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Primary tumors with a mixed invasive breast carcinoma of no-special type (IBC-NST) and invasive lobular cancer (ILC) histology are present in approximately five percent of all patients with breast cancer and are understudied at the metastatic level. Here, we characterized the histology of metastases from two patients with primary mixed IBC-NST/ILC from the postmortem tissue donation program UPTIDER (NCT04531696). The 14 and 43 metastatic lesions collected at autopsy had morphological features and E-cadherin staining patterns consistent with pure ILC. While our findings still require further validation, they may challenge current clinical practice and imaging modalities used in these patients., Competing Interests: Declaration of Competing interest All authors declare to have no conflict of interest, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Research on metastatic cancer has been hampered by limited sample availability. Here we present the breast cancer post-mortem tissue donation program UPTIDER and show how it enabled sampling of a median of 31 (range: 5-90) metastases and 5-8 liquids per patient from its first 20 patients. In a dedicated experiment, we show the mild impact of increasing time after death on RNA quality, transcriptional profiles and immunohistochemical staining in tumor tissue samples. We show that this impact can be counteracted by organ cooling. We successfully generated ex vivo models from tissue and liquid biopsies from distinct histological subtypes of breast cancer. We anticipate these and future findings of UPTIDER to elucidate mechanisms of disease progression and treatment resistance and to provide tools for the exploration of precision medicine strategies in the metastatic setting., (© 2024. The Author(s).)

OBJECTIVE: To explore whether preoperative pain intensity, pain cognitions, and quantitative sensory measures influence the established effectiveness of perioperative pain neuroscience education (PPNE) on health-related quality of life at 1 year after surgery for lumbar radiculopathy. DESIGN: Secondary analysis of a triple-blinded randomized controlled trial. METHODS: Participants (n = 90) were Dutch-speaking adults (18-65 years) who were scheduled for surgery for lumbar radiculopathy in 3 Belgian hospitals. They were randomized (1:1) to receive PPNE (n = 41) or perioperative biomedical education (n = 49). Linear mixed models were built for health-related quality of life (ie, SF-6D utility values, Physical and Mental Component of the 36-item Short Form Health Survey) using the following independent variables: therapy, time, and preoperative scores for back and leg pain intensity, pain catastrophizing, kinesiophobia, hypervigilance, and quantitative sensory measures. RESULTS: The impact of PPNE on SF-6D utility values over time was influenced by kinesiophobia (F = 3.30, P = .02) and leg pain intensity (F = 3.48, P = .02). Regardless of the intervention, back pain intensity negatively influenced SF-6D values over time (F = 3.99, P = .009). The Physical Component scores were negatively impacted by back pain intensity (F = 9.08, P = .003) and were influenced over time by leg pain intensity (F = 2.87, P = .04). The Mental Component scores were negatively impacted by back pain intensity (F = 6.64, P = .01) and pain catastrophizing (F = 5.42, P = .02), as well as hypervigilance (F = 3.16, P = .03) and leg pain intensity (F = 3.12, P = .03) over time. CONCLUSION: PPNE may be more effective than perioperative biomedical education in improving postoperative health utility values in patients who reported higher kinesiophobia and leg pain intensity before surgery for lumbar radiculopathy. J Orthop Sports Phys Ther 2024;54(4):1-10. Epub 8 January 2024. doi:10.2519/jospt.2024.12051 .

We present a protocol for the rapid postmortem bedside procurement of selected tissue samples using an endoscopic endonasal surgical technique that we adapted from skull base surgery. We describe steps for the postmortem collection of blood, cerebrospinal fluid, a nasopharyngeal swab, and tissue samples; the clean-up procedure; and the initial processing and storage of the samples. This protocol was validated with tissue samples procured postmortem from COVID-19 patients and can be applied in another emerging infectious disease. For complete details on the use and execution of this protocol, please refer to Khan et al. (2021) 1 and Khan et al. (2022). 2 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

In people with nonspecific chronic spinal pain (nCSP), disability and quality of life are associated with clinical, cognitive, psychophysical, and demographic variables. However, evidence regarding the interactions between these variables is only limited to this population. Therefore, this study aims to explore path models explaining the multivariate contributions of such variables to disability and quality of life in people with nCSP. This secondary analysis uses baseline data from a randomized controlled trial including 120 participants with nCSP. Structural equation modeling was used to explore path models for the Pain Disability Index (PDI), the Short Form 36-item physical (SF-36 PC), and mental (SF-36 MC) component scores. All models included sex, pain catastrophizing, kinesiophobia, hypervigilance, and pain intensity. Additionally, the PDI and SF-36 PC models included pressure pain thresholds (PPTs) at the dominant pain site (ie, neck or low back). Significant associations were found between sex, pain cognitions, pain intensity, and PPTs. Only pain catastrophizing significantly directly influenced the PDI (P ≤ .001) and SF-36 MC (P = .014), while the direct effects on the SF-36 PC from kinesiophobia (P = .008) and pain intensity (P = .006) were also significant. However, only the combined effect of all pain cognitions on the SF-36 PC was mediated by pain intensity (P = .019). Our findings indicate that patients' pain-related cognitions have an adverse effect on their physical health-related quality of life via a negative influence on their pain intensity in people with nCSP. PERSPECTIVE: This secondary analysis details a network analysis confirming significant interactions between sex, pain cognitions, pain intensity, and PPTs in relation to disability and health-related quality of life in people with chronic spinal pain. Moreover, its findings establish the importance of pain cognitions and pain intensity for these outcomes. TRIALS REGISTRATION: Clinicaltrials.gov (NCT02098005)., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Chronic pain is the most prevalent disease worldwide, leading to substantial disability and socioeconomic burden. Therefore, it can be regarded as a public health disease and major challenge to scientists, clinicians and affected individuals. Behavioral lifestyle factors, such as, physical (in)activity, stress, poor sleep and an unhealthy diet are increasingly recognized as perpetuating factors for chronic pain. Yet, current management options for patients with chronic pain often do not address lifestyle factors in a personalized multimodal fashion. This state-of-the-art clinical perspective aims to address this gap by discussing how clinicians can simultaneously incorporate various lifestyle factors into a personalized multimodal lifestyle intervention for individuals with chronic pain. To do so the available evidence on (multimodal) lifestyle interventions targeting physical (in)activity, stress, sleep and nutritional factors, specifically, was reviewed and synthetized from a clinical point of view. First, advise is provided on how to design a personalized multimodal lifestyle approach for a specific patient. Subsequently, best-evidence recommendations on how to integrate physical (in)activity, stress, sleep and nutritional factors as treatment targets into a personalized multimodal lifestyle approach are outlined. Evidence supporting such a personalized multimodal lifestyle approach is growing, but further studies are needed.

(1) Background: Surgical phases form the basic building blocks for surgical skill assessment, feedback, and teaching. The phase duration itself and its correlation with clinical parameters at diagnosis have not yet been investigated. Novel commercial platforms provide phase indications but have not been assessed for accuracy yet. (2) Methods: We assessed 100 robot-assisted partial nephrectomy videos for phase durations based on previously defined proficiency metrics. We developed an annotation framework and subsequently compared our annotations to an existing commercial solution (Touch Surgery, Medtronic™). We subsequently explored clinical correlations between phase durations and parameters derived from diagnosis and treatment. (3) Results: An objective and uniform phase assessment requires precise definitions derived from an iterative revision process. A comparison to a commercial solution shows large differences in definitions across phases. BMI and the duration of renal tumor identification are positively correlated, as are tumor complexity and both tumor excision and renorrhaphy duration. (4) Conclusions: The surgical phase duration can be correlated with certain clinical outcomes. Further research should investigate whether the retrieved correlations are also clinically meaningful. This requires an increase in dataset sizes and facilitation through intelligent computer vision algorithms. Commercial platforms can facilitate this dataset expansion and help unlock the full potential, provided that the phase annotation details are disclosed.

Background: Perioperative education should be improved to decrease unfavourable outcomes after lumbar surgery. This trial aimed to compare effectiveness in terms of pain, quality of life, pain cognition, surgical experience, healthcare use, work resumption, and cost-effectiveness of perioperative pain neuroscience education (PPNE) vs traditional biomedical education (perioperative biomedical education [PBE]) in people undergoing surgery for lumbar radiculopathy., Methods: In this multicentre RCT (ClinicalTrials.gov: NCT02630732), patients undergoing surgery for lumbar radiculopathy in three Belgian hospitals were randomised to receive PPNE or PBE. Both groups received one preoperative and one postoperative one-to-one education session and a booklet (balanced interventions), with an essentially different content (PPNE: biopsychosocial; PBE: biomedical). Pain was the primary outcome (Visual Analogue Scales+quantitative sensory testing). Assessments were at 3 days, 6 weeks, and 6 and 12 months after surgery., Results: Between March 2016 and April 2020, participants were randomly assigned to PPNE (n=58) or PBE (n=62). At 12 months, PPNE did not lead to significantly better pain outcomes, but it did result in more favourable 36-item Short Form Health Survey physical component (additional increase: 46.94; 95% confidence interval [CI]: 14.16-79.73; medium effect), Tampa Scale of Kinesiophobia (additional decrease: 3.15; 95% CI: 0.25-6.04; small effect), and Pain Catastrophising Scale (additional decrease: 6.18; 95% CI: 1.97-10.39; medium effect) scores. Females of the PPNE group showed higher probability for work resumption (95% vs 60% in the PBE group). PPNE was cost-effective compared with PBE (incremental costs: €-2732; incremental quality-adjusted life years: 0.012)., Conclusions: Perioperative pain neuroscience education showed superior clinical and cost-effectiveness than perioperative biomedical education in people undergoing surgery for lumbar radiculopathy., Clinical Trial Registration: NCT02630732., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Anti-HER2 antibody-drug conjugates (ADCs) have shown important efficacy in HER2-low metastatic breast cancer (mBC). Criteria for receiving ADCs are based on a single assay on the primary tumour or a small metastatic biopsy. We assessed the intra-patient inter-metastasis heterogeneity of HER2-low status in HER2-negative mBC., Patients and Methods: We included samples of 10 patients (7 ER-positive and 3 ER-negative) donated in the context of our post-mortem tissue donation program UPTIDER. Excisional post-mortem biopsies of 257 metastases and 8 breast tumours underwent central HER2 immunohistochemistry (IHC), alongside 41 pre-mortem primary or metastatic samples. They were classified as HER2-zero, HER2-low (HER2-1+ or HER2-2+, in situ hybridisation [ISH] negative) or HER2-positive (HER2-3+ or HER2-2+, ISH-positive) following ASCO/CAP guidelines 2018. HER2-zero was further subdivided into HER2-undetected (no staining) and HER2-ultralow (faint staining in ≤10% of tumour cells)., Results: Median post-mortem interval was 2.5 h. In 8/10 patients, HER2-low and HER2-zero metastases co-existed, with the proportion of HER2-low lesions ranging from 5% to 89%. A total of 32% of metastases currently classified as HER2-zero were HER2-ultralow. Intra-organ inter-metastasis heterogeneity of HER2-scores was observed in the liver in 3/6 patients. Patients with primary ER-positive disease had a higher proportion of HER2-low metastases as compared to ER-negative disease (46% versus 8%, respectively). At the metastasis level, higher percentages of ER-expressing cells were observed in HER2-low or -ultralow as compared to HER2-undetected metastases., Conclusions: Important intra-patient inter-metastasis heterogeneity of HER2-low status exists. This questions the validity of HER2-low in its current form as a theranostic marker., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TG, MDS, FR, KVB, MM, AM, H-LN, EI, SL, AP, GZ, FM, SVB, AS, IN, PN, WVDB, GF, CD: no conflicts to declare. KP: research grants paid to institution: MSD and Sanofi, speaker fees and honoraria for consultancy and advisory board functions: Astra Zeneca, Eli Lilly, Exact Sciences, Focus Patient, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, speaker fees and honoraria for consultancy and advisory board functions paid to institution: Astra Zeneca, Eli Lilly, Exact Sciences, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, stock options: Need Inc, travel grants: Astra Zeneca, Novartis, Pfizer, PharmaMar, Roche. HW: his institution received financial compensation on his behalf for advisory boards, lecture fees and/or consultancy fees from Immutep Pty, MSD, Astrazenca, Daiichi, AbbVie, Lilly, Roche, EISAI, Pfizer, Sirtex, Gilead. He received travel support from Pfizer and Roche., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Pain is an individualized experience for the person suffering from chronic pain. Significant strides have been made in the last few decades in understanding various biological changes that coincide with chronic pain. This state-of-the-art overview looks at the current evidence related to the biology of chronic pain and the implications these findings have on the delivery of pain neuroscience education (PNE). The paper summarizes the various (epi)genetic, neural, endocrine, and immune factors discovered and explored in the scientific literature concerning chronic pain. Each of these biological factors has various implications for the content and delivery of PNE. We discuss the future directions these biological factors have for the clinical implementation of PNE by linking the importance of behavior change, optimizing the learning environment, and using an individualized multimodal treatment approach with PNE. In addition, future directions for research of PNE based on these biological factors are provided with importance placed on individualized patient-centered care and how PNE can be used with traditional modes of care and growing trends with other care methods. PNE was originally and continues to be rooted in understanding chronic pain biology and how that understanding can improve patient care and outcomes.

(1) Background: Dysregulation in serotonergic and noradrenergic systems may be implicated in the neurobiophysiological mechanisms underlying pain-related cognitive impairment in chronic whiplash-associated disorders (CWAD). This study aimed to unravel the role of serotonergic and noradrenergic descending pathways in cognitive functioning at rest and in response to exercise in people with CWAD. (2) Methods: 25 people with CWAD were included in this double-blind, randomized, controlled crossover study. Endogenous descending serotonergic and noradrenergic inhibitory mechanisms were modulated by using a single dose of a selective serotonin reuptake inhibitor (Citalopram) or a selective norepinephrine reuptake inhibitor (Atomoxetine). Cognitive performance was studied at rest and in response to exercise (1) without medication intake; (2) after intake of Citalopram; and (3) after intake of Atomoxetine. (3) Results: After Atomoxetine intake, selective attention improved compared with the no medication day ( p < 0.05). In contrast, a single dose of Citalopram had no significant effect on cognitive functioning at rest. When performing pairwise comparisons, improvements in selective attention were found after exercise for the no medication condition ( p < 0.05). In contrast, after intake of Citalopram or Atomoxetine, selective and sustained attention worsened after exercise. (4) Conclusions: A single dose of Atomoxetine improved selective attention only in one Stroop condition, and a single dose of Citalopram had no effect on cognitive functioning at rest in people with CWAD. Only without medication intake did selective attention improve in response to exercise, whereas both centrally acting medications worsened cognitive performance in response to a submaximal aerobic exercise bout in people with CWAD.

Objective: The present cross-sectional study aims to unravel associations of pain intensity and cognitions with quantitative sensory testing in people scheduled for surgery for lumbar radiculopathy. Additionally, insight will be provided into the presence of dysfunctional nociceptive processing and maladaptive pain cognitions in this population., Design: Cross-sectional study., Setting: Data from three hospitals in Belgium., Subjects: The final sample comprised 120 participants with lumbar radiculopathy scheduled for surgery, included between March 2016 and April 2019., Methods: Self-reported pain intensity was assessed on a visual analog scale, and pain cognitions were assessed with self-reported questionnaires (Pain Catastrophizing Scale, Tampa Scale for Kinesiophobia, and Pain Vigilance and Awareness Questionnaire). Quantitative sensory testing (detection thresholds, pain thresholds, temporal summation, and conditioned pain modulation) was evaluated, as well., Results: Evidence was found for the presence of an impaired inhibitory response to nociceptive stimuli and maladaptive pain cognitions in this population. Kinesiophobia was found to be present to a maladaptive degree in the majority of the patients (n = 106 [88%]). Significant, but weak, associations between electrical pain thresholds at the sural nerves and leg pain intensity (sural nerve symptomatic side: r = -0.23; P = 0.01; non-symptomatic side: r = -0.22; P = 0.02) and kinesiophobia levels (sural nerve non-symptomatic side: r = -0.26; P = 0.006) were identified., Conclusions: Electrical detection thresholds and correlates for endogenous nociceptive facilitation and inhibition were not found to be related to any of the pain cognitions or to pain intensity in people scheduled to undergo surgery for lumbar radiculopathy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This cross-sectional study explored associations between demographics, pain intensity and cognitions on the one hand and healthcare use (HCU) on the other hand in people undergoing surgery for lumbar radiculopathy. HCU during the 2 months preceding surgery was evaluated using a retrospective questionnaire. Demographics included sex, age and level of education and equivalent income. Back and leg pain intensity were evaluated using a visual analogue scale. Pain cognitions were assessed with the Tampa scale of kinesiophobia, the pain catastrophizing scale and the pain vigilance and awareness questionnaire. The sample comprised 120 participants (52% males; 49 years (Quartile (Q)1-Q3: 37.3-57.43)). The number of visits to the general practitioner was associated with sex (incidence rate ratio (IRR) for males = 0.811; p = 0.050), pain catastrophizing (IRR = 1.010; p = 0.041), pain magnification (IRR = 1.058; p = 0.004) and leg pain intensity (IRR = 1.004; p = 0.038). The number of neurosurgeon visits was associated with level of education (IRR moderate education = 1.518; p = 0.016 (reference: low education)). Receiving zero physiotherapy visits was associated with higher back pain intensity (Beta = 0.018; p = 0.028). Highest level of analgesics used was associated with sex (IRR for males = 0.502; p = 0.047) and leg pain (IRR = 1.014; p = 0.034). Only the association between general practitioner visits and pain magnification remained significant in multivariable analyses (IRR = 1.061; p = 0.033). The results suggest a rather indirect relationship between HCU and demographics, pain intensity and cognitions, involving a potential interplay between several patient- and healthcare system-related factors.

Background: Currently, evidence regarding fear avoidance beliefs as potential predictors for lumbar surgery outcomes seems insufficient and strong conclusions are not yet available., Objective: This systematic review aimed to evaluate the predictive value of preoperative fear avoidance beliefs for postoperative pain intensity, functional status, and health-related quality of life following surgery for lumbar degenerative disease., Study Design: Systematic review and best evidence synthesis., Methods: An extensive search was performed in PubMed/Medline, EMBASE, PsycINFO, CINAHL and the Cochrane library for articles published up until October 2021. Two independent reviewers performed the screening, data extraction, and quality assessment, with a third independent reviewer consulting to resolve any disagreement. Observational studies that included patients undergoing surgery for lumbar degenerative disease, as well as evaluated fear avoidance beliefs (i.e., pain-related fear, pain catastrophizing, pain anxiety) in relation to a surgical outcome measure (i.e., pain intensity, functional status and health-related quality of life) were included in the review. The CHARMS- and QUIPS-tools were used for data extraction and quality assessment, respectively. A best evidence synthesis was performed resulting in conclusions regarding strong, moderate, conflicting, and limited levels of evidence., Results: A total of 24 studies (n = 17,881) were included in this review. Following best evidence synthesis, 3 included studies reported no significant predictive value of preoperative pain-related fear for postoperative pain intensity resulting in moderate evidence for this relationship. Moderate evidence was also found indicating no significant predictive value of preoperative pain-related fear for postoperative functional status, as 6 out of 8 relevant studies reported this result. Only one study reported on the predictive value of preoperative pain catastrophizing for postoperative health-related quality of life, resulting in limited evidence for the absence of this predictive relationship. All other relationships were found to have conflicting evidence., Limitations: To evaluate surgical outcome, only patient-reported outcome measures as used by spine registries were included. Thus, our findings cannot be extrapolated to all surgery outcomes following lumbar degenerative disease and should only be interpreted in relation to postoperative pain intensity, functional status, or health-related quality of life., Conclusion: Best evidence synthesis showed moderate evidence indicating that preoperative pain-related fear is not a significant predictor for postoperative pain and function following surgery for lumbar degenerative disease. Additionally, limited evidence was found for a lack of predictive value of preoperative pain catastrophizing for postoperative health-related quality of life. As current evidence regarding the predictive value of preoperative fear avoidance beliefs following such a surgery is mixed, further research is required before more definitive conclusions can be made.

Every year, thousands of suspicious deaths are accounted for by an overdose of opioids. Occasionally all traditional matrices are unavailable due to decomposition. Skeletal tissue may pose a valid alternative. However, reference data on postmortem concentrations in bone tissue and bone marrow (BM) is sparse. Therefore, a liquid chromatography--tandem mass spectrometry method was developed and fully validated for the analysis of four opioids and two metabolites (tramadol, O-desmethyltramadol, morphine, fentanyl, norfentanyl, codeine) in bone tissue and BM. Sample preparation was performed using solid phase extraction (BM), methanolic extraction (bone) and a protein precipitation (whole blood). All validation parameters were successfully fulfilled. This method was applied to analyze 22 forensic cases involving opioids. All six opioids were proven to be detectable and quantifiable in all specimens sampled. When tramadol blood concentrations were correlated with bone concentrations, a linear trend could be detected. The same was seen between tramadol blood and BM concentration. A similar linear trend was seen when correlating codeine blood concentration with bone and BM concentration. Although some variability was detected, the same linear trend was seen for morphine. For fentanyl and norfentanyl, the sample size was too small to draw conclusions, regarding correlation. As far as the authors know this is the first-time fentanyl and norfentanyl are quantified in skeletal tissue. In conclusion, due to the absence of reference data for drugs in skeletal tissue, these findings are a step forward toward a more thorough understanding of drug concentration found in postmortem skeletal tissue., (© The Author(s) 2021. Published by Oxford University Press.)

Purpose: The primary goal of this study was to compare the health-related quality of life (HRQoL) of people with lumbar radiculopathy to age- and sex-adjusted population norms. Additionally, it aimed to explore the associations between the HRQoL difference scores and measures related to pain cognitions, pain intensity, and endogenous nociceptive modulation., Methods: Using answers from the Short Form 36-item Health Survey and UK population norms, SF-6D difference scores were calculated. A one-sample t test was used to assess the SF-6D difference scores. Univariate and multivariate regression analyses were used to assess the associations between SF-6D difference scores and pain intensity [Visual Analogue Scale (VAS) for back and leg pain], pain cognitions [Pain Catastrophizing Scale (PCS), Tampa Scale for Kinesiophobia (TSK), Pain Vigilance and Awareness Questionnaire (PVAQ)], and correlates for endogenous nociceptive modulation using quantitative sensory testing., Results: One hundred and twenty people with lumbar radiculopathy scheduled for surgery were included in this study. The mean SF-6D difference score of - 0.26 [SD = 0.09] was found to be significantly less than 0 [95%CI: - 0.27 to - 0.24]. Univariate analyses showed a significant influence from PCS, TSK, and PVAQ on the SF-6D difference scores. The final multivariate regression model included PCS and PVAQ, with only PCS maintaining a statistically significant regression coefficient [b = - 0.002; 95% CI: - 0.004 to - 0.001]., Conclusion: People diagnosed with lumbar radiculopathy report significantly lower HRQoL scores when compared with age- and sex-adjusted UK norm values. Even though all examined pain cognitions were found to have a significant association, pain catastrophizing showed the most significant relation to the SF-6D difference scores., Clinical Trial Registration: ClinicalTrials.gov Identifier No. NCT02630732. Date of registration: November 25, 2015., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Alcohol-associated liver disease (ALD) represents a spectrum of histopathological changes, including alcoholic steatosis, steatohepatitis, and cirrhosis. One of the early responses to excessive alcohol consumption is lipid accumulation in the hepatocytes. Lipid ω-hydroxylation of medium- and long-chain fatty acid metabolized by the cytochrome P450 4A (CYP4A) family is an alternative pathway for fatty acid metabolism. The molecular mechanisms of CYP4A in ALD pathogenesis have not been elucidated. In this study, WT and Shp-/- mice were fed with a modified ethanol-binge, National Institute on Alcohol Abuse and Alcoholism model (10 days of ethanol feeding plus single binge). Liver tissues were collected every 6 hours for 24 hours and analyzed using RNA-Seq. The effects of REV-ERBα agonist (SR9009, 100 mg/kg/d) or CYP4A antagonist (HET0016, 5 mg/kg/d) in ethanol-fed mice were also evaluated. We found that hepatic Cyp4a10 and Cyp4a14 expression were significantly upregulated in WT mice, but not in Shp-/- mice, fed with ethanol. ChIP quantitative PCR and promoter assay revealed that REV-ERBα is the transcriptional repressor of Cyp4a10 and Cyp4a14. Rev-Erbα-/- hepatocytes had a marked induction of both Cyp4a genes and lipid accumulation. REV-ERBα agonist SR9009 or CYP4A antagonist HET0016 attenuated Cyp4a induction by ethanol and prevented alcohol-induced steatosis. Here, we have identified a role for the SHP/REV-ERBα/CYP4A axis in the pathogenesis of ALD. Our data also suggest REV-ERBα or CYP4A as the potential therapeutic targets for ALD.

RNA analysis of post-mortem tissues, or thanatotranscriptomics, has become a topic of interest in forensic science due to the essential information it can provide in forensic investigations. Several studies have previously investigated the effect of death on gene transcription, but it has never been conducted with samples of the same individual. For the first time, a longitudinal mRNA expression analysis study was performed with post-mortem human blood samples from individuals with a known time of death. The results reveal that, after death, two clearly differentiated groups of up- and down-regulated genes can be detected. Pathway analysis suggests active processes that promote cell survival and DNA damage repair, rather than passive degradation, are the source of early post-mortem changes of gene expression in blood. In addition, a generalized linear model with an elastic net restriction predicted post-mortem interval with a root mean square error of 4.75 h. In conclusion, we demonstrate that post-mortem gene expression data can be used as biomarkers to estimate the post-mortem interval though further validation using independent sample sets is required before use in forensic casework., (© 2021. The Author(s).)

Background: Pain neuroscience education (PNE) combined with cognition-targeted exercises is an effective treatment for people with chronic spinal pain (CSP). However, it is unclear why some patients benefit more from this treatment. We expect that patients with more pronounced maladaptive pain cognitions, such as kinesiophobia, might show poorer treatment responses., Objective: The objective of this study was to assess the influence of baseline kinesiophobia levels on the treatment outcomes of PNE combined with cognition-targeted exercises in people with CSP. This study was a secondary analysis of a multicenter, double-blind, randomized controlled trial., Methods: Outcome measures included a numeric rating scale for pain (NRS), the Pain Disability Index (PDI), quality of life (Medical Outcomes Study 36-Item Health Survey [SF-36]), Pain Catastrophizing Scale (PCS), and Pain Vigilance and Awareness Questionnaire (PVAQ). Regression models were built using treatment (PNE plus cognition-targeted exercises or neck/back school plus general exercises), baseline scores on the Tampa Scale for Kinesiophobia (TSK), and time (in months) as independent variables., Results: A significant 3-way interaction effect was found for the models of PDI, PCS, PVAQ, and the SF-36 mental domain, with estimates of -0.01, -0.01, -0.01, and 0.07, respectively. A significant effect of baseline TSK scores was found for the physical domain of the SF-36 (estimate = -3.16). For the NRS, no significant effect of baseline TSK scores was found., Conclusion: Our findings indicate that PNE plus cognition-targeted exercises can successfully decrease the unfavorable influence of pretreatment kinesiophobia on disability, mental health, pain catastrophizing, and hypervigilance over time in people with CSP. Nevertheless, higher scores in pretreatment kinesiophobia might still be a key factor for the lack of improvement in pain catastrophizing and hypervigilance following treatment. Regardless of the followed treatment program, pretreatment kinesiophobia was also shown to significantly influence physical health in people with CSP., Impact: This study provides novel insight into the unfavorable influence of kinesiophobia on treatment outcomes in people with CSP, and how PNE plus cognition-targeted exercises can limit this impact. Because this is one of the first studies to research possible predictors of this experimental treatment, its findings motivate further exploration of other possible influencing factors for treatment success of PNE plus cognition-targeted exercises., Lay Summary: People with chronic spinal pain and high levels of fear of movement were found to have worse treatment outcomes compared to people with low levels of fear of movement. However, our experimental treatment, which includes pain neuroscience education combined with exercise therapy that reintroduces specific movements patients might fear, can decrease this negative influence of fear of movement in these patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Pain neuroscience education (PNE) and motivational interviewing (MI) have been widely implemented and tested in the field of chronic pain management, and both strategies have been shown to be effective in the short term (small effect sizes) for the management of chronic pain. PNE uses contemporary pain science to educate patients about the biopsychosocial nature of the chronicity of their pain experience. The goal of PNE is to optimize patients' pain beliefs/perceptions to facilitate the acquisition of adaptive pain-coping strategies. MI, on the other hand, is a patient-centered communication style for eliciting and enhancing motivation for behavior change by shifting the patient away from a state of indecision or uncertainty. Conceptually, PNE and MI appear to be complementary interventions, with complementary rather than overlapping effects; MI primarily improves cognitive and behavioral awareness and, potentially, adherence to treatment principles, whereas PNE potentially increases pain knowledge/beliefs, awareness, and willingness to explore psychological factors that are potentially associated with pain. Therefore, combining PNE with MI might lead to improved outcomes with larger and longer-lasting effect sizes. The combined use of PNE and MI in patients having chronic pain is introduced here, along with a description of how clinicians might be able to integrate PNE and MI in the treatment of patients experiencing chronic pain. Clinical trials are needed to examine whether combining PNE with MI is superior to PNE or MI alone for improving pain and quality of life in patients having chronic pain., (© 2020 American Physical Therapy Association.)

Blood analysis is the golden standard in the field of forensic toxicology. However, when extended decomposition of the remains has occurred, alternative matrices are required. Skeletal tissue may provide an appropriate sample of choice since it is very resistant to putrefaction. However, today, the absence of reference data of drug concentrations in skeletal tissue poses a problem to meaningfully and reliably conduct toxicological testing on human skeletal material. The present study investigates the viability of skeletal tissue as an alternative matrix to evaluate xenobiotic consumption in legal cases. Blood, bone tissue and bone marrow of different forensic cases were screened for 415 compounds of forensic interest. Afterwards, methadone, clomipramine, citalopram and their respectively metabolites positive samples were quantified using fully validated methods. Sample preparation was carried out by SPE (whole blood and bone marrow), methanol extraction (bone sections) or protein precipitation (whole blood). All samples were analyzed using liquid chromatography coupled to a triple quad mass spectrometer. Multiple drugs were successfully identified in all sampled matrices. In bone (marrow) not as many substances were detected as in blood but it poses a valid alternative when blood is not available. Especially bone marrow showed big potential with a concordance of 80.5% with blood. Clomipramine, citalopram and their metabolites were proven to be detectable and quantifiable in all specimens sampled. Bone marrow showed the highest concentrations followed by blood and bone tissue. When citalopram blood concentrations were correlated with the bone concentrations, a linear trend could be detected. The same was seen between blood and bone marrow for citalopram concentrations. Methadone was also proven to be detectable in all specimens sampled. However, its metabolites EMDP and EDPP were absent or below the LOD in some samples. Overall, methadone concentrations were higher in bone marrow than in bone. With exception of one case, blood concentrations were higher than bone concentrations. For methadone, a linear trend could be found between blood and bone concentration. Comparing methadone concentrations in blood and bone marrow an exponential trend could be seen. In conclusion, these findings show the potential forensic value of bone and bone marrow as an alternative matrix. Aside to that, a standard protocol for the sample collection and processing is proposed., Competing Interests: Declaration of Competing Interest The authors state that there is no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Context: Alloplastic temporomandibular joint replacement., Aims: To search for evidence for the use of periprosthetic autologous fat transplantation., Setting and Design: Systematic review., Materials and Methods: We searched in PubMed Central, Elsevier ScienceDirect Complete, Wiley Online Library Journals, Ovid Lippincott Williams and Wilkins, and Cochrane Library plus Results. Six studies reported improved results with the use of autologous fat graft (AFG) in patients treated with a total joint replacement, mainly about increased mobility. Three studies involved patients from the same surgeon with increased inclusions and increased follow-up period. A 1997 study by Wolford showed a significant difference in heterotopic bone formation between patients treated with AFG, compared to those who were not, indicating the potential and usefulness of AFG., Conclusion: A prospective multicenter randomized controlled trial of this promising concept is warranted before justifying common application because of the added morbidity and the questionable advantage., Competing Interests: There are no conflicts of interest.

In recent years, the increasing number of asphyxiation cases due to helium inhalation is remarkable. All described cases in the literature where diagnosed as suicide. In this article, however, we describe a triple infant homicide in which helium, as balloon gas, was administered to three young children after sedation causing asphyxiation and death through the medical findings and toxicological analysis. During autopsy, in addition to standard toxicological samples, gas samples from lungs as well as lung tissue itself were directly collected into headspace vials. Besides routine toxicological analysis, which revealed toxic levels of doxylamine, qualitative analysis on gas and lung samples was performed using headspace gas chromatography-mass spectrometry. As carrier gas, the commonly used helium was replaced by nitrogen. In gas samples from lungs of all three children, no helium was found. Nevertheless, lung tissue samples were found positive on helium. Therefore, sedation followed by asphyxia due to helium inhalation can strongly be assumed as the cause of death of all three children., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown., Methods: We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer., Results: Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P=0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P=0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P=0.02). Acute side effects of regional nodal irradiation were modest., Conclusions: In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. (Funded by Fonds Cancer; ClinicalTrials.gov number, NCT00002851.).

Purpose: To investigate the occurrence of early radiation-induced changes in regional cardiac function using strain rate imaging (SRI) by tissue Doppler echocardiography., Methods and Materials: We included 20 left-sided and 10 right-sided breast cancer patients receiving radiotherapy (RT) to the breast or chest wall. Standard echocardiography and SRI were performed before RT (baseline), immediately after RT (post-RT), and at 2 months follow-up (FUP) after RT. Regional strain (S) and strain rate (SR) values were obtained from all 18 left ventricular (LV) segments. Data were compared to the regional radiation dose., Results: A reduction in S was observed post-RT and at FUP in left-sided patients (S(post-RT): -17.6 ± 1.5%, and S(FUP): -17.4 ± 2.3%, vs. S(baseline): -19.5 ± 2.1%, p < 0.001) but not in right-sided patients. Within the left-sided patient group, S and SR were significantly reduced after RT in apical LV segments (S(post-RT): -15.3 ± 2.5%, and S(FUP): -14.3 ± 3.7%, vs. S(baseline): -19.3 ± 3.0%, p < 0.01; and SR(post-RT): -1.06 ± 0.15 s(-1), and SR(FUP): -1.16 ± 0.28 s(-1), vs. SR(baseline): -1.29 ± 0.27 s(-1), p = 0.01), but not in mid- or basal segments. Furthermore, we observed that segments exposed to more than 3 Gy showed a significant decrease in S after RT (S(post-RT): -16.1 ± 1.6%, and S(FUP): -15.8 ± 3.4%, vs. S(baseline): -18.9 ± 2.6%, p < 0.001). This could not be observed in segments receiving less than 3 Gy., Conclusions: SRI shows a dose-related regional decrease in myocardial function after RT. It might be a useful tool in the evaluation of modern RT techniques, with respect to cardiac toxicity., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We evaluated an isocentric technique for conformal irradiation of the breast, internal mammary, and medial supra-clavicular lymph nodes (IM-MS LN) using the oblique parasternal photon (OPP) technique. For 20 breast cancer patients, the OPP technique was compared with a conventional mixed-beam technique (2D) and a conformal partly wide tangential (PWT) technique, using dose-volume histogram analysis and normal tissue complication probabilities (NTCPs). The 3D techniques resulted in a better target coverage and homogeneity than did the 2D technique. The homogeneity index for the IM-MS PTV increased from 0.57 for 2D to 0.90 for PWT and 0.91 for OPP (both p < 0.001). The OPP technique was able to reduce the volume of heart receiving more than 30 Gy (V(30)), the cardiac NTCP, and the volume of contralateral breast receiving 5 Gy (V(5)) compared with the PWT plans (all p < 0.05). There is no significant difference in mean lung dose or lung NTCP between both 3D techniques. Compared with the PWT technique, the volume of lung receiving more than 20 Gy (V(20)) was increased with the OPP technique, whereas the volume of lung receiving more than 40 Gy (V(40)) was decreased (both p < 0.05). Compared with the PWT technique, the OPP technique can reduce doses to the contralateral breast and heart at the expense of an increased lung V(20)., (Copyright © 2011 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Embryonal rhabdomyosarcoma (RMS) is a rare malignant mesenchymal tumour that is believed to arise from cells committed to a skeletal muscle lineage. The head and neck region is among the most frequent locations for embryonal RMS in adults. We present a retrospective review of seven patients treated in our institution between 2000 and 2008. The age at diagnosis ranged from 19 to 41 years. One patient received primary surgery followed by adjuvant radiotherapy. Six inoperable patients were treated along a single chemotherapy protocol: the VIA-VIP regimen (a combination of vincristine, ifosfamide and doxorubicin (VIA) in alternation with etoposide, ifosfamide and cisplatin (VIP) administered in 3-weekly cycles), followed by local therapy, involving radiation therapy and/or surgery. An objective response to chemotherapy was observed in all six patients. Three out of seven patients remain disease-free with a median follow up of 4.5 years. Although the prognosis of head and neck embryonal RMS is worse in adults than in children, a multimodality treatment combining surgery, radiotherapy and intensive chemotherapy is feasible and effective in this population.

Introduction: The EORTC 22922/10925 trial investigated the potential survival benefit and toxicity of elective irradiation of the internal mammary and medial supraclavicular (IM-MS) nodes Accrual completed in January 2004 and first results are expected in 2012. We present the toxicity reported until year 3 after treatment., Patients and Methods: At each visit, toxicity was reported but severity was not graded routinely. Toxicity rates and performance status (PS) changes at three years were compared by chi(2) tests and logistic regression models in all the 3,866 of 4,004 patients eligible to the trial who received the allocated treatment., Results: Only lung (fibrosis; dyspnoea; pneumonitis; any lung toxicities) (4.3% vs. 1.3%; p < 0.0001) but not cardiac toxicity (0.3% vs. 0.4%; p = 0.55) significantly increased with IM-MS treatment. No significant worsening of the PS was observed (p = 0.79), suggesting that treatment-related toxicity does not impair patient's daily activities., Conclusions: IM-MS irradiation seems well tolerated and does not significantly impair WHO PS at three years. A follow-up period of at least 10 years is needed to determine whether cardiac toxicity is increased after radiotherapy.

Objective: To evaluate the incidence and localization of regional recurrences after definitive (chemo-) radiotherapy for head and neck squamous cell carcinoma (HNSCC)., Methods: From May 1987 to March 2008, 368 patients with advanced HNSCC were irradiated to 66-80.5 Gray in 6-7 weeks, with (37%) or without (63%) concomitant chemotherapy (Cisplatinum 100mg/m(2)) every 3 weeks. No planned neck dissections were performed. Data on clinical outcome were retrospectively reviewed, location of the original nodal disease and the regional recurrence was indicated on imaging and correlated with radiation dose., Results: Mean follow-up was 34 months (range: 50 days-216 months). Three-year overall survival and disease-specific survival were 55% and 62%, respectively. Loco-regional, local and regional controls were 58%, 65%, and 80%, respectively. Forty-one patients (11.1%) relapsed in the neck, but only 11 patients (2.99%) developed a true isolated regional recurrence, 6 of whom could be successfully salvaged by surgery. Only 2 patients (0.54%) developed an isolated recurrence in the electively treated nodal levels., Conclusion: Isolated nodal recurrences are uncommon and recurrences in the electively treated neck are extremely uncommon.

Retrospective studies suggest that single nucleotide polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene predict reduced tamoxifen metabolism, better tolerance and worse treatment outcome. We hypothesized that women with this genotype lack tamoxifen-induced endometrial and biochemical changes in follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG). We identified 56 breast cancer patients attending the follow-up clinic with a homozygous mutant (HM) status for the CYP2D6*4 null variant. Here, we report a detailed assessment of tamoxifen activity in 19 CYP2D6 HM women, while they were using tamoxifen either for metastatic (n = 5) or for early disease (n = 14). We assessed response to tamoxifen in metastatic disease. Endometrial appearances and serum levels of FSH and SHBG were assessed from retrospective and prospective testing. Our findings do suggest that the presence of two CYP2D6*4 alleles does not exclude a durable response of tamoxifen in metastatic breast cancer. The transvaginal ultrasonographic appearance of the endometrium in CYP2D6*4/*4 patients on tamoxifen is similar as seen in the normal population of tamoxifen users. The endometrium is increased in thickness with subepithelial cysts and endometrial polyps. Serum levels of FSH and SHBG in CYP2D6*4 HM tamoxifen users were in the range of what would be expected during tamoxifen treatment in the general population. Our findings do show CYP2D6*4/*4 carriers to have activity of tamoxifen on breast cancer, endometrium and serum levels of FSH and SHBG. They support clinical trials prospectively testing the effect of CYP2D6 genetic variability in response to tamoxifen before denying this drug to breast cancer patients only based on their CYP2D6*4 status.

Time measurements were performed on daily treatment delivery with the aim to quantify the impact of quality assurance (QA) using an electronic portal imaging device (EPID) on RT delivery time and to validate the time burden of intensity modulated radiation therapy (IMRT) as an example of advanced technology. Both increased QA and the delivery of IMRT were found to be significant parameters determining daily treatment time (TT), which in turn translates in increased treatment costs.

Background: Gynecologic cancer during pregnancy is a special challenge because cancer or its treatment may affect not only the pregnant women in general but directly involve the reproductive tract and fetus. Currently, there are no guidelines on how to deal with this special coincidence., Methods: An international consensus meeting on staging and treatment of gynecological malignancies during pregnancy was organised including a systematic literature search, and interpretation followed by a physical meeting of all participants with intensive discussion. In the absence of large trials and randomized studies, recommendations were based on available literature data and personal experience thus representing a low but best achievable level of evidence., Findings: Randomized trials and prospective studies on cancer treatment during pregnancy are lacking. Gynecological cancer during pregnancy is a demanding problem, and multidisciplinary expertise should be available. Counseling both parents on the maternal prognosis and fetal risk is needed. When there is a firm desire to continue the pregnancy, gynecological cancer can be treated in selected cases. The staging and treatment should follow the standard approach as much as possible. Guidelines for safe pelvic surgery during pregnancy are presented. Mainly in cervical and ovarian cancer, chemotherapy and an alternative surgical approach need to be considered. Administration of chemotherapy during the second or third trimester may probably not increase the incidence of congenital malformations. Until now, the long-term outcome of children in utero exposed to oncological treatment modalities is poorly documented, but preterm birth on its own is associated with cognitive impairment. Delivery should be postponed preferably until after a gestational age of 35 weeks., Interpretation: Further research including international registries for gynecologic cancer in pregnancy is urgently needed. The gathering of both available literature and personal experience allowed only suggesting models for treatment of gynecologic cancer in pregnancy.

Introduction: Prognostic subgroup classification of operable breast cancers using cDNA clustering of breast cancer-related genes resembles the classification based on the combined immunohistochemical (IHC) expression of the hormone and HER-2 receptors. We here report the short-term disease-free interval (DFI) of operable breast cancers by their joint hormone receptor/HER-2 phenotype., Patients and Methods: Short-term follow-up (FU) of a prospective cohort of 1,958 breast-cancer patients primary operated at our institution between 2000 and 2005. Receptors were evaluated using IHC. Steroid receptors were considered positive for any nuclear staining; HER-2 for strong (3+) membrane staining or positive fluorescence in situ hybridization (FISH). Kaplan-Meier (KM) DFI curves were calculated for any relapse defined as a local, regional, contralateral, or distant breast cancer event for the six predefined breast cancer subgroups: ER + PR + HER-2 - (PPN), ER + PR - HER-2 - (PNN), ER + PR + HER-2 + (PPP), ER - PR - HER-2 - (NNN), ER - PR - HER-2 + (NNP), and ER + PR - HER-2 + (PNP). P-values were calculated for comparison of the six different survival curves using two possible adaptations for multiple testing. A multivariate model for the receptors predicting DFI did incorporate local and systemic adjuvant therapy., Results: Median patient age was 57 years (ranges 26-96) and median FU was 3.35 years. Overall, DFI at median FU was 91%; 94% for PPN, 89% for PNN, 86% for NNN, 81% for PPP, 80% for PNP, and 76% for NNP cases. Some receptor subgroups had a significantly better DFI than others based on multiple testing, especially when the PPN group was compared against the four most frequent subtypes. The multivariate model with local and systemic adjuvant therapy confirmed the prognostic value of ER, PR, and HER-2 for short-term DFI., Conclusion: It is possible to distinguish short-term prognostic breast cancer subgroups only on the basis of ER, PR, and HER-2 even when stratified for local and systemic adjuvant therapy. While gene expression profiles based on microarray data of over hundreds of genes will probably teach us much about breast cancer biology, heterogeneity, and prognosis, we emphasize the important short-term prognostic value of currently used IHC markers for ER, PR, and HER-2.

Purpose: To evaluate the feasibility and efficacy of a hyperfractionated accelerated radiotherapy (RT) schedule combined with concomitant chemotherapy (Cx) in patients with locally advanced head-and-neck squamous cell carcinoma., Methods and Materials: Between 2004 and 2007, a total of 90 patients with locoregionally advanced head-and-neck squamous cell carcinoma underwent irradiation according to a hybrid fractionation schedule consisting of 20 fractions of 2 Gy (once daily) followed by 20 fractions of 1.6 Gy (twice daily) to a total dose of 72 Gy. Concomitant Cx (cisplatinum 100 mg/m(2)) was administered at the start of Weeks 1 and 4. Treatment outcome and toxicity were retrospectively compared with a previous patient group (n = 73) treated with the same schedule, but without concomitant Cx, between 2001 and 2004., Results: The locoregional control (LRC) rate was 70% after 2 years. Two-year overall and 2-year disease-free survival rates were 74% and 60%, respectively. In comparison with the RT-only group, an improvement of 15% in both LRC (p = 0.03) and overall survival (p = 0.09) was observed. All patients were treated to full radiation dose according to protocol, although the Cx schedule had to be adjusted in 12 patients. No acute Grade 4 or 5 toxicity was seen, but incidences of Grade 3 acute mucositis (74.5% vs. 50.7%; p = 0.002) and dysphagia (82.2% vs. 47.9%; p < 0.001) were significantly higher in the chemoradiotherapy group compared with patients treated with RT alone., Conclusion: With this chemoradiotherapy regimen, excellent LRC and survival rates were achieved, with acceptable acute toxicity.

Aims: To examine the frequency of axillary lymph node (ALN) invasion of operable breast cancers by their combined oestrogen receptor (ER), progesterone receptor (PR) and HER-2 status., Methods: 2227 recently operated cases in one centre were retrieved from the Multidisciplinary Breast Centre database and stratified according to their combined immunohistochemical (IHC) expression of ER/PR/HER-2 status. An equivocal HER-2 status was further analysed by Fluorescence in situ Hybridisation (FISH). The following 6 groups were considered: ER(-)PR(-)HER-2(-) (NNN; triple negative), ER(-)PR(-)HER-2(+) (NNP), ER(+)PR(-)HER-2(-) (PNN), ER(+)PR(-)HER-2(+) (PNP), ER(+)PR(+)HER-2(- )(PPN), ER(+)PR(+)HER-2(+) (PPP; triple positive). For ALN, the following variables were tested in uni- and multivariate models: age at diagnosis (years), tumour size (mm), tumour grade, ER, PR, HER-2 and the combined steroid receptor and HER-2 status. Likelihood ratio chi(2)-tests were used for univariate analysis and logistic regression for multivariate analysis., Results: Triple positive tumours had a higher likelihood of being ALN positive than others (56.2% versus 35.7%; P<0.0001). Univariate logistic regression also withheld age, size, grade and HER-2 as predictors of ALN involvement. Final multivariate logistic regression revealed age, size, grade and PPP versus non-PPP to be independent predictors of ALN involvement; the odds ratio (OR) and 95% CI for PPP versus non-PPP tumours was 2.169 (1.490-3.156)., Conclusion: Our data provide insight into the natural history of triple positive breast carcinomas. Such tumours are more likely ALN positive than those with another steroid receptor and HER-2 status. How these findings correlate with breast cancer prognosis remains to be investigated.

Purpose: To investigate the impact of the boost dose to the primary tumour bed in the framework of breast conserving therapy on local control, cosmetic results, fibrosis and overall survival for patients with early stage breast cancer., Patients and Methods: Five thousand five hundred and sixty-nine patients after lumpectomy followed by whole breast irradiation of 50 Gy were randomised. After a microscopically complete lumpectomy (5318 patients), the boost doses were either 0 or 16 Gy, while after a microscopically incomplete (251 patients) lumpectomy randomisation was between 10 and 26 Gy. The results at a median follow-up of 10 years are presented., Results: At 10 years, the cumulative incidence of local recurrence was 10.2% versus 6.2% for the 0 Gy and the 16 Gy boost groups (p < 0.0001) and 17.5% versus 10.8% for the 10 and 26 Gy boost groups, respectively (p > 0.1). There was no statistically significant interaction per age group but recurrences tended to occur earlier in younger patients. As younger patients had a higher cumulative risk of local relapse by year 10, the magnitude of the absolute 10-year risk reduction achieved with the boost decreased with increasing age. Development of fibrosis was significantly dependent on the boost dose with a 10-year rate for severe fibrosis of 1.6% after 0 Gy, 3.3% after 10 Gy, 4.4% after 16 Gy and 14.4% after 26 Gy, respectively., Conclusion: An increase of the dose with 16 Gy improved local control for patients after a complete lumpectomy only. The development of fibrosis was clearly dose dependent. With 10 years median follow-up, no impact of survival was observed.

Background: The negative association between the oestrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER-2) in breast cancer travels in both directions. ER+ tumours are less likely HER-2+ and HER-2+ tumours are less likely ER+., Methods: We studied the age-related immunohistochemical (IHC) expression of ER, progesterone receptor (PR) and HER-2 in 2,227 tumours using age as a continuous variable. Steroid receptors were considered positive for any nuclear staining of invasive cancer cells and for HER-2, either for strong expression by IHC (score 3+) or gene amplification by fluorescence in situ hybridisation (FISH). Based on nonparametric regression, the age-related association between steroid receptors and HER-2 was presented as likelihood curves., Results: The association between ER or PR and HER-2 is age-related. The age-related expression of ER and PR is HER-2 dependent. In HER-2(-) cases, the odds ratio (OR) for being ER+ was 2.594 (95% CI = 1.874-3.591) up to age 50 and age-independent thereafter; for PR-expression the OR was 2.687 (95% CI = 1.780-4.057) up to age 45 and 0.847 (95% CI = 0.761-0.942) thereafter. In HER-2+ cases, the OR was 0.806 (95% CI = 0.656-0.991) to be ER+ and 0.722 (95% CI = 0.589-0.886) to be PR+. The age-related OR for breast cancers to be HER-2+ is steroid receptor dependent. Taking together, ER+PR+HER-2+ breast cancers appear on average 5.4 years earlier than breast cancers of any other ER/PR/HER-2 phenotype (95% CI = 3.3-7.5; P < 0.0001)., Conclusion: There is a qualitative interaction between age and expression of steroid and HER-2 receptors. Our findings suggest a strong age-related selective growth advantage for breast tumour cells belonging to the ER+PR+HER-2+ subgroup.

Background: Adenocarcinoma is the most frequent histological subtype of paranasal sinus malignancy diagnosed in Belgium. Classical treatment consists of an external surgical approach (lateral rhinotomy with medial maxillectomy or craniofacial resection) followed by radiotherapy. The role, possibilities, and limitations of endoscopic sinus surgery (ESS) are to date unknown., Methods: We studied 44 patients with primary (not treated previously) adenocarcinoma treated with endoscopic sinus surgery and radiotherapy between 1992 and 2004., Results: The median follow-up of the patients alive at the end of the study period was 36 months. For the 3-year follow-up, the overall survival, disease-specific survival, and local control rate were 81%, 91%, and 73%, respectively. Corresponding rates for the 5-year follow-up were 53%, 83%, and 62%. Union Internationale Contre le Cancer T classification did not appear to influence these results., Conclusions: Endoscopic sinus surgery followed by radiotherapy for primary adenocarcinoma of the paranasal sinuses gives oncological results comparable to those of standard external approaches.

Introduction: Xerostomia is a common complication of radiotherapy for head and neck cancer. Symptomatic treatment consists of stringent oral hygiene to prevent oral infections and saliva substitutes to increase comfort. The aim of the study was to evaluate the clinical effectiveness of the BioXtra (BX) dry mouth care system., Materials and Methods: A xerostomia questionnaire consisting of 3 parts (xerostomia symptom score, quality of life (QoL) survey and visual analogue scale (VAS)) was completed by 34 patients suffering from radiation-induced xerostomia, before and after 4 weeks of treatment with the BioXtra moisturizing gel, toothpaste and mouthwash., Results: The BioXtra products significantly diminished the most common symptoms of xerostomia. Mean VAS score at the start of treatment was 59.8. After treatment, this decreased to 36.4 (p < 0.001). Twenty-six patients (77%) responded to treatment, 11 of these patients (32%) reported a major improvement. Quality of life significantly improved under treatment: mean QoL score at the start was 59.4; this increased to 70.5 (p < 0.001). None of the 34 patients reported any adverse effects and all but 1 patient found the BX dry mouth care system easy to use., Conclusions: The results of this study suggest that the BioXtra dry mouth care system is effective in reducing the symptoms of radiation-induced xerostomia and improving the quality of life of xerostomia patients, even if a proportion of the benefit is due to a placebo effect. However, further research is necessary to evaluate the efficacy of BioXtra on oral health.

Purpose: To evaluate the clinical outcome and toxicity of post-operative intensity-modulated radiotherapy (IMRT) for malignancies of the nasal cavity and paranasal sinuses., Methods and Materials: Twenty-five patients with histological proven cancer of the paranasal sinuses (n=21) or nasal cavity (n=4) were post-operatively treated with IMRT at the Leuven department to a total dose of 60 Gy (n=15) or 66 Gy (n=10). Both acute and chronic toxicity were prospectively scored in all patients., Results: Median follow-up was 27 months (range: 12-47 months) among surviving patients. The actuarial 2-year local control (LC), overall survival (OS) and disease-free survival (DFS) rates were 81%, 88% and 77%, respectively. One patient developed isolated distant metastasis, while none of the patients developed regional failure. No grade 3 or 4 toxicity was reported, either acute or chronic. No radiation-induced blindness or brain necrosis was reported to date, although longer follow-up has to be awaited for definitive results., Conclusion: Post-operative IMRT for sinonasal cancer resulted in similar local control and survival rates as conventional or 3D-conformal radiotherapy techniques, and was associated with little acute toxicity. Longer follow-up is necessary to confirm the lack of late complications.

Purpose: To evaluate the long-term clinical outcome and toxicity of conventional and three-dimensional conformal radiotherapy for malignancies of the nasal cavity and paranasal sinuses., Methods and Materials: Between January 1976 and February 2003, 127 patients with histologically proven cancer of the paranasal sinuses (n = 119) or nasal cavity (n = 8) were treated with preoperative (n = 61), postoperative (n = 51), or primary (n = 15) radiotherapy, using conventional (n = 74) or three-dimensional conformal (n = 53) techniques. No elective neck irradiation of the cervical lymph nodes was performed in N0 patients., Results: Median follow-up was 5.6 years (range, 3-307 months) for all patients, and 7.3 years (range, 47-307 months) for patients still alive at the close-out date. The actuarial 5-year local control, overall survival, and disease-free survival rates were 53%, 54%, and 37%, respectively. Only 6 (5%) of all 127 patients and 4 (3%) of 122 originally N0 patients developed a regional failure in the neck. Distant metastasis occurred in 20% of patients. Both primary tumor extent and lymph node involvement were the most important prognostic factors, together with squamous cell carcinoma histology., Conclusion: Local failure remains the dominant cause of poor outcome for patients with sinonasal cancer, despite aggressive local treatment with combined surgery and radiotherapy in operable patients. Distant metastasis and certainly regional relapse were much less common sites of failure. Overall survival remains poor, suggesting the need for more efficacious local and possibly systemic therapy.

Background: Our aim was to determine feasibility and efficacy of a hybrid radiotherapy schedule in locally advanced head and neck cancer., Methods: Seventy-three patients with locally advanced head and neck cancer were irradiated according to a hybrid accelerated schedule consisting of 20 fractions of 2 Gy (once daily), followed by 20 fractions of 1.6 Gy (twice daily), to a total dose of 72 Gy., Results: Locoregional control was 55% after 2 years. Overall survival was 59%, disease-specific survival was 63%, and disease-free survival was 46%. Acute toxicity was prospectively scored in all 73 patients: the most frequent toxicities were mucositis (50.7%, grade 3), dysphagia (47.9%, grade 3), and dermatitis (34.5%, grade 3). All patients were treated to full dose, without treatment interruption., Conclusion: With this regimen, acceptable locoregional control and survival rates are achieved. Toxicity was well manageable, suggesting that a combination of this schedule with concomitant chemotherapy is possible and could lead to further improvement in the treatment of locally advanced head and neck cancer.

Objective: Arthralgia, skeletal and muscle pain have been reported in postmenopausal women under treatment with third generation aromatase inhibitors (AIs). However, the pathogenesis and anatomic correlate of musculoskeletal pains have not been thoroughly evaluated. Moreover, the impact of AI-induced musculoskeletal symptoms on normal daily functioning needs to be further explored., Patients and Methods: We examined 12 consecutive non-metastatic breast cancer patients who reported severe musculoskeletal pain under a third generation AI; 11 were on letrozole and 1 on exemestane. Clinical rheumatological examination and serum biochemistry were performed. Radiological evaluation of the hand/wrist joints were performed using ultrasound (US) and/or magnetic resonance imaging (MRI)., Results: The most common reported symptom was severe early morning stiffness and hand/wrist pain causing impaired ability to completely close/stretch the hand/fingers and to perform daily activities and work-related skills. Six patients had to discontinue treatment due to severe symptoms. Trigger finger and carpal tunnel syndrome were the most frequently reported clinical signs. US showed fluid in the tendon sheath surrounding the digital flexor tendons. On MRI, an enhancement and thickening of the tendon sheath was a constant finding in all 12 patients., Conclusions: Musculoskeletal pains in breast cancer patients under third generation AIs can be severe, debilitating, and can limit compliance. Characteristic tenosynovial, and in some patients joint changes on US and MRI were observed in this series and have not been reported before.

Purpose: To determine whether the effect of an additional "boost" radiation after breast conservative therapy (BCT) on local control depends on age and evaluate the impact of a treatment policy with a threshold for age., Patients and Methods: We used data from EORTC 22881-10882 trial, with median follow-up of 77.4 months. Patients receiving BCT and 50Gy whole breast irradiation were randomized to no boost and 16Gy boost (N=5318)., Results: In univariate analysis, a boost reduced local failure by a factor of 2 (P<0.0001). Multivariate analysis showed local control increased with age (P=0.0003). There was no evidence that the relative effect of a boost on local control depends on age (P=0.97) However in younger patients the 5-year local failure was higher, therefore the absolute reduction was greater. If the threshold-age for boost treatment were set at 40 years, 8.4% of the study population would receive a boost, resulting in a 5-year local failure of 6.1% in the study population. Changing the threshold-age to 60 years, 67% of the study population would receive a boost and the 5-year local failure would be reduced to 4.4%., Conclusions: In younger patients a boost dose resulted in a greater absolute reduction of local failure. The relative risk reduction was however similar for all ages. Applying a treatment policy with a threshold-age of 60 would result in 0.6% increase in local failure in the total study population, while sparing the boost to 1/3 of the patients.

The EORTC 22922/10925 trial randomly compares irradiation or no irradiation of the internal mammary and medio supraclavicular (IM-MS) nodes for stage I-III breast cancer. We report on the characteristics of 4004 participating patients, aspects of quality assurance and compliance to protocol treatment. The actual population has intermediate-risk disease: 51.8% stage II, 56% positive axillary nodes. The allocated treatment was not followed in 3.2% in the IM-MS irradiation arm versus 2% in the no IM-MS irradiation arm. In the IM-MS arm, there were major deviations for dose in 0.8%, surgery-to-radiotherapy time interval in 3.9% and in overall treatment time in 0.9% cases. Major deviations were found in 7.9% patients in the IM-MS group and in 2% patients in the no IM-MS group. In the final trial analysis, a sensitivity analysis should evaluate the subgroup of patients receiving an optimal treatment to verify the robustness of the results and the true impact of IM-MS irradiation.

A dry mouth or xerostomia is one of the most common complications during and after radiotherapy for head and neck cancer, because irreparable damage is caused to the salivary glands, which are included in the radiation fields. Xerostomia not only significantly impairs the quality of life of potentially cured cancer patients, it may also lead to severe and long-term oral disorders. Because management of xerostomia is rarely effective, prevention is paramount. Several strategies have been developed to avoid radiation-induced salivary dysfunction without compromising definitive oncologic treatment. These include salivary gland-sparing radiation techniques, such as 3-dimensional conformal or intensity-modulated radiotherapy, concomitant cytoprotectants, and surgical salivary gland transfer. However, these preventive approaches are not applicable to all patients, and comprehensive scientific research that incorporates new biological insights is warranted to optimize the therapeutic index of radiotherapy for head and neck cancer., ((c) 2006 American Cancer Society.)

Background and Purpose: A quality assurance (QA) program in conjunction with the EORTC trial investigating the role of adjuvant internal mammary and medial supraclavicular irradiation in stage I-III breast cancer is presented. The results of a dummy run procedure and of an individual case review are compared to each other. The effects of recommendations based on QA procedures on the protocol compliance are evaluated., Material and Methods: Prior to protocol activation all participating institutes were asked to produce treatment plans according to the guidelines of the protocol based on manual outlines of an average patient. Thereafter, they were asked to provide data on each of their first six randomized patients., Results: The dummy run provided a lot of information on specific treatment techniques. In the individual case review, additional patient- and tumor-related data were collected, showing the use of anatomic information for treatment planning. A comparison between both procedures revealed that the individual case reports concurred more accurately with protocol guidelines than the dummy run., Conclusion: It was observed that the number of systematic protocol deviations was substantially decreased in trial patients compared to the dummy run case. Therefore, it is concluded that this extensive QA program had a positive effect on the consistency of all institutes participating in the trial.

Purpose: To investigate the incidence and anatomic localization of retropharyngeal (RP) nodal involvement in patients with squamous cell carcinoma of the oropharynx., Methods and Materials: The CT studies of 208 patients presenting with oropharyngeal carcinoma were retrospectively analyzed. The location of the nodal neck disease was registered according to recent consensus guidelines for target volume delineation, and special attention was given to the RP nodes. To obtain statistically significant predictors for RP nodal involvement, univariate and multivariate analyses were performed., Results: RP adenopathies were present in 16% of all patients and in 23% of those patients with nodal disease in other neck sites. Ipsilateral involvement of Level II and contralateral involvement of Level III predicted for involvement of the ipsilateral RP nodes on multivariate analysis (p < 0.05). A solitary ipsilateral RP node was present in 3 (9%) of 34 patients with RP nodes; 2 of these 3 patients had a primary posterior pharyngeal wall tumor. No patients presented with a solitary contralateral RP node., Conclusion: Given the high incidence of RP nodal involvement in oropharyngeal cancer-16% of all patients and 23% of patients with pathologic nodal disease in other neck sites-RP nodes should be included in the target volume, especially in node-positive necks. In node-negative necks, inclusion of RP nodes into the target volume is advised in posterior pharyngeal wall tumors.

Purpose: To investigate the impact of involvement of retropharyngeal lymph nodes on the prognosis of squamous cell carcinoma of the oropharynx., Methods and Materials: The pretreatment computed tomographic scans of 208 patients with squamous cell carcinoma of the oropharynx were reviewed for the presence of metastatic retropharyngeal lymph nodes. All patients were treated at the Leuven department between 1984 and 2003: by radiotherapy alone in 84.1% of patients, by surgery with postoperative radiotherapy in 11.5%, and by concomitant chemoradiotherapy in 4.4%. Retropharyngeal node involvement was present in 34 (16%) patients. The influence on recurrence (local and regional), distant metastasis, and survival was retrospectively analyzed. Median follow-up was 47 months (3.9 years), and results were analyzed for 201 patients., Results: At 5 years, patients with retropharyngeal adenopathy had significantly more regional recurrences (45% vs. 10%, p = 0.004). Involvement of retropharyngeal lymph nodes significantly (relative risk 4.29 [95% confidence interval 3.33-5.25], p = 0.01) and independently predicted regional recurrence in multivariate analysis. Disease-specific survival was significantly lower in the retropharyngeal node positive group (38% vs. 58%, p = 0.03)., Conclusions: Retropharyngeal node involvement has a negative impact on the prognosis of squamous cell cancer of the oropharynx. Patients are particularly at risk for regional recurrence, resulting in worse disease-specific survival. Retropharyngeal node involvement should be taken into account in designing the treatment plan for these patients.