A phase Ib/II study of eribulin in combination with cyclophosphamide in patients with advanced breast cancer.

PURPOSE: We hypothesized that eribulin combined with cyclophosphamide (EC) would be an effective combination with tolerable toxicity for the treatment of advanced breast cancer (ABC). METHODS: Patients with histologically confirmed metastatic or unresectable ABC with any number of prior lines of therapy were eligible to enroll. In the dose escalation cohort, dose level 0 was defined as eribulin 1.1 mg/m2 and cyclophosphamide 600 mg/m2, and dose level 1 was defined as eribulin 1.4 mg/m2 and cyclophosphamide 600 mg/m2. Eribulin was given on days 1 and 8 and cyclophosphamide on day 1 of a 21-day cycle. In the dose expansion cohort, enrollment was expanded at dose level 1. The primary objective was clinical benefit rate (CBR), and secondary objectives were response rate (RR), duration of response (DOR), progression-free survival (PFS), and safety. RESULTS: No dose-limiting toxicities were identified in the dose escalation cohort (n = 6). In the dose expansion cohort, an additional 38 patients were enrolled for a total of 44 patients, including 31 patients (70.4%) with hormone receptor-positive (HR +)/HER2- disease, 12 patients (27.3%) with triple-negative breast cancer (TNBC), and 1 patient (2.3%) with HR + /HER2 + disease. Patients had a median age of 56 years (range 33-82 years), 1 prior line of hormone therapy (range 0-6), and 2 prior lines of chemotherapy (range 0-7). CBR was 79.5% (35/44; 7 partial response, 28 stable disease) and the median DOR was 16.4 weeks (range 13.8-21.1 weeks). Median PFS was 16.4 weeks (95% CI: 13.8-21.1 weeks). The most common grade 3/4 adverse event was neutropenia (47.7%, n = 21). Fourteen of 26 patients (53.8%) with circulating tumor cell (CTC) data were CTC-positive ([Formula: see text] 5 CTC/7.5 mL) at baseline. Median PFS was shorter in patients who were CTC-positive vs. negative (13.1 vs 30.6 weeks, p = 0.011). CONCLUSION: In heavily pretreated patients with ABC, treatment with EC resulted in an encouraging CBR of 79.5% and PFS of 16.4 weeks, which compares favorably to single-agent eribulin. Dose reduction and delays were primarily due to neutropenia. The contribution of cyclophosphamide to eribulin remains unclear but warrants further evaluation. NCT01554371.

Secondary Modification of S100B Influences Anti Amyloid-ß Aggregation Activity and Alzheimer's Disease Pathology.

Proteinaceous aggregates accumulate in neurodegenerative diseases such as Alzheimer's Disease (AD), inducing cellular defense mechanisms and altering the redox status. S100 pro-inflammatory cytokines, particularly S100B, are activated during AD, but recent findings reveal an unconventional molecular chaperone role for S100B in hindering Aß aggregation and toxicity. This suggests a potential protective role for S100B at the onset of Aß proteotoxicity, occurring in a complex biochemical environment prone to oxidative damage. Herein, we report an investigation in which extracellular oxidative conditions are mimicked to test if the susceptibility of S100B to oxidation influences its protective activities. Resorting to mild oxidation of S100B, we observed methionine oxidation as inferred from mass spectrometry, but no cysteine-mediated crosslinking. Structural analysis showed that the folding, structure, and stability of oxidized S100B were not affected, and nor was its quaternary structure. However, studies on Aß aggregation kinetics indicated that oxidized S100B was more effective in preventing aggregation, potentially linked to the oxidation of Met residues within the S100:Aß binding cleft that favors interactions. Using a cell culture model to analyze the S100B functions in a highly oxidative milieu, as in AD, we observed that Aß toxicity is rescued by the co-administration of oxidized S100B to a greater extent than by S100B. Additionally, results suggest a disrupted positive feedback loop involving S100B which is caused by its oxidation, leading to the downstream regulation of IL-17 and IFN-α2 expression as mediated by S100B.

"Usual" interstitial pneumonia with autoimmune features: a prospective study on a cohort of idiopathic pulmonary fibrosis patients.

OBJECTIVES: The classification interstitial pneumonia with autoimmune features (IPAF) includes patients with interstitial lung disease (ILD) associated with autoimmune characteristics insufficient to reach classification criteria for a specific autoimmune disease (SAD). These criteria are divided into three domains: clinical, serological and morphological. The latter domain does not include the usual interstitial pneumonia (UIP) pattern, which is deemed not to be significantly associated with SAD. Therefore, the enrolment of these patients is more difficult, requiring at least one item from both of the other domains. The objective of this study is to evaluate the rate of progression towards SAD of a cohort of UIP patients satisfying only one IPAF domain (we called this group "UIPAF") compared with classic idiopathic pulmonary fibrosis (IPF). METHODS: We prospectively enrolled IPF patients with radiologic and/or histologic UIP pattern, followed jointly by rheumatologists and pulmonologists from January 2017 to January 2021, with a minimum follow-up of 12 months. RESULTS: We enrolled 190 IPF patients, 38 (20%) of whom were classified as UIPAF. IPF and UIPAF patients were similar for general characteristics, severity and prognosis, at presentation and at annual check-up. However, 28.9% of UIPAF patients progressed towards SAD, compared with 2% of IPF patients (χ2=30.4, p≤0.0001). CONCLUSIONS: The association between a single clinical or serological domain of IPAF and UIP pattern is predictive for the development of a SAD if compared with isolated UIP. ILD can be the first manifestation of SAD, even with a UIP pattern, therefore, the morphological domain of IPAF criteria could be removed.

Reshaping Treatment Paradigms for Advanced Renal Cell Cancer Patients and Improving Patient Management : Optimal Management for Renal Cell Cancer Patients.

OPINION STATEMENT: The treatment of renal cell carcinoma (RCC) is one of the great success stories in the field of oncology, which was revolutionized with the development of therapies aimed at disrupting crucial pathways. Tumor biology of RCC has provided insight into the disease through elucidation of the role of vascular endothelial growth-factor (VEGF) and the mammalian target of rapamycin (mTOR). Targeted agents against VEGF and mTOR, as well as agents targeting relevant immunomodulatory pathways, have shown clinical benefit for advanced disease. The targeted agents are highly effective in achieving a response and survival, particularly in high-risk patients. These include the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) axitinib and cabozantinib, and programmed cell death 1 protein (PD-1) immune checkpoint inhibitors (ICI) nivolumab and pembrolizumab. There is a wealth of evidence investigating different therapeutic options and combinations for first-line treatment of advanced RCC including the CheckMate 214 study, KEYNOTE-426, JAVELIN Renal 101, and CheckMate 9ER. Dual ICI and combination agents targeting the programmed cell death protein 1/programmed cell death protein ligand 1 (PD1/PDL1) and VEGF, began to demonstrate superiority over previously accepted standards in advanced clear-cell RCC. Data from a number of clinical studies are available to help physicians with evidence-based decisions for the sequence of second-line and future treatments for patients with progressive RCC. In this review, we focus on essentials for clinicians treating patients with clear-cell RCC.

CDK4/6 inhibitors: mechanisms of resistance and potential biomarkers of responsiveness in breast cancer.

Hormone receptor (HR)-positive, HER2-negative tumors represent the most common form of metastatic breast cancer (MBC), and endocrine therapy has been the mainstay treatment for several decades. Recently, a novel drug class called CDK4/6 inhibitors in combination with endocrine therapy have remarkably improved the outcome of patients with HR-positive, HER2-negative MBC by targeting the cell cycle machinery and overcoming aspects of endocrine resistance. Several potential cell-cycle-specific and nonspecific mechanisms of resistance to CDK4/6 inhibitors have been reported in recent studies. This review discusses potential resistance mechanisms to CDK4/6 inhibitors, the use of biomarkers to guide treatment for HR-positive, HER2-negative MBC and possible approaches to overcome resistance to CDK4/6 inhibitors.

Approximately 70% of breast cancers are hormone receptor (HR)-positive. A CDK4/6 inhibitor combined with endocrine therapy is the first-line standard of care for patients with HR-positive, HER-2 negative advanced breast cancer. Markers to predict the efficacy of CDK4/6 inhibitors in HR-positive, HER2-negative advanced breast cancer are limited. In this review, we summarize the use of CDK4/6 inhibitors in breast cancer, as well as possible approaches to overcome resistance to CDK4/6 inhibitors.

Innovations in community-based mental health care: an overview of meta-analyses.

In the last four decades, mental health services for people with Severe Mental Illness (SMI) have seen asylums replaced by a balanced model of Community Mental Healthcare (CMH). Innovative approaches and strategies in the field of CMH have been extensively researched. However, this research has been hampered by issues limiting their capacity to inform clinicians and policymakers. We conducted an overview of meta-analyses of the effectiveness of innovative CMH models focussing on clinical and psychosocial outcomes in comparisons with standard care in adults with SMI. Based on the 12 eligible studies, we appraised, synthesised and graded the resulting evidence. There was moderate quality evidence that case management, Early Intervention Services (EIS) and caregiver-directed interventions were superior to standard care in reducing hospital admission. In relation to psychosocial outcomes, EIS showed high quality evidence of a small effect on global functioning. There was moderate quality evidence for a similar effect of Intensive Case Management, and for a large effect of family intervention. For quality of life, both EIS and self-management education had a small effect, with moderate quality. The level of research about effective CMH models is therefore substantial. However, several gaps related to innovative CMH not yet covered in meta-analytic synthesis, need to be filled.

Optimal Treatment for Patients with Oligometastatic Prostate Cancer.

Oligometastatic prostate cancer (PCa) can be defined as cancer with a limited number of metastases, typically fewer than 5 lesions, and involves lesions contained within the axial versus the appendicular skeleton. Patients can present with de novo oligometastatic, oligorecurrent, or oligoprogressive PCa. Oligometastatic PCa patients demonstrate considerable improvements in survival outcomes, with a better prognosis than patients with extensive metastatic disease. However, the management of patients that present with nonsymptomatic oligometastatic PCa remains difficult. In the oligometastatic setting, the benefit of local therapies such as prostatectomy and radiotherapy on survival outcomes is an intriguing topic; however, their impact on oncological outcomes is still unknown.

Dynamic flow and shear stress as key parameters for intestinal cells morphology and polarization in an organ-on-a-chip model.

Gut-on-a-chip microfluidic devices have emerged as versatile and practical systems for modeling the human intestine in vitro. Cells cultured under microfluidic conditions experience the effect of shear stress, used as a biomechanical cue to promote a faster cell polarization in Caco-2 cells when compared with static culture conditions. However, published systems to date have utilized a constant flow rate that fails to account for changes in cell shear stress ([Formula: see text]) resulting from changes in cell elongation that occur with differentiation. In this study, computational fluid dynamics (CFD) simulations predict that cells with villi-like morphology experience a [Formula: see text] higher than bulge-like cells at the initial growth stages. Therefore, we investigated the use of a dynamic flow rate to maintain a constant [Formula: see text] across the experiment. Microscopic assessment of cell morphology and dome formation confirmed the initiation of Caco-2 polarization within three days. Next, adopting our dynamic approach, we evaluated whether the following decreased flow could still contribute to complete cell differentiation if compared with the standard constant flow methodology. Caco-2 cells polarized under both conditions, secreted mucin-2 and villin and formed tight junctions and crypt-villi structures. Gene expression was not impacted using the dynamic flow rate. In conclusion, our dynamic flow approach still facilitates cell differentiation while enabling a reduced consumption of reagents.

Extracellular Vesicles from Mesenchymal Stem Cells Exert Pleiotropic Effects on Amyloid-ß, Inflammation, and Regeneration: A Spark of Hope for Alzheimer's Disease from Tiny Structures?

No cure yet exists for devastating Alzheimer's disease (AD), despite many years and humongous efforts to find efficacious pharmacological treatments. So far, neither designing drugs to disaggregate amyloid plaques nor tackling solely inflammation turned out to be decisive. Mesenchymal stem cells (MSCs) and, in particular, extracellular vesicles (EVs) originating from them could be proposed as an alternative, strategic approach to attack the pathology. Indeed, MSC-EVs-owing to their ability to deliver lipids/proteins/enzymes/microRNAs endowed with anti-inflammatory, amyloid-ß degrading, and neurotrophic activities-may be exploited as therapeutic tools to restore synaptic function, prevent neuronal death, and slow down memory impairment in AD. Herein the results presented in the most recently published studies on this topic are critically evaluated, providing a strong rationale for possible employment of MSC-EVs in AD. Also see the video abstract here https://youtu.be/tBtDbnlRUhg.

Vascularized Pericranial Flap as a Method to Prevent Persistent Skull Defects After Craniectomy for Sagittal Synostosis.

ABSTRACT: Some cranial defects resulting from sagittal craniectomy for craniosynostosis never completely close and require cranioplasty. This study evaluates the results of 2 methods to minimize such defects: (1) trapezoidal craniectomy that is narrower posteriorly (2) vascularized pericranial flap that is sewn to the dura under a rectangular craniectomy.Children who underwent primary open sagittal craniectomy with biparietal morcellation (with/without frontal cranioplasty) for single-suture nonsyndromic sagittal synostosis from 2013 through 2018 were included. Children were excluded if there was a dural tear, if they had no 1-year follow-up, or if they had unmeasured and/or uncounted skull defects. Surgeries were divided into (1) standard craniectomy, (2) trapezoidal craniectomy, or (3) craniectomy with pericranial flap. Differences in percentage of children with defects and mean total defect area 1 year postsurgery were compared between the 3 groups.We reviewed 148 cases. After exclusions, 34 of 53 children (64%) who underwent standard craniectomy, 6 of 17 children (35%) who had pericranial flaps, and 5 of 11 children (46%) who underwent trapezoidal craniectomy had defects 1 year postsurgery. The percentage of children with defects (P = 0.0364) but not the defect area was significantly higher in the standard craniectomy than in the pericranial flap group. The percentage of subjects with defects was not significantly different between the standard and the trapezoidal craniectomy groups.Sewing a vascularized pericranial flap to the dura at the craniectomy site may protect against persistent bony defects after sagittal craniectomy for craniosynostosis. Longer follow-up is needed to determine if this technique leads to lower rates of cranioplasty.

Expression Analysis of Zinc Transporters in Nervous Tissue Cells Reveals Neuronal and Synaptic Localization of ZIP4.

In the last years, research has shown that zinc ions play an essential role in the physiology of brain function. Zinc acts as a potent neuromodulatory agent and signaling ions, regulating healthy brain development and the function of both neurons and glial cells. Therefore, the concentration of zinc within the brain and its cells is tightly controlled. Zinc transporters are key regulators of (extra-) cellular zinc levels, and deregulation of zinc homeostasis and zinc transporters has been associated with neurodegenerative and neuropsychiatric disorders. However, to date, the presence of specific family members and their subcellular localization within brain cells have not been investigated in detail. Here, we analyzed the expression of all zinc transporters (ZnTs) and Irt-like proteins (ZIPs) in the rat brain. We further used primary rat neurons and rat astrocyte cell lines to differentiate between the expression found in neurons or astrocytes or both. We identified ZIP4 expressed in astrocytes but significantly more so in neurons, a finding that has not been reported previously. In neurons, ZIP4 is localized to synapses and found in a complex with major postsynaptic scaffold proteins of excitatory synapses. Synaptic ZIP4 reacts to short-term fluctuations in local zinc levels. We conclude that ZIP4 may have a so-far undescribed functional role at excitatory postsynapses.

MRI prediction of pathological response in locally advanced rectal cancer: when apparent diffusion coefficient radiomics meets conventional volumetry.

AIM: To investigate the role of diffusion-weighted imaging (DWI), T2-weighted (W) imaging, and apparent diffusion coefficient (ADC) histogram analysis before, during, and after neoadjuvant chemoradiotherapy (CRT) in the prediction of pathological response in patients with locally advanced rectal cancer (LARC). MATERIALS AND METHODS: Magnetic resonance imaging (MRI) at 1.5 T was performed in 43 patients with LARC before, during, and after CRT. Tumour volume was measured on both T2-weighted (VT2W) and on DWI at b=1,000 images (Vb,1,000) at each time point, hence the tumour volume reduction rate (ΔVT2W and ΔVb,1,000) was calculated. Whole-lesion (three-dimensional [3D]) first-order texture analysis of the ADC map was performed. Imaging parameters were compared to the pathological tumour regression grade (TRG). The diagnostic performance of each parameter in the identification of complete responders (CR; TRG4), partial responders (PR; TRG3) and non-responders (NR; TRG0-2) was evaluated by multinomial regression analysis and receiver operating characteristics curves. RESULTS: After surgery, 11 patients were CR, 22 PR, and 10 NR. Before CRT, predictions of CR resulted in an ADC value of the 75th percentile and median, with good accuracy (74% and 86%, respectively) and sensitivity (73% and 82%, respectively). During CRT, the best predictor of CR was ΔVT2W (-58.3%) with good accuracy (81%) and excellent sensitivity (91%). After CRT, the best predictors of CR were ΔVT2W (-82.8%) and ΔVb, 1,000 (-86.8%), with 84% accuracy in both cases and 82% and 91% sensitivity, respectively. CONCLUSIONS: The median ADC value at pre-treatment MRI and ΔVT2W (from pre-to-during CRT MRI) may have a role in early and accurate prediction of response to treatment. Both ΔVT2W and ΔVb,1,000 (from pre-to-post CRT) can help in the identification of CR after CRT.

Predictors of vitamin A status among pregnant women in Western Brazilian Amazon.

Determining the predictors of serum retinol at mid-pregnancy is relevant for planning interventions aimed at improving vitamin A status of pregnant women and their offspring. This prospective study assessed predictors of serum retinol at the beginning of the third trimester of pregnancy. We enrolled 442 pregnant women living in the urban area of Cruzeiro do Sul, Western Brazilian Amazon. Demographic, socio-economic, environmental and clinical characteristics as well as obstetric history, anthropometric, dietary and biochemical data, including serum retinol, were gathered between 16 and 20 gestational weeks. Serum retinol also measured at the beginning of the third trimester of pregnancy (approximately 28 gestational weeks) was the outcome of interest. Multiple linear regression models were used to evaluate associations with the outcome. Overall, the following variables explained serum retinol at the beginning of the third trimester of pregnancy in the adjusted model (R 2 = 11·1 %): seasonality (winter season - November to April; ß=0·134; 95 % CI 0·063, 0·206), weekly consumption of Amazonian fruits (ß=0·087; 95 % CI 0·012, 0·162) and retinol concentrations between 16 and 20 gestational weeks (ß=0·045; 95 % CI 0·016, 0·074) were positively associated, whereas having a smoker in the house was negatively associated (ß=-0·087; 95 % CI: -0·166, -0·009). Consumption of pro-vitamin A-rich fruits by pregnant women should be encouraged. Passive smoking may play a role in decreasing vitamin A status as a proxy of smoking exposure during pregnancy.

Epigenetic mechanisms underlie the crosstalk between growth factors and a steroid hormone.

Crosstalk between growth factors (GFs) and steroid hormones recurs in embryogenesis and is co-opted in pathology, but underlying mechanisms remain elusive. Our data from mammary cells imply that the crosstalk between the epidermal GF and glucocorticoids (GCs) involves transcription factors like p53 and NF-κB, along with reduced pausing and traveling of RNA polymerase II (RNAPII) at both promoters and bodies of GF-inducible genes. Essentially, GCs inhibit positive feedback loops activated by GFs and stimulate the reciprocal inhibitory loops. As expected, no alterations in DNA methylation accompany the transcriptional events instigated by either stimulus, but forced demethylation of regulatory regions broadened the repertoire of GF-inducible genes. We report that enhancers, like some promoters, are poised for activation by GFs and GCs. In addition, within the cooperative interface of the crosstalk, GFs enhance binding of the GC receptor to DNA and, in synergy with GCs, promote productive RNAPII elongation. Reciprocally, within the antagonistic interface GFs hyper-acetylate chromatin at unmethylated promoters and enhancers of genes involved in motility, but GCs hypoacetylate the corresponding regions. In conclusion, unmethylated genomic regions that encode feedback regulatory modules and differentially recruit RNAPII and acetylases/deacetylases underlie the crosstalk between GFs and a steroid hormone.

HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?

Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs). An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs. Studies were classified as "high quality" (HQ) if IHC overexpression was defined as presence of moderate/strong staining or "low quality" (LQ) where "any" expression was considered positive. Of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5 % (95 % CI 18.9-34.1 %). When HQ studies were analyzed (n = 27 studies), extrahepatic BTCs showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma: 19.9 % (95 % CI 12.8-27.1 %) vs. 4.8 % (95 % CI 0-14.5 %), respectively, p value 0.0049. HER2 amplification rate was higher in patients selected by HER2 overexpression compared to "unselected" patients: 57.6 % (95 % CI 16.2-99 %) vs. 17.9 % (95 % CI 0.1-35.4 %), respectively, p value 0.0072. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9 % (95 % CI 9.7-46.1 %) and 26.5 % (one study), respectively. Up to 20 % of extrahepatic BTCs appear to be HER2 overexpressed; of these, close to 60 % appear to be HER2 amplified, while HER3 is overexpressed or amplified in about 25 % of patients. Clinical relevance for targeted therapy should be tested in prospective clinical trials.

Cross-Lagged Relations Between Exercise Capacity and Psychological Distress During Cardiac Rehabilitation.

Background: Poorer mental health is associated with lower exercise capacity, above and beyond the effect of other cardiovascular risk factors. However, the directionality of this relationship remains unclear. Purpose: The main aim of the present study was to clarify, with a cross-lagged panel design, the relationship between psychological status and exercise capacity among patients in a cardiac rehabilitation (CR) program. Methods: A clinical sample of 212 CR patients completed exercise-capacity testing and measures of depression and anxiety (Hospital Anxiety and Depression Scale) pre-CR and post-CR. Demographic and clinical data, including BMI and smoking history, were also collected. Multivariate stepwise regression analysis was performed to identify the best predictors of exercise capacity at discharge. Structural equation modeling was utilized to quantify the cross-lagged effect between exercise capacity and psychological distress. Results: Multivariate regression analysis revealed that higher levels of psychological distress pre-CR are predictively associated with less improvement in exercise capacity post-CR, beyond the effects of age, sex, and baseline functional status. Results from structural equation modeling supported a 1-direction association, with psychological distress pre-CR predicting lower exercise capacity post-CR over and above autoregressive effects. Conclusions: Study results did not support the hypothesis of a bidirectional relationship between psychological distress and EC. High levels of psychological distress pre-CR appeared to be longitudinally associated with lower exercise capacity post-CR, but not vice versa. This finding highlights the importance of assessing and treating both anxiety and depression in the early phase of secondary prevention programs.

Could perfusion heterogeneity at dynamic contrast-enhanced MRI be used to predict rectal cancer sensitivity to chemoradiotherapy?

AIM: To evaluate whether perfusion heterogeneity of rectal cancer prior to chemoradiotherapy (CRT) using histogram analysis of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) quantitative parameters can predict response to treatment. MATERIALS AND METHODS: Twenty-one patients with histologically proven rectal adenocarcinoma were enrolled prospectively. All patients underwent 1.5 T DCE-MRI before CRT. Tumour volumes were drawn on Ktrans and Ve maps, using T2-weighted (W) images as reference, and the following first-order texture parameters of Ve and Ktrans values were extracted: 25th, 50th, 75th percentile, mean, standard deviation, skewness, and kurtosis. After CRT, patients underwent surgery and according with Rödel's tumour regression grade (TRG), they were classified as poor responders "non-GR" (TRG 0-2) and good responders "GR" (TRG 3-4). Differences between GR and non-GR in DCE-MRI first-order texture parameters were evaluated using the Mann-Whitney test, and their role in the prediction of response was investigated using receiver operating characteristic (ROC) curve analysis. RESULTS: Sixteen (76%) patients were classified as GR and five (24%) were non-GR. Skewness and kurtosis of Ve was significantly higher in non-GR (4.886±1.320 and 36.402±24.486, respectively) than in GR patients (1.809±1.280, p=0.003 and 6.268±8.130, p= 0.011). Ve skewness <3.635 was able to predict GR with an area under the ROC curve (AUC) of 0.988, sensitivity 93.8%, specificity 80%, and accuracy 90.5%. Ve kurtosis <21.095 was able to predict response with an AUC of 0.963, sensitivity 93.8%, specificity 80%, and accuracy 90.5%. Other parameters were not different between groups or predictors of response. CONCLUSION: Ve skewness and kurtosis seem to be promising in the prediction of response to CRT in rectal cancer patients.

Could early tumour volume changes assessed on morphological MRI predict the response to chemoradiation therapy in locally-advanced rectal cancer?

AIM: To investigate the potential role of an additional magnetic resonance imaging (MRI) examination performed during neoadjuvant chemoradiation therapy (CRT) in the prediction of pathological response in locally advanced rectal cancer (LARC). MATERIAL AND METHODS: Forty-eight consecutive patients with LARC underwent neoadjuvant CRT. MRI studies at 1.5 T, including high-resolution T2-weighted sequences that were acquired parallel and perpendicular to the main axis of the tumour were performed before (preMRI), during (midMRI), and 6-8 weeks after the end of CRT (postMRI). Cancer volumes (Vpre, Vmid, Vpost) were drawn manually and the reduction rate calculated (ΔVmid, ΔVpost). According to Rödel's pathological tumour regression grade (TRG), patients were considered non-responders (NR; TRG0-2), partial responders (PR; TRG3), and complete responders (CR; TRG4). Multivariate regression analysis was performed to identify the best MRI predictors of NR, PR, and CR. RESULTS: Twenty-five patients were considered PR (52%), 13 CR (27%), and 10 NR (22%). Tumour shrinkage mainly occurred shortly after CRT (ΔVmid: CR: 80±10% versus PR: 56±19% versus NR: 28±22%, p=2.2×10-16). Vmid, Vpost, ΔVmid, and ΔVpost correlated with TRG (p<0.001). At multivariate analysis, the combined assessment of Vmid and ΔVmid was selected as the best predictor of response to CRT, in that it distinguishes CR, PR, and NR early and accurately (81.5%). CONCLUSION: MidMRI allows final response assessment to neoadjuvant CRT earlier and better than the MRI performed after the end of CRT. MRI findings at midMRI may be useful to tailor patient treatment.

Prospective surveillance and targeted physiotherapy for arm morbidity after breast cancer surgery: a pilot randomized controlled trial.

OBJECTIVE: To evaluate prospective surveillance and targeted physiotherapy (PSTP) compared to education (EDU) on the prevalence of arm morbidity and describe the associated program cost. DESIGN: Pilot randomized single-blinded controlled trial. SETTING: Urban with assessments and treatment delivered in hospitals. PARTICIPANTS: Women scheduled for breast cancer surgery. INTERVENTIONS: Participants were randomly assigned (1:1) to PSTP ( n = 21) or EDU ( n = 20) and assessed presurgery and 12 months postsurgery. All participants received usual care, namely, preoperative education and provision of an education booklet with postsurgical exercises. The PSTP group was monitored for arm morbidity every three months and referred for physiotherapy if arm morbidity was identified. The EDU group received three education sessions on nutrition, stress and fatigue management. MAIN OUTCOME MEASURES: Arm morbidity was based on changes in the surgical arm(s) from presurgery in four domains: (1) shoulder range of motion, (2) strength, (3) volume, and (4) upper body function. Complex arm morbidity indicated ≥2 domains impaired. Second, the cost of the PSTP program was described. RESULTS: At 12 months, 18 (49%) participants (10 PSTP and 8 EDU) had arm morbidity, with EDU participants presenting more complex arm morbidity compared to PSTP participants. PSTP participants attended 4.4 of 5 assessments with 90% retention. The PSTP program cost was $150 covered by the Health Care Provider and the Patient Out-of-Pocket Travel cost was CAN$40. CONCLUSION: Our results suggest that PSTP is feasible among women with breast cancer for early identification of arm morbidity. A larger study is needed to determine the cost and effectiveness benefits.

The uncertain climate footprint of wetlands under human pressure.

Significant climate risks are associated with a positive carbon-temperature feedback in northern latitude carbon-rich ecosystems, making an accurate analysis of human impacts on the net greenhouse gas balance of wetlands a priority. Here, we provide a coherent assessment of the climate footprint of a network of wetland sites based on simultaneous and quasi-continuous ecosystem observations of CO2 and CH4 fluxes. Experimental areas are located both in natural and in managed wetlands and cover a wide range of climatic regions, ecosystem types, and management practices. Based on direct observations we predict that sustained CH4 emissions in natural ecosystems are in the long term (i.e., several centuries) typically offset by CO2 uptake, although with large spatiotemporal variability. Using a space-for-time analogy across ecological and climatic gradients, we represent the chronosequence from natural to managed conditions to quantify the "cost" of CH4 emissions for the benefit of net carbon sequestration. With a sustained pulse-response radiative forcing model, we found a significant increase in atmospheric forcing due to land management, in particular for wetland converted to cropland. Our results quantify the role of human activities on the climate footprint of northern wetlands and call for development of active mitigation strategies for managed wetlands and new guidelines of the Intergovernmental Panel on Climate Change (IPCC) accounting for both sustained CH4 emissions and cumulative CO2 exchange.