A qualitative stakeholder analysis of beliefs, facilitators, and barriers for a feasible prehabilitation program before lung cancer surgery.

BACKGROUND: In order to develop a feasible prehabilitation program before surgery of NSCLC, this study aimed to gain insight into beliefs, facilitators, and barriers of (1) healthcare professionals to refer patients to a prehabilitation program, (2) patients to participate in and adhere to a prehabilitation program, and (3) informal caregivers to support their loved ones. METHODS: Semi-structured interviews were conducted with healthcare professionals, patients who underwent surgery for NSCLC, and their informal caregivers. The capability, opportunity, and motivation for behavior-model (COM-B) guided the development of the interview questions. Results were analyzed thematically. RESULTS: The interviews were conducted with twelve healthcare professionals, seventeen patients, and sixteen informal caregivers. Four main themes were identified: (1) content of prehabilitation and referral, (2) organizational factors, (3) personal factors for participation, and (4) environmental factors. Healthcare professionals mentioned that multiple professionals should facilitate the referral of patients to prehabilitation within primary and secondary healthcare involved in prehabilitation, considering the short preoperative period. Patients did not know that a better preoperative physical fitness and nutritional status would make a difference in the risk of postoperative complications. Patients indicated that they want to receive information about the aim and possibilities of prehabilitation. Most patients preferred a group-based physical exercise training program organized in their living context in primary care. Informal caregivers could support their loved one when prehabilitation takes place by doing exercises together. CONCLUSION: A prehabilitation program should be started as soon as possible after the diagnosis of lung cancer. Receiving information about the purpose and effects of prehabilitation in a consult with a physician seems crucial to patients and informal caregivers to be involved in prehabilitation. Support of loved ones in the patient's own living context is essential for adherence to a prehabilitation program.

Management of obstructive sleep apnea syndrome type 1 in children and adolescents - A French consensus.

This document is the outcome of a group of experts brought together at the request of the French Society of Sleep Research and Medicine to provide recommendations for the management of obstructive sleep apnea syndrome type 1 (OSA1) in children. The recommendations are based on shared experience and published literature. OSA1 is suspected when several nighttime respiratory symptoms related to upper airway obstruction are identified on clinical history taking. A specialist otolaryngologist examination, including nasofibroscopy, is essential during diagnosis. A sleep study for OSA1 is not mandatory when at least two nighttime symptoms (including snoring) are noted. Therapeutic management must be individualized according to the location of the obstruction. Ear, nose, and throat (ENT) surgery is often required, as hypertrophy of the lymphoid tissues is the main cause of OSA1 in children. According to clinical findings, orthodontic treatment generally associated with specialized orofacial-myofunctional therapy might also be indicated. Whatever treatment is chosen, follow-up must be continuous and multidisciplinary, in a network of trained specialists.

Glycogen synthase 1 targeting reveals a metabolic vulnerability in triple-negative breast cancer.

BACKGROUND: Hypoxia-induced glycogen turnover is implicated in cancer proliferation and therapy resistance. Triple-negative breast cancers (TNBCs), characterized by a hypoxic tumor microenvironment, respond poorly to therapy. We studied the expression of glycogen synthase 1 (GYS1), the key regulator of glycogenesis, and other glycogen-related enzymes in primary tumors of patients with breast cancer and evaluated the impact of GYS1 downregulation in preclinical models. METHODS: mRNA expression of GYS1 and other glycogen-related enzymes in primary breast tumors and the correlation with patient survival were studied in the METABRIC dataset (n = 1904). Immunohistochemical staining of GYS1 and glycogen was performed on a tissue microarray of primary breast cancers (n = 337). In four breast cancer cell lines and a mouse xenograft model of triple-negative breast cancer, GYS1 was downregulated using small-interfering or stably expressed short-hairpin RNAs to study the effect of downregulation on breast cancer cell proliferation, glycogen content and sensitivity to various metabolically targeted drugs. RESULTS: High GYS1 mRNA expression was associated with poor patient overall survival (HR 1.20, P = 0.009), especially in the TNBC subgroup (HR 1.52, P = 0.014). Immunohistochemical GYS1 expression in primary breast tumors was highest in TNBCs (median H-score 80, IQR 53-121) and other Ki67-high tumors (median H-score 85, IQR 57-124) (P < 0.0001). Knockdown of GYS1 impaired proliferation of breast cancer cells, depleted glycogen stores and delayed growth of MDA-MB-231 xenografts. Knockdown of GYS1 made breast cancer cells more vulnerable to inhibition of mitochondrial proteostasis. CONCLUSIONS: Our findings highlight GYS1 as potential therapeutic target in breast cancer, especially in TNBC and other highly proliferative subsets.

Validation and discussion of clinical practicability of the 2022 graded prognostic assessment for NSCLC adenocarcinoma patients with brain metastases in a routine clinical cohort.

Introduction: The goal of this analysis is to validate the 2022 graded prognostic assessment (GPA) for patients with brain metastases from adenocarcinoma of the lung and to discuss its clinical practicability. Methods/material: 137 patients with adenocarcinoma of the lung were included in this analysis. The disease specific GPA for NSCLC, Lung-molGPA and the GPA for NSCLC adenocarcinoma were calculated. Overall survival was calculated for each GPA group. Additionally, expected and actual OS in the prognostic groups of the GPA available at the time of the patients' diagnosis was compared. Results: Median overall survival (OS) from diagnosis of brain metastases was 15 months (95% confidence interval (CI) 9.7-20.3 months). The median OS in the three individual prognostic groups was 7 months for GPA 0-1, 16 months for GPA 1.5-2, 33 months for GPA 2.5-3 and not reached for GPA 3.5-4 (p<0.001). Median survival times for the individual groups were similar to those published in the original GPA publication. Regarding the expected and actual OS when using the available GPA at the time of diagnosis there was an underestimation of survival of more than 3 months for all except the worst prognosis group. Conclusion: We were able to validate the 2022 GPA for NSCLC adenocarcinoma patients with brain metastases in a similar cohort from a non-academic center. However, the practical applicability regarding the expected median OS might be limited due to the constantly evolving treatment landscape and the consecutive improvement in overall survival.

High-dose re-irradiation of intracranial lesions - Efficacy and safety including dosimetric analysis based on accumulated EQD2Gy dose EQD calculation.

INTRODUCTION: The use of cranial re-irradiation is growing with improving overall survival and the advent of high-precision radiotherapy techniques. Still the value of re-irradiation needs careful evaluation regarding safety and efficacy. We analyzed dosimetric and clinical data of patients receiving cranial re-irradiation using EQD2 sum plans. METHODS AND MATERIAL: We retrospectively analyzed the data of 76 patients who received repeated cranial radiotherapy from 02/2013 to 09/2016. 34 patients suffered from recurrent primary brain tumors, 42 from brain metastases. Dosimetric analysis was performed accumulating EQD2 dose distributions based on rigid image registration. Clinical and radiological data was collected at follow-ups including toxicity, local control and overall survival. RESULTS: In total 76 patients had at least 2 courses of intracranial radiotherapy. The median accumulated prescription EQD2 dose was 96.5 Gy2 for all radiation courses combined. The median D(0.1 cc) of the brain for patients receiving more than 100 Gy2 was 114 Gy2 with a highest dose of 161.5 Gy2. 74% of patients suffered from low grade (G1-G2) acute toxicity, only two high grade (>G3) toxicities were recorded.Median overall survival from the time of first re-irradiation was 57 weeks (range 4-186 weeks). The median time to local failure for patients with a primary brain tumor was not reached and 24 weeks (range 1-77 weeks) for patients with brain metastases. CONCLUSION: Repeated radiotherapy appears both safe and efficient in patients with recurrent primary or secondary brain tumors with doses to the brain up to 120 Gy2 EQD2, doses below 100 Gy2 for brainstem and doses below 75 Gy2 EQD2 to chiasm and optic nerves.

Urgency of surgery as an indicator for the occurrence of surgical site infections: data from over 100,000 surgical procedures.

BACKGROUND: The risk for surgical site infections (SSIs) is influenced by patient- and procedure-related factors. Urgent surgery represents a challenge in operative medicine and is frequently linked to a variety of complications, including SSIs. AIM: We aimed to investigate whether urgency was significantly associated with SSI occurrence, and determine whether collection of this variable provided useful information for SSI surveillance. METHODS: We performed a retrospective data analysis of caesarean sections (C-sections) and colon surgeries conducted between 2017 and 2019 within the German national SSI surveillance network. A multivariable logistic regression model was utilized to determine the influence of urgency on SSI occurrence. For this purpose, data on procedures and SSIs were associated with available department- and patient-related parameters. FINDINGS: A total of 115,648 procedures were included in the analysis: 78,288 C-sections and 37,360 colon surgeries. For C-sections, the SSI rate per 100 procedures was 0.98 (95% confidence interval: 0.85-1.11) for urgent and 0.46 (0.40-0.53) for elective procedures (P<0.001). For open colon surgeries, SSI rates were 9.66 (8.89-10.49) for urgent and 8.60 (8.13-9.11) for elective procedures (P<0.001). For laparoscopic colon surgeries, SSI rates did not differ significantly. Multivariable analysis revealed that urgency significantly increased the likelihood of SSI occurrence only for C-sections. CONCLUSION: Urgency significantly increased the SSI risk of C-sections, but not colon surgeries. Hence, collection of this variable is useful for SSI surveillance of C-sections, but may be dispensable for other procedures. Future analyses on the matter should therefore focus on other procedure types.

Re-irradiation in the thorax - An analysis of efficacy and safety based on accumulated EQD2 doses.

INTRODUCTION: Thoracic re-irradiation remains a challenge regarding the balance of local efficacy and acceptable toxicities. In this retrospective analysis we analyzed dosimetrical and clinical data of patients treated with thoracic re-irradiation based on accumulated EQD2Gy doses. METHODS AND MATERIAL: We retrospectively analyzed the data of 42 consecutive single-institutional patients treated with repeated courses of thoracic radiotherapy from 12/2011 to 01/2017. Accumulated EQD2 dose distributions were calculated and dose parameters for organs at risk and target volumes were analysed. RESULTS: The median prescription dose was 42.2 Gy (10-70.6 Gy) for all RT courses. The median Dmean of both lungs was 10.1 Gy3 (range: 1.9 Gy3-17.9 Gy3) with a maximum D0.1 cc of 253.86 Gy3. The median D0.1 cc of the esophagus was 62.2 Gy3 with a maximum of 103.78 Gy3. The maximum D0.1 cc for the bronchial tree was 187.33 Gy3 (median 74.35 Gy3) and for the Aorta 216.1 Gy3 (median 70.9 Gy3). Median OS after first re-irradiation was 19 months (range 1-45 months). 12-month local control after a course of re-irradiation was 52.6%. 80% of patients suffered from a G1-G2 toxicity, most frequently coughing. One patient suffered from a G5 complication probably unrelated to re-irradiation. CONCLUSION: Even though several organs at risk received maximum accumulated doses of >100 Gy3, thoracic reirradiation resulted in an acceptable toxicity profile. Local tumor control and overall survival remained encouraging even after multiple courses of thoracic radiotherapy.

Distress, problems, referral wish, and supportive health care use in breast cancer survivors beyond the first year after chemotherapy completion.

PURPOSE: We examined distress levels, problems, referral wish, and supportive health care use in a cross-sectional group of breast cancer survivors at two-time points with a 1-year time interval. Also, factors related to continuing elevated distress were explored. METHODS: Breast cancer survivors, 1-5 years after chemotherapy completion, filled in the Dutch Distress Thermometer/Problem List (DT/PL) and questions on background characteristics at study inclusion (T1). DT/PL responses and health care use were discussed during semi-structured interviews. One year later, re-assessment took place (T2). The data were analyzed by descriptive and univariate analyses. Continuing elevated distress was defined as a DT score ≥ 5 at T1 and T2. RESULTS: Seventy-three survivors completed all questionnaires (response = 84.6%). Eighteen (25%) experienced continuing elevated distress. Fatigue (T1 N = 48 (66%); T2 N = 41 (56%)) and lack of physical fitness (T1 N = 44 (60%); T2 N = 36 (49%)) were most often reported. Time since diagnosis, health care use, and practical, social, emotional and physical problems were significantly associated with continuing elevated distress. Between diagnosis and T1, N = 49(67%) used supportive healthcare services, mostly a psychologist and/or a physical/lymphedema therapist, and between T1 and T2, 39 (53%) did. At T1, 8 (11%) expressed a referral wish and at T2, 11 (16%) did. CONCLUSIONS: Screening and management of distress, problems, and referral wish are important, even years after chemotherapy completion as a substantial proportion of breast cancer survivors continue to report elevated distress and problems. Special attention should be paid to survivors reporting physical problems, especially fatigue and lack of physical fitness, since these problems are most strongly related to continuing elevated distress.

Enhanced pulmonary uptake on 18F-FES-PET/CT scans after irradiation of the thoracic area: related to fibrosis?

RATIONALE: The use of 16α-[18F]fluoro-17ß-estradiol (FES) positron emission tomography (PET) in clinical dilemmas and for therapy decision-making in lesions expressing estrogen receptors is growing. However, on a considerable number of FES PET scans, previously performed in a research and clinical setting in our institution, FES uptake was noticed in the lungs without an oncologic substrate. We hypothesized that this uptake was related to pulmonary fibrosis as a result of radiation therapy. This descriptive study therefore aimed to investigate whether radiation therapy in the thoracic area is possibly related to enhanced pulmonary, non-tumor FES uptake. METHODS: All FES-PET/CT scans performed in our institution from 2008 to 2017 were retrospectively analyzed. Scans from patients who had received irradiation in the thoracic area prior to the scan were compared to scans of patients who had never received irradiation in the thoracic area. The primary outcome was the presence of enhanced non-tumor FES uptake in the lungs, defined as visually increased FES uptake in the absence of an oncologic substrate on the concordant (contrast-enhanced) CT scan. All CT scans were evaluated for the presence of fibrosis or oncologic substrates. RESULTS: A total of 108 scans were analyzed: 70 scans of patients with previous irradiation in the thoracic area and 38 of patients without. Enhanced non-tumor FES uptake in the lungs was observed in 39/70 irradiated patients (56%), versus in 9/38 (24%) of non-irradiated patients. Fibrosis was present in 37 of the 48 patients with enhanced non-tumor FES uptake (77%), versus in 15 out of 60 (25%) patients without enhanced non-tumor uptake, irrespective of radiotherapy (p < 0.001). CONCLUSION: After irradiation of the thorax, enhanced non-tumor uptake on FES-PET can be observed in the radiation field in a significant proportion of patients. This seems to be related to fibrosis. When observing enhanced FES uptake in the lungs, this should not be interpreted as metastases. Information on recent radiation therapy or history of pulmonary fibrosis should therefore be taken into consideration.

The use of melatonin in adult psychiatric disorders: Expert recommendations by the French institute of medical research on sleep (SFRMS).

Melatonin is a hormone secreted by the pineal gland at night. This hormone has many physiological functions, the main one being to synchronise individuals' biological rhythms. Exogenous melatonin has the same chronobiotic action, even at small doses (0.125mg). In addition, a sleep-inducing (soporific) action appears to occur in a dose-effect relationship, i.e. as the dose increases. In psychiatric disorders, these two effects could have interesting applications in clinical practice. The French institute of medical research on sleep (SFRMS) appointed a group of experts to conduct a consensus conference to study the indications of melatonin and the conditions of its prescription. An account of the conclusions on adult psychiatric disorders (presented orally at the Congress on Sleep in Marseille, 23 November 2017) is given here. Exogenous melatonin proves to be useful among patients with a stabilized psychiatric disorder or in remission, to prevent relapse in case of associated complaints of insomnia, poor quality sleep or delayed sleep phase syndrome. During acute phases, melatonin could be used as an adjuvant treatment when there are insomnia symptoms, in mood disorders (bipolar disorder, major depressive disorder, seasonal affective disorder), in attention deficit hyperactivity disorder (ADHD), in peri-surgical anxiety and in schizophrenia. In somatoform disorders, melatonin is a possible treatment for painful symptoms in fibromyalgia, irritable bowel syndrome, functional dyspeptic syndrome and temporomandibular joint dysfunction.

89Zr-trastuzumab PET supports clinical decision making in breast cancer patients, when HER2 status cannot be determined by standard work up.

BACKGROUND: Up-to-date information on human epidermal growth factor receptor 2 (HER2) status in breast cancer (BC) is important, as expression can vary during the course of the disease, necessitating anti-HER2 therapy adjustments. Repeat biopsies, however, are not always possible. In this feasibility trial we assessed whether 89Zr-trastuzumab PET could support diagnostic understanding and aid clinical decision making, when HER2 status could not be determined by standard work up. Additionally, HER2 status on circulating tumour cells (CTCs) was assessed. PATIENTS AND METHODS: 89Zr-trastuzumab PET was performed in patients if disease HER2 status remained unclear after standard work up (bone scan, 18F-FDG PET, CT and if feasible a biopsy). PET result and central pathologic revision of available tumour biopsies were reported to the referring physician. CTC HER2 status prior to PET was evaluated afterwards and therefore not reported. Diagnostic understanding and treatment decision questionnaires were completed by the referring physicians before, directly after and ≥ 3 months after 89Zr-trastuzumab PET. RESULTS: Twenty patients were enrolled: 8 with two primary cancers (HER2-positive and HER2-negative BC or BC and non-BC), 7 with metastases inaccessible for biopsy, 4 with prior HER2-positive and -negative metastases and 1 with primary BC with equivocal HER2 status. 89Zr-trastuzumab PET was positive in 12 patients, negative in 7 and equivocal in 1 patient. In 15/20 patients, 89Zr-trastuzumab PET supported treatment decision. The scan altered treatment of 8 patients, increased physicians' confidence without affecting treatment in 10, and improved physicians' disease understanding in 18 patients. In 10/20 patients CTCs were detected; 6/10 showed HER2 expression. CTC HER2 status was not correlated to 89Zr-trastuzumab PET result or treatment decision. CONCLUSION: 89Zr-trastuzumab PET supports clinical decision making when HER2 status cannot be determined by standard work up. The impact of CTC HER2 status needs to be further explored.

Hospital ownership: a risk factor for nosocomial infection rates?

BACKGROUND: In some countries, a relationship between hospital ownership and the occurrence of healthcare-associated infection (HCAI) rates has been described. AIM: To investigate the association between hospital ownership and occurrence of HCAI in Germany. METHODS: Five different components of the German national nosocomial infection surveillance system were analysed with regard to the influence of hospital ownership in the period 2014-2016. Endpoints included ventilator-associated pneumonia, central-venous-catheter-associated bloodstream infections, urinary-catheter-associated urinary tract infections, surgical site infections (SSI) following hip prosthesis and colon surgery, meticillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile infections (CDI) and hand rub consumption per 1000 patient-days. Three hospital ownership types (public, non-profit and private) were analysed using univariate and multi-variate methods. FINDINGS: The distribution of hospitals according to the three ownership types was similar in all components. In total, 661 intensive care units (ICUs), 149 departments performing colon procedures, and 349 departments performing hip prosthesis were included. In addition, 568 hospitals provided their MRSA rates and 236 provided their CDI rates, and 1833 ICUs and 12,934 non-ICUs provided their hand rub consumption data. In general, the differences between the hospital types were rather small and not significant for the ICUs. In the multi-variate analysis, public hospitals had a lower SSI rate following hip prosthesis (odds ratio 0.80, 95% confidence interval 0.65-0.99). CONCLUSION: Hospital ownership was not found to have a major influence on the incidence of HCAI in Germany.

Axillary staging for breast cancer during pregnancy: feasibility and safety of sentinel lymph node biopsy.

BACKGROUND: Safety of sentinel lymph node (SLN) biopsy for breast cancer during pregnancy is insufficiently explored. We investigated efficacy and local recurrence rate in a large series of pregnant patients. PATIENTS AND METHODS: Women diagnosed with breast cancer who underwent SLN biopsy during pregnancy were identified from the International Network on Cancer, Infertility and Pregnancy, the German Breast Group, and the Cancer and Pregnancy Registry. Chart review was performed to record technique and outcome of SLN biopsy, locoregional and distant recurrence, and survival. RESULTS: We identified 145 women with clinically N0 disease who underwent SLN during pregnancy. The SLN detection techniques were as follows: 99mTc-labeled albumin nanocolloid only (n = 96; 66.2%), blue dye only (n = 14; 9.7%), combined technique (n = 15; 10.3%), or unknown (n = 20; 13.8%). Mapping was unsuccessful in one patient (0.7%) and she underwent an axillary lymph node dissection (ALND). Mean number of SLNs was 3.2 (interquartile range 1-3; missing n = 15). Positive SLNs were found in 43 (29.7%) patients and 34 subsequently underwent ALND. After a median follow-up of 48 months (range 1-177), 123 (84.8%) patients were alive and free of disease. Eleven patients experienced a locoregional relapse, including 1 isolated ipsilateral axillary recurrence (0.7%). Eleven (7.6%) patients developed distant metastases, of whom 9 (6.2%) died of breast cancer. No neonatal adverse events related to SLN procedure during pregnancy were reported. CONCLUSIONS: SLN biopsy during pregnancy has a comparably low axillary recurrence rate as in nonpregnant women. Therefore, this method can be considered during pregnancy instead of standard ALND for early-stage, clinically node-negative breast cancer.

Characterization of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program.

Background: Male breast cancer (BC) is rare, managed by extrapolation from female BC. The International Male BC Program aims to better characterize and manage this disease. We report the results of part I, a retrospective joint analysis of cases diagnosed during a 20-year period. Methods: Patients with follow-up and tumor samples, treated between 1990 and 2010, in 93 centers/9 countries. Samples were centrally analyzed in three laboratories (the United Kingdom, the Netherlands and the United States). Results: Of 1822 patients enrolled, 1483 were analyzed; 63.5% were diagnosed between 2001 and 2010, 57 (5.1%) had metastatic disease (M1). Median age at diagnosis: 68.4 years. Of 1054 M0 cases, 56.2% were node-negative (N0) and 48.5% had T1 tumors; 4% had breast conserving surgery (BCS), 18% sentinel lymph-node biopsy; half received adjuvant radiotherapy; 29.8% (neo)adjuvant chemotherapy and 76.8% adjuvant endocrine therapy (ET), mostly tamoxifen (88.4%). Per central pathology, for M0 tumors: 84.8% ductal invasive carcinomas, 51.5% grade 2; 99.3% estrogen receptor (ER)-positive; 81.9% progesterone receptor (PR)-positive; 96.9% androgen receptor (AR)-positive [ER, PR or AR Allred score ≥3]; 61.1% Ki67 expression low (<14% positive cells); using immunohistochemistry (IHC) surrogates, 41.9% were Luminal-A-like, 48.6% Luminal-B-like/HER-2-negative, 8.7% HER-2-positive, 0.3% triple negative. Median follow-up: 8.2 years (0.0-23.8) for all, 7.2 years (0.0-23.2), for M0, 2.6 years (0.0-12.7) for M1 patients. A significant improvement over time was observed in age-corrected BC mortality. BC-specific-mortality was higher for men younger than 50 years. Better overall (OS) and recurrence-free survival (RFS) were observed for highly ER+ (P = 0.001), highly PR+ (P = 0.002), highly AR+ disease (P = 0.019). There was no association between OS/RFS and HER-2 status, Ki67, IHC subtypes nor grade. Conclusions: Male BC is usually ER, PR and AR-positive, Luminal B-like/HER2-negative. Of note, 56% patients had T1 tumors but only 4% had BCS. ER was highly positive in >90% of cases but only 77% received adjuvant ET. ER, PR and AR were associated with OS and RFS, whereas grade, Ki67 and IHC surrogates were not. Significant improvement in survival over time was observed.

Performance of BRCA1/2 mutation prediction models in male breast cancer patients.

To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), BRCAPRO (BRCA probability) and the Myriad prevalence table ("Myriad"). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed vs predicted carriers and assessed the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) for each model. BOADICEA predicted the total number of BRCA1/2 mutation carriers quite accurately (observed/predicted ratio: 0.94). When a cut-off of 10% and 20% prior probability was used, BRCAPRO showed a non-significant better performance (observed/predicted ratio BOADICEA: 0.81, 95% confidence interval [CI]: [0.60-1.09] and 0.79, 95% CI: [0.57-1.09], vs. BRCAPRO: 1.02, 95% CI: [0.75-1.38] and 0.94, 95% CI: [0.68-1.31], respectively). Myriad underestimated the number of carriers in up to 69% of the cases. BRCAPRO showed a non-significant, higher AUC than BOADICEA (0.798 vs 0.776). Myriad showed a significantly lower AUC (0.671). BRCAPRO and BOADICEA can efficiently identify MBC patients as BRCA1/2 mutation carriers. Besides their general applicability, these tools will be of particular value in countries with limited healthcare resources.

Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial.

BACKGROUND: Only human epidermal growth factor receptor (HER)2 status determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has been validated to predict efficacy of HER2-targeting antibody-drug-conjugate trastuzumab emtansine (T-DM1). We propose molecular imaging to explore intra-/interpatient heterogeneity in HER2 mapping of metastatic disease and to identify patients unlikely to benefit from T-DM1. PATIENTS AND METHODS: HER2-positive mBC patients with IHC3+ or FISH ≥ 2.2 scheduled for T-DM1 underwent a pretreatment HER2-positron emission tomography (PET)/computed tomography (CT) with (89)Zr-trastuzumab. [(18)F]2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT was performed at baseline and before T-DM1 cycle 2. Patients were grouped into four HER2-PET/CT patterns according to the proportion of FDG-avid tumor load showing relevant (89)Zr-trastuzumab uptake (>blood pool activity): patterns A and B were considered positive (>50% or all of the tumor load 'positive'); patterns C and D were considered negative (>50% or all of the tumor load 'negative'). Early FDG-PET/CT was defined as nonresponding when >50% of the tumor load showed no significant reduction of FDG uptake (<15%). Negative (NPV) and positive predictive values (PPV) of HER2-PET/CT, early FDG response and their combination were assessed to predict morphological response (RECIST 1.1) after three T-DM1 cycles and time-to-treatment failure (TTF). RESULTS: In the 56 patients analyzed, 29% had negative HER2-PET/CT while intrapatient heterogeneity (patterns B and C) was found in 46% of patients. Compared with RECIST1.1, respective NPV/PPV for HER2-PET/CT were 88%/72% and 83%/96% for early FDG-PET/CT. Combining HER2-PET/CT and FDG-PET/CT accurately predicted morphological response (PPV and NPV: 100%) and discriminated patients with a median TTF of only 2.8 months [n = 12, 95% confidence interval (CI) 1.4-7.6] from those with a TTF of 15 months (n = 25, 95% CI 9.7-not calculable). CONCLUSIONS: Pretreatment imaging of HER2 targeting, combined with early metabolic response assessment holds great promise for improving the understanding of tumor heterogeneity in mBC and for selecting patients who will/will not benefit from T-DM1. CLINICALTRIALSGOV IDENTIFIER: NCT01565200.

Prognostic impact of transcription factor Fra-1 in ER-positive breast cancer: contribution to a metastatic phenotype through modulation of tumor cell adhesive properties.

PURPOSE: The transcription factor Fos-related antigen-1 (Fra-1) has been described to affect the morphology, motility and invasive potential of breast cancer cells. Since tumor cell adhesion plays an essential role in the metastatic process, especially for extravasation from blood vessels, we investigated the influence of Fra-1 on breast cancer cell interactions with the endothelium. METHODS: Using Fra-1-overexpressing MCF7 [weakly invasive, estrogen receptor (ER)-positive] and MDA MB231 (strongly invasive, ER-negative) cells, we performed dynamic cell flow adhesion assays on surfaces coated with E-selectin or with human pulmonary microvascular endothelial cells. RESULTS: We found a significant increased adhesion of Fra-1-overexpressing MCF7 cells to E-selectin but also to activate endothelial cells, whereas the MDA MB231 cell line showed moderate enhanced cell rolling and tethering on both coated surfaces. These different adhesion behaviors corresponded to an up-regulation of various adhesion-related proteins such as CD44 and integrin α5 in Fra-1-overexpressing MCF7 cells measured by microarray analysis and flow cytometry in comparison with no deregulation of key adhesion molecules observed in Fra-1-overexpressing MDA MB231 cells. In line with these results and based on cDNA microarray data of breast cancer patients (n = 197), high Fra-1 expression significantly correlates with shorter overall survival and higher rate of lung metastasis in ER-positive breast cancer patients (n = 130), but has no impact on the prognosis of patients with ER-negative tumors. CONCLUSION: Thus, in addition to its pro-invasive and pro-migratory effect, Fra-1 might influence the metastatic potential of breast cancer cells by changing the expression of adhesion molecules, resulting in increased adherence to endothelial cells under flow conditions.

Regional distribution of nosocomial infections due to ESBL-positive Enterobacteriaceae in Germany: data from the German National Reference Center for the Surveillance of Nosocomial Infections (KISS).

Surveillance systems for hospital infections are reporting increasing rates of extended-spectrum ß-lactamase (ESBL)-positive Enterobacteriaceae in Europe. We aimed to perform a national survey on this trend and on the regional distribution of nosocomial infections due to ESBL-positive Enterobacteriaceae in German hospitals. Data from 2007 to 2012 from two components of the German national nosocomial infection surveillance system were used for this analysis. The data derive from intensive care units and surgical departments. Independent factors determining the proportion of ESBL-positive Enterobacteriaceae among nosocomial infections due to Enterobacteriaceae and changes in its regional distribution (broken down into German federal states) were calculated by regression analysis. From 2007 to 2012, the data showed a significantly increasing proportion of ESBL-positive Enterobacteriaceae in surgical site infections (from 11.46 to 15.38, 134%, p 0.003), urinary tract infections (9.36 to 16.56, 177%, p <0.001) and lower respiratory tract infections (11.91 to 14.70, 123%, p <0.001) due to Enterobacteriaceae. Factors independently associated with a growing proportion were: Thuringia (p 0.009; odds ratio (OR) 1.53), North Rhine-Westphalia (p <0.001; OR 1.41) and general surgery ward (p 0.002; OR 1.47). The proportion of ESBL-positive Enterobacteriaceae in nosocomial infections has significantly increased in Germany over the last 6 years. Hospitals in Central Germany and surgical departments in all of Germany are especially affected by this development.