Towards the automatic calculation of the EQUAL Candida Score: Extraction of CVC-related information from EMRs of critically ill patients with candidemia in Intensive Care Units.

OBJECTIVES: Candidemia is the most frequent invasive fungal disease and the fourth most frequent bloodstream infection in hospitalized patients. Its optimal management is crucial for improving patients' survival. The quality of candidemia management can be assessed with the EQUAL Candida Score. The objective of this work is to support its automatic calculation by extracting central venous catheter-related information from Italian text in clinical notes of electronic medical records. MATERIALS AND METHODS: The sample includes 4,787 clinical notes of 108 patients hospitalized between January 2018 to December 2020 in the Intensive Care Units of the IRCCS San Martino Polyclinic Hospital in Genoa (Italy). The devised pipeline exploits natural language processing (NLP) to produce numerical representations of clinical notes used as input of machine learning (ML) algorithms to identify CVC presence and removal. It compares the performances of (i) rule-based method, (ii) count-based method together with a ML algorithm, and (iii) a transformers-based model. RESULTS: Results, obtained with three different approaches, were evaluated in terms of weighted F1 Score. The random forest classifier showed the higher performance in both tasks reaching 82.35%. CONCLUSION: The present work constitutes a first step towards the automatic calculation of the EQUAL Candida Score from unstructured daily collected data by combining ML and NLP methods. The automatic calculation of the EQUAL Candida Score could provide crucial real-time feedback on the quality of candidemia management, aimed at further improving patients' health.

Circulating Tumor DNA After Neoadjuvant Chemotherapy in Breast Cancer Is Associated With Disease Relapse.

PURPOSE: Detection of circulating tumor DNA (ctDNA) after neoadjuvant chemotherapy in patients with early-stage breast cancer may allow for early detection of relapse. In this study, we analyzed ctDNA using a personalized, tumor-informed multiplex polymerase chain reaction-based next-generation sequencing assay. METHODS: Plasma samples (n = 157) from 44 patients were collected before neoadjuvant therapy (baseline), after neoadjuvant therapy and before surgery (presurgery), and serially postsurgery including a last follow-up sample. The primary end point was event-free survival (EFS) analyzed using Cox regression models. RESULTS: Thirty-eight (86%), 41 (93%), and 38 (86%) patients had baseline, presurgical, and last follow-up samples, respectively. Twenty patients had hormone receptor-positive/human epidermal growth factor receptor 2-negative, 13 had triple-negative breast cancer, and 11 had human epidermal growth factor receptor 2-positive disease. Baseline ctDNA detection was observed in 22/38 (58%) patients and was significantly associated with Ki67 > 20% (P = .036) and MYC copy-number gain (P = .0025, false discovery rate = 0.036). ctDNA detection at presurgery and at last follow-up was observed in 2/41 (5%) and 2/38 (5%) patients, respectively. Eight relapses (seven distant and one local) were noted (median follow-up 3.03 years [range, 0.39-5.85 years]). After adjusting for pathologic complete response (pCR), ctDNA detection at presurgery and at last follow-up was associated with shorter EFS (hazard ratio [HR], 53; 95% CI, 4.5 to 624; P < .01, and HR, 31; 95% CI, 2.7 to 352; P < .01, respectively). Association between baseline detection and EFS was not observed (HR, 1.4; 95% CI, 0.3 to 5.9; P = .67). CONCLUSION: The presence of ctDNA after neoadjuvant chemotherapy is associated with relapse in early-stage breast cancer, supporting interventional trials for testing the clinical utility of ctDNA monitoring in this setting.

Ovarian Function and Fertility Preservation in Breast Cancer: Should Gonadotropin-Releasing Hormone Agonist be administered to All Premenopausal Patients Receiving Chemotherapy?

Chemotherapy-induced premature ovarian insufficiency (POI) is one of the potential drawbacks of chemotherapy use of particular concern for newly diagnosed premenopausal breast cancer patients. Temporary ovarian suppression obtained pharmacologically with the administration of a gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy has been specifically developed as a method to counteract chemotherapy-induced gonadotoxicity with the main goal of diminishing the risk of POI. In recent years, important clinical evidence has become available on the efficacy and safety of this strategy that should now be considered a standard option for ovarian function preservation in premenopausal breast cancer patients, including women who are not interested in conceiving after treatment or that would not be candidates for fertility preservation strategies because of their age. Nevertheless, in women interested in fertility preservation, this is not an alternative to gamete cryopreservation, which remains as the first option to be offered. In this setting, temporary ovarian suppression with GnRHa during chemotherapy should be also proposed following gamete cryopreservation or to women who have no access, refuse, or have contraindications to surgical fertility preservation techniques. In this article, we present an overview about the role of temporary ovarian suppression with GnRHa during chemotherapy in breast cancer patients by addressing the available clinical evidence with the aim of identifying both the best candidates for the use of this strategy and the still existing gray zones requiring further investigation.

Oncofertility counselling in premenopausal women with HER2-positive breast cancer.

A complete oncofertility counselling should be offered to all premenopausal patients before the administration of anticancer treatments. This important discussion is a crucial step for allowing them to take fully informed decisions about the proposed therapy and its potential long-term consequences as well as on their need and interest of accessing the available strategies for ovarian function and/or fertility preservation. In premenopausal women with HER2-positive early breast cancer, limited evidence exists to counsel them about the potential added gonadotoxicity of targeted agents beyond the damage already caused by chemotherapy. In addition, the prognostic role of treatment-induced amenorrhea in this setting was unknown. In our exploratory analysis within the ALTTO (BIG 2-06) trial, we have recently described the rates of treatment-induced amenorrhea after chemotherapy plus trastuzumab and/or lapatinib and the prognostic value of developing this side effect according to the hormone receptor status of their tumours. We observed similar rates of treatment-induced amenorrhea in the four anti-HER2 treatment arms. The lack of an increased rate of treatment-induced amenorrhea in the dual anti-HER2 blockade arm suggests the possible gonadal safety of these agents. In addition, women with HER2-positive/hormone receptor-positive tumours showed significantly better survival outcomes if they developed treatment-induced amenorrhea, while no difference was observed for those with HER2-positive/hormone receptor-negative disease. Future research efforts are needed to address the gonadotoxicity of the new available targeted agents as well as to elucidate which is the best adjuvant endocrine therapy in premenopausal women with HER2-positive/hormone receptor-positive disease.

Impact of ovarian function suppression in premenopausal women with estrogen receptor-positive early breast cancer.

PURPOSE OF REVIEW: This manuscript aims at providing an updated overview on the role of adding ovarian function suppression to tamoxifen or an aromatase inhibitor as adjuvant endocrine therapy in premenopausal women with estrogen receptor-positive early breast cancer. RECENT FINDINGS: Until recently, tamoxifen alone was the only recommended adjuvant treatment option for premenopausal women with estrogen receptor-positive disease. However, recent important evidence has contributed to significantly modify the endocrine treatment landscape in this setting. SUMMARY: With the only exception of patients with low-risk clinical-pathological features characterized by excellent survival outcomes with tamoxifen alone, the use of ovarian function suppression is to be considered standard of care for most of premenopausal women with estrogen receptor-positive disease. Regarding the choice of its best partner as endocrine agent, the available data suggest that the higher the risk of disease recurrence the larger benefit can be observed with a more profound estrogen deprivation that can be obtained with ovarian function suppression and an aromatase inhibitor as compared to ovarian function suppression and tamoxifen. Despite the significant improvement in our understanding on the role of ovarian function suppression in this setting, several unanswered questions remain and further research efforts are needed in the field.

Single-agent PARP inhibitors for the treatment of patients with BRCA-mutated HER2-negative metastatic breast cancer: a systematic review and meta-analysis.

Single-agent poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved as the first targeted therapy available for patients with BRCA-mutated HER2-negative metastatic breast cancer. This meta-analysis aimed to better evaluate activity, efficacy and safety of single-agent PARPi in this population. A systematic search of Medline, Embase and conference proceedings up to 31 January 2018 was conducted to identify randomised controlled trials (RCTs) investigating single-agent PARPi versus monochemotherapy in patients with BRCA-mutated HER2-negative metastatic breast cancer. Using the random-effect model, we calculated summary risk estimates (pooled HR and OR with 95% CI) for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), any grade and grade 3-4 adverse events (AEs), treatment discontinuation rate and time to deterioration in quality of life (QoL). Two RCTs (n=733) were included. As compared with monochemotherapy, single-agent PARPi significantly improved PFS (HR 0.56(95% CI 0.45 to 0.70)) and ORR (OR 4.15 (95% CI 2.82 to 6.10)), with no difference in OS (HR 0.82 (95% CI 0.64 to 1.05)). Single-agent PARPi significantly increased risk of anaemia and any grade headache, but reduced risk of neutropenia and any grade palmar-plantar erythrodysesthesia syndrome as compared with monochemotherapy. No significant differences in other AEs and treatment discontinuation rate were observed. Patients treated with PARPi experienced a significant delayed time to QoL deterioration (HR 0.40 (95% CI 0.29 to 0.54)). Single-agent PARPi showed to be an effective, well tolerated and useful treatment in maintaining QoL of patients with BRCA-mutated HER2-negative metastatic breast cancer.

Potential Benefit of Intra-operative Administration of Ketorolac on Breast Cancer Recurrence According to the Patient's Body Mass Index.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in some countries as analgesics in primary cancer surgery. Retrospective studies suggest that NSAIDs could reduce breast cancer recurrences. Because NSAIDs also act on biological mechanisms present in patients with increased adiposity, we aimed at assessing whether the intra-operative administration of ketorolac or diclofenac would be associated with a reduction of recurrence in patients with elevated body mass index (BMI). Methods: We considered two institutional retrospective series of 827 and 1007 patients evaluating the administration of ketorolac (n = 529 with, n = 298 without) or diclofenac (n = 787 with, n = 220 without). The BMI subgroups were defined as less than 25 kg/m2 (lean) and 25 or more kg/m2 (overweight and obese). Cumulative incidence estimation of distant metastases as well as Fine-Gray and Dixon-Simon models was used. These analyses were adjusted for clinico-pathological variables. All statistical tests were two-sided. Results: The administration of ketorolac was statistically significantly associated with decreased incidence of distant recurrences (adjusted hazard ratio [aHR]= 0.59, 95% confidence interval [CI] = 0.37 to 0.96, P = .03). In particular, the association was evident in the high-body mass index (BMI) group of patients (aHR = 0.55, 95% CI = 0.31 to 0.96, P = .04). The administration of diclofenac was not statistically significantly associated with decreased incidence of distant recurrences, either in the global population or in the BMI subgroups. Conclusions: These results show that the intra-operative administration of ketorolac, but not diclofenac, is statistically significantly associated with a reduction of distant recurrences in patients with increased BMI. Altogether, this study points to a potentially important repositioning of ketorolac in the intra-operative treatment of patients with elevated BMI that, if prospectively validated, might be as impactful as and cheaper than adjuvant systemic anticancer therapies.

Risk of adverse events with the addition of targeted agents to endocrine therapy in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis.

BACKGROUND: Combining targeted agents and endocrine therapy (ET) improves outcomes in hormone receptor-positive metastatic breast cancer patients but increases the risk of adverse events (AEs). This meta-analysis aims to estimate the comparative risk of AEs with ET in addition to targeted agents in this setting. METHODS: A systematic literature search of MEDLINE, EMBASE, Cochrane Library and conference proceedings up to July 17th 2017 was conducted to identify randomized controlled trials investigating ET with or without CDK4/6, mTOR, PI3K inhibitors and anti-HER2 agents. We calculated summary risk estimates (odds ratio, OR) and 95% confidence intervals (CI) for each AE within each class of targeted agents for each trial, and pooled analysis using the random and fixed effect models. RESULTS: Sixteen studies (n=8529 patients) were included. The addition of targeted agents to ET was associated with a significant higher risk of grade 3-4 AEs: OR 2.86 (95% CI 2.49-3.27) for CDK4/6 inhibitors, 1.88 (95% CI 1.39-2.53) for mTOR inhibitors, 2.05 (95% CI 1.63-2.58) for PI3K inhibitors, and 2.48 (95% CI 1.09-5.66) for anti-HER2 agents. The highest class-specific risks were neutropenia grade 3-4 for CDK4/6 inhibitors (OR 40.77; 95% CI 19.52-85.19), stomatitis grade 3-4 for mTOR inhibitors (OR 11.92; 95% CI 3.68-38.57), hyperglycemia grade 3-4 for PI3K inhibitors (OR 40.93; 95% CI 10.08-166.22) and diarrhea for anti-HER2 agents (OR 9.93; 95% CI 4.71-20.95). CONCLUSIONS: Adding targeted agents to ET is associated with a significant increased risk of AEs. The risk of developing different AEs varies largely according to the type of agent used.

Viable Options for Fertility Preservation in Breast Cancer Patients: A Focus on Latin America.

Thanks to the improved survival outcomes observed in recent years, a growing attention has been given to the quality of life issues faced by young women with breast cancer such as fertility preservation and concerns related to future pregnancies. However, several challenges remain for young women with breast cancer considering undergoing fertility preservation strategies. Further specific issues on this regard should be taken into account in Latin America, where patients and physicians face particular barriers that hinder the routine adoption of this practice. Hence, further efforts are needed to overcome these deficiencies and improve the correct referral of breast cancer patients to fertility preservation strategies. The aim of the present review is to focus on the risk of anticancer treatment-related premature ovarian failure and infertility in young breast cancer patients, to summarize the current knowledge on the available options for fertility preservation, and to discuss the safety issues of pregnancy in breast cancer survivors. Furthermore, this review aims to highlight the specific clinical challenges in this field encountered by healthcare providers and young breast cancer patients from Latin American countries.

Ovarian Function Suppression in Premenopausal Women with Early-Stage Breast Cancer.

OPINION STATEMENT: Breast cancers arising in young women are biologically more aggressive, and most of these patients are candidates to receive aggressive treatments that include the use of chemotherapy. As most of these tumors express the hormone receptors (i.e., luminal disease), these patients are also candidates to adjuvant endocrine therapy. Chemotherapy-induced amenorrhea showed to be prognostic in young patients with luminal breast cancer. However, the role of ovarian function suppression (OFS) in addition to standard adjuvant treatments has been largely debated over the past years. Recently, several studies have provided important insights on the role of OFS. Currently, the use of tamoxifen alone without prior cytotoxic therapy can be considered a very effective treatment option in young patients with hormone receptor-positive breast cancer at low risk of relapse. On the other hand, for patients at higher risk of relapse as those who are candidates to (neo)adjuvant chemotherapy, OFS proved to be beneficial, and therefore luteinizing hormone-releasing hormone agonists (LHRHa) should be considered in addition to tamoxifen or aromatase inhibitors (AI). However, toxicity is considerable and patients should be actively engaged in decision-making. Finally, in young breast cancer patients who are candidates to (neo)adjuvant chemotherapy, loss of ovarian function and fertility may be a concern. Besides other techniques, recent results showed that temporary OFS with LHRHa during cytotoxic treatment can be considered a reliable strategy to preserve gonadal function and fertility. Despite the recent advances in the field, several gray zones remain unanswered: the role of OFS plus AI in women who remained premenopausal after 5 years of tamoxifen, the optimal extended approach in women treated with 5 years of OFS plus AI, and the role of temporary OFS with LHRHa during chemotherapy in the specific subgroup of patients with BRCA mutations and in women undergoing this strategy after prior embryo/oocyte cryopreservation.