Neutrophil gelatinase-associated lipocalin (NGAL) predicts response to neoadjuvant chemotherapy and clinical outcome in primary human breast cancer

In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor prognosis. In neoadjuvant chemotherapy (NACT) pathological complete response (pCR) is a predictor for outcome. The aim of this study was to evaluate NGAL as a predictor of response to NACT and to validate NGAL as a prognostic factor for clinical outcome in patients with primary BC. Immunohistochemistry was performed on tissue microarrays from 652 core biopsies from BC patients, who underwent NACT in the GeparTrio trial. NGAL expression and intensity was evaluated separately. NGAL was detected in 42.2% of the breast carcinomas in the cytoplasm. NGAL expression correlated with negative hormone receptor (HR) status, but not with other baseline parameters. NGAL expression did not correlate with pCR in the full population, however, NGAL expression and staining intensity were significantly associated with higher pCR rates in patients with positive HR status. In addition, strong NGAL expression correlated with higher pCR rates in node negative patients, patients with histological grade 1 or 2 tumors and a tumor size <40 mm. In univariate survival analysis, positive NGAL expression and strong staining intensity correlated with decreased disease-free survival (DFS) in the entire cohort and different subgroups, including HR positive patients. Similar correlations were found for intense staining and decreased overall survival (OS). In multivariate analysis, NGAL expression remained an independent prognostic factor for DFS. The results show that in low-risk subgroups, NGAL was found to be a predictive marker for pCR after NACT. Furthermore, NGAL could be validated as an independent prognostic factor for decreased DFS in primary human BC

Analysis of the suitability of existing medical ontologies for building a scalable semantic interoperability solution supporting multi-site collaboration in oncology

Semantic interoperability is essential to facilitate efficient collaboration in heterogeneous multi-site healthcare environments. The deployment of a semantic interoperability solution has the potential to enable a wide range of informatics supported applications in clinical care and research both within as ingle healthcare organization and in a network of organizations. At the same time, building and deploying a semantic interoperability solution may require significant effort to carryout data transformation and to harmonize the semantics of the information in the different systems. Our approach to semantic interoperability leverages existing healthcare standards and ontologies, focusing first on specific clinical domains and key applications, and gradually expanding the solution when needed. An important objective of this work is to create a semantic link between clinical research and care environments to enable applications such as streamlining the execution of multi-centric clinical trials, including the identification of eligible patients for the trials. This paper presents an analysis of the suitability of several widely-used medical ontologies in the clinical domain: SNOMED-CT, LOINC, MedDRA, to capture the semantics of the clinical trial eligibility criteria, of the clinical trial data (e.g., Clinical Report Forms), and of the corresponding patient record data that would enable the automatic identification of eligible patients. Next to the coverage provided by the ontologies we evaluate and compare the sizes of the sets of relevant concepts and their relative frequency to estimate the cost of data transformation, of building the necessary semantic mappings, and of extending the solution to new domains. This analysis shows that our approach is both feasible and scalable

Design of the Multicompartment Mathematical Model of the Lungs

Mechanical ventilation or artificial lung ventilation is an invasive procedure which is used to assist or replace spontaneous breathing. In positive pressure ventilation, air is pushed into the trachea and through the respiratory system causing an overstretching of the airways and theMechanical ventilation or artificial lung ventilation is an invasive procedure which is used to assist or replace spontaneous breathing. In positive pressure ventilation, air is pushed into the trachea and through the respiratory system causing an overstretching of the airways and the alveoli, leading to ventilator induced lung injury (VILI). It is therefore necessary to monitor the pressure distribution in a patient?s respiratory system so as to avoid such injuries. This thesis describes a five compartment mathematical model of the respiratory system, it describes an experimental measurement on the five compartment physical model and analyses the ventilatory data such as pressure distribution for the measurement with different added dead space into the structure of the model. The mathematical model shall be useful in simulating the performance of a ventilator under different ventilatory regimes and to analyse the pressure distribution in each compartment under changing parameters of the ventilator such as PEEP and I: E ratio. For the purpose of writing, the process was split into two parts, physical model and mathematical model. The first part describes the physical five compartment model and the experimental measurement done and analysis of the pressure distribution in each compartment of the model. The second part describes the design and development of the mathematical model corresponding to the physical model of the respiratory system and the realization of mathematical simulations of the physically measured experiments

Radiation Recall Dermatitis in Patients Treated with Sorafenib

Introduction. Radiation recall dermatitis (RRD) is a phenomenon that occurs in previously irradiated areas shortly after administration of a chemotherapeutic agent. As the use of sorafenib expands, the incidence of radiation recall dermatitis induced by sorafenib will likely increase. Here, we report on a patient who developed RRD and describe his clinical characteristics along with a review of the literature. Case Presentation. Our patient was treated with palliative radiation therapy (RT) to a painful metastatic hepatocellular carcinoma lesion in the right forearm. He completed his radiation course with grade 1 dermatitis, which had resolved by the time he was started on sorafenib 400 mg twice daily 7 days afterwards. On the 21st day after RT, he presented with desquamation and erythema in the previously irradiated area of the right forearm, consistent with RRD. The sorafenib was discontinued and his symptoms subsequently resolved with conservative topical management. Conclusions. Although the pathophysiologic mechanism of sorafenib-related radiation recall dermatitis remains to be investigated, practitioners should be aware of its presence and management in order to improve clinical outcomes

HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group

Sorafenib in the Treatment of Early Breast Cancer: Results of the Neoadjuvant Phase II Study - SOFIA

BACKGROUND Sorafenib was tested for neoadjuvant treatment with an anthracycline/taxane-based chemotherapy in the open-label, multicentre, single-arm phase II study, 'SOFIA'. PATIENTS AND METHODS INCLUSION CRITERIA WERE: HER2 negative, cT3, cT4 or cT2 cN+, M0 primary breast cancer. Patients received 4 × epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2) (EC) intravenously (i.v.) in 3-weekly cycles followed or preceded by 12 weeks of paclitaxel (Pw) 80 mg/m(2). In cohort 1, sorafenib started at 800 mg daily with chemotherapy. An initial daily sorafenib dose of 200 mg was escalated, based on individual toxicities, every 3 weeks in cohort 2 (starting with EC) and every 2 weeks in cohort 3 (starting with Pw). The primary objective was to identify the most feasible regimen; secondary objectives were safety, pathological complete response (pCR) at surgery and pharmacokinetics. RESULTS Of the 36 recruited patients, 7/12 patients completed the study in cohort 1 and 24/24 patients in cohorts 2 and 3. The median cumulative sorafenib dose per patient was 37%, 65% and 46% in cohorts 1, 2 and 3, respectively. The main grade 3-4 toxicities were neutropenia and hand-foot syndrome. The pCR (ypT0/is) rate was 27.7%. No pharmacokinetic interaction was observed between sorafenib and epirubicin. CONCLUSION Sorafenib EC-Pw is feasible if the starting dose is 200 mg, escalated every 3 weeks based on the patients' individual toxicities

Case report: IORT as an alternative treatment option for breast cancer patients with difficulty staying still

BackgroundAdministering radiation therapy to individuals with intellectual disabilities (ID) and psychiatric patients taking antipsychotics poses challenges, especially with whole breast irradiation (WBI) due to difficulty staying still (DSS). In such scenarios, intraoperative radiotherapy (TARGIT-IORT) provides an alternative. Although prior studies have shown its applicability in special cases where WBI may be contraindicated, there is a paucity of literature emphasizing its role in patients with ID and psychiatric conditions who have DSS. Therefore, our case series aims to highlight the applicability of administering TARGIT-IORT in such patients.Case reportsFour breast cancer patients underwent lumpectomy and TARGIT-IORT. Among them, two patients had ID, with one experiencing a decreased range of motion. The other two had psychiatric disorders, including schizophrenia and bipolar disorder, both manifesting involuntary movements and DSS. Three patients had invasive ductal carcinoma (IDC), and one had invasive lobular carcinoma (ILC). All patients undergoing TARGIT-IORT tolerated the procedure well. Notably, none of the patients exhibited evidence of disease on follow-up.ConclusionOur study underscores the potential use of TARGIT-IORT as a viable treatment option for breast cancer patients with intellectual and psychiatric disabilities. Unlike traditional EBRT, TARGIT-IORT offers a single radiation dose, addressing challenges associated with compliance or DSS. Our findings demonstrate positive outcomes and tolerance, especially in patients where standard oncologic procedures are difficult to achieve. TARGIT-IORT could also benefit breast cancer patients with concurrent movement disorders like Parkinson’s disease and other movement disorders. Nonetheless, future studies are needed to reinforce its applicability for patients with DSS

T Cell-Mediated Antitumor Immunity Cooperatively Induced By TGFβR1 Antagonism and Gemcitabine Counteracts Reformation of the Stromal Barrier in Pancreatic Cancer.

The desmoplastic stroma of pancreatic cancers forms a physical barrier that impedes intratumoral drug delivery. Attempts to modulate the desmoplastic stroma to increase delivery of administered chemotherapy have not shown positive clinical results thus far, and preclinical reports in which chemotherapeutic drugs were coadministered with antistromal therapies did not universally demonstrate increased genotoxicity despite increased intratumoral drug levels. In this study, we tested whether TGFβ antagonism can break the stromal barrier, enhance perfusion and tumoral drug delivery, and interrogated cellular and molecular mechanisms by which the tumor prevents synergism with coadministered gemcitabine. TGFβ inhibition in genetically engineered murine models (GEMM) of pancreas cancer enhanced tumoral perfusion and increased intratumoral gemcitabine levels. However, tumors rapidly adapted to TGFβ-dependent stromal modulation, and intratumoral perfusion returned to pre-treatment levels upon extended TGFβ inhibition. Perfusion was governed by the phenotypic identity and distribution of cancer-associated fibroblasts (CAF) with the myelofibroblastic phenotype (myCAFs), and myCAFs which harbored unique genomic signatures rapidly escaped the restricting effects of TGFβ inhibition. Despite the reformation of the stromal barrier and reversal of initially increased intratumoral exposure levels, TGFβ inhibition in cooperation with gemcitabine effectively suppressed tumor growth via cooperative reprogramming of T regulatory cells and stimulation of CD8 T cell-mediated antitumor activity. The antitumor activity was further improved by the addition of anti-PD-L1 immune checkpoint blockade to offset adaptive PD-L1 upregulation induced by TGFβ inhibition. These findings support the development of combined antistroma anticancer therapies capable of impacting the tumor beyond the disruption of the desmoplastic stroma as a physical barrier to improve drug delivery

Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Premenopausal Patients With Early Breast Cancer: A Systematic Review and Meta-Analysis of Individual Patient–Level Data

Purpose The role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal women remains controversial. This systematic review and meta-analysis using individual patient-level data was conducted to better assess the efficacy and safety of this strategy in patients with early breast cancer. Methods The trials in which premenopausal women with early breast cancer were randomly assigned to receive (neo)adjuvant chemotherapy alone or with concurrent GnRHa were eligible for inclusion. Primary end points were premature ovarian insufficiency (POI) rate and post-treatment pregnancy rate. Disease-free survival and overall survival were secondary end points. Because each study represents a cluster, statistical analyses were performed using a random effects model. Results A total of 873 patients from five trials were included. POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted odds ratio, 0.38; 95% CI, 0.26 to 0.57; P &lt; .001). A total of 37 (10.3%) patients had at least one post-treatment pregnancy in the GnRHa group and 20 (5.5%) in the control group (incidence rate ratio, 1.83; 95% CI, 1.06 to 3.15; P = .030). No significant differences in disease-free survival (adjusted hazard ratio, 1.01; 95% CI, 0.72 to 1.42; P = .999) and overall survival (adjusted hazard ratio, 0.67; 95% CI, 0.42 to 1.06; P = .083) were observed between groups. Conclusion Our findings provide evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced POI and potentially improve future fertility in premenopausal patients with early breast cancer

HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Introduction Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, P <0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, P <0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (P = 0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group