From free-text electronic health records to structured cohorts: Onconum, an innovative methodology for real-world data mining in breast cancer.

PURPOSE: A considerable amount of valuable information is present in electronic health records (EHRs) however it remains inaccessible because it is embedded into unstructured narrative documents that cannot be easily analyzed. We wanted to develop and evaluate a methodology able to extract and structure information from electronic health records in breast cancer. METHODS: We developed a software platform called Onconum (ClinicalTrials.gov Identifier: NCT02810093) which uses a hybrid method relying on machine learning approaches and rule-based lexical methods. It is based on natural language processing techniques that allows a targeted analysis of free-text medical data related to breast cancer, independently of any pre-existing dictionary, in a French context (available in N files). We then evaluated it on a validation cohort called Senometry. FINDINGS: Senometry cohort included 9,599 patients with breast cancer (both invasive and in situ), treated between 2000 and 2017 in the breast cancer unit of Strasbourg University Hospitals. Extraction rates ranged from 45 to 100%, depending on the type of each parameter. Precision of extracted information was 68%-94% compared to a structured cohort, and 89%-98% compared to manually structured databases and it retrieved more rare occurrences compared to another database search engine (+17%). INTERPRETATION: This innovative method can accurately structure relevant medical information embedded in EHRs in the context of breast cancer. Missing data handling is the main limitation of this method however multiple sources can be incorporated to reduce this limit. Nevertheless, this methodology does not need neither pre-existing dictionaries nor manually annotated corpora. It can therefore be easily implemented in non-English-speaking countries and in other diseases outside breast cancer, and it allows prospective inclusion of new patients.

Correlation between daily life aluminium exposure and breast cancer risk: A systematic review.

BACKGROUND: Epidemiological data indicate that the role of environmental factors on breast cancer (BC) incidence remains undetermined. Our daily life exposure to aluminium (Al) is suspected to influence BC development. This review proposes a state of the art on the association between Al and BC risk combined with a critical point of view on the subject. METHODS: We searched the PubMed database using terms related to Al and BC up to November 18, 2022. Reports were eligible if they were cohort or case-control studies or meta-analyses. FINDINGS: Six studies focused on the relationship between deodorant and antiperspirant use and BC incidence and didn't produce consistent results. Among 13 studies relating Al content in mammary tissues and BC risk, results are not unanimous to validate higher Al content in tumor tissues compared to healthy ones. We detail parameters that could explain this conclusion: the absence of statistical adjustments on BC risk factors in studies, the confusion between deodorant and antiperspirant terms, the non-assessment of global Al exposure, and the focus on Al in mammary tissues whereas a profile of several metals seems more appropriate. The clinical studies are retrospective. They were carried out on small cohorts and without a long follow-up. On the other hand, studies on cell lines have shown the carcinogenic potential of aluminum. Moreover, studies considered BC as a unique group whereas BC is a heterogeneous disease with multiple tumor subtypes determining the tumor aggressiveness. CONCLUSION: In light of the precautionary principle and based on the data obtained, it is better to avoid antiperspirants that contain Al. Deodorants without aluminum are not implicated in breast cancer, either clinically or fundamentally.

STARD3: A New Biomarker in HER2-Positive Breast Cancer.

Pathological complete response (pCR) after neoadjuvant systemic treatment (NST) is an important prognostic factor in HER2-positive breast cancer. The majority of HER2-positive breast cancers are amplified at the HER2 gene locus, several genes are co-amplified with HER2, and a subset of them are co-expressed. The STARD3 gene belongs to the HER2 amplicon, and its role as a predictive marker was never addressed. The objective of this study was to investigate the predictive value of STARD3 protein expression on NST pathological response in HER2-positive breast cancer. In addition, we studied the prognostic value of this marker. METHODS: We conducted a retrospective study between 2007 and 2020 on 112 patients with non-metastatic HER2-positive breast cancer treated by NST and then by surgery. We developed an immunohistochemistry assay for STARD3 expression and subcellular localization and determined a score for STARD3-positivity. As STARD3 is an endosomal protein, its expression was considered positive if the intracellular signal pattern was granular. RESULTS: In this series, pCR was achieved in half of the patients. STARD3 was positive in 86.6% of cases and was significantly associated with pCR in univariate analysis (p = 0.013) and after adjustment on other known pathological parameters (p = 0.044). Performances on pCR prediction showed high sensitivity (96%) and negative predictive value (87%), while specificity was 23% and positive predictive value was 56%. Overall, specific, relapse-free, and distant metastasis-free survivals were similar among STARD3 positive and negative groups, independently of other prognosis factors. CONCLUSION: NST is an opportunity for HER2-positive cancers. In this series of over a hundred HER2-positive and non-metastatic patients, a STARD3-negative score was associated with the absence of pathological complete response. This study suggests that determining STARD3 overexpression status on initial biopsies of HER2-positive tumors is an added value for the management of a subset of patients with high probability of no pathological response.

Innovative approach to lymphadenectomy in breast sarcoma.

Lymphatic dissemination is thought to be a rare event in breast sarcomas. The decision to perform axillary clearance is challenging. In our prospective cohort, we aimed to evaluate the frequency and factors determining lymph node (LN) involvement in breast sarcomas, with the aim of proposing a decision tree/algorithm for the realization of LN clearance in breast sarcomas. PATIENTS AND METHODS: Fourty-five women were surgically treated for breast sarcomas from 1982 to 2020. Angiosarcomas and other sarcomas were compared in terms of LN involvement, recurrence, and mortality. RESULTS: Twenty-three patients underwent axillary lymphadenectomy. Initial LN involvement was diagnosed in one case of D2-40 positive, primary angiosarcoma for which preoperative imaging detected a suspicious LN confirmed by preoperative histology. Among the 22 patients who had no initial axillary lymphadenectomy, two patients with D2-40 positive angiosarcoma had recurrent cancer in LN (internal mammary group in 1 and homolateral axilla in 1). The average follow-up in the overall population was 6.2 years (±8.3). The cohort's overall recurrence rate was 33% (15/45) and the time of recurrence after initial surgery was on average 2.4 years (±3.1). For the three patients with LN metastases, time to recurrence after surgery was 3.7 years (±4.5). There was no significant difference in the overall recurrence rate depending on whether or not lymphadenectomy was initially performed (respectively 26% vs 41% OR=1.11, P=0.29). DISCUSSION/CONCLUSION: Systematic axillary clearance leads to overtreatment in breast sarcomas. A decision tree, including radiological examination of the axilla, histological type of sarcoma, and D2-40 positivity, could be a decision aid in the choice of axillary clearance.

Protective role of melatonin in breast cancer: what we can learn from women with blindness.

PURPOSE: This review proposes an overall vision of the protective and therapeutic role of melatonin in breast cancer: from the specific cases of blind women and their reduction of breast cancer incidence to all clinical uses of the sleep hormone in breast cancer. METHODS: We reviewed studies focused on (1) the correlation between blindness and breast cancer, (2) the correlation between melatonin and breast cancer occurrence in the general population, (3) melatonin therapeutic use in breast cancer, and (4) we discussed the properties of melatonin that could explain an anticancer effect. RESULTS: (1) Seven studies of breast cancer risk in blind women related significant incidence decreases, up to 57%, among totally blind women. The limited number of studies and the absence of adjustment for confounding factors in most studies limit conclusions. None of these studies established melatonin profiles to determine whether blind women with a decreased breast cancer incidence produced higher levels of melatonin. (2) In the general population, 5 meta-analyses and 12 prospective-cohort studies focused on melatonin levels at recruitment and breast cancer occurrence. All reported the absence of correlation in premenopausal women, whereas in postmenopausal women, most studies showed significantly decreased risk for women with highest melatonin levels. (3) The therapeutic interest of melatonin associated with chemotherapy, radiotherapy, and hormonotherapy is poorly documented in breast cancer to conclude on a positive effect. (4) Melatonin effects on mammary carcinogenesis were only reported in in vitro and animal studies that demonstrated antiestrogenic, antioxidant, oncostatic, and immunomodulatory properties. CONCLUSION: The preventive role of high endogenous melatonin on breast cancer as well as its beneficial therapeutic use remains to be proven.

Coffee consumption and breast cancer risk: a narrative review in the general population and in different subtypes of breast cancer.

PURPOSE: Most of the existing literature reports no association or a slight negative association between coffee consumption and the risk of developing breast cancer. However, the level of risk differs when considering various subgroups, such as menopausal status, hormonal status of the tumor or genetic mutations. The present review based on a literature search sets the point on the potential influence of a common daily drink, coffee, on the risk of developing breast cancer in the general population, in different subgroups of women and the consequences of drinking coffee after breast cancer has been diagnosed and treated. RESULTS: This review confirms that in the general population, there is no association between coffee intake and breast cancer risk or a slight protective effect, even at high dosages. Coffee is inversely associated with breast cancer risk in postmenopausal women and in women carrying a BRCA1 mutation. Possible risk differences exist between slow and fast caffeine metabolizers and with weight. Coffee consumption after breast cancer diagnosis and surgery, associated with tamoxifen and/or radiotherapy, reduced the occurrence of early events. The effects of coffee intake are less clear in other subgroups, mainly premenopausal women, women carrying a BRCA2 mutation and tumors with variable hormonal status (positive or negative for ER/PR) and would need additional studies.

Sex specific relationships between infants' mental rotation ability and amiotic sex hormones.

Sex differences in mental rotation, robust in adults, have recently been reported for infants' looking times although the pattern of results is not completely conclusive. In this context, organizational effects of gonadal steroids affecting the neural circuitry underlying spatial cognition could be (partly) responsible for the early sex difference. In the present study testosterone and estradiol levels measured in amniotic fluid via ultra performance liquid chromatography and tandem mass spectrometry were used to examine the role of prenatal sex hormones on infants' looking times during mental rotation. N = 208 six-month-old infants participated in an expectation of violation task with 3D cube figures. Mental rotation was defined as the difference in looking times for familiar versus mirrored cube figures whereas vigilance was defined as the sum of both looking times. Sex differences were absent for mental rotation as well as for vigilance. Most importantly, however, for boys mental rotation but not vigilance was correlated with prenatal testosterone but not with estradiol. For girls mental rotation but not vigilance was correlated with prenatal estradiol but not with testosterone although it has to be noted that the testosterone values for girls suffered from a floor effect. Only 5% of the within-sex variance was due to prenatal sex hormones indicating small effects. These findings extend our knowledge concerning organizational effects of prenatal sex hormones on the brain circuitry underlying spatial cognition.

A novel machine learning-derived decision tree including uPA/PAI-1 for breast cancer care.

Background uPA and PAI-1 are breast cancer biomarkers that evaluate the benefit of chemotherapy (CT) for HER2-negative, estrogen receptor-positive, low or intermediate grade patients. Our objectives were to observe clinical routine use of uPA/PAI-1 and to build a new therapeutic decision tree integrating uPA/PAI-1. Methods We observed the concordance between CT indications proposed by a canonical decision tree representative of French practices (not including uPA/PAI-1) and actual CT prescriptions decided by a medical board which included uPA/PAI-1. We used a method of machine learning for the analysis of concordant and non-concordant CT prescriptions to generate a novel scheme for CT indications. Results We observed a concordance rate of 71% between indications proposed by the canonical decision tree and actual prescriptions. Discrepancies were due to CT contraindications, high tumor grade and uPA/PAI-1 level. Altogether, uPA/PAI-1 were a decisive factor for the final decision in 17% of cases by avoiding CT prescription in two-thirds of cases and inducing CT in other cases. Remarkably, we noted that in routine practice, elevated uPA/PAI-1 levels seem not to be considered as a sufficient indication for CT for N≤3, Ki 67≤30% tumors, but are considered in association with at least one additional marker such as Ki 67>14%, vascular invasion and ER-H score <150. Conclusions This study highlights that in the routine clinical practice uPA/PAI-1 are never used as the sole indication for CT. Combined with other routinely used biomarkers, uPA/PAI-1 present an added value to orientate the therapeutic choice.

A prospective study to assess the clinical utility of serum HER2 extracellular domain in breast cancer with HER2 overexpression.

PURPOSE: We explored the clinical utility of human epidermal growth factor receptor-2 extracellular domain (HER2/ECD) in patients treated for an invasive breast cancer with HER2 overexpression. METHODS: We prospectively studied HER2/ECD levels in the sera of 334 women included between 2007 and 2014, all treated with trastuzumab. HER2/ECD levels were measured at diagnosis, during treatments, and along the follow-up. We investigated the relationship of HER2/ECD with other clinicopathological parameters at diagnosis, its prognosis value, and its utility during the monitoring of a neoadjuvant treatment and the follow-up. RESULTS: Elevated HER2/ECD at diagnosis correlated positively with parameters associated with tumor aggressiveness. Disease-free survival of non-metastatic patients was significantly shorter in patients with high HER2/ECD at diagnosis (HR = 13.6, 95 % CI 1.6-113.6, P < 0.0001). Progression-free survival of metastatic patients was better for patients with low HER2/ECD (HR = 2.6, 95 % CI 1.2-5.3, P = 0.033). A multivariate analysis revealed that HER2/ECD level at diagnosis was an independent prognosis factor. During neoadjuvant therapy, a significant decrease in HER2/ECD was reported only for the complete histological response group (P = 0.031). During the follow-up, HER2/ECD helped predict relapse, disease progression, and metastases before imaging in 18.6 % cases of the studied cohort. CONCLUSIONS: HER2/ECD is a prognosis factor that is valuable in evaluating the neoadjuvant treatment efficiency. HER2/ECD also appears to be a helpful surveillance biomarker for the early diagnosis of relapses and to predict the fate of metastases. This study brings evidences to support the use of HER2/ECD in the management of HER2-positive breast cancer.

A Metabolomic Approach (1H HRMAS NMR Spectroscopy) Supported by Histology to Study Early Post-transplantation Responses in Islet-transplanted Livers.

Intrahepatic transplantation of islets requires a lot of islets because more than 50% of the graft is lost during the 24 hours following transplantation. We analyzed, in a rat model, early post-transplantation inflammation using systemic inflammatory markers, or directly in islet-transplanted livers by immunohistochemistry. 1H HRMAS NMR was employed to investigate metabolic responses associated with the transplantation. Inflammatory markers (Interleukin-6, α2-macroglobulin) are not suitable to follow islet reactions as they are not islet specific. To study islet specific inflammatory events, immunohistochemistry was performed on sections of islet transplanted livers for thrombin (indicator of the instant blood-mediated inflammatory reaction (IBMIR)) and granulocytes and macrophages. We observed a specific correlation between IBMIR and granulocyte and macrophage infiltration after 12 h. In parallel, we identified a metabolic response associated with transplantation: after 12 h, glucose, alanine, aspartate, glutamate and glutathione were significantly increased. An increase of glucose is a marker of tissue degradation, and could be explained by immune cell infiltration. Alanine, aspartate and glutamate are inter-connected in a common metabolic pathway known to be activated during hypoxia. An increase of glutathione revealed the presence of antioxidant protection. In this study, IBMIR visualization combined with 1H HRMAS NMR facilitated the characterization of cellular and molecular pathways recruited following islet transplantation.

Metabolomic profile of the adrenal gland: from physiology to pathological conditions.

In this study, we i) assessed the metabolic profile of the normal adrenal cortex and medulla of adult human subjects by means of (1)H-high-resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR) spectroscopy; ii) compared the biochemical profile of adenoma (Ad), adrenal cortical carcinoma (ACC), and pheochromocytoma (PCC) samples with that of healthy adrenal tissue samples; and iii) investigated the metabolic differences between ACCs and Ads as well as between ACCs and PCCs. Sixty-six tissue samples (13 adrenal cortical tissue, eight medullary tissue, 13 Ad, 12 ACC, and 20 PCC samples) were analyzed. Adrenaline and noradrenaline were undetectable in cortical samples representing the metabolic signature of the tissue derived from neural crest. Similarity between the metabolic profile of Ads and that of the normal adrenal cortex was shown. Inversely, ACC samples clearly made up a detached group exhibiting the typical stigmata of neoplastic tissue such as choline-containing compounds, biochemical markers of anaerobic processes, and increased glycolysis. Significantly higher levels of lactate, acetate, and total choline-containing compounds played a major role in the differentiation of ACCs from Ads. Moreover, the high fatty acid content of ACCs contributed to the cluster identification of ACCs. Of the 14 sporadic PCC samples, 12 exhibited predominant or exclusive noradrenaline secretion. The noradrenaline:adrenaline ratio was inverted in the normal medullary tissue samples. Multiple endocrine neoplasia type 2- and NF1-related PCC samples exhibited both adrenaline and noradrenaline secretion. In the von Hippel-Lindau disease-related PCC samples, only noradrenaline secretion was detected by HRMAS NMR spectroscopy. This study is one of the first applications of metabolomics to adrenal pathophysiology and it is the largest study to report HRMAS NMR data related to the adrenal cortex and adrenal cortical tumors.

Functional changes with feeding in the gastro-intestinal epithelia of the Burmese python (Python molurus).

The morphology of the digestive system in fasting and refed Burmese pythons was determined, as well as the localization of the proton (H(+), K(+)-ATPase) and sodium (Na(+), K(+)-ATPase) pumps. In fasting pythons, oxyntopeptic cells located within the fundic glands are typically non-active, with a thick apical tubulovesicular system and numerous zymogen granules. They become active Immediately after feeding but return to a non-active state 3 days after the Ingestion of the prey. The proton pump, expressed throughout the different fasting/feeding states, is either sequestered in the tubulovesicular system in non-active cells or located along the apical digitations extending within the crypt lumen in active cells. The sodium pump is rapidly upregulated in fed animals and is classically located along the baso-lateral membranes of the gastric oxyntopeptic cells. In the Intestine, it is only expressed along the lateral membranes of the enterocytes, i.e., above the lateral spaces and not along the basal side of the cells. Thus, solute transport within the Intestinal lining is mainly achieved through the apical part of the cells and across the lateral spaces while absorbed fat massively crosses the entire height of the cells and flows into the Intercellular spaces. Therefore, in the Burmese python, the gastrointestinal cellular system quickly upregulates after feeding, due to Inexpensive cellular changes, passive mechanisms, and the progressive activation and synthesis of key enzymes such as the sodium pump. This cell plasticity also allows anticipation of the next fasting and feeding periods.