Development of Neural Mechanisms Underlying Threat Processing: Associations With Childhood Social Reticence and Adolescent Anxiety.

Background: Social reticence in early childhood is characterized by shy and anxiously avoidant behavior, and it confers risk for pediatric anxiety disorders later in development. Aberrant threat processing may play a critical role in this association between early reticent behavior and later psychopathology. The goal of this longitudinal study is to characterize developmental trajectories of neural mechanisms underlying threat processing and relate these trajectories to associations between early-childhood social reticence and adolescent anxiety. Methods: In this 16-year longitudinal study, social reticence was assessed from 2 to 7 years of age; anxiety symptoms and neural mechanisms during the dot-probe task were assessed at 10, 13, and 16 years of age. The sample included 144 participants: 71 children provided data at age 10 (43 girls, meanage = 10.62), 85 at age 13 (46 girls, meanage = 13.25), and 74 at age 16 (36 girls, meanage = 16.27). Results: A significant interaction manifested among social reticence, anxiety symptoms, and time, on functional connectivity between the left amygdala and the left dorsolateral prefrontal cortex, voxelwise p < .001, clusterwise familywise error p < .05. Children with high social reticence showed a negative association between amygdala-dorsolateral prefrontal cortex connectivity and anxiety symptoms with age, compared to children with low social reticence, suggesting distinct neurodevelopmental pathways to anxiety. Conclusions: These findings were present across all conditions, suggesting task-general effects in potential threat processing. Additionally, the timing of these neurodevelopmental pathways differed for children with high versus low social reticence, which could affect the timing of effective preventive interventions.

The role of anxiety and gender in anticipation and avoidance of naturalistic anxiety-provoking experiences during adolescence: An ecological momentary assessment study.

Objective: Anxiety symptoms often increase in late childhood/early adolescence, particularly among girls. However, few studies examine anxiety-relevant gender differences during anticipation and avoidance of naturalistic experiences during adolescence. The current study uses ecological momentary assessment (EMA) to examine associations among clinical anxiety, gender, anticipation, and attempted avoidance of person-specific anxiety-provoking experiences in youth ages 8-18. Method: 124 youth (73 girls) completed 7 consecutive days of EMA. Seventy participants (42 girls) met criteria for one or more anxiety disorders, while the remaining 54 were healthy controls (31 girls). Participants reported the experience that they were "most worried about happening that day" and completed ratings about that event including whether they attempted to avoid that experience. Multilevel models examined whether diagnostic group (anxious, healthy), gender (boys, girls), or their interaction predicted anticipatory ratings or avoidance of these experiences. Results: Analyses revealed significant diagnostic group by gender interactions for anticipatory ratings. Specifically, anxious girls reported greater worry and predicted more negative outcomes related to future experiences. However, only a main effect of diagnostic group emerged for attempted avoidance. Finally, anticipatory worry predicted higher rates of attempted avoidance, but this association did not vary by diagnostic group, gender, or their interaction. Conclusion: These findings extend the literature on the interplay of anticipation and avoidance to person-specific naturalistic experiences in pediatric anxiety. They reveal that anxious girls report more anticipatory anxiety and worry, while avoidance of real-world anxiety-provoking scenarios is a key concern for anxious youth independent of gender. By using EMA to examine person-specific anxiety-inducing experiences we can begin to understand how these processes and experiences unfold in the real world.

Is interpretation bias for threat content specific to youth anxiety symptoms/diagnoses? A systematic review and meta-analysis.

Anxiety is the most common mental health problem in youth. Numerous studies have identified that youth anxiety is associated with interpretation bias or the attribution of threatening meaning to ambiguity. Interpretation bias has been proposed as a mechanism underlying the development and maintenance of pediatric anxiety. Theoretically, interpretation bias should be content-specific to individual youth anxiety symptom domains. However, extant studies have reported conflicting findings of whether interpretation bias is indeed content specific to youth anxiety symptoms or diagnoses. The present meta-analysis aimed to synthesize the literature and answer the question: is the relationship between interpretation bias and anxiety content specific? Search of PubMed and PsycINFO databases from January 1, 1960 through May 28, 2019 yielded 9967 citations, of which 19 studies with 20 comparisons and 2976 participants met eligibility criteria. Meta-analysis with random effects models was conducted to examine an overall effect (Pearson r) between anxiety domain and content-specific interpretation bias in single sample studies, and an overall effect size difference (Cohen's d) in studies comparing anxious to non-anxious youth. Results support a content specific correlation between interpretation bias and anxiety symptom domain in single sample studies (r = 0.18, p = 0.03). However, it is currently undetermined whether this relationship holds in studies that compare the relationship between content-specific interpretation bias and anxiety in anxious versus non-anxious youth. A variety of methodologic considerations across studies are discussed, with implications for further investigation of interpretation bias and youth anxiety.

Like parent, like child: Is parent interpretation bias associated with their child's interpretation bias and anxiety? A systematic review and meta-analysis.

BACKGROUND: Anxiety disorders are the most prevalent psychiatric problem across the lifespan, with typical onset during the pediatric period. Prior literature has examined cognitive mechanisms associated with youth anxiety and identified interpretation bias, the threatening appraisal of ambiguity, as a ubiquitous correlate and likely mechanism. A small set of studies have examined interpretation bias and anxiety in parent-child dyads, although results about this potential relationship are conflicted. This systematic review and meta-analysis investigates the association between parent interpretation bias with child interpretation bias and child anxiety. METHODS: Eight studies met the rigorous inclusion criteria, which required direct assessment of interpretation bias in both youth and parent. RESULTS: Meta-analysis with a random effects model indicated a small and significant correlation between parent and child interpretation biases (r = 0.14, p < .01), as well as a small and significant correlation between parent interpretation bias and child anxiety (r =  = 0.20, p = .01). LIMITATIONS: As only eight studies were included in this meta-analysis, reflecting the state of the extant literature, it is possible that, as data accumulate and this work continues in the future, results may or may not be replicated. CONCLUSIONS: Despite variability in findings across the included empirical studies, the current meta-analysis suggests that a correlational relationship between parent interpretation bias and child bias/anxiety exists. This work has implications for conceptualizing parent interpretation bias as a possible explanatory mechanism underlying youth interpretation bias and anxiety.

The Transdiagnostic Origins of Anxiety and Depression During the Pediatric Period: Linking NIMH Research Domain Criteria (RDoC) Constructs to Ecological Systems.

In the last decade, an abundance of research has utilized the NIMH Research Domain Criteria (RDoC) framework to examine mechanisms underlying anxiety and depression in youth. However, relatively little work has examined how these mechanistic intrapersonal processes intersect with context during childhood and adolescence. The current paper covers reviews and meta-analyses that have linked RDoC-relevant constructs to ecological systems in internalizing problems in youth. Specifically, cognitive, biological, and affective factors within the RDoC framework were examined. Based on these reviews and some of the original empirical research they cover, we highlight the integral role of ecological factors to the RDoC framework in predicting onset and maintenance of internalizing problems in youth. Specific recommendations are provided for researchers using the RDoC framework to inform future research integrating ecological systems and development. We advocate for future research and research funding to focus on better integration of the environment and development into the RDoC framework.

Long-term symptoms of polyneuropathy in breast and colorectal cancer patients treated with and without adjuvant chemotherapy.

BACKGROUND: The aim of this study was to assess chemotherapy-induced polyneuropathy (CIPN) 5 years after adjuvant chemotherapy in patients with breast and colorectal cancer. The association of CIPN with quality of life, anxiety, and depression was analyzed. METHODS: Of a set of 100 patients with breast cancer and of 74 with colorectal cancer who had undergone surgery and adjuvant chemotherapy in 2011-2012, 80 and 52 patients alive, respectively, were included together with two reference groups of 249 breast cancer patients and 83 colorectal cancer patients who had undergone surgery only. All patients were sent a questionnaire on alcohol consumption, smoking habits, comorbidity, medicine consumption, and oxaliplatin-specific questions, as well as the Michigan Neuropathy Screening Instrument questionnaire (MNSIq), the Douleur Neuropathique 4 Questions (DN4q), the EQ-5D, and the Hospital Anxiety and Depression Scale. Possible polyneuropathy was defined as the presence of numbness and/or tingling in the feet, secondly as a score of ≥4 on the MNSIq. Possible painful polyneuropathy was defined as pain in both feet and a score ≥3 on the DN4q. RESULTS: The prevalence of possible polyneuropathy defined by numbness and/or tingling in the feet was 38.8% (28.1-50.3) after adjuvant docetaxel and 57.7% (43.2-71.3) after adjuvant oxaliplatin, with no significant difference from a previous 1-year follow-up (P >.35). Fewer had possible polyneuropathy as defined by the MNSIq. Patients with possible polyneuropathy after adjuvant chemotherapy reported significantly lower quality of life than patients treated with surgery only. CONCLUSION: Symptoms of polyneuropathy following adjuvant docetaxel and oxaliplatin persist 5 years after treatment and affect quality of life negatively.

Developmental pathways to social anxiety and irritability: The role of the ERN.

Early behaviors that differentiate later biomarkers for psychopathology can guide preventive efforts while also facilitating pathophysiological research. We tested whether error-related negativity (ERN) moderates the link between early behavior and later psychopathology in two early childhood phenotypes: behavioral inhibition and irritability. From ages 2 to 7 years, children (n = 291) were assessed longitudinally for behavioral inhibition (BI) and irritability. Behavioral inhibition was assessed via maternal report and behavioral responses to novelty. Childhood irritability was assessed using the Child Behavior Checklist. At age 12, an electroencephalogram (EEG) was recorded while children performed a flanker task to measure ERN, a neural indicator of error monitoring. Clinical assessments of anxiety and irritability were conducted using questionnaires (i.e., Screen for Child Anxiety Related Disorders and Affective Reactivity Index) and clinical interviews. Error monitoring interacted with early BI and early irritability to predict later psychopathology. Among children with high BI, an enhanced ERN predicted greater social anxiety at age 12. In contrast, children with high childhood irritability and blunted ERN predicted greater irritability at age 12. This converges with previous work and provides novel insight into the specificity of pathways associated with psychopathology.

Advancing clinical neuroscience through enhanced tools: Pediatric social anxiety as an example.

BACKGROUND: Clinical researchers face challenges when trying to quantify diverse processes engaged during social interactions. We report results from two studies, each demonstrating the potential utility of tools for examining processes engaged during social interactions. METHOD: In the first study, youth (n = 57) used a smartphone-based tool to rate mood and responses to social events. A subset (n = 20) completed the second, functional magnetic resonance imaging study. This second study related anxiety to error-evoked brain responses in two social conditions-while being observed and when alone. We also combined these tools to bridge clinical, social-contextual, and neural levels of measurement. RESULTS: Results from the first study showed an association between negatively-perceived social experiences and a range of negative emotions. In the second study there was a positive correlation during error monitoring between social-anxiety severity and context-specific activation of the pregenual anterior cingulate cortex. Finally, during imaging, the perceived quality of peer interactions as assessed using the smartphone-based tool, interacted with social context to predict levels of activation in the hippocampus and superior frontal gyrus. CONCLUSIONS: By improving measurement, enhanced tools may provide new means for studying relationships among anxiety, brain function, and social interactions.

Inhibitory control and emotion dysregulation: A framework for research on anxiety.

While emotional dysregulation is a broad construct, the current paper adopts a narrow approach to facilitate translational neuroscience research on pediatric anxiety. The paper first presents data on an adapted version of the antisaccade task and then integrates these data into a research framework. Data on an adapted version of the antisaccade task were collected in 57 youth, including 35 seeking treatment for an anxiety disorder. Associations were examined between performance on the antisaccade task and (a) age, (b) performance on other cognitive-control tasks (i.e., the stop-signal delay and flanker tasks), and (c) level of anxiety symptoms. Better performance on the antisaccade task occurred in older relative to younger subjects and correlated with better performance on the flanker task. Across the 57 youth, higher levels of anxiety correlated with shorter latency for correct antisaccades. These data can be placed within a three-step framework for translational neuroscience research. In the first step, a narrow index of emotion dysregulation is targeted. In the second step, this narrow index is linked to other correlated indicators of the same underlying narrow latent construct. In the third and final step, associations are examined with clinical outcomes and response to treatment.

Diagnostic and Prognostic MicroRNA Biomarkers for Prostate Cancer in Cell-free Urine.

BACKGROUND: Widespread use of prostate-specific antigen (PSA) testing for prostate cancer (PC) detection has led to extensive overdiagnosis and overtreatment. Urine-based microRNA (miRNA) biomarkers could be useful in PC diagnosis and prognosis. OBJECTIVE: To train and validate urine-based microRNA (miRNA) biomarkers that may assist in PC diagnosis and prognosis. DESIGN, SETTING, AND PARTICIPANTS: We profiled the expression levels of 92 miRNAs via reverse transcriptase-poymerase chain reaction in cell-free urine samples from 29 patients with benign prostatic hyperplasia (BPH) and 215 patients with clinically localized PC (cohort 1). Our findings were validated in an independent cohort of 29 BPH patients and 220 patients with clinically localized PC (cohort 2). RESULTS AND LIMITATIONS: We identified and validated several deregulated miRNAs in urine samples from PC patients. In addition, we trained a novel diagnostic three-miRNA model (miR-222-3p*miR-24-3p/miR-30c-5p) that distinguished BPH and PC patients with an area under the curve (AUC) of 0.95 in cohort 1, and was successfully validated in cohort 2 (AUC 0.89). Furthermore, we trained a novel prognostic three-miRNA model (miR-125b-5p*let-7a-5p/miR-151-5p) that predicted time to biochemical recurrence after radical prostatectomy independently of routine clinicopathological parameters in cohort 1, and was successfully validated in cohort 2. CONCLUSIONS: Future clinical implementation of our novel diagnostic and prognostic three-miRNA signatures could help in primary diagnosis of PC and guide treatment decisions. Further validation studies are warranted. PATIENT SUMMARY: Using two large patient cohorts, we searched for novel prostate cancer biomarkers in urine. We found two new sets of microRNA biomarkers in urine that could accurately predict the presence of prostate cancer and the likelihood of recurrence after prostatectomy. Further studies are needed before an actual clinical test can be developed.

Chronic Pain and Neuropathy Following Adjuvant Chemotherapy.

Objective: To determine symptoms and characteristics of chronic sensory neuropathy in patients treated with oxaliplatin and docetaxel, including patterns of somatosensory abnormalities, pain descriptors, and psychological functioning. Design: A retrospective cross-sectional study. Setting: A chronic pain research center. Subjects: Thirty-eight patients with chronic peripheral pain and/or dysesthesia following chemotherapy. Methods: Sensory profiles, psychological functioning, and quality of life were assessed using standardized questionnaires. In addition, standardized quantitative sensory testing and nerve conduction studies were carried out. Results: The sensory profiles and clinical symptoms were very similar in the two groups. Pricking, numbness, and burning were common descriptors in both groups, and the predominant finding was sensory loss to A beta-mediated sensory modalities with decreased mechanical and vibration detection thresholds. A high frequency of abnormalities in thermal sensory limen and the presence of paradoxical heat sensation seem to be sensitive markers of small fiber loss. Both groups had mainly sensory, axonal large fiber or mixed fiber polyneuropathy, which tended to be most severe in the oxaliplatin group. Conclusions: Both oxaliplatin-induced and docetaxel-induced polyneuropathies represent a significant problem that affects the daily life of the patients. Our results, defining the somatosensory phenotype, can improve the understanding of the pathophysiological mechanisms useful for future studies in the tailored treatment of prevention of chemotherapy-induced peripheral neuropathy and pain.

Novel diagnostic and prognostic classifiers for prostate cancer identified by genome-wide microRNA profiling.

PURPOSE: This study investigates the diagnostic and prognostic biomarker potential of miRNAs in prostate cancer (PC). RESULTS: We identified several new deregulated miRNAs between non-malignant (NM) and PC tissue samples and between more/less aggressive PC subgroups. We also developed and validated a novel 13-miRNA diagnostic classifier with high sensitivity and specificity for PC. Finally, we trained a new 3-miRNA prognostic classifier (miR-185-5p+miR-221-3p+miR-326) that predicted time to biochemical recurrence (BCR) independently of routine clinicopathological variables in a training radical prostatectomy (RP) cohort (n = 126) as well as in two independent validation cohorts (n = 110 and n = 99). EXPERIMENTAL DESIGN: After RT-qPCR-based profiling of 752 miRNAs in 13 NM and 134 PC tissue samples (cohort 1), we selected 93 top candidate diagnostic/prognostic miRNAs for validation in two independent patient sets (cohort 2: 19 NM and 138 PC; cohort 3: 28 NM and 113 PC samples). Diagnostic potential was assessed by ROC curve analysis and prognostic potential by Kaplan-Meier, uni- and multivariate Cox regression analyses. BCR after RP was used as endpoint. CONCLUSIONS: This is the first report of a miRNA signature with significant independent prognostic value demonstrated in three PC patient cohorts.

Pattern of failure in 5001 patients treated for glottic squamous cell carcinoma with curative intent - A population based study from the DAHANCA group.

PURPOSE: To describe the pattern of failure in a national consecutive cohort of patients with glottic squamous cell carcinomas (SCC) treated with primary radiotherapy (RT) with curative intent over a 41-year period. MATERIALS AND METHODS: All patients undergoing curative treatment for a glottic SCC diagnosed in Denmark between 1971 and 2011 were included and followed from the first contact with the oncology center to death or February 15, 2015. RESULTS: 5001 patients were identified of whom 98% had primary RT. The median follow-up was 9.1 years/5.7 years (patients alive/patients who died). Ten patients were lost to follow-up. In total 1511 failures were observed; of these 93%, 11% and 5% included T site, N site, and M site, respectively. For patients diagnosed in the 70s and the 00s, respectively, the five-year incidences were: local failure (32% vs 19%), loco-regional failure (34% vs 21%), laryngectomy (26% vs 10%), laryngectomy-free survival (48% vs 62%), disease-free survival (62% vs 68%), and overall survival (62% vs 68%). The five-year incidence of ultimate failure (13-16%) remained statistically unchanged. CONCLUSION: From the 70s to the 00s a continually improving primary disease-control was observed with a concurrent decrease in the incidence of laryngectomy. The survival rate was significantly higher in the 00s compared to the previous three decades.

Chemotherapy-induced pain and neuropathy: a prospective study in patients treated with adjuvant oxaliplatin or docetaxel.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer therapy. This study evaluates symptoms of CIPN and CIPN-related pain and its influence on psychological functioning and potential predictors of chronic CIPN and pain. In this large prospective questionnaire study, 174 patients receiving adjuvant oxaliplatin or docetaxel were consecutively included. Patients were asked to complete a questionnaire with validated questions on peripheral neuropathy, pain, anxiety and depression, and quality of life at baseline, after the first cycle, halfway through therapy, and 1 year after baseline. Chronic CIPN symptoms (tingling and/or numbness) in the feet at 1-year follow-up were present in 63.6% of patients without preexisting neuropathy in the oxaliplatin group and in 44.8% in the docetaxel group, whereas pain in hands and feet was found in 31.3% and 35.1%, respectively. Both groups had significantly different pain profiles, and persistent pain in the docetaxel group was found to have effect on psychological function. Cumulative dose predicted oxaliplatin-induced neuropathy (P = 0.004), whereas endocrine therapy predicted peripheral pain in the docetaxel group (P = 0.04). There are important differences in acute neuropathic symptoms and chronic pain profiles in patients after oxaliplatin and docetaxel treatment. It is, however, important to recognize that chronic peripheral pain may be unrelated to neuropathy and can be caused by concomitant treatments. Future studies should focus on characterizing and distinguishing CIPN-related pain from other types of pain to determine the best outcome measures for trials on prevention or relief.

Prognostic factors for overall survival in metastatic colorectal cancer using a stop-and-go FLIRI-based treatment strategy.

PURPOSE: To determine overall survival and baseline prognostic variables in a cohort of patients with metastatic colorectal cancer receiving a FLIRI-based stop-and-go treatment strategy. METHODS: Clinical information was collected from patient files in consecutive patients treated with palliative combination chemotherapy using a stop-and-go strategy from September 2007 until June 2011. The primary outcome was overall survival. Cox regression analysis was used to examine the effect of prognostic variables on survival. Baseline variables were performance status, primary tumor site, status of primary tumor (resected or unresected), synchronous metastases, >1 metastatic site, liver-only metastases, alkaline phosphatase (>300 U/l), lactate dehydrogenase (>300 U/l), platelets (>400 × 10(9)/l), and leucocytes (>10 × 10(9)/l). RESULTS: We included 314 patients (median age 64.5 (57-70) years). Median overall survival was 20.9 (95 % confidence interval (CI), 19.1-223.4) months with a median follow-up of 21.3 months (interquartile range (IQR) 13-34.8). Independent prognostic markers of decreased survival were PS 1 and 2 vs. 0 hazard ratio (HR) 1.47 (95 % CI 1.14-1.91, p = 0.003) and HR 2.06 (95 % CI 1.19-3.56, p = 0.01), colon as the primary tumor site HR 1.43 (95 % CI 1.09-1.88, p = 0.009), unresected primary tumor HR 2.22 (95 % CI 1.61-3.07, p < 0.001), and elevated leucocytes (>10 × 10(9)/l) HR 1.53 (95 % CI 1.12-2.09, p = 0.007). CONCLUSIONS: Overall survival in metastatic colorectal cancer using a FLIRI-based stop-and-go strategy in an unselected consecutive cohort proved comparable to RCTs from the same period. Baseline prognostic markers of poorer prognosis were PS 1 or 2, colon as primary tumor site, unresected primary tumor, and leucocytes >10 × 10(9)/l. These variables are all easy accessible in daily clinical practice.

Word sense disambiguation across two domains: biomedical literature and clinical notes.

The aim of this study is to explore the word sense disambiguation (WSD) problem across two biomedical domains-biomedical literature and clinical notes. A supervised machine learning technique was used for the WSD task. One of the challenges addressed is the creation of a suitable clinical corpus with manual sense annotations. This corpus in conjunction with the WSD set from the National Library of Medicine provided the basis for the evaluation of our method across multiple domains and for the comparison of our results to published ones. Noteworthy is that only 20% of the most relevant ambiguous terms within a domain overlap between the two domains, having more senses associated with them in the clinical space than in the biomedical literature space. Experimentation with 28 different feature sets rendered a system achieving an average F-score of 0.82 on the clinical data and 0.86 on the biomedical literature.

Estrogenic effect of soy isoflavones on mammary gland morphogenesis and gene expression profile.

We examined the effect of 17beta-estradiol (E2) and soy isoflavones' exposure on morphogenesis and global gene expression in the murine mammary gland. Three exposure regimens were applied: isoflavones added to the diet throughout either the lactational period (via the dams) or the postweaning period and E2 administered orally during the lactational period. Whole mounts of mammary glands were evaluated both in juvenile and adult animals with respect to branching morphogenesis and terminal end bud (TEB) formation. At postnatal day (PND) 28, we observed a significant increase in branching morphogenesis in all treated groups with the most pronounced effect after E2 exposure. For the E2-treated animals there was also a significant increase in TEB formation. At PNDs 42-43 the postweaning isoflavone and the E2 groups showed a transient reduction in the number of TEBs. A similar response after isoflavone and E2 exposure was further substantiated by changes in gene expression, since the same groups of genes were up- and downregulated, particularly in the E2 and postweaning isoflavone regimen. All changes in gene expression correlated with changes in the cellular composition of the gland, i.e., more and larger TEBs and ducts. The results suggest an estrogenic response of physiological doses of isoflavones on mammary gland development at both the morphological and molecular level, which resembled that induced by puberty.

Loco-regional recurrence after mastectomy in high-risk breast cancer--risk and prognosis. An analysis of patients from the DBCG 82 b&c randomization trials.

BACKGROUND AND PURPOSE: In the DBCG 82 b&c trials, 3,083 patients with stages II and III breast cancer were randomised to receive post-mastectomy radiotherapy (RT) versus no RT in addition to systemic therapy. The study showed a decrease in loco-regional recurrences and an improved survival in patients receiving RT. The aim of the present study was to identify risk factors for loco-regional recurrence (LRR), to evaluate the treatment of LRR and to examine the prognosis after LRR. PATIENTS AND METHODS: The 18-year probabilities of LRR were calculated for different prognostic factors using the Kaplan-Meier method. The efficacy of different LRR treatments was compared. The 5-year survival and distant metastases (DM) probability after LRR was calculated with regard to initial randomization group, primary tumor and recurrence related variables. RESULTS: Of the 3,083 patients, 535 had a LRR alone as first site of failure. In univariate analyses, large primary tumor size, ductal carcinoma, high malignancy grade, fascia invasion, few removed nodes, many positive nodes and extracapsular invasion were all risk factors for developing LRR. Combined treatment with surgery and RT at the time of LRR increased the persistent loco-regional control. The 5-year probability of subsequent DM was 73% irrespective of initial randomization group. In multivariate analysis, large primary tumor size, many positive nodes, extracapsular invasion, supra/infraclaviculary failures, multiple LRR and a short interval less than 2 years to first LRR were poor prognostic factors for survival. CONCLUSIONS: Twenty-seven percent of LRR patients had no DM 5 years after failure. Initial randomization group did not alter the prognosis after LRR. Combined treatment of the LRR with surgery and RT improved persistent loco-regional control compared with surgery or RT alone.

Study of failure pattern among high-risk breast cancer patients with or without postmastectomy radiotherapy in addition to adjuvant systemic therapy: long-term results from the Danish Breast Cancer Cooperative Group DBCG 82 b and c randomized studies.

PURPOSE: Postmastectomy radiotherapy (RT) in high-risk breast cancer patients can reduce locoregional recurrences (LRRs) and improve disease-free and overall survival. The aim of this analysis was to examine the overall disease recurrence pattern among patients randomly assigned to receive treatment with or without RT. PATIENTS AND METHODS: A long-term follow-up was performed among the 3,083 patients from the Danish Breast Cancer Cooperative Group 82 b and c trials, except in those already recorded with distant metastases (DM) or contralateral breast cancer (CBC). The end points were LRR, DM, and CBC, and the follow-up continued until DM, CBC, emigration, or death. Information was selected from medical records, general practitioners, and the National Causes of Death Registry. The median potential follow-up time was 18 years. RESULTS: The 18-year probability of any first breast cancer event was 73% and 59% (P < .001) after no RT and RT, respectively (relative risk [RR], 0.68; 95% CI, 0.63 to 0.75). The 18-year probability of LRR (with or without DM) was 49% and 14% (P < .001) after no RT and RT, respectively (RR, 0.23; 95% CI, 0.19 to 0.27). The 18-year probability of DM subsequent to LRR was 35% and 6% (P < .001) after no RT and RT, respectively (RR, 0.15; 95% CI, 0.11 to 0.20), whereas the probability of any DM was 64% and 53% (P < .001) after no RT versus RT, respectively (RR, 0.78; 95% CI, 0.71 to 0.86). CONCLUSION: Postmastectomy RT changes the disease recurrence pattern in high-risk breast cancer patients; fewer patients have LRR as first site of recurrence, and overall fewer patients have DM.