Prognostic role of FGFR1 amplification in early-stage non-small cell lung cancer.

Background:Recently, fibroblast growth factor receptor 1 (FGFR1) was discovered in squamous cell carcinomas (SCC) of the lung with FGFR1 amplification described as a promising predictive marker for anti-FGFR inhibitor treatment. Only few data are available regarding prevalence, prognostic significance and clinico-pathological characteristics of FGFR1-amplified and early-stage non-small cell lung carcinomas (NSCLC). We therefore investigated the FGFR1 gene status in a large number of well-characterised early-stage NSCLC.Methods:FGFR1 gene status was evaluated using a commercially available fluorescent in situ hybridisation (FISH) probe on a tissue microarray (TMA). This TMA harbours 329 resected, formalin-fixed and paraffin-embedded, nodal-negative NSCLC with a UICC stage I-II. The FISH results were correlated with clinico-pathological features and overall survival (OS).Results:The prevalence of an FGFR1 amplification was 12.5% (41/329) and was significantly (P<0.0001) higher in squamous cell carcinoma (SCC) (20.7%) than in adenocarcinoma (2.2%) and large cell carcinoma (13%). Multivariate analysis revealed significantly (P=0.0367) worse 5-year OS in patients with an FGFR1-amplified NSCLC.Conclusions:FGFR1 amplification is common in early-stage SCC of the lung and is an independent and adverse prognostic marker. Its potential role as a predictive marker for targeted therapies or adjuvant treatment needs further investigation.

Clinical and epidemiological characteristics of breast cancer metastases

Introduction. Breast cancer is a highly variable disease, and long-term outcomes for individual patients are difficult to predict. We evaluated a retrospective cohort of early stage breast cancer (ESBC) patients based on a variety of clinical and epidemiological factors, specifically looking at the distribution of metastasis and associations with these clinical and epidemiological factors. ^ Methods. Patients were derived from the Early Stage Breast Cancer Repository (ESBCR) with a breast cancer diagnosed between 1985 and 2000. We conducted univariate and multivariate analysis of the data to evaluate associations between characteristics and occurrence of overall, visceral, and bone metastasis. Visceral metastasis was defined as lung, liver, peritoneal, lymph node (thoracic, abdominal, pelvis), and contralateral breast cancer. ^ Results. Overall, 394 (16%) patients developed a metastasis. Of these, 83% were visceral and 17% were bone. Multivariate analyses identified the following variables to be associated with metastasis: Any metastasis: age at diagnosis, stage, ER/PR status, hormone treatment, and type of surgery (1)Visceral metastasis: age at diagnosis, stage, hormone treatment, and type of surgery (2) Bone metastasis –Alcohol use, stage, and ER/PR status ^ Discussion/conclusion. ER-/PR- status has previously been found to be associated with bone metastasis, as we confirm in our cohort. We report an association between alcohol use and bone metastasis whereas previous studies find an association with recurrence. Distribution of metastases varies from previous studies. Typically, previous studies reported bone metastasis >30%, yet our study found 17%. Previous studies varied in design, and definition of visceral metastasis. Future research is needed to further elucidate prognostic factors associated with specific metastases A more thorough understanding of what might predict which ESBC patients will develop metastases can help direct future treatment. Future studies of this nature could include the Perou intrinsic subtypes, biomarkers like Ki-67, and genetic analyses such as Oncotype DX or MammaPrint.^

Retrospective assesment of the levonorgestrel intrauterine device to treat complex atypical hyperplasia and early endometrioid endometrial cancer

Objective: The primary objective of this project was to describe the efficacy of the Levonorgestrel Intrauterine Device (LIUD) for treatment of Complex Endometrial Cancer (CAH) and Grade 1 Endometrial Cancer (G1EEC) in terms of rate of Complete Response (CR) and Partial Response (PR) after 6 months of therapy. Finally, we assessed if any clinical or pathologic features were associated with response to the LIUD. ^ Methods: This study was a retrospective case series designed to report the response rate of patients with CAH or G1EEC treated with LIUD therapy. In addition, this study has a laboratory component to assess molecular predictors of response to LIUD therapy. Retrospective data already collected from patients diagnosed with CAH or EEC grade 1 and treated with LIUD therapy at MD Anderson Cancer Center (MDACC) were used for this study. Patients from all ethnic and race groups were included. A Complete Response (CR) was defined in patients diagnosed with CAH if pathologic report at 6 months demonstrated either no evidence of hyperplasia or no atypia in the setting of simple or complex hyperplasia. Partial Response (PR) was recorded if disease downgraded to only CAH from G1EEC. No Response (NR) was recorded if pathologic report demonstrates no change (Stable Disease, SD) or progression to cancer (Progressive Disease, PD). We calculated the proportion of patients with complete response to LIUD therapy with 95% confidence interval. We compared the response rates (CR/PR vs NR) by obesity status (Obese if BMI > 40 kg/m2 vs non-obese if BMI <= 40 kg/m2) as well as other clinical and pathologic factors, such as age, uterine size (median size), and presence of exogenous progesterone effect. ^ Results: There were 39 patients diagnosed with either CAH or G1EEC treated with the LIUD. Of 39 patients, 12 did not have pathological results of biopsy at 6months time period. Of 27 evaluable patients, 17 were diagnosed with CAH and 10 with G1EEC. Overall response rate (RR) was 78% (95% CI = 62-94%) at 6 months, 18 patients had CR (4 in G1EEC; 14 in CAH), 3 patients had PR (3 in G1EEC), 3 had SD (1 in CAH; 2 in G1EEC), 3 had PD (2 in CAH; 1 in G1EEC). After histology stratification, RR at 6 months was 82.35% (14/17; 95%CI = 67.4-97.3%) in CAH and 70% (7/10; 95% CI = 41-98.4%) in G1EEC. ^ There was no difference in response (R) and no response (NR) based on BMI (p=0.56). He observed a trend showing association between age with response (p=0.1). There was no association between uterine size and response to therapy (p=0.17). We recorded strong association between exogenous progesterone effect and response. ^ Conclusion: LIUD therapy for the treatment of CAH and G1EEC may be effective and safe. Presence of exogenous progesterone effect may predict the response to LIUD therapy at earlier time points. There is need of further studies with larger sample size to explore the relationship of response with other clinical and pathologic factors^

Social and economically influenced factors associated with breast cancer treatment among blacks and whites. A qualitative study

Background: Despite the fact breast cancer mortality has declined in recent years, the mortality gap between African-American and white women continues to grow. A part of these disparities may be due to either inadequately following guideline recommended treatment or treatment delays. Although racial/ethnic disparities in breast cancer treatment and mortality have been extensively documented, the mechanisms by which these disparities occur remain largely unknown. Social and economically influenced factors such as choice of providers, distance of treatment facility, transportation, health insurance, and job related factors may also contribute to racial differences in breast cancer treatment; however, these have not been explored sufficiently in previous research. ^ Aim: The purpose of this study was to evaluate the role of social and economically influenced factors that may contribute to racial disparities in the receipt of guideline recommended treatment using the Health Disparities Model. ^ Methods: In this qualitative comparative case study, data from medical records, structured telephone interviews, and in-depth patient interviews explored the relationship between social and economically influenced factors and breast cancer treatment. Transcripts were analyzed using standard iterative process followed by immersion/crystallization approach. Participants were identified through rapid ascertainment from the New Jersey Cancer Registry and this study included 8 African-American and 8 white women aged 20-85 years old diagnosed with early stage breast cancer between 2003-2007, matched on age, race, and physician recommended treatment. ^ Results: We did not identify differences by race in factors that influenced the receipt of breast cancer treatment among the individual matched pairs. Four prominent themes emerged among women from both groups who experienced similar difficulties influenced by socioeconomic factors. Choice of providers, distance of facility, health insurance, and job related factors all contributed to breast cancer treatment experience among these women. Conclusions: We identified common issues influenced by socioeconomic factors and its relation with the receipt of breast cancer treatment, regardless of race. However, more research is needed to study the additional factors conveying racial differences affecting breast cancer treatment. ^

Evidence supporting exercise interventions for persons in early-stage Alzheimer’s disease

The purpose of this article is to grade research evidence supporting exercise-based interventions for persons with early-stage dementias and to report the recommendations of a consensus panel. The search produced 11 data based articles testing the effects of exercise interventions on a variety of outcomes. The body of evidence to support exercise interventions in the prevention and treatment of Alzheimer’s disease is growing and has potential as a treatment modality following translational studies in recreation therapy and other fields.

Differences in Epidural and Analgesic Use in Patients with Apparent Stage I Endometrial Cancer treated by open versus laparoscopic surgery: results from the randomised LACE trial

Objectives: We compared post-operative analgesic requirements between women with early stage endometrial cancer treated by total abdominal hysterectomy (TAH) or total laparoscopic hysterectomy (TLH). Methods: 760 patients with apparent stage I endometrial cancer were treated in the international, multicentre, prospective randomised trial (LACE) by TAH (n=353) or TLH (n=407) (2005-2010). Epidural, opioid and non-opioid analgesic requirements were collected until ten months after surgery. Results: Baseline demographics and analgesic use were comparable between treatment arms. TAH patients were more likely to receive epidural analgesia than TLH patients (33% vs 0.5%, p<0.001) during the early postoperative phase. Although opioid use was comparable in the TAH vs TLH groups during postoperative 0-2 days (99.7% vs 98.5%, p 0.09), a significantly higher proportion of TAH patients required opioids 3-5 days (70% vs 22%, p<0.0001), 6-14 days (35% vs 15%, p<0.0001), and 15-60 days (15% vs 9%, p 0.02) post-surgery. Mean pain scores were significantly higher in the TAH versus TLH group one (2.48 vs 1.62, p<0.0001) and four weeks (0.89 vs 0.63, p 0.01) following surgery. Conclusion: Treatment of early stage endometrial cancer with TLH is associated with less frequent use of epidural, lower post-operative opioid requirements and better pain scores than TAH.

EUELC project : a multi-centre, multipurpose study to investigate early stage NSCLC, and to establish a biobank for ongoing collaboration

The European Early Lung Cancer (EUELC) project aims to determine if specific genetic alterations occurring in lung carcinogenesis are detectable in the respiratory epithelium. In order to pursue this objective, nonsmall cell lung cancer (NSCLC) patients with a very high risk of developing progressive lung cancer were recruited from 12 centres in eight European countries: France, Germany, southern Ireland, Italy, the Netherlands, Poland, Spain and the UK. In addition, NSCLC patients were followed up every 6 months for 36 months. A European Bronchial Tissue Bank was set up at the University of Liverpool (Liverpool, UK) to optimise the use of biological specimens. The molecular - pathological investigations were subdivided into specific work packages that were delivered by EUELC Partners. The work packages encompassed mutational analysis, genetic instability, methylation profiling, expression profiling utilising immunohistochemistry and chip-based technologies, as well as in-depth analysis of FHIT and RARβ genes, the telomerase catalytic subunit hTERT and genotyping of susceptibility genes in specific pathways. The EUELC project engendered a tremendous collaborative effort, and it enabled the EUELC Partners to establish protocols for assessing molecular biomarkers in early lung cancer with the view to using such biomarkers for early diagnosis and as intermediate end-points in future chemopreventive programmes. Copyright©ERS Journals Ltd 2009.

Overexpression of the mammalian target of rapamycin (mTOR) and angioinvasion are poor prognostic factors in early stage NSCLC: A verification study

Background: A recent study by Dhillon et al. [12], identified both angioinvasion and mTOR as prognostic biomarkers for poor survival in early stage NSCLC. The aim of this study was to verify the above study by examining the angioinvasion and mTOR expression profile in a cohort of early stage NSCLC patients and correlate the results to patient clinico-pathological data and survival. Methods: Angioinvasion was routinely recorded by the pathologist at the initial assessment of the tumor following resection. mTOR was evaluated in 141 early stage (IA-IIB) NSCLC patients (67 - squamous; 60 - adenocarcinoma; 14 - others) using immunohistochemistry (IHC) analysis with an immunohistochemical score (IHS) calculated (% positive cells × staining intensity). Intensity was scored as follows: 0 (negative); 1+ (weak); 2+ (moderate); 3+ (strong). The range of scores was 0-300. Based on the previous study a cut-off score of 30 was used to define positive versus negative patients. The impact of angioinvasion and mTOR expression on prognosis was then evaluated. Results: 101 of the 141 tumors studied expressed mTOR. There was no difference in mTOR expression between squamous cell carcinoma and adenocarcinoma. Angioinvasion (p= 0.024) and mTOR staining (p= 0.048) were significant univariate predictors of poor survival. Both remained significant after multivariate analysis (p= 0.037 and p= 0.020, respectively). Conclusions: Our findings verify angioinvasion and mTOR expression as new biomarkers for poor outcome in patients with early stage NSCLC. mTOR expressing patients may benefit from novel therapies targeting the mTOR survival pathway. © 2011 Elsevier Ireland Ltd.

Prognostic value of hTERT mRNA expression in surgical samples of lung cancer patients : the European Early Lung Cancer Project

Lung cancer is the most important cause of cancer-related mortality. Resectability and eligibility for treatment with adjuvant chemotherapy is determined by staging according to the TNM classification. Other determinants of tumour behaviour that predict disease outcome, such as molecular markers, may improve decision-making. Activation of the gene encoding human telomerase reverse transcriptase (hTERT) is implicated in the pathogenesis of lung cancer, and consequently detection of hTERT mRNA might have prognostic value for patients with early stage lung cancer. A cohort of patients who underwent a complete resection for early stage lung cancer was recruited as part of the European Early Lung Cancer (EUELC) project. In 166 patients expression of hTERT mRNA was determined in tumour tissue by quantitative real-time RT-PCR and related to that of a house-keeping gene (PBGD). Of a subgroup of 130 patients tumour-distant normal tissue was additionally available for hTERT mRNA analysis. The correlation between hTERT levels of surgical samples and disease-free survival was determined using a Fine and Gray hazard model. Although hTERT mRNA positivity in tumour tissue was significantly associated with clinical stage (Fisher's exact test p=0.016), neither hTERT mRNA detectability nor hTERT mRNA levels in tumour tissue were associated with clinical outcome. Conversely, hTERT positivity in adjacent normal samples was associated with progressive disease, 28% of patients with progressive disease versus 7.5% of disease-free patients had detectable hTERT mRNA in normal tissue [adjusted HR: 3.60 (1.64-7.94), p=0.0015]. hTERT mRNA level in tumour tissue has no prognostic value for patients with early stage lung cancer. However, detection of hTERT mRNA expression in tumour-distant normal lung tissue may indicate an increased risk of progressive disease.

Age-specific differences in oncogenic pathway deregulation seen in human breast tumors.

PURPOSE: To define the biology driving the aggressive nature of breast cancer arising in young women. EXPERIMENTAL DESIGN: Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young or=65 years), 411 eligible patients (n = 200or=65 years) with clinically-annotated Affymetrix microarray data were identified. GSEA, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts. RESULTS: In comparing deregulation of oncogenic pathways between age groups, a higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in breast tumors arising in younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with a higher probability of PI3K, Myc, and beta-catenin, conferred a worse prognosis (HR = 4.15). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, with concurrent low probability of PI3K, Myc and beta-catenin deregulation, was associated with poorer outcome (HR = 2.7). In multivariate analyses, genomic clusters of pathway deregulation illustrate prognostic value. CONCLUSION: Results demonstrate that breast cancer arising in young women represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinico-pathologic variables. These results should enable refinement of targeted treatment strategies in this clinically challenging situation.

Defining Target Volumes for Stereotactic Ablative Radiotherapy of Early-stage Lung Tumours:A Comparison of Three-dimensional F-fluorodeoxyglucose Positron Emission Tomography and Four-dimensional Computed Tomography

Aims: High local control rates are achieved in stage I lung cancer using stereotactic ablative radiotherapy. Target delineation is commonly based on four-dimensional computed tomography (CT) scans. Target volumes defined by positron emission tomography/computed tomography (PET/CT) are compared with those defined by four-dimensional CT and conventional ('three-dimensional') F-fluorodeoxyglucose (F-FDG) PET/CT. Materials and methods: For 16 stage I non-small cell lung cancer tumours, six approaches for deriving PET target volumes were evaluated: manual contouring, standardised uptake value (SUV) absolute threshold of 2.5, 35% of maximum SUV (35%SUV), 41% of SUV (41%SUV) and two different source to background ratio techniques (SBR-1 and SBR-2). PET-derived target volumes were compared with the internal target volume (ITV) from the modified maximum intensity projection (MIP ITV). Volumetric and positional correlation was assessed using the Dice similarity coefficient (DSC). Results: PET-based target volumes did not correspond to four-dimensional CT-based target volumes. The mean DSC relative to MIP ITV were: PET manual = 0.64, SUV2.5 = 0.64, 35%SUV = 0.63, 41%SUV = 0.57. SBR-1 = 0.52, SBR-2 = 0.49. PET-based target volumes were smaller than corresponding MIP ITVs. Conclusions: Conventional three-dimensional F-FDG PET-derived target volumes for lung stereotactic ablative radiotherapy did not correspond well with those derived from four-dimensional CT, including those in routine clinical use (MIP ITV). Caution is required in using three-dimensional PET for motion encompassing target volume delineation. © 2012 The Royal College of Radiologists.

Defining target volumes for stereotactic ablative radiotherapy of early-stage lung tumours: a comparison of three-dimensional 18F-fluorodeoxyglucose positron emission tomography and four-dimensional computed tomography.:PETCT versus 4DCT for SABR in Early Stage NSCLC

AIMS: High local control rates are achieved in stage I lung cancer using
stereotactic ablative radiotherapy. Target delineation is commonly based on
four-dimensional computed tomography (CT) scans. Target volumes defined by
positron emission tomography/computed tomography (PET/CT) are compared with those defined by four-dimensional CT and conventional ('three-dimensional')
(18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT.

MATERIALS AND METHODS: For 16 stage I non-small cell lung cancer tumours, six
approaches for deriving PET target volumes were evaluated: manual contouring,
standardised uptake value (SUV) absolute threshold of 2.5, 35% of maximum SUV
(35%SUV(MAX)), 41% of SUV(MAX) (41%SUV(MAX)) and two different source to
background ratio techniques (SBR-1 and SBR-2). PET-derived target volumes were compared with the internal target volume (ITV) from the modified maximum
intensity projection (MIP(MOD) ITV). Volumetric and positional correlation was
assessed using the Dice similarity coefficient (DSC).

RESULTS: PET-based target volumes did not correspond to four-dimensional CT-based target volumes. The mean DSC relative to MIP(MOD) ITV were: PET manual = 0.64, SUV2.5 = 0.64, 35%SUV(MAX) = 0.63, 41%SUV(MAX) = 0.57. SBR-1 = 0.52, SBR-2 =0.49. PET-based target volumes were smaller than corresponding MIP ITVs.

CONCLUSIONS: Conventional three-dimensional (18)F-FDG PET-derived target volumes for lung stereotactic ablative radiotherapy did not correspond well with those derived from four-dimensional CT, including those in routine clinical use
(MIP(MOD) ITV). Caution is required in using three-dimensional PET for motion
encompassing target volume delineation.

Skin-reducing mastectomy and one-stage implant reconstruction with a myodermal flap: A safe and effective technique in risk-reducing and therapeutic mastectomy

Introduction: Immediate reconstruction following mastectomy for breast cancer has been shown to be oncologically safe and associated with improved psychosocial outcomes for patients. Bostwick described a technique for one-stage implant based reconstruction, combining skin-sparing mastectomy with concurrent reduction of the skin envelope. This report reviews the experience of a single centre using skin-reducing mastectomy and one-stage implant reconstruction in both early stage breast cancer and risk-reducing mastectomy, with specific reference to frequency of complications, implant loss and oncological outcomes.

Methods and results: A retrospective review was undertaken to identify women who had undergone skin-reducing mastectomy and one-stage implant reconstruction using a de-epithelialised dermal flap, between October 2008 and October 2012. One hundred and four consecutive mastectomies, with reconstruction, were performed by two surgeons on 64 patients. No complications were seen in 43.8% of patients. At three months, four implants were lost (3.8% of breast reconstructions, 6.3% of patients), due to either peri-implant infection or mastectomy skin flap necrosis. One patient required unplanned return to theatre for evacuation of a haematoma. Minor mastectomy skin flap necrosis was seen in 10 breasts (9.6% of reconstructed breasts) and superficial wound infection in 8 breasts (7.7% of reconstructed breasts). All of these complications were managed conservatively and none required operative intervention. At a median follow up of 35 months (4-53 months) there had been one episode of ipsilateral axillary nodal recurrence.

Conclusion: One-stage implant reconstruction using a myo-dermal flap technique following skin-reducing mastectomy is safe and should be considered in selected patients. Most complications are minor and will resolve with conservative management. Major complications such as implant failure or immediate reoperation, were relatively uncommon (6.3% patients, 3.8% of reconstructed breasts). Early follow-up suggests that oncological outcomes are satisfactory, but longer follow-up is required to substantiate this. (C) 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.