Deep representation learning of tissue metabolome and computed tomography annotates NSCLC classification and prognosis.

The rich chemical information from tissue metabolomics provides a powerful means to elaborate tissue physiology or tumor characteristics at cellular and tumor microenvironment levels. However, the process of obtaining such information requires invasive biopsies, is costly, and can delay clinical patient management. Conversely, computed tomography (CT) is a clinical standard of care but does not intuitively harbor histological or prognostic information. Furthermore, the ability to embed metabolome information into CT to subsequently use the learned representation for classification or prognosis has yet to be described. This study develops a deep learning-based framework -- tissue-metabolomic-radiomic-CT (TMR-CT) by combining 48 paired CT images and tumor/normal tissue metabolite intensities to generate ten image embeddings to infer metabolite-derived representation from CT alone. In clinical NSCLC settings, we ascertain whether TMR-CT results in an enhanced feature generation model solving histology classification/prognosis tasks in an unseen international CT dataset of 742 patients. TMR-CT non-invasively determines histological classes - adenocarcinoma/squamous cell carcinoma with an F1-score = 0.78 and further asserts patients' prognosis with a c-index = 0.72, surpassing the performance of radiomics models and deep learning on single modality CT feature extraction. Additionally, our work shows the potential to generate informative biology-inspired CT-led features to explore connections between hard-to-obtain tissue metabolic profiles and routine lesion-derived image data.

Interval cancer in the Córdoba Breast Tomosynthesis Screening Trial (CBTST): comparison of digital breast tomosynthesis plus digital mammography to digital mammography alone.

PURPOSE: This work aims to compare the interval cancer rate and interval cancer characteristics between women screened with digital breast tomosynthesis (DBT) + digital mammography (DM) and those screened with DM alone. METHODS: The interval cancer rate and interval cancer characteristics of the study population included in the Córdoba Breast Tomosynthesis Screening Trial (CBTST) were compared to a contemporary control population screened with DM. The tumour characteristics of screen-detected and interval cancers were also compared. Contingency tables were used to compare interval cancer rates. The chi-square test and Fisher's exact test were used to compare the qualitative characteristics of the cancers whereas Student's t test and the Mann-Whitney U test were used to analyse quantitative features. RESULTS: A total of 16,068 screening exams with DBT + DM were conducted within the CBTST (mean age 57.59 ± 5.9 [SD]) between January 2015 and December 2016 (study population). In parallel, 23,787 women (mean age 58.89 ± 5.9 standard deviation [SD]) were screened with DM (control population). The interval cancer rate was lower in the study population than in the control population (15 [0.93‰; 95% confidence interval (CI): 0.73, 1.14] vs 43 [1.8‰; 95% CI: 1.58, 2.04] respectively; p = 0.045). The difference in rate was more marked in women with dense breasts (0.95‰ in the study population vs 3.17‰ in the control population; p = 0.031). Interval cancers were smaller in the study population than in the control population (p = 0.031). CONCLUSIONS: The interval cancer rate was lower in women screened with DBT + DM compared to those screened with DM alone. These differences were more pronounced in women with dense breasts. CLINICAL RELEVANCE STATEMENT: Women screened using tomosynthesis and digital mammography had a lower rate of interval cancer than women screened with digital mammography, with the greatest difference in the interval cancer rate observed in women with dense breasts. KEY POINTS: • The interval cancer rate was lower in the study population (digital breast tomosynthesis [DBT] + digital mammography [DM]) than in the control population (DM). • The difference in interval cancer rates was more pronounced in women with dense breasts. • Interval cancers were smaller in the study population (DBT + DM) than in the control population (DM).

Impact of real-life use of artificial intelligence as support for human reading in a population-based breast cancer screening program with mammography and tomosynthesis.

OBJECTIVES: To evaluate the impact of using an artificial intelligence (AI) system as support for human double reading in a real-life scenario of a breast cancer screening program with digital mammography (DM) or digital breast tomosynthesis (DBT). MATERIAL AND METHODS: We analyzed the performance of double reading screening with mammography and tomosynthesis after implementarion of AI as decision support. The study group consisted of a consecutive cohort of 1 year screening between March 2021 and March 2022 where double reading was performed with concurrent AI support that automatically detects and highlights lesions suspicious of breast cancer in mammography and tomosynthesis. Screening performance was measured as cancer detection rate (CDR), recall rate (RR), and positive predictive value (PPV) of recalls. Performance in the study group was compared using a McNemar test to a control group that included a screening cohort of the same size, recorded just prior to the implementation of AI. RESULTS: A total of 11,998 women (mean age 57.59 years ± 5.8 [sd]) were included in the study group (5049 DM and 6949 DBT). Comparing global results (including DM and DBT) of double reading with vs. without AI support, we observed an increase in CDR, PPV, and RR by 3.2/‰ (5.8 vs. 9; p < 0.001), 4% (10.6 vs. 14.6; p < 0.001), and 0.7% (5.4 vs. 6.1; p < 0.001) respectively. CONCLUSION: AI used as support for human double reading in a real-life breast cancer screening program with DM and DBT increases CDR and PPV of the recalled women. CLINICAL RELEVANCE STATEMENT: Artificial intelligence as support for human double reading improves accuracy in a real-life breast cancer screening program both in digital mammography and digital breast tomosynthesis. KEY POINTS: • AI systems based on deep learning technology offer potential for improving breast cancer screening programs. • Using artificial intelligence as support for reading improves radiologists' performance in breast cancer screening programs with mammography or tomosynthesis. • Artificial intelligence used concurrently with human reading in clinical screening practice increases breast cancer detection rate and positive predictive value of the recalled women.

Preoperative breast MRI positively impacts surgical outcomes of needle biopsy-diagnosed pure DCIS: a patient-matched analysis from the MIPA study.

OBJECTIVES: To investigate the influence of preoperative breast MRI on mastectomy and reoperation rates in patients with pure ductal carcinoma in situ (DCIS). METHODS: The MIPA observational study database (7245 patients) was searched for patients aged 18-80 years with pure unilateral DCIS diagnosed at core needle or vacuum-assisted biopsy (CNB/VAB) and planned for primary surgery. Patients who underwent preoperative MRI (MRI group) were matched (1:1) to those who did not receive MRI (noMRI group) according to 8 confounding covariates that drive referral to MRI (age; hormonal status; familial risk; posterior-to-nipple diameter; BI-RADS category; lesion diameter; lesion presentation; surgical planning at conventional imaging). Surgical outcomes were compared between the matched groups with nonparametric statistics after calculating odds ratios (ORs). RESULTS: Of 1005 women with pure unilateral DCIS at CNB/VAB (507 MRI group, 498 noMRI group), 309 remained in each group after matching. First-line mastectomy rate in the MRI group was 20.1% (62/309 patients, OR 2.03) compared to 11.0% in the noMRI group (34/309 patients, p = 0.003). The reoperation rate was 10.0% in the MRI group (31/309, OR for reoperation 0.40) and 22.0% in the noMRI group (68/309, p < 0.001), with a 2.53 OR of avoiding reoperation in the MRI group. The overall mastectomy rate was 23.3% in the MRI group (72/309, OR 1.40) and 17.8% in the noMRI group (55/309, p = 0.111). CONCLUSIONS: Compared to those going directly to surgery, patients with pure DCIS at CNB/VAB who underwent preoperative MRI had a higher OR for first-line mastectomy but a substantially lower OR for reoperation. CLINICAL RELEVANCE STATEMENT: When confounding factors behind MRI referral are accounted for in the comparison of patients with CNB/VAB-diagnosed pure unilateral DCIS, preoperative MRI yields a reduction of reoperations that is more than twice as high as the increase in overall mastectomies. KEY POINTS: • Confounding factors cause imbalance when investigating the influence of preoperative MRI on surgical outcomes of pure DCIS. • When patient matching is applied to women with pure unilateral DCIS, reoperation rates are significantly reduced in women who underwent preoperative MRI. • The reduction of reoperations brought about by preoperative MRI is more than double the increase in overall mastectomies.

Screening and diagnostic breast MRI: how do they impact surgical treatment? Insights from the MIPA study.

OBJECTIVES: To report mastectomy and reoperation rates in women who had breast MRI for screening (S-MRI subgroup) or diagnostic (D-MRI subgroup) purposes, using multivariable analysis for investigating the role of MRI referral/nonreferral and other covariates in driving surgical outcomes. METHODS: The MIPA observational study enrolled women aged 18-80 years with newly diagnosed breast cancer destined to have surgery as the primary treatment, in 27 centres worldwide. Mastectomy and reoperation rates were compared using non-parametric tests and multivariable analysis. RESULTS: A total of 5828 patients entered analysis, 2763 (47.4%) did not undergo MRI (noMRI subgroup) and 3065 underwent MRI (52.6%); of the latter, 2441/3065 (79.7%) underwent MRI with preoperative intent (P-MRI subgroup), 510/3065 (16.6%) D-MRI, and 114/3065 S-MRI (3.7%). The reoperation rate was 10.5% for S-MRI, 8.2% for D-MRI, and 8.5% for P-MRI, while it was 11.7% for noMRI (p ≤ 0.023 for comparisons with D-MRI and P-MRI). The overall mastectomy rate (first-line mastectomy plus conversions from conserving surgery to mastectomy) was 39.5% for S-MRI, 36.2% for P-MRI, 24.1% for D-MRI, and 18.0% for noMRI. At multivariable analysis, using noMRI as reference, the odds ratios for overall mastectomy were 2.4 (p < 0.001) for S-MRI, 1.0 (p = 0.957) for D-MRI, and 1.9 (p < 0.001) for P-MRI. CONCLUSIONS: Patients from the D-MRI subgroup had the lowest overall mastectomy rate (24.1%) among MRI subgroups and the lowest reoperation rate (8.2%) together with P-MRI (8.5%). This analysis offers an insight into how the initial indication for MRI affects the subsequent surgical treatment of breast cancer. KEY POINTS: • Of 3065 breast MRI examinations, 79.7% were performed with preoperative intent (P-MRI), 16.6% were diagnostic (D-MRI), and 3.7% were screening (S-MRI) examinations. • The D-MRI subgroup had the lowest mastectomy rate (24.1%) among MRI subgroups and the lowest reoperation rate (8.2%) together with P-MRI (8.5%). • The S-MRI subgroup had the highest mastectomy rate (39.5%) which aligns with higher-than-average risk in this subgroup, with a reoperation rate (10.5%) not significantly different to that of all other subgroups.

A cannabidiol aminoquinone derivative activates the PP2A/B55α/HIF pathway and shows protective effects in a murine model of traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is characterized by a primary mechanical injury and a secondary injury associated with neuroinflammation, blood-brain barrier (BBB) disruption and neurodegeneration. We have developed a novel cannabidiol aminoquinone derivative, VCE-004.8, which is a dual PPARγ/CB2 agonist that also activates the hypoxia inducible factor (HIF) pathway. VCE-004.8 shows potent antifibrotic, anti-inflammatory and neuroprotective activities and it is now in Phase II clinical trials for systemic sclerosis and multiple sclerosis. Herein, we investigated the mechanism of action of VCE-004.8 in the HIF pathway and explored its efficacy in a preclinical model of TBI. METHODS: Using a phosphoproteomic approach, we investigated the effects of VCE-004.8 on prolyl hydroxylase domain-containing protein 2 (PHD2) posttranslational modifications. The potential role of PP2A/B55α in HIF activation was analyzed using siRNA for B55α. To evaluate the angiogenic response to the treatment with VCE-004.8 we performed a Matrigel plug in vivo assay. Transendothelial electrical resistance (TEER) as well as vascular cell adhesion molecule 1 (VCAM), and zonula occludens 1 (ZO-1) tight junction protein expression were studied in brain microvascular endothelial cells. The efficacy of VCE-004.8 in vivo was evaluated in a controlled cortical impact (CCI) murine model of TBI. RESULTS: Herein we provide evidence that VCE-004.8 inhibits PHD2 Ser125 phosphorylation and activates HIF through a PP2A/B55α pathway. VCE-004.8 induces angiogenesis in vivo increasing the formation of functional vessel (CD31/α-SMA) and prevents in vitro blood-brain barrier (BBB) disruption ameliorating the loss of ZO-1 expression under proinflammatory conditions. In CCI model VCE-004.8 treatment ameliorates early motor deficits after TBI and attenuates cerebral edema preserving BBB integrity. Histopathological analysis revealed that VCE-004.8 treatment induces neovascularization in pericontusional area and prevented immune cell infiltration to the brain parenchyma. In addition, VCE-004.8 attenuates neuroinflammation and reduces neuronal death and apoptosis in the damaged area. CONCLUSIONS: This study provides new insight about the mechanism of action of VCE-004.8 regulating the PP2A/B55α/PHD2/HIF pathway. Furthermore, we show the potential efficacy for TBI treatment by preventing BBB disruption, enhancing angiogenesis, and ameliorating neuroinflammation and neurodegeneration after brain injury.

Stand-Alone Use of Artificial Intelligence for Digital Mammography and Digital Breast Tomosynthesis Screening: A Retrospective Evaluation.

Background Use of artificial intelligence (AI) as a stand-alone reader for digital mammography (DM) or digital breast tomosynthesis (DBT) breast screening could ease radiologists' workload while maintaining quality. Purpose To retrospectively evaluate the stand-alone performance of an AI system as an independent reader of DM and DBT screening examinations. Materials and Methods Consecutive screening-paired and independently read DM and DBT images acquired between January 2015 and December 2016 were retrospectively collected from the Tomosynthesis Cordoba Screening Trial. An AI system computed a cancer risk score (range, 1-100) for DM and DBT examinations independently. AI stand-alone performance was measured using the area under the receiver operating characteristic curve (AUC) and sensitivity and recall rate at different operating points selected to have noninferior sensitivity compared with the human readings (noninferiority margin, 5%). The recall rate of AI and the human readings were compared using a McNemar test. Results A total of 15 999 DM and DBT examinations (113 breast cancers, including 98 screen-detected and 15 interval cancers) from 15 998 women (mean age, 58 years ± 6 [standard deviation]) were evaluated. AI achieved an AUC of 0.93 (95% CI: 0.89, 0.96) for DM and 0.94 (95% CI: 0.91, 0.97) for DBT. For DM, AI achieved noninferior sensitivity as a single (58.4%; 66 of 113; 95% CI: 49.2, 67.1) or double (67.3%; 76 of 113; 95% CI: 58.2, 75.2) reader, with a reduction in recall rate (P < .001) of up to 2% (95% CI: -2.4, -1.6). For DBT, AI achieved noninferior sensitivity as a single (77%; 87 of 113; 95% CI: 68.4, 83.8) or double (81.4%; 92 of 113; 95% CI: 73.3, 87.5) reader, but with a higher recall rate (P < .001) of up to 12.3% (95% CI: 11.7, 12.9). Conclusion Artificial intelligence could replace radiologists' readings in breast screening, achieving a noninferior sensitivity, with a lower recall rate for digital mammography but a higher recall rate for digital breast tomosynthesis. Published under a CC BY 4.0 license. See also the editorial by Fuchsjäger and Adelsmayr in this issue.

Magnetic resonance imaging before breast cancer surgery: results of an observational multicenter international prospective analysis (MIPA).

OBJECTIVES: Preoperative breast magnetic resonance imaging (MRI) can inform surgical planning but might cause overtreatment by increasing the mastectomy rate. The Multicenter International Prospective Analysis (MIPA) study investigated this controversial issue. METHODS: This observational study enrolled women aged 18-80 years with biopsy-proven breast cancer, who underwent MRI in addition to conventional imaging (mammography and/or breast ultrasonography) or conventional imaging alone before surgery as routine practice at 27 centers. Exclusion criteria included planned neoadjuvant therapy, pregnancy, personal history of any cancer, and distant metastases. RESULTS: Of 5896 analyzed patients, 2763 (46.9%) had conventional imaging only (noMRI group), and 3133 (53.1%) underwent MRI that was performed for diagnosis, screening, or unknown purposes in 692/3133 women (22.1%), with preoperative intent in 2441/3133 women (77.9%, MRI group). Patients in the MRI group were younger, had denser breasts, more cancers ≥ 20 mm, and a higher rate of invasive lobular histology than patients who underwent conventional imaging alone (p < 0.001 for all comparisons). Mastectomy was planned based on conventional imaging in 22.4% (MRI group) versus 14.4% (noMRI group) (p < 0.001). The additional planned mastectomy rate in the MRI group was 11.3%. The overall performed first- plus second-line mastectomy rate was 36.3% (MRI group) versus 18.0% (noMRI group) (p < 0.001). In women receiving conserving surgery, MRI group had a significantly lower reoperation rate (8.5% versus 11.7%, p < 0.001). CONCLUSIONS: Clinicians requested breast MRI for women with a higher a priori probability of receiving mastectomy. MRI was associated with 11.3% more mastectomies, and with 3.2% fewer reoperations in the breast conservation subgroup. KEY POINTS: • In 19% of patients of the MIPA study, breast MRI was performed for screening or diagnostic purposes. • The current patient selection to preoperative breast MRI implies an 11% increase in mastectomies, counterbalanced by a 3% reduction of the reoperation rate. • Data from the MIPA study can support discussion in tumor boards when preoperative MRI is under consideration and should be shared with patients to achieve informed decision-making.

AI-based Strategies to Reduce Workload in Breast Cancer Screening with Mammography and Tomosynthesis: A Retrospective Evaluation.

Background The workflow of breast cancer screening programs could be improved given the high workload and the high number of false-positive and false-negative assessments. Purpose To evaluate if using an artificial intelligence (AI) system could reduce workload without reducing cancer detection in breast cancer screening with digital mammography (DM) or digital breast tomosynthesis (DBT). Materials and Methods Consecutive screening-paired and independently read DM and DBT images acquired from January 2015 to December 2016 were retrospectively collected from the Córdoba Tomosynthesis Screening Trial. The original reading settings were single or double reading of DM or DBT images. An AI system computed a cancer risk score for DM and DBT examinations independently. Each original setting was compared with a simulated autonomous AI triaging strategy (the least suspicious examinations for AI are not human-read; the rest are read in the same setting as the original, and examinations not recalled by radiologists but graded as very suspicious by AI are recalled) in terms of workload, sensitivity, and recall rate. The McNemar test with Bonferroni correction was used for statistical analysis. Results A total of 15 987 DM and DBT examinations (which included 98 screening-detected and 15 interval cancers) from 15 986 women (mean age ± standard deviation, 58 years ± 6) were evaluated. In comparison with double reading of DBT images (568 hours needed, 92 of 113 cancers detected, 706 recalls in 15 987 examinations), AI with DBT would result in 72.5% less workload (P < .001, 156 hours needed), noninferior sensitivity (95 of 113 cancers detected, P = .38), and 16.7% lower recall rate (P < .001, 588 recalls in 15 987 examinations). Similar results were obtained for AI with DM. In comparison with the original double reading of DM images (222 hours needed, 76 of 113 cancers detected, 807 recalls in 15 987 examinations), AI with DBT would result in 29.7% less workload (P < .001), 25.0% higher sensitivity (P < .001), and 27.1% lower recall rate (P < .001). Conclusion Digital mammography and digital breast tomosynthesis screening strategies based on artificial intelligence systems could reduce workload up to 70%. Published under a CC BY 4.0 license.

Solving the preoperative breast MRI conundrum: design and protocol of the MIPA study.

Despite its high diagnostic performance, the use of breast MRI in the preoperative setting is controversial. It has the potential for personalized surgical management in breast cancer patients, but two of three randomized controlled trials did not show results in favor of its introduction for assessing the disease extent before surgery. Meta-analyses showed a higher mastectomy rate in women undergoing preoperative MRI compared to those who do not. Nevertheless, preoperative breast MRI is increasingly used and a survey from the American Society of Breast Surgeons showed that 41% of respondents ask for it in daily practice. In this context, a large-scale observational multicenter international prospective analysis (MIPA study) was proposed under the guidance of the European Network for the Assessment of Imaging in Medicine (EuroAIM). The aims were (1) to prospectively and systematically collect data on consecutive women with a newly diagnosed breast cancer, not candidates for neoadjuvant therapy, who are offered or not offered breast MRI before surgery according to local practice; (2) to compare these two groups in terms of surgical and clinical endpoints, adjusting for covariates. The underlying hypotheses are that MRI does not cause additional mastectomies compared to conventional imaging, while reducing the reoperation rate in all or in subgroups of patients. Ninety-six centers applied to a web-based call; 36 were initially selected based on volume and quality standards; 27 were active for enrollment. On November 2018, the target of 7000 enrolled patients was reached. The MIPA study is presently at the analytic phase. Key Points • Breast MRI has a high diagnostic performance but its utility in the preoperative setting is controversial. • A large-scale observational multicenter prospective study was launched to compare women receiving with those not receiving preoperative MRI. • Twenty-seven centers enrolled more than 7000 patients. The study is presently at the analytic phase.

Prospective study aiming to compare 2D mammography and tomosynthesis + synthesized mammography in terms of cancer detection and recall. From double reading of 2D mammography to single reading of tomosynthesis.

OBJECTIVES: To evaluate tomosynthesis compared with 2D-mammography in cancer detection and recalls in a screening-programme, and assess performing synthesized instead of 2D, and compare double reading of 2D with single reading of tomosynthesis. METHODS: Women (age 50-69 years) participating in the screening-programme were included. 2D-mammography and tomosynthesis were performed. There were four reading models: 2D-mammography (first); 2D-mammography (second); tomosynthesis + synthesized (third); tomosynthesis + synthesized + 2D (fourth reading). Paired double reading of 2D (first+second) and tomosynthesis (third+fourth) were analysed. RESULTS: In 16,067 participants, there were 98 cancers and 1,196 recalls. Comparing double reading of 2D with single reading of tomosynthesis, there was an increase of 12.6 % in cancer detection with the third reading (p= 0.043) and 6.9 % with the fourth reading (p=0.210), and a decrease in recalls of 40.5 % (p<0.001) and 44.4 % (p<0.001), respectively. With double reading of both techniques, there was an increase in cancer detection of 17.4 % (p = 0.004) and a decrease in recalls of 12.5 % (p = 0.001) with tomosynthesis. CONCLUSION: Single reading of tomosynthesis plus synthesized increased cancer detection and decreased recalls compared with double reading 2D. 2D did not improve results when added to tomosynthesis. KEY POINTS: • Tomosynthesis increases cancer detection and decreases recall rates versus 2D mammography. • Synthesized-mammography avoids performing 2D, showing higher cancer detection. • Single reading of tomosynthesis + synthesized is feasible as a new practice.

Breast cancer is associated to impaired glucose/insulin homeostasis in premenopausal obese/overweight patients.

The association between breast cancer (BCa) presence and altered glucose/insulin metabolism is controversial likely due to an inaccurate insulin resistance (IR) assessment and inappropriate stratification of patients by body-mass index (BMI) and menopausal state. 148 women with suspect of sporadic BCa were stratified by BMI and menopause. Fasting levels of glucose, insulin, glycohemoglobin and selected IR-related and tumor-derived markers were measured. Glucose/insulin levels during OGTT were used to calculate insulin resistance/sensitivity indexes. Analysis of 77 BCa-bearing patients and 71 controls showed an association between BCa and IR as demonstrated by impaired glucose/insulin homeostasis (increased fasting- and OGTT-induced glucose levels) and deteriorated IR indexes, which was especially patent in premenopausal women. The association between BCa presence and IR was markedly influenced by BMI, being obese BCa patients significantly more insulin resistant than controls. BCa presence was associated to elevated levels of IR (glucose, triglycerides) and tumor-derived (VEGF) markers, especially in overweight/obese patients. BCa presence is associated to IR in overweight/obese premenopausal but not in premenopausal normal weight or postmenopausal women. Our data support a bidirectional relationship between dysregulated/imbalanced glucose/insulin metabolism and BCa, as tumor- and IR-markers are correlated with the impairment of glucose/insulin metabolism in overweight/obese premenopausal BCa patients.

Factors Associated With Disease Recurrence in Breast Cancer Patients With Negative Sentinel Lymph Node Biopsy.

INTRODUCTION: The objective of our study was to assess recurrence after negative sentinel lymph node biopsy (SLNB) and to determine the risk factors related to local and distant recurrence in this group of patients. MATERIALS AND METHODS: We conducted a prospective observational study from 2006 to 2011. It included 607 patients with early-stage breast cancer and negative SLNB with a 5-year follow-up period. RESULTS: The disease-free survival rate was 98.5% and 96.5% at 2 and 5 years, respectively. Multivariate analysis identified the following prognostic factors for disease recurrence: tumor necrosis (hazard ratio [HR], 4.89; 95% confidence interval [CI], 1.61-14.89; P = .005), lymphovascular invasion (HR, 3.46; 95% CI, 1.14-10.55; P = .029), T2 tumor size (HR, 4.35; 95% CI, 1.40-13.52; P = .011), and moderate to severe lymphoplasmacytic stromal infiltration (HR, 3.06; 95% CI, 1.18-7.96; P = .022). CONCLUSION: Recurrence in patients with negative SLNB was satisfactorily low. Nevertheless, determining the prognostic factors related to a greater recurrence rate could help identify high-risk patients and influence systemic adjuvant therapy.

Lack of cortistatin or somatostatin differentially influences DMBA-induced mammary gland tumorigenesis in mice in an obesity-dependent mode.

BACKGROUND: Somatostatin (SST) and cortistatin (CORT), two structurally and functionally related peptides, share a family of widespread receptors (sst1-5) to exert apparently similar biological actions, including endocrine/metabolic regulation and suppression of tumor cell proliferation. However, despite their therapeutic potential, attempts to apply SST-analogs to treat breast cancer have yielded unsatisfactory results. Actually, the specific roles of SST and CORT in mammary gland tumorigenesis (MGT), particularly in relation to metabolic dysregulation (i.e. obesity), remain unknown. METHODS: The role of endogenous SST and CORT in carcinogen-induced MGT was investigated under normal (lean) and obesity conditions. To that end, SST- and CORT-knockout (KO) mice and their respective littermate-controls, fed low-fat (LF) or high-fat (HF) diets, were treated with 7,12-dimethyl-benza-anthracene (DMBA) once a week (wk) for 3 wk, and MGT was monitored for 25 wk. Additionally, we examined the effect of SST or CORT removal in the development of the mammary gland. RESULTS: Lack of SST did not alter DMBA-induced MGT incidence under lean conditions; conversely, lack of endogenous CORT severely aggravated DMBA-induced MGT in LF-fed mice. These differences were not attributable to altered mammary gland development. HF-diet modestly increased the sensitivity to DMBA-induced carcinogenesis in control mice, whereas, as observed in LF-fed CORT-KO, HF-fed CORT-KO mice exhibited aggravated tumor incidence, discarding a major influence of obesity on these CORT actions. In marked contrast, HF-fed SST-KO mice exhibited much higher tumor incidence than LF-fed SST-KO mice, which could be associated with higher mammary complexity. CONCLUSIONS: Endogenous SST and CORT distinctly impact on DMBA-induced MGT, in a manner that is strongly dependent on the metabolic/endocrine milieu (lean vs. obese status). Importantly, CORT, rather than SST, could represent a major inhibitor of MGT under normal/lean-conditions, whereas both neuropeptides would similarly influence MGT under obesity conditions. The mechanisms mediating these different effects likely involve mammary development and hormones, but the precise underlying factors are still to be fully elucidated. However, our findings comprise suggestive evidence that CORT-like molecules, rather than classic SST-analogs, may help to identify novel tools for the medical treatment of breast cancer.

Obesity alters gene expression for GH/IGF-I axis in mouse mammary fat pads: differential role of cortistatin and somatostatin.

Locally produced growth hormone (GH) and IGF-I are key factors in the regulation of mammary gland (MG) development and may be important in breast cancer development/progression. Somatostatin (SST) and cortistatin (CORT) regulate GH/IGF-I axis at various levels, but their role in regulating GH/IGF-I in MGs remains unknown. Since obesity alters the expression of these systems in different tissues and is associated to MG (patho) physiology, we sought to investigate the role of SST/CORT in regulating GH/IGF-I system in the MGs of lean and obese mice. Therefore, we analyzed GH/IGF-I as well as SST/CORT and ghrelin systems expression in the mammary fat pads (MFPs) of SST- or CORT-knockout (KO) mice and their respective littermate-controls fed a low-fat (LF) or a high-fat (HF) diet for 16 wks. Our results demonstrate that the majority of the components of GH/IGF-I, SST/CORT and ghrelin systems are locally expressed in mouse MFP. Expression of elements of the GH/IGF-I axis was significantly increased in MFPs of HF-fed control mice while lack of endogenous SST partially suppressed, and lack of CORT completely blunted, the up-regulation observed in obese WT-controls. Since SST/CORT are known to exert an inhibitory role on the GH/IGFI axis, the increase in SST/CORT-receptor sst2 expression in MFPs of HF-fed CORT- and SST-KOs together with an elevation on circulating SST in CORT-KOs could explain the differences observed. These results offer new information on the factors (GH/IGF-I axis) involved in the endocrine/metabolic dysregulation of MFPs in obesity, and suggest that CORT is not a mere SST sibling in regulating MG physiology.

Endothelial damage and vascular calcification in patients with chronic kidney disease.

Vascular calcification (VC) is a frequent complication of chronic kidney disease (CKD) and is a predictor of cardiovascular morbidity and mortality. In the present study, we investigated the potential involvement of endothelial microparticles (MPs) and endothelial progenitor cells (EPCs) in the generation of VC in CKD patients. The number of circulating EMPs is greater in patients with VC than without VC (307 ± 167 vs. 99 ± 75 EMPs/µl, P < 0.001). The percentage of EPCs is significantly lower in patient with VC than in patients without VC (0.14 ± 0.11% vs. 0.25 ± 0.18%, P = 0.002). The number of EPCs expressing osteocalcin (OCN) was higher in VC patients (349 ± 63 cells/100,000) than in non-VC patients (139 ± 75 cells/100,000, P < 0.01). In vitro, MPs obtained from CKD patients were able to induce OCN expression in EPCs from healthy donors; the increase in OCN expression was more accentuated if MPs were obtained from CKD patients with VC. MPs from CKD patients also induced OCN expression in vascular smooth muscle cells and fibroblasts. In CKD patients, the rise in endothelial MPs associated with a decrease in the number of EPCs, suggesting an imbalance in the processes of endothelial damage and repair in CKD patients, mainly those with VC. Our results suggest that EPCs, through OCN expression, may directly participate in the process of VC.

Effectiveness of an absorbable fibrin sealant patch to reduce lymphoceles formation after axillary lymphadenectomy for breast cancer: a matched-pair analysis.

BACKGROUND: This study evaluated the use of TachoSil as an adjunctive therapy for reducing axillary lymphocele formation. METHODS: Eighty-six patients diagnosed with breast cancer N+ and treated with axillary lymphadenectomy received a TachoSil patch in the axillary wound. Using a database of patients without placing a hemostatic patch, we applied a matched case-control in a 1-to-2 fashion. Multiple and logistic regression analyses were used to evaluate postoperative results. RESULTS: Patient group with TachoSil showed a significantly lower drainage volume (P < .001) and the length of stay was significantly shorter (P < .001). The number of patients with evacuative punctures was 24.5% in the group with patch versus 51.2% in the control group (P < .001). In multivariate analysis, the use of TachoSil was a significant predictor of reducing axillary drainage volume (P < .001), mean length of hospital stay (P = .001), and number of evacuative punctures of lymphocele (odds ratio .264, 95% confidence interval .144 to .484, P < .001). CONCLUSION: The use of TachoSil in axillary lymphadenectomy may be a safe and useful treatment option for reducing axillary drainage volume, incidence of symptomatic lymphocele, and hospital stay.

Consenso sobre la biopsia selectiva del ganglio centinela en el cáncer de mama. Revisión 2013 de la Sociedad Española de Senología y Patología Mamaria / Consensus on sentinel lymph node biopsy in breast cancer. Review of the Spanish Society of Senology and Breast Pathology 2013

La biopsia selectiva del ganglio centinela es una técnica diagnóstica aceptada como el procedimiento de elección para la estadificación axilar del cáncer de mama. En este documento, correspondiente a la última Reunión de Consenso celebrada en Valencia y organizada por la Sociedad Española de Senología y Patología Mamaria, se actualizan los consensos previos y se reflejan las conclusiones acerca de las últimas propuestas en el manejo del ganglio centinela en el cáncer de mama (AU)

Sentinel lymph node biopsy is currently a widely accepted diagnostic technique and is the procedure of choice for axillary staging of breast cancer. In this article, following the latest Consensus Meeting held in Valencia organized by the Spanish Society of Senology and Breast Pathology, previous consensus are updated. Also discussed are conclusions related to the latest trends in the management of the sentinel node in breast cancer (AU)