics Is an Independent Risk Factor of Outcome after Allogeneic Stem Cell Transplantation

In allogeneic stem cell transplantation (ASCT), systemic broad-spectrum antibiotics are frequently used for treatment of infectious complications, but their effect on microbiota composition is still poorly understood. This retrospective analysis of 621 patients who underwent ASCT at the University Medical Center of Regensburg and Memorial Sloan Kettering Cancer Center in New York assessed the impact of timing of peritransplant antibiotic treatment on intestinal microbiota composition as well as transplant-related mortality (TRM) and overall survival. Early exposure to antibiotics was associated with lower urinary 3-indoxyl sulfate levels (P < .001) and a decrease in fecal abundance of commensal Clostridiales (P = .03) compared with late antibiotic treatment, which was particularly significant (P = .005) for Clostridium cluster XlVa in the Regensburg group. Earlier antibiotic treatment before ASCT was further associated with a higher TRM (34%, 79/236) compared with post-ASCT (21%, 62/297, P = .001) or no antibiotics (7%, 6/88, P < .001). Timing of antibiotic treatment was the dominant independent risk factor for TRM (HR, 2.0; P <= .001) in multivariate analysis besides increase age (HR, 2.15; P = .004), reduced Karnofsky performance status (HR, 1.47; P = .03), and female donor male recipient sex combination (HR, 1.56; P = .02) A competing risk analysis revealed the independent effect of early initiation of antibiotics on graft-versus-host disease-related TRM (P = .004) in contrast to infection related TRM and relapse (not significant). The poor outcome associated with early administration of antibiotic therapy that is active against commensal organisms, and specifically the possibly protective Clostridiales, calls for the use of Clostridiales-sparing antibiotics and rapid restoration of microbiota diversity after cessation of antibiotic treatment. (C) 2017 American Society for Blood and Marrow Transplantation

Synaptojanin 2 is a druggable mediator of metastasis and the gene is overexpressed and amplified in breast cancer

Amplified HER2, which encodes a member of the epidermal growth factor receptor (EGFR) family, is a target of effective therapies against breast cancer. In search for similarly targetable genomic aberrations, we identified copy number gains in SYNJ2, which encodes the 5'-inositol lipid phosphatase synaptojanin 2, as well as overexpression in a small fraction of human breast tumors. Copy gain and overexpression correlated with shorter patient survival and a low abundance of the tumor suppressor microRNA miR-31. SYNJ2 promoted cell migration and invasion in culture and lung metastasis of breast tumor xenografts in mice. Knocking down SYNJ2 impaired the endocytic recycling of EGFR and the formation of cellular lamellipodia and invadopodia. Screening compound libraries identified SYNJ2-specific inhibitors that prevented cell migration but did not affect the related neural protein SYNJ1, suggesting that SYNJ2 is a potentially druggable target to block cancer cell migration