Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor-Positive Breast Cancer.

Importance: Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor-positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking. Objective: To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer. Design, Setting, and Participants: This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])-high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022. Main Outcomes and Measures: Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses. Results: Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, -0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction = .006) or tamoxifen plus OFS (absolute benefit, -1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively. Conclusions and Relevance: In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.

Closing the gap: prognostic and predictive biomarker validation for personalized care in a Latin American hormone-dependent breast cancer cohort.

BACKGROUND: Several guidelines recommend the use of different classifiers to determine the risk of recurrence (ROR) and treatment decisions in patients with HR+HER2- breast cancer. However, data are still lacking for their usefulness in Latin American (LA) patients. Our aim was to evaluate the comparative prognostic and predictive performance of different ROR classifiers in a real-world LA cohort. METHODS: The Molecular Profile of Breast Cancer Study (MPBCS) is an LA case-cohort study with 5-year follow-up. Stages I and II, clinically node-negative HR+HER2- patients (n = 340) who received adjuvant hormone therapy and/or chemotherapy, were analyzed. Time-dependent receiver-operator characteristic-area under the curve, univariate and multivariate Cox proportional hazards regression (CPHR) models were used to compare the prognostic performance of several risk biomarkers. Multivariate CPHR with interaction models tested the predictive ability of selected risk classifiers. RESULTS: Within this cohort, transcriptomic-based classifiers such as the recurrence score (RS), EndoPredict (EP risk and EPClin), and PAM50-risk of recurrence scores (ROR-S and ROR-PC) presented better prognostic performances for node-negative patients (univariate C-index 0.61-0.68, adjusted C-index 0.77-0.80, adjusted hazard ratios [HR] between high and low risk: 4.06-9.97) than the traditional classifiers Ki67 and Nottingham Prognostic Index (univariate C-index 0.53-0.59, adjusted C-index 0.72-0.75, and adjusted HR 1.85-2.54). RS (and to some extent, EndoPredict) also showed predictive capacity for chemotherapy benefit in node-negative patients (interaction P = .0200 and .0510, respectively). CONCLUSION: In summary, we could prove the clinical validity of most transcriptomic-based risk classifiers and their superiority over clinical and immunohistochemical-based methods in the heterogenous, real-world node-negative HR+HER2- MPBCS cohort.

Choosing Wisely in oncology in Latin America: what SLACOM does not recommend in the care of cancer patients in Latin America: Ten essential recommendations to avoid harmful onclogy procedures in Latin America.

Choosing Wisely is an initiative by the American Board of Internal Medicine (ABIM) and ABIM Foundation to deter unnecessary medical treatments and procedures. Faced with the burden of modern technologies and treatments, it is crucial to identify practices lacking value in daily care. The Latin American and Caribbean Society (SLACOM), comprising cancer control experts, deems it vital to tailor this initiative for enhancing cancer care in the region. Through a modified DELPHI methodology involving two rounds of electronic questionnaires and a hybrid meeting to discuss key points of contention, ten essential recommendations were identified and prioritised to avoid harmful oncology procedures in our region. These consensus-based recommendations, contextualised for Latin America, have been compiled and shared to benefit patients. The Scientific Committee, consisting of prominent oncologists and health experts, collaborates remotely to drive this project forward.

Adjuvant Endocrine Therapy in Premenopausal Breast Cancer: 12-Year Results From SOFT.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The Suppression of Ovarian Function Trial (SOFT; ClinicalTrials.gov identifier: NCT00066690) randomly assigned premenopausal women with hormone receptor-positive breast cancer to 5 years of adjuvant tamoxifen, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. The primary analysis compared disease-free survival (DFS) between tamoxifen plus OFS versus tamoxifen alone; exemestane plus OFS versus tamoxifen was a secondary objective. After 8 years, SOFT reported a significant reduction in recurrence and improved overall survival (OS) with adjuvant tamoxifen plus OFS versus tamoxifen alone. Here, we report outcomes after median follow-up of 12 years. DFS remained significantly improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.82; 95% CI, 0.69 to 0.98) with a 12-year DFS of 71.9% with tamoxifen, 76.1% with tamoxifen plus OFS, and 79.0% with exemestane plus OFS. OS was improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.78; 95% CI, 0.60 to 1.01) and was 86.8% with tamoxifen, 89.0% with tamoxifen plus OFS, and 89.4% with exemestane plus OFS at 12 years. Among those who received prior chemotherapy for human epidermal growth factor receptor-2-negative tumors, OS was 78.8% with tamoxifen, 81.1% with tamoxifen plus OFS, and 84.4% with exemestane plus OFS. In conclusion, after 12 years, there remains a benefit from including OFS in adjuvant endocrine therapy, with an absolute improvement in OS more apparent with higher baseline risk of recurrence.[Media: see text].

[Recommendations about the Programming of Medical Activities in Medical Oncology of the Chilean Society of Medical Oncology]. / Recomendaciones acerca de la Programación de las Actividades Médicas en Oncología Médica de la Sociedad Chilena de Oncología Médica.

The incidence of cancer is increasing, which translates into a higher demand for medical oncology services every day. Work overload and, consequently, the development of burnout is present in up to 50% of medical oncology staff. AIM: The objective of this publication is to expose the current situation and to establish recommendations for the scheduling of the medical activities in medical oncology considering the different types of care delivery and the necessary time for these to improve patient care while protecting the physician wellbeing. MATERIALS AND METHODS: A review of the national and international literature was carried out regarding the scheduling of medical oncology care, and a web seminar was held with national medical specialists in oncology. RESULTS: We were able to show that there are no standard schedules, and there is a great dispersion in the number of patients treated in the different centers at the national level. CONCLUSION: The Chilean Society for Medical Oncology considers essential to standardize medical programming in the different oncology services, in order to assure the best care for cancer patients and to protect the medical personnel from work overload.

Socioeconomic, Clinical, and Molecular Features of Breast Cancer Influence Overall Survival of Latin American Women.

Molecular profile of breast cancer in Latin-American women was studied in five countries: Argentina, Brazil, Chile, Mexico, and Uruguay. Data about socioeconomic characteristics, risk factors, prognostic factors, and molecular subtypes were described, and the 60-month overall cumulative survival probabilities (OS) were estimated. From 2011 to 2013, 1,300 eligible Latin-American women 18 years or older, with a diagnosis of breast cancer in clinical stage II or III, and performance status ≦̸1 were invited to participate in a prospective cohort study. Face-to-face interviews were conducted, and clinical and outcome data, including death, were extracted from medical records. Unadjusted associations were evaluated by Chi-squared and Fisher's exact tests and the OS by Kaplan-Meier method. Log-rank test was used to determine differences between cumulative probability curves. Multivariable adjustment was carried out by entering potential confounders in the Cox regression model. The OS at 60 months was 83.9%. Multivariable-adjusted death hazard differences were found for women living in Argentina (2.27), Chile (1.95), and Uruguay (2.42) compared with Mexican women, for older (≥60 years) (1.84) compared with younger (≤40 years) women, for basal-like subtype (5.8), luminal B (2.43), and HER2-enriched (2.52) compared with luminal A subtype, and for tumor clinical stages IIB (1.91), IIIA (3.54), and IIIB (3.94) compared with stage IIA women. OS was associated with country of residence, PAM50 intrinsic subtype, age, and tumor stage at diagnosis. While the latter is known to be influenced by access to care, including cancer screening, timely diagnosis and treatment, including access to more effective treatment protocols, it may also influence epigenetic changes that, potentially, impact molecular subtypes. Data derived from heretofore understudied populations with unique geographic ancestry and sociocultural experiences are critical to furthering our understanding of this complexity.

nAMD: optimization of patient care and patient-oriented information with the help of an internet-based survey.

PURPOSE: This survey was conducted to identify factors that influence how patients with neovascular age-related macular degeneration (nAMD) deal with their disease and information that are considered useful from a patient's point of view. METHODS: A total of 5035 patients with nAMD living in Germany were interviewed via internet-based cross-sectional survey, where the following information was collected: personal data, disease awareness, and patients' needs. In addition, a Quality of Life questionnaire (SF-12v2) could be completed. RESULTS: Out of the 5035 participants, more males than females participated (55% vs 45%), and most participants were in the age groups 76 to 85 years (37%) and 66 to 75 years (35%). Seventy-three percent of patients rated their understanding of the disease as at least sufficient, and more than two-thirds of the patients (68%) were aware that their disease needs to be controlled on a regular basis and treated on an "as needed" basis. Regarding potential risk factors for AMD, most participants were aware of age (89%), but only 39% of hereditary load and 33% of smoking as evidence-based risk factors, indicating a need for further information. The doctor remains the major source of information (93%), with internet (29%), brochures (14%), opticians (13%), or patient support groups (4%) with only limited contribution. Distance to the treatment center was identified as one of the factors, which had the greatest influence on patients' compliance. A "treat as needed" regime turned out to be the preferred control and treatment schedule in contrast to a "fixed appointment" every 4 weeks. CONCLUSION: This internet-based survey appears to be representative for nAMD patients. To increase patients' compliance, proximity to the treatment center and a "treat as needed" regime turned out to be important factors as well as patients' awareness of their disease. In this regard, the reported desire for more information indicates that patients' knowledge still needs to be improved. Our results will help to further optimize patient care and patient-oriented information.

The Transcriptomic Portrait of Locally Advanced Breast Cancer and Its Prognostic Value in a Multi-Country Cohort of Latin American Patients.

Purposes: Most molecular-based published studies on breast cancer do not adequately represent the unique and diverse genetic admixture of the Latin American population. Searching for similarities and differences in molecular pathways associated with these tumors and evaluating its impact on prognosis may help to select better therapeutic approaches. Patients and Methods: We collected clinical, pathological, and transcriptomic data of a multi-country Latin American cohort of 1,071 stage II-III breast cancer patients of the Molecular Profile of Breast Cancer Study (MPBCS) cohort. The 5-year prognostic ability of intrinsic (transcriptomic-based) PAM50 and immunohistochemical classifications, both at the cancer-specific (OSC) and disease-free survival (DFS) stages, was compared. Pathway analyses (GSEA, GSVA and MetaCore) were performed to explore differences among intrinsic subtypes. Results: PAM50 classification of the MPBCS cohort defined 42·6% of tumors as LumA, 21·3% as LumB, 13·3% as HER2E and 16·6% as Basal. Both OSC and DFS for LumA tumors were significantly better than for other subtypes, while Basal tumors had the worst prognosis. While the prognostic power of traditional subtypes calculated with hormone receptors (HR), HER2 and Ki67 determinations showed an acceptable performance, PAM50-derived risk of recurrence best discriminated low, intermediate and high-risk groups. Transcriptomic pathway analysis showed high proliferation (i.e. cell cycle control and DNA damage repair) associated with LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Terms related to both innate and adaptive immune responses were seen predominantly upregulated in Basal tumors, and, to a lesser extent, in HER2E, with respect to LumA and B tumors. Conclusions: This is the first study that assesses molecular features at the transcriptomic level in a multicountry Latin American breast cancer patient cohort. Hormone-related and proliferation pathways that predominate in PAM50 and other breast cancer molecular classifications are also the main tumor-driving mechanisms in this cohort and have prognostic power. The immune-related features seen in the most aggressive subtypes may pave the way for therapeutic approaches not yet disseminated in Latin America. Clinical Trial Registration: ClinicalTrials.gov (Identifier: NCT02326857).

Cancer control in Latin America and the Caribbean: recent advances and opportunities to move forward.

The increasing burden of cancer represents a substantial problem for Latin America and the Caribbean. Two Lancet Oncology Commissions in 2013 and 2015 highlighted potential interventions that could advance cancer care in the region by overcoming existing challenges. Areas requiring improvement included insufficient investment in cancer control, non-universal health coverage, fragmented health systems, inequitable concentration of cancer services, inadequate registries, delays in diagnosis or treatment initiation, and insufficient palliative services. Progress has been made in key areas but remains uneven across the region. An unforeseen challenge, the COVID-19 pandemic, strained all resources, and its negative effect on cancer control is expected to continue for years. In this Series paper, we summarise progress in several aspects of cancer control since 2015, and identify persistent barriers requiring commitment of additional resources to reduce the cancer burden in Latin America and the Caribbean.

Perioperative chemotherapy in locally advanced gastric cancer in Chile: from evidence to daily practice.

Gastric cancer (GC) is a leading cause of cancer death in Chile. Although recommended in international guidelines since 2006, perioperative chemotherapy was not available to patients in the public health system in Chile until 2016. We conducted an observational study to assess the feasibility of this strategy in public hospitals in Chile (Observational Study of Perioperative Chemotherapy in Locally Advanced Gastric Cancer - PRECISO). Patients with locally advanced, operable GC were offered to receive preoperative chemotherapy with Epirubicin + Cisplatin + Capecitabine (ECX) for three cycles followed by curative surgery. Staging included abdominal CT scan and laparoscopy if peritoneal carcinomatosis was suspected. Postoperative ECX for three cycles was recommended. Between August 2010 and March 2013, 110 patients were screened and 61 enrolled. Median age was 62 years (23-76 years) and most patients had good performance status at baseline (Eastern Cooperative Oncology Group performance status score (ECOG) 0: 42, ECOG 1: 19). Tumour site was proximal in 32 (52%) and medial and distal in 29 (48%) patients. All but four patients (n = 57, 93%) completed three cycles of preoperative chemotherapy. Fifty-six patients were operated and 54 (89%) had a curative resection. Thirty-three patients (54%) had pT0-2, and 18 (30%) had pN0 tumours, with two patients achieving a complete response. As of 20 December 2020, 39 patients died, 32 due to GC, one within 30 days of surgery, two due to intestinal obstruction at 5 and 3 months after surgery and four due to other causes. Five-year survival rate was 38%. We conclude that perioperative chemotherapy is feasible in public hospitals in Chile and should be offered to patients with locally advanced GC.

Social Distancing and Economic Crisis During COVID-19 Pandemic Reduced Cancer Control in Latin America and Will Result in Increased Late-Stage Diagnoses and Expense.

Since December 2019, the world has been mired in an infectious pandemic that has displaced other health priorities for 21st century populations. Concerned about this situation, Latin American experts on cancer decided to evaluate the impact of the pandemic on cancer control in the region. The analysis was based on information obtained from public sources and scientific publications and included the characteristics of the health care and cancer control prior to the pandemic, the COVID-19 pandemic and measures implemented by the governments of the region, and the regional impact of the pandemic on cancer control together with the costs of cancer care and possible impact of the pandemic on cancer expense. We compared 2019 and 2020 data corresponding to the period March 16-June 30 and found a significant reduction in the number of first-time visits to oncology services (variable depending on the country between -28% and -38%) and a corresponding reduction in pathology (between -6% and -50%), cancer surgery (between -28% and -70%), and chemotherapy (between -2% and -54%). Furthermore, a significant reduction in cancer screening tests was found (PAP smear test studies: between -46% and -100%, mammography: between -32% and -100%, and fecal occult blood test: -73%). If this situation becomes a trend, the health and economic impact will be compounded in the postpandemic period, with an overload of demand on health services to ensure diagnostic tests and consequent treatments. On the basis of this information, a set of prevention and mitigation measures to be immediately implemented and also actions to progressively strengthen health systems are proposed.

Gallstones, Body Mass Index, C-Reactive Protein, and Gallbladder Cancer: Mendelian Randomization Analysis of Chilean and European Genotype Data.

BACKGROUND AND AIMS: Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C-reactive protein (CRP) level as a marker of chronic inflammation. APPROACH AND RESULTS: We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (P = 9 × 10-5 ) and Europeans (P = 9 × 10-5 ). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (P = 0.03), while higher CRP concentrations increased GBC risk in Europeans (P = 4.1 × 10-6 ). European results suggest causal effects of BMI on gallstone disease (P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. CONCLUSIONS: Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk.

Genomic Aberrations and Late Recurrence in Postmenopausal Women with Hormone Receptor-positive Early Breast Cancer: Results from the SOLE Trial.

PURPOSE: Women with hormone receptor-positive early breast cancers have a persistent risk of relapse and biomarkers for late recurrence are needed. We sought to identify tumor genomic aberrations associated with increased late-recurrence risk. EXPERIMENTAL DESIGN: In a secondary analysis of Study of Letrozole Extension trial, a case-cohort-like sampling selected 598 primary breast cancers for targeted next-generation sequencing analysis of gene mutations and copy-number gains (CNGs). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence-free intervals (BCFIs and DRFIs) were analyzed using weighted Cox models. RESULTS: Analysis of mutations and CNGs was successfully performed for 403 and 350 samples, including 148 and 134 patients with breast cancer recurrences (median follow-up time, 5.2 years), respectively. The most frequent alterations were PIK3CA mutations (42%) and CNGs of CCND1 (15%), ERBB2 (10%), FGFR1 (8%), and MYC (8%). PIK3CA mutations and MYC CNGs were associated with lower (P = 0.03) and higher (P = 0.004) tumor grade, respectively; a higher Ki-67 was seen in tumor with CCND1, ERBB2, and MYC CNGs (P = 0.01, P < 0.001, and P = 0.03, respectively). FGFR1 CNG was associated with an increased risk of late events in univariate analyses [17/29 patients; BCFI: HR, 3.2; 95% confidence interval (CI), 1.48-6.92; P = 0.003 and DRFI: HR, 3.5; 95% CI, 1.61-7.75; P = 0.002) and in multivariable models adjusted for clinicopathologic factors. CONCLUSIONS: Postmenopausal women with hormone receptor-positive early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.

Epigenome-Wide Analysis of Methylation Changes in the Sequence of Gallstone Disease, Dysplasia, and Gallbladder Cancer.

BACKGROUND AND AIMS: Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract. Most cases of GBC are diagnosed in low-income and middle-income countries, and research into this disease has long been limited. In this study we therefore investigate the epigenetic changes along the model of GBC carcinogenesis represented by the sequence gallstone disease → dysplasia → GBC in Chile, the country with the highest incidence of GBC worldwide. APPROACH AND RESULTS: To perform epigenome-wide methylation profiling, genomic DNA extracted from sections of formalin-fixed, paraffin-embedded gallbladder tissue was analyzed using Illumina Infinium MethylationEPIC BeadChips. Preprocessed, quality-controlled data from 82 samples (gallstones n = 32, low-grade dysplasia n = 13, high-grade dysplasia n = 9, GBC n = 28) were available to identify differentially methylated markers, regions, and pathways as well as changes in copy number variations (CNVs). The number and magnitude of epigenetic changes increased with disease development and predominantly involved the hypermethylation of cytosine-guanine dinucleotide islands and gene promoter regions. The methylation of genes implicated in Wnt signaling, Hedgehog signaling, and tumor suppression increased with tumor grade. CNVs also increased with GBC development and affected cyclin-dependent kinase inhibitor 2A, MDM2 proto-oncogene, tumor protein P53, and cyclin D1 genes. Gains in the targetable Erb-B2 receptor tyrosine kinase 2 gene were detected in 14% of GBC samples. CONCLUSIONS: Our results indicate that GBC carcinogenesis comprises three main methylation stages: early (gallstone disease and low-grade dysplasia), intermediate (high-grade dysplasia), and late (GBC). The identified gradual changes in methylation and CNVs may help to enhance our understanding of the mechanisms underlying this aggressive disease and eventually lead to improved treatment and early diagnosis of GBC.

Activin-mediated alterations of the fibroblast transcriptome and matrisome control the biomechanical properties of skin wounds.

Matrix deposition is essential for wound repair, but when excessive, leads to hypertrophic scars and fibrosis. The factors that control matrix deposition in skin wounds have only partially been identified and the consequences of matrix alterations for the mechanical properties of wounds are largely unknown. Here, we report how a single diffusible factor, activin A, affects the healing process across scales. Bioinformatics analysis of wound fibroblast transcriptome data combined with biochemical and histopathological analyses of wounds and functional in vitro studies identify that activin promotes pro-fibrotic gene expression signatures and processes, including glycoprotein and proteoglycan biosynthesis, collagen deposition, and altered collagen cross-linking. As a consequence, activin strongly reduces the wound and scar deformability, as identified by a non-invasive in vivo method for biomechanical analysis. These results provide mechanistic insight into the roles of activin in wound repair and fibrosis and identify the functional consequences of alterations in the wound matrisome at the biomechanical level.

ABCB1/4 gallbladder cancer risk variants identified in India also show strong effects in Chileans.

BACKGROUND: The first large-scale genome-wide association study of gallbladder cancer (GBC) recently identified and validated three susceptibility variants in the ABCB1 and ABCB4 genes for individuals of Indian descent. We investigated whether these variants were also associated with GBC risk in Chileans, who show the highest incidence of GBC worldwide, and in Europeans with a low GBC incidence. METHODS: This population-based study analysed genotype data from retrospective Chilean case-control (255 cases, 2042 controls) and prospective European cohort (108 cases, 181 controls) samples consistently with the original publication. RESULTS: Our results confirmed the reported associations for Chileans with similar risk effects. Particularly strong associations (per-allele odds ratios close to 2) were observed for Chileans with high Native American (=Mapuche) ancestry. No associations were noticed for Europeans, but the statistical power was low. CONCLUSION: Taking full advantage of genetic and ethnic differences in GBC risk may improve the efficiency of current prevention programs.

Correction: Quality of life under extended continuous versus intermittent adjuvant letrozole in lymph node-positive, early breast cancer patients: the SOLE randomised phase 3 trial.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The potential for polyphosphate metabolism in Archaea and anaerobic polyphosphate formation in Methanosarcina mazei.

Inorganic polyphosphate (polyP) is ubiquitous across all forms of life, but the study of its metabolism has been mainly confined to bacteria and yeasts. Few reports detail the presence and accumulation of polyP in Archaea, and little information is available on its functions and regulation. Here, we report that homologs of bacterial polyP metabolism proteins are present across the major taxa in the Archaea, suggesting that archaeal populations may have a greater contribution to global phosphorus cycling than has previously been recognised. We also demonstrate that polyP accumulation can be induced under strictly anaerobic conditions, in response to changes in phosphate (Pi) availability, i.e. Pi starvation, followed by incubation in Pi replete media (overplus), in cells of the methanogenic archaeon Methanosarcina mazei. Pi-starved M. mazei cells increased transcript abundance of the alkaline phosphatase (phoA) gene and of the high-affinity phosphate transport (pstSCAB-phoU) operon: no increase in polyphosphate kinase 1 (ppk1) transcript abundance was observed. Subsequent incubation of Pi-starved M. mazei cells under Pi replete conditions, led to a 237% increase in intracellular polyphosphate content and a > 5.7-fold increase in ppk1 gene transcripts. Ppk1 expression in M. mazei thus appears not to be under classical phosphate starvation control.

Quality of life under extended continuous versus intermittent adjuvant letrozole in lymph node-positive, early breast cancer patients: the SOLE randomised phase 3 trial.

BACKGROUND: In the phase III SOLE trial, the extended use of intermittent versus continuous letrozole for 5 years did not improve disease-free survival in postmenopausal women with hormone receptor-positive breast cancer. Intermittent therapy with 3-month breaks may be beneficial for patients' quality of life (QoL). METHODS: In the SOLE QoL sub-study, 956 patients completed the Breast Cancer Prevention Trial (BCPT) symptom and further QoL scales up to 24 months after randomisation. Differences in change of QoL from baseline between the two administration schedules were tested at 12 and 24 months using repeated measures mixed-models. The primary outcome was change in hot flushes at 12 months. RESULTS: There was no difference in hot flushes at 12 months between the two schedules, but patients receiving intermittent letrozole reported significantly more improvement at 24 months. They also indicated less worsening in vaginal problems, musculoskeletal pain, sleep disturbance, physical well-being and mood at 12 months. Overall, 25-30% of patients reported a clinically relevant worsening in key symptoms and global QoL. CONCLUSION: Less symptom worsening was observed during the first year of extended treatment with the intermittent administration. For women experiencing an increased symptom burden of extended adjuvant endocrine therapy, an intermittent administration is a safe alternative. CLINICAL TRIAL INFORMATION: Clinical trial information: NCT00651456.

An effective procedure for skin stiffness measurement to improve Paediatric Burn Care.

BACKGROUND: The objective evaluation of scar quality plays a crucial role in improving burn surgery and scar rehabilitation. Suction-based skin measurements were proposed as a method to objectively determine the mechanical properties of scars, yet their use is limited, in particular for paediatric burn care. A new device was developed which provides essential advantages for scar assessment. The aim of this study was to assess its reliability, intra- and interobserver variability. METHODS: The new device, "Nimble", consists of a lightweight probe that measures the negative pressure needed to obtain a predefined tissue elevation, revealing information on the stiffness of the tissue. 29 former paediatric burn patients were included. Three observers measured the tissue stiffness of a predefined location on the scar and on healthy skin using the Nimble, and the established suction device, the Cutometer®. The reliability of both instruments in distinguishing between healthy skin and scar was assessed by means of the intraclass correlation coefficient. RESULTS: The Nimble successfully differentiated between scar tissue and healthy skin in 92%, the Cutometer in 80% of the patients (p<0.05). Inter- and intraobserver variability of the Nimble (ICCs) were excellent. For the majority of the calculated ICC values the Nimble exceeded the Cutometer®. CONCLUSION: The new device enables reliable and safe measurement of the stiffness of scars. Measurements are less susceptible to patient non-compliance and observer dependency. The Nimble might therefore constitute an easy to use tool for the systematic assessment of scars, thus supporting decision-making in paediatric burn care.