Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition that often progresses to more advanced stages, such as metabolic dysfunction-associated steatohepatitis (MASH). MASH is characterized by inflammation and hepatocellular ballooning, in addition to hepatic steatosis. Despite the relatively high incidence of MASH in the population and its potential detrimental effects on human health, this liver disease is still not fully understood from a pathophysiological perspective. Deregulation of polyamine levels has been detected in various pathological conditions, including neurodegenerative diseases, inflammation, and cancer. However, the role of the polyamine pathway in chronic liver disorders such as MASLD has not been explored. In this study, we measured the expression of liver ornithine decarboxylase (ODC1), the rate-limiting enzyme responsible for the production of putrescine, and the hepatic levels of putrescine, in a preclinical model of MASH as well as in liver biopsies of patients with obesity undergoing bariatric surgery. Our findings reveal that expression of ODC1 and the levels of putrescine, but not spermidine nor spermine, are elevated in hepatic tissue of both diet-induced MASH mice and patients with biopsy-proven MASH compared with control mice and patients without MASH, respectively. Furthermore, we found that the levels of putrescine were positively associated with higher aspartate aminotransferase concentrations in serum and an increased SAF score (steatosis, activity, fibrosis). Additionally, in in vitro assays using human HepG2 cells, we demonstrate that elevated levels of putrescine exacerbate the cellular response to palmitic acid, leading to decreased cell viability and increased release of CK-18. Our results support an association between the expression of ODC1 and the progression of MASLD, which could have translational relevance in understanding the onset of this disease. © 2024 The Pathological Society of Great Britain and Ireland.

Hepatocyte PPARγ contributes to the progression of non-alcoholic steatohepatitis in male and female obese mice.

Non-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ). However, the relevance of hepatocyte PPARγ in NASH associated with obesity is still poorly understood. In this study, hepatocyte PPARγ was knocked out (PpargΔHep) in male and female mice after the development of high-fat diet-induced obesity. The diet-induced obese mice were then maintained on their original diet or switched to a high fat, cholesterol, and fructose (HFCF) diet to induce NASH. Hepatic PPARγ expression was mostly derived from hepatocytes and increased by high fat diets. PpargΔHep reduced HFCF-induced NASH progression without altering steatosis, reduced the expression of key genes involved in hepatic fibrosis in HFCF-fed male and female mice, and decreased the area of collagen-stained fibrosis in the liver of HFCF-fed male mice. Moreover, transcriptomic and metabolomic data suggested that HFCF-diet regulated hepatic amino acid metabolism in a hepatocyte PPARγ-dependent manner. PpargΔHep increased betaine-homocysteine s-methyltransferase expression and reduced homocysteine levels in HFCF-fed male mice. In addition, in a cohort of 102 obese patients undergoing bariatric surgery with liver biopsies, 16 cases were scored with NASH and were associated with increased insulin resistance and hepatic PPARγ expression. Our study shows that hepatocyte PPARγ expression is associated with NASH in mice and humans. In male mice, hepatocyte PPARγ negatively regulates methionine metabolism and contributes to the progression of fibrosis.

Nicotinamide N-methyltransferase upregulation contributes to palmitate-elicited peroxisome proliferator-activated receptor transactivation in hepatocytes.

Peroxisome proliferator-activated receptor γ (PPARγ) plays a pivotal role in regulating lipid metabolism and hepatic PPARγ transactivation contributes to fatty liver development. Fatty acids (FAs) are well-known endogenous ligands for PPARγ. Palmitate, a 16-C saturated FA (SFA) and the most abundant SFA in human circulation, is a strong inducer of hepatic lipotoxicity, a central pathogenic factor for various fatty liver diseases. In this study, using both alpha mouse liver 12 (AML12) and primary mouse hepatocytes, we investigated the effects of palmitate on hepatic PPARγ transactivation and underlying mechanisms, as well as the role of PPARγ transactivation in palmitate-induced hepatic lipotoxicity, all of which remain ambiguous currently. Our data revealed that palmitate exposure was concomitant with both PPARγ transactivation and upregulation of nicotinamide N-methyltransferase (NNMT), a methyltransferase catalyzing the degradation of nicotinamide, the predominant precursor for cellular NAD+ biosynthesis. Importantly, we discovered that PPARγ transactivation by palmitate was blunted by NNMT inhibition, suggesting that NNMT upregulation plays a mechanistic role in PPARγ transactivation. Further investigations uncovered that palmitate exposure is associated with intracellular NAD+ decline and NAD+ replenishment with NAD+-enhancing agents, nicotinamide and nicotinamide riboside, obstructed palmitate-induced PPARγ transactivation, implying that cellular NAD+ decline resulted from NNMT upregulation represents a potential mechanism behind palmitate-elicited PPARγ transactivation. At last, our data showed that the PPARγ transactivation marginally ameliorated palmitate-induced intracellular triacylglycerol accumulation and cell death. Collectively, our data provided the first-line evidence supporting that NNMT upregulation plays a mechanistic role in palmitate-elicited PPARγ transactivation, potentially through reducing cellular NAD+ contents.NEW & NOTEWORTHY Hepatic PPARγ transactivation contributes to fatty liver development. Saturated fatty acids (SFAs) induce hepatic lipotoxicity. Here, we investigated whether and how palmitate, the most abundant SFA in the human blood, affects PPARγ transactivation in hepatocytes. We reported for the first time that upregulation of nicotinamide N-methyltransferase (NNMT), a methyltransferase catalyzing the degradation of nicotinamide, the predominant precursor for cellular NAD+ biosynthesis, plays a mechanistic role in regulating palmitate-elicited PPARγ transactivation through reducing intracellular NAD+ contents.

ATF4-mediated CD36 upregulation contributes to palmitate-induced lipotoxicity in hepatocytes.

Hepatic lipotoxicity plays a central role in the pathogenesis of nonalcoholic fatty liver disease; however, the underlying mechanisms remain elusive. Here, using both cultured hepatocytes (AML-12 cells and primary mouse hepatocytes) and the liver-specific gene knockout mice, we investigated the mechanisms underlying palmitate-elicited upregulation of CD36, a class B scavenger receptor mediating long-chain fatty acids uptake, and its role in palmitate-induced hepatolipotoxicity. We found that palmitate upregulates hepatic CD36 expression. Despite being a well-established target gene of PPARγ transactivation, our data demonstrated that the palmitate-induced CD36 upregulation in hepatocytes is in fact PPARγ-independent. We previously reported that the activation of ATF4, one of three canonical pathways activated upon endoplasmic reticulum (ER) stress induction, contributes to palmitate-triggered lipotoxicity in hepatocytes. In this study, our data revealed for the first time that ATF4 plays a critical role in mediating hepatic CD36 expression. Genetic inhibition of ATF4 attenuated CD36 upregulation induced by either palmitate or ER stress inducer tunicamycin in hepatocytes. In mice, tunicamycin upregulates liver CD36 expression, whereas hepatocyte-specific ATF4 knockout mice manifest lower hepatic CD36 expression when compared with control animals. Furthermore, we demonstrated that CD36 upregulation upon palmitate exposure represents a feedforward mechanism in that siRNA knockdown of CD36 in hepatocytes blunted ATF4 activation induced by both palmitate and tunicamycin. Finally, we confirmed that the ATF4-CD36 pathway activation contributes to palmitate-induced hepatolipotoxicity as genetic inhibition of either ATF4 or CD36 alleviated cell death and intracellular triacylglycerol accumulation. Collectively, our data demonstrate that CD36 upregulation by ATF4 activation contributes to palmitate-induced hepatic lipotoxicity.NEW & NOTEWORTHY We provided the initial evidence that ATF4 is a principal transcription factor mediating hepatic CD36 expression in that both palmitate- and ER stress-elicited CD36 upregulation was blunted by ATF4 gene knockdown in hepatocytes, and hepatocyte-specific ATF4 knockout mice manifested lower hepatic CD36 expression. We further confirmed that the ATF4-CD36 pathway activation contributes to palmitate-induced hepatolipotoxicity as genetic inhibition of either ATF4 or CD36 alleviated cell death and intracellular triacylglycerol accumulation in response to exogenous palmitate exposure.

Long-term outcomes of high-risk HR-positive and HER2-negative early breast cancer patients from GEICAM adjuvant studies and El Álamo IV registry.

PURPOSE: The monarchE trial showed that the addition of abemaciclib improves efficacy in patients with high-risk early breast cancer (EBC). We analyzed the long-term outcomes of a population similar to the monarchE trial to put into context the potential benefit of abemaciclib. METHODS: HR-positive/HER2-negative EBC patients eligible for the monarchE study were selected from 3 adjuvant clinical trials and a breast cancer registry. Patients with ≥ 4 positive axillary lymph nodes (N +) or 1-3 N + with tumor size ≥ 5 cm and/or histologic grade 3 and/or Ki67 ≥ 20%, who had undergone surgery with curative intent and had received anthracyclines ± taxanes and endocrine therapy in the neoadjuvant and /or adjuvant setting were included. We performed analysis of Invasive Disease-Free Survival (iDFS), Distant Disease-Free Survival (dDFS) and Overall Survival (OS) at 5 and 10 years, as well as yearly (up to 10) of Invasive Relapse Rate (IRR), Distant Relapse Rate (DRR) and Death Rate (DR). RESULTS: A total of 1,617 patients were analyzed from the GEICAM-9906 (312), GEICAM-2003-10 (210), and GEICAM-2006-10 (160) trials plus 935 from El Álamo IV. With a median follow-up of 10.1 years, the 5 and 10 years iDFS rates were 75.2% and 57.0%, respectively. The dDFS and OS rates at 5 years were 77.4% and 88.8% and the respective figures at 10 years were 59.7% and 70.9%. CONCLUSIONS: This data points out the need for new therapies for those patients. A longer follow-up of the monarchE study to see the real final benefit with abemaciclib is warranted. TRIAL REGISTRATION: ClinTrials.gov: GEICAM/9906: NCT00129922; GEICAM/ 2003-10: NCT00129935 and GEICAM/ 2006-10: NCT00543127.

De novo 3D models of SARS-CoV-2 RNA elements from consensus experimental secondary structures.

The rapid spread of COVID-19 is motivating development of antivirals targeting conserved SARS-CoV-2 molecular machinery. The SARS-CoV-2 genome includes conserved RNA elements that offer potential small-molecule drug targets, but most of their 3D structures have not been experimentally characterized. Here, we provide a compilation of chemical mapping data from our and other labs, secondary structure models, and 3D model ensembles based on Rosetta's FARFAR2 algorithm for SARS-CoV-2 RNA regions including the individual stems SL1-8 in the extended 5' UTR; the reverse complement of the 5' UTR SL1-4; the frameshift stimulating element (FSE); and the extended pseudoknot, hypervariable region, and s2m of the 3' UTR. For eleven of these elements (the stems in SL1-8, reverse complement of SL1-4, FSE, s2m and 3' UTR pseudoknot), modeling convergence supports the accuracy of predicted low energy states; subsequent cryo-EM characterization of the FSE confirms modeling accuracy. To aid efforts to discover small molecule RNA binders guided by computational models, we provide a second set of similarly prepared models for RNA riboswitches that bind small molecules. Both datasets ('FARFAR2-SARS-CoV-2', https://github.com/DasLab/FARFAR2-SARS-CoV-2; and 'FARFAR2-Apo-Riboswitch', at https://github.com/DasLab/FARFAR2-Apo-Riboswitch') include up to 400 models for each RNA element, which may facilitate drug discovery approaches targeting dynamic ensembles of RNA molecules.

p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity.

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor survival and resistance to conventional therapies. PI3K signaling is implicated in both disease initiation and progression, and specific inhibitors of selected PI3K p110 isoforms for managing solid tumors are emerging. We demonstrate that increased activation of PI3K signals cooperates with oncogenic Kras to promote aggressive PDAC in vivo. The p110γ isoform is overexpressed in tumor tissue and promotes carcinogenesis via canonical AKT signaling. Its selective blockade sensitizes tumor cells to gemcitabine in vitro, and genetic ablation of p110γ protects against Kras-induced tumorigenesis. Diet/obesity was identified as a crucial means of p110 subunit up-regulation, and in the setting of a high-fat diet, p110γ ablation failed to protect against tumor development, showing increased activation of pAKT and hepatic damage. These observations suggest that a careful and judicious approach should be considered when targeting p110γ for therapy, particularly in obese patients.

Regression Models for Symbolic Interval-Valued Variables.

This paper presents new approaches to fit regression models for symbolic internal-valued variables, which are shown to improve and extend the center method suggested by Billard and Diday and the center and range method proposed by Lima-Neto, E.A.and De Carvalho, F.A.T. Like the previously mentioned methods, the proposed regression models consider the midpoints and half of the length of the intervals as additional variables. We considered various methods to fit the regression models, including tree-based models, K-nearest neighbors, support vector machines, and neural networks. The approaches proposed in this paper were applied to a real dataset and to synthetic datasets generated with linear and nonlinear relations. For an evaluation of the methods, the root-mean-squared error and the correlation coefficient were used. The methods presented herein are available in the the RSDA package written in the R language, which can be installed from CRAN.

GEICAM Guidelines for the Management of Patients with Breast Cancer During the COVID-19 Pandemic in Spain.

Breast cancer (BC) is the most common cancer in women in Spain. During the COVID-19 pandemic caused by the SARS-CoV-2 virus, patients with BC still require timely treatment and follow-up; however, hospitals are overwhelmed with infected patients and, if exposed, patients with BC are at higher risk for infection and serious complications if infected. Thus, health care providers need to evaluate each BC treatment and in-hospital visit to minimize pandemic-associated risks while maintaining adequate treatment efficacy. Here we present a set of guidelines regarding available options for BC patient management and treatment by BC subtype in the context of the COVID-19 pandemic. Owing to the lack of evidence about COVID-19 infection, these recommendations are mainly based on expert opinion, medical organizations' and societies' recommendations, and some published evidence. We consider this a useful tool to facilitate medical decision making in this health crisis situation we are facing. IMPLICATIONS FOR PRACTICE: This work presents a set of guidelines regarding available options for breast cancer (BC) patient management and treatment by BC subtype in the context of the COVID-19 pandemic. Owing to the suddenness of this health crisis, specialists have to make decisions with little evidence at hand. Thus, these expert guidelines may be a useful tool to facilitate medical decision making in the context of a worldwide pandemic with no resources to spare.

Real-world effectiveness of dual HER2 blockade with pertuzumab and trastuzumab for neoadjuvant treatment of HER2-positive early breast cancer (The NEOPETRA Study).

PURPOSE: Neoadjuvant clinical trials with dual HER2 blockade with pertuzumab and trastuzumab plus chemotherapy demonstrated high rates of pathological complete response (pCR) in HER2-positive early breast cancer (BC). We investigated whether the benefit on pCR seen in clinical trials is confirmed in a real-world setting. METHODS: Multicenter, retrospective study in patients with HER2-positive early BC receiving neoadjuvant treatment with pertuzumab and trastuzumab in routine clinical practice (n = 243). The primary endpoint was total pCR (tpCR) (ypT0/is ypN0). RESULTS: A total of 243 evaluable patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes in 74.1% of patients, with single-agent taxane in 11.1% of patients and with platinum-based chemotherapy (CT) in 14.4% of patients. The tpCR rate was 66.4%:71% with anthracyclines and taxanes, 59.3% with single-agent taxane, and 48.6% with platinum-based combinations. The tpCR rate was higher among patients with hormone receptor (HR)-negative tumors (80.9%) vs HR-positive tumors (55.4%) (p < 0.001). A pCR in the breast (ypT0/is) was achieved in 67.6% of patients. Of 143 patients who showed radiological complete response (rCR) (62%), 112 (78.3%) patients also achieved tpCR. Assessment of rCR by magnetic resonance imaging (MRI) showed the highest negative predictive value (NPV) for predicting tpCR (83.5%). Breast-conserving surgery was performed in 58.7% of patients. Grade 3 and grade 4 toxicities were reported in 33 (18.2%) and 12 (6.6%) patients, respectively. No toxicity leading to death was reported. CONCLUSIONS: This real-world analysis shows that neoadjuvant pertuzumab, trastuzumab, and chemotherapy achieve comparable or even higher rates of tpCR than those seen in clinical trials. The pCR benefit is higher in HR-negative tumors. The assessment of rCR by MRI showed the highest ability for predicting pCR. In addition, this neoadjuvant strategy confers an acceptable safety profile.

Phase III study to evaluate patient's preference of subcutaneous versus intravenous trastuzumab in HER2-positive metastatic breast cancer patients: Results from the ChangHER study (GEICAM/2012-07).

OBJECTIVE: We compared patients' preferences for intravenous (IV-t) versus subcutaneous (SC-t) trastuzumab administration. METHODS: Phase III, open-label, multicentre study in HER2-positive metastatic breast cancer. Patients were receiving IV-t for at least 4 months without progression. Randomisation was 1:1 to administer 2 cycles of SC-t with vial followed by 2 cycles with single injection device (SID) or the reverse sequence (600mg SC-t every 3 weeks for 4 cycles). PRIMARY OBJECTIVE: patients' preference for IV-t versus SC-t; secondary objectives: patients' preference for vial versus SID, healthcare professional (HCP) preference and safety. RESULTS: We randomised 166 patients in 26 sites. Median number of previous lines of chemotherapy and/or endocrine therapy was 1 (1-7). Median duration of prior IV-t was 1.8 years (0.3-14). Of the159 patients completing the questionnaires, 86.2% preferred SC-t, 6.9% preferred IV-t, and 6.9% had no preference. Patients preferred SID (59.2%) over vial (26.3%). Most (87.2%) HCP preferred SC-t of whom 51.3% and 28.2% preferred SID and vial respectively. Related adverse events included G1-2 injection site reactions in 18 patients (10.8%), G1 pain in 8 (4.8%), G1-2 allergic reaction in 2 (1.2%), one G3 heart failure and 1 G2 ejection fraction decrease. CONCLUSIONS: SC-t is preferred with no safety impact.

Phase III evaluating the addition of fulvestrant (F) to anastrozole (A) as adjuvant therapy in postmenopausal women with hormone receptor-positive HER2-negative (HR+/HER2-) early breast cancer (EBC): results from the GEICAM/2006-10 study.

PURPOSE: GEICAM/2006-10 compared anastrozole (A) versus fulvestrant plus anastrozole (A + F) to test the hypothesis of whether a complete oestrogen blockade is superior to aromatase inhibitors alone in breast cancer patients receiving hormone adjuvant therapy. METHODS: Multicenter, open label, phase III study. HR+/HER2- EBC postmenopausal patients were randomized 1:1 to adjuvant A (5 years [year]) or A + F (A plus F 250 mg/4 weeks for 3 year followed by 2 year of A). Stratification factors: prior chemotherapy (yes/no); number of positive lymph nodes (0/1-3/≥ 4); HR status (both positive/one positive) and site. PRIMARY OBJECTIVE: disease-free survival (DFS). Planned sample size: 2852 patients. RESULTS: The study has an early stop due to the financer decision with 870 patients (437 randomized to A and 433 to A + F). Patient characteristics were well balanced. After a median follow-up of 6.24y and 111 DFS events (62 in A and 49 in A + F) the Hazard Ratio for DFS (combination vs. anastrozole) was 0.84 (95% CI 0.58-1.22; p = 0.352). The proportion of patients disease-free in arms A and A + F at 5 year and 7 year were 90.8% versus 91% and 83.6% versus 86.7%, respectively. Most relevant G2-4 toxicities (≥ 5% in either arm) with A versus A + F were joint pain (14.7%; 13.7%), fatigue (2.5%; 7.2%), bone pain (3%; 6.5%), hot flushes (3.5%; 5%) and muscle pain (2.8%; 5.1%). CONCLUSIONS: The GEICAM/2006-10 study did not show a statistically significant increase in DFS by adding adjuvant F to A, though no firm conclusions can be drawn because of the limited sample size due to the early stop of the trial. ClinicalTrials.gov: NCT00543127.

Development and validation of a sexual relations satisfaction scale in patients with breast cancer - "SEXSAT-Q".

PURPOSE: Because the currently available questionnaires to evaluate sexual changes on breast cancer women only address the sexual sphere with a few questions our purpose was to develop a questionnaire that assesses changes in sexual dysfunction and satisfaction in women treated for breast cancer. METHODS: A sample was selected of women aged between 18 and 65 who had had surgery for breast cancer, completed neoadjuvant/adjuvant chemotherapy treatment and could be receiving adjuvant hormonal treatment, with an active sex life at least 3 months before starting treatment. Metastatic disease was excluded. A questionnaire structured in 4 dimensions was developed. The MOS SF-12 and QLQ-BR23 questionnaires were also provided. The following metric properties were evaluated: item analysis; internal consistency; temporal stability; construct validity; concurrent, convergent and divergent validity; and feasibility. RESULTS: Three samples were recruited: a pilot sample of 20; a reduction sample of 152; and a validation sample of 148. The presence of 6 dimensions was confirmed: 1) Loss of sex drive; 2) worsening of body image; 3) psychological coping; 4) discomfort during intercourse; 5) satisfaction with sexual relations; and 6) satisfaction with breast reconstruction. Good goodness-of-fit statistics were obtained (χ2/df = 1.5, GFI = 0.9, AGFI = 0.84, CFI = 0.959, RMSEA = 0.062). Reliability was good (α = 0.855), as was test-retest stability (r = 0.838). The correlation with the convergent questionnaires proved to be higher than that obtained with generic measurements. CONCLUSIONS: We were able to develop a short questionnaire (17 items) capable of measuring sexual satisfaction in women with breast cancer with good metric properties.

Prevalence of Burnout Among Pain Medicine Physicians and Its Potential Effect upon Clinical Outcomes in Patients with Oncologic Pain or Chronic Pain of Nononcologic Origin.

Objective: To evaluate the prevalence of burnout among physicians treating patients with chronic pain and to assess the potential relationships between the presence of burnout and patients' clinical outcomes such as pain relief, satisfaction with pain control, and quality of life. Design: An observational, prospective, and noncomparative study. Setting: Pain medicine clinics. Subjects: Physicians from medical departments involved in the management of chronic pain. Patients aged ≥18 years who exhibited moderate chronic pain lasting at least three months. Methods: Physicians were evaluated with the Maslach Burnout Inventory-Human Services Survey (MBI-HSS). Patients were evaluated with the Charlson Comorbidity Index, the Brief Pain Inventory-Short Form (BPI-SF), the EuroQol-5D (EQ-5D), and ad hoc instruments for evaluating satisfaction with pain control, the extent to which the treatment met patients' expectations, and subjective impressions of improvement. Results: Of the 301 physician participants, 22 (7.3%, 95% confidence interval [CI] = 4.9 to 10.8) met the criteria of burnout. Burnout was higher among physicians from pain units, while none of the 35 primary care physicians reported burnout. The presence of burnout was positively associated with patients' pain relief (odds ratio [OR] = 1.423, 95% CI = 1.090 to 1.858) but not with satisfaction with pain control or quality of life. Of the remaining independent variables, being treated by pain unit physicians was significantly associated with worse pain relief (OR = 0.592, 95% CI = 0.507 to 0.691), lower satisfaction (ß = -0.680, 95% CI = -0.834 to -0.525), and worse quality of life (ß = -4.047, 95% CI = -5.509 to -2.585) compared with being treated by physicians from other specialties (e.g., traumatologists, oncologists, etc.). Conclusions: Our study shows a lack of negative or clinically relevant (as shown by the negligible to small effect sizes) impact of burnout on patient-reported outcomes (namely, pain relief, satisfaction, and quality of life) in patients with chronic pain who are treated by pain medicine physicians.

Neoadjuvant Therapy with Weekly Nanoparticle Albumin-Bound Paclitaxel for Luminal Early Breast Cancer Patients: Results from the NABRAX Study (GEICAM/2011-02), a Multicenter, Non-Randomized, Phase II Trial, with a Companion Biomarker Analysis.

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) is an alternative to standard taxanes for breast cancer (BC) treatment. We evaluated nab-Paclitaxel efficacy as neoadjuvant treatment for early estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) disease. MATERIALS AND METHODS: Women with ER+, HER2-, stage II-III BC were treated preoperatively with four cycles of weekly nab-Paclitaxel (150 mg/m2), 3 weeks on and 1 week off. We hypothesized that poor pathological response rate (residual cancer burden [RCB] III; Symmans criteria) would be ≤16%. RESULTS: Eighty-one patients with a median age of 47 years were treated; 64.2% were premenopausal, and 69% of tumors were stage II. Residual cancer burden III rate was 28.4% (95% confidence interval [CI]: 18.6%-38.2%), RCB 0+I (good response) rate was 24.7% (95% CI: 15.3%-34.1%) and RCB 0 (complete response) rate was 7.4% (95% CI: 1.7%-13.1%). Objective response rate by magnetic resonance imaging was 76.5% and rate of conversion to breast conserving surgery was 40.0%. The most frequent grade 3 and 4 toxicity was neutropenia (12.3% and 3.7% of patients, respectively), without any febrile neutropenia. Sensory neuropathy grade 2 and 3 were seen in 25.9% and 2.5% of patients, respectively. Tumor secreted protein, acidic, cysteine-rich (SPARC) overexpression was significantly associated with RCB 0 (odds ratio: 0.079; 95% CI: 0.009-0.689; p = .0216). CONCLUSION: Despite failing to confirm an RCB III rate ≤16% in nab-Paclitaxel-treated patients, the RCB 0+I rate indicates a significant drug antitumor activity with low rates of grade 3-4 toxicity. Our exploratory biomarker analysis suggests a potential predictive role of complete response for SPARC. Confirmatory analyses are warranted, adapting dose and schedule to decrease peripheral neurotoxicity. (Trial registration: European Clinical Trials Database study number: 2011-004476-10; ClinicalTrials.gov: NCT01565499). IMPLICATIONS FOR PRACTICE: The pathological response rate (residual cancer burden [RCB]; Symmans criteria) of nanoparticle albumin-bound paclitaxel administered as neoadjuvant treatment for early estrogen receptor-positive, human epidermal growth factor receptor 2-negative disease was evaluated. Whereas poor response (RCB III) was 24.7%, similar to that for docetaxel, good response (RCB 0+I) reached 23.0%, far superior to the 13% for docetaxel, while keeping toxicity low. Exploratory biomarker analysis suggests secreted protein, acidic, cysteine-rich overexpression in tumor cells as a potential predictor of complete response (RCB 0). Findings point to an encouraging single-agent neoadjuvant treatment with low toxicity, which warrants future research and development.

High Proliferation Predicts Pathological Complete Response to Neoadjuvant Chemotherapy in Early Breast Cancer.

BACKGROUND: In the neoadjuvant setting, changes in the proliferation marker Ki67 are associated with primary endocrine treatment efficacy, but its value as a predictor of response to chemotherapy is still controversial. PATIENTS AND METHODS: We analyzed 262 patients with centralized basal Ki67 immunohistochemical evaluation derived from 4 GEICAM (Spanish Breast Cancer Group) clinical trials of neoadjuvant chemotherapy for breast cancer. The objective was to identify the optimal threshold for Ki67 using the receiver-operating characteristic curve method to maximize its predictive value for chemotherapy benefit. We also evaluated the predictive role of the defined Ki67 cutoffs for molecular subtypes defined by estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). RESULTS: A basal Ki67 cutpoint of 50% predicted pathological complete response (pCR). Patients with Ki67 >50% achieved a pCR rate of 40% (36 of 91) versus a pCR rate of 19% in patients with Ki67 ≤ 50% (33 of 171) (p = .0004). Ki67 predictive value was especially relevant in ER-HER2- and ER-HER2+ patients (pCR rates of 42% and 64%, respectively, in patients with Ki67 >50% versus 15% and 45%, respectively, in patients with Ki67 ≤ 50%; p = .0337 and .3238, respectively). Both multivariate analyses confirmed the independent predictive value of the Ki67 cutpoint of 50%. CONCLUSION: Basal Ki67 proliferation index >50% should be considered an independent predictive factor for pCR reached after neoadjuvant chemotherapy, suggesting that cell proliferation is a phenomenon closely related to chemosensitivity. These findings could help to identify a group of patients with a potentially favorable long-term prognosis. IMPLICATIONS FOR PRACTICE: The use of basal Ki67 status as a predictive factor of chemotherapy benefit could facilitate the identification of a patient subpopulation with high probability of achieving pathological complete response when treated with primary chemotherapy, and thus with a potentially favorable long-term prognosis.

Morality and Intimate Partner Violence: Do Men in Court-Mandated Psychological Treatment Hold a Sacred Moral Vision of the World and Themselves?

This article examines the characterization of men in a court-mandated treatment for violence against their partners as holding a sacred vision of the 5 moral foundations and of their own morality. This characterization is compatible with the assumption that a sacred moral world is easily threatened by reality and that may be associated to violent defensive actions. The results from latent class analyses reveal (a) a 4-class distribution depending exclusively on the intensity with which all participants (violent and nonviolent) tend to sacralize the actions proposed in the Moral Foundations Sacredness Scale and (b) a greater prevalence of the violent participants among the classes that are more prone to sacralize. They also show that they hold an inflated moral vision of themselves: They think they are much more moral than intelligent than others who have never been charged with criminal behavior (Muhammad Ali effect).

Standard versus continuous administration of capecitabine in metastatic breast cancer (GEICAM/2009-05): a randomized, noninferiority phase II trial with a pharmacogenetic analysis.

BACKGROUND: The approved capecitabine regimen as monotherapy in metastatic breast cancer (MBC) is 1,250 mg/m(2) twice daily for 2 weeks on and 1 week off (Cint). Dose modifications are often required because of severe hand-foot syndrome (HFS). We tested a continuous regimen with a lower daily dose but a similar cumulative dose in an attempt to reduce the severity of adverse events (AEs) while maintaining efficacy. METHODS: We randomized 195 patients with HER-2/neu-negative MBC to capecitabine 800 mg/m(2) twice daily throughout the 21-day cycle (Ccont) or to Cint to assess noninferiority in the percentage of patients free of progression at 1 year. Secondary endpoints included efficacy and safety. Associations between polymorphisms in capecitabine metabolism-related genes and drug response were assessed. RESULTS: The percentage of patients free of progression at 1 year was 27.3% with Cint versus 25.3% with Ccont (difference of -2.0%; 95% confidence interval: -15.5% to 11.5%, exceeding the 15% deemed noninferior). Differences regarding other efficacy variables were also not found. Grade 3-4 HFS was the most frequent AE (41.1% in Cint vs. 42.3% in Ccont). Grade 3-4 neutropenia, thrombocytopenia, diarrhea, and stomatitis were more frequent with Cint. A 5' untranslated region polymorphism in the carboxylesterase 2 gene was associated with HFS. One polymorphism in cytidine deaminase and two in thymidine phosphorylase were associated with survival. CONCLUSION: Our study was unable to show noninferiority with the continuous capecitabine regimen (Ccont) compared with the approved intermittent regimen (Cint). Further investigation is required to improve HFS. Polymorphisms in several genes might contribute to interindividual differences in response to capecitabine.

Characterizing visual asymmetries in contrast perception using shaded stimuli.

Previous research has shown a visual asymmetry in shaded stimuli where the perceived contrast depended on the polarity of their dark and light areas (Chacón, 2004). In particular, circles filled out with a top-dark luminance ramp were perceived with higher contrast than top-light ones although both types of stimuli had the same physical contrast. Here, using shaded stimuli, we conducted four experiments in order to find out if the perceived contrast depends on: (a) the contrast level, (b) the type of shading (continuous vs. discrete) and its degree of perceived three-dimensionality, (c) the orientation of the shading, and (d) the sign of the perceived contrast alterations. In all experiments the observers' tasks were to equate the perceived contrast of two sets of elements (usually shaded with opposite luminance polarity), in order to determine the subjective equality point. Results showed that (a) there is a strong difference in perceived contrast between circles filled out with luminance ramp top-dark and top-light that is similar for different contrast levels; (b) we also found asymmetries in contrast perception with different shaded stimuli, and this asymmetry was not related with the perceived three-dimensionality but with the type of shading, being greater for continuous-shading stimuli;