Multidisciplinary clinical guidelines in proactive monitoring, early diagnosis, and effective management of trastuzumab deruxtecan (T-DXd)-induced interstitial lung disease (ILD) in breast cancer patients.

Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate (ADC), has altered the treatment landscape in breast cancer (BC), irrespective of the HR-receptor status. The use of the agent is increasing, despite the finding that exposure to T-DXd increases the risk of interstitial lung disease (ILD), particularly in BC patients. Although T-DXd-related ILD can be potentially severe and life-threatening, most low-grade cases can be treated safely using a multidisciplinary approach comprising early and accurate diagnosis, effective management, close monitoring, and the prompt administration of steroids. Additionally, increasing patients' education on ILD symptoms ensures close attention and enables prompt reporting, enhancing patient outcomes. It is recommended that predictive biomarkers are assessed in patients with risk factors for developing ILD. Currently, diagnostic criteria comprise newly identified pulmonary opacities, the relation of symptom onset to medication initiation, and the exclusion of other causes of ILD. The general condition of patients is weakened during the management of ILD (BC progression and corticosteroid treatment). Consequently, BC chemotherapy might be attenuated. This highlights the importance of preventing (high-grade) ILD, especially since its use is expanded. Identifying high-risk patients, diagnosing, and customizing treatment is, however, challenging and additional information on patient selection is often not fully clarified. In this paper, we provide updated multidisciplinary clinical guidance for patient selection, proactive monitoring, early diagnosis, and effectively management of T-DXd-induced ILD in HER2-positive BC patients. We describe the risk factors for developing ILD, patients' characteristics of ILD, and the histopathological and radiographic characteristics of ILD, including real-world clinical practice reports. These recommendations provide a structured step-by-step approach for managing each suspected BC-related ILD grade.

The Future of Breast Cancer Research in the Survivorship Field.

Prevalence of survivors of breast cancer has been steadily increasing in the last 20 years. Currently, more than 90% of women diagnosed with early-stage breast cancer are expected to be alive at 5 years from diagnosis thanks to early detection and breakthrough innovations in multimodal treatment strategies. Alongside this advancement in clinical outcomes, survivors of breast cancer might experience several specific challenges and present with unique needs. Survivorship trajectories after diagnosis and treatment of breast cancer can be significantly impacted by long-lasting and severe treatment-related side effects, including physical problems, psychological distress, fertility issues in young women, and impaired social and work reintegration, which add up to patients' individual risk of cancer recurrence and second primary malignancies. Alongside cancer-specific sequelae, survivors still present with general health needs, including management of chronic preexisting or ensuing conditions. Survivorship care should implement high-quality, evidence-based strategies to promptly screen, identify, and address survivors' needs in a comprehensive way and minimize the impact of severe treatment sequelae, preexisting comorbidities, unhealthy lifestyles, and risk of recurrence on quality of life. This narrative review focuses on core areas of survivorship care and discuss the state of the art and future research perspectives in key domains including selected long-term side effects, surveillance for recurrences and second cancers, well-being promotion, and specific survivors' needs.

Homologous Recombination Repair Deficiency and the Immune Response in Breast Cancer: A Literature Review.

The success of cancer immunotherapy with immune checkpoint blockade (ICB) has demonstrated the importance of targeting a preexisting immune response in a broad spectrum of tumors. This is particularly novel and relevant for less immunogenic tumors, such as breast cancer (BC), where the efficacy of ICB was more evident in the triple-negative (TNBC) subtype, in earlier stages, and in association with chemotherapy. Tumors harboring homologous recombination DNA repair (HRR) deficiency (HRD) are supposed to have a higher number of mutations, hence a higher tumor mutational burden, which could potentially make them more sensitive to immunotherapy. However, the mechanisms involved in ICB sensitivity and patient selection are still yet to be defined in BC: whether the innate system could play a role and how the adaptive immunity could be linked with HRR pathways are the two key points of debate that we will discuss in this article. The aim of this review was to close the loop between what was found in clinical trial results so far, go back to laboratory theory and preclinical results and point out what needs to be clarified from now on.

Scoring of tumor-infiltrating lymphocytes: From visual estimation to machine learning.

The extent of tumor-infiltrating lymphocytes (TILs), along with immunomodulatory ligands, tumor-mutational burden and other biomarkers, has been demonstrated to be a marker of response to immune-checkpoint therapy in several cancers. Pathologists have therefore started to devise standardized visual approaches to quantify TILs for therapy prediction. However, despite successful standardization efforts visual TIL estimation is slow, with limited precision and lacks the ability to evaluate more complex properties such as TIL distribution patterns. Therefore, computational image analysis approaches are needed to provide standardized and efficient TIL quantification. Here, we discuss different automated TIL scoring approaches ranging from classical image segmentation, where cell boundaries are identified and the resulting objects classified according to shape properties, to machine learning-based approaches that directly classify cells without segmentation but rely on large amounts of training data. In contrast to conventional machine learning (ML) approaches that are often criticized for their "black-box" characteristics, we also discuss explainable machine learning. Such approaches render ML results interpretable and explain the computational decision-making process through high-resolution heatmaps that highlight TILs and cancer cells and therefore allow for quantification and plausibility checks in biomedical research and diagnostics.

Immuno-oncology-101: overview of major concepts and translational perspectives.

Cancer immunotherapy is demonstrating impressive clinical benefit in different malignancies and clinical oncologists are increasingly turning their attention to immune-oncology. It is now well recognized that innate and adaptive immune cells infiltrating tumors are associated with clinical outcomes and responses to treatments, and can be harnessed to patients' benefit. Considerable advances have also been made in understanding how cancers escape from immune attack. Targeting of immunological escape processes regulated by the expression of immune checkpoint receptors and ligands and the down-modulation of tumor antigen presentation is the basis of immuno-oncology treatments. Despite recent achievements, there remain a number of unresolved issues in order to successfully implement cancer immunotherapy in many cancers. Importantly, clinical biomarkers are still needed for better optimization of emerging combination immunotherapies and better treatment tailoring. In this review, we summarize the function of innate and adaptive immune cells in anti-tumor immunity and the general mechanisms exploited by tumor cells to escape and inhibit immune responses as well as therapeutic strategies developed to overcome these mechanisms and discuss emerging biomarkers in immuno-oncology.

Antiviral activity and metal ion-binding properties of some 2-hydroxy-3-methoxyphenyl acylhydrazones.

Here we report on the results obtained from an antiviral screening, including herpes simplex virus, vaccinia virus, vesicular stomatitis virus, Coxsackie B4 virus or respiratory syncytial virus, parainfluenza-3 virus, reovirus-1 and Punta Toro virus, of three 2-hydroxy-3-methoxyphenyl acylhydrazone compounds in three cell lines (i.e. human embryonic lung fibroblast cells, human cervix carcinoma cells, and African Green monkey kidney cells). Interesting antiviral EC50 values are obtained against herpes simplex virus-1 and vaccinia virus. The biological activity of acylhydrazones is often attributed to their metal coordinating abilities, so potentiometric and microcalorimetric studies are here discussed to unravel the behavior of the three 2-hydroxy-3-methoxyphenyl compounds in solution. It is worth of note that the acylhydrazone with the higher affinity for Cu(II) ions shows the best antiviral activity against herpes simplex and vaccinia virus (EC50 ~ 1.5 µM, minimal cytotoxic concentration = 60 µM, selectivity index = 40).

Tumor-infiltrating lymphocytes in patients with HER2-positive breast cancer treated with neoadjuvant chemotherapy plus trastuzumab, lapatinib or their combination: A meta-analysis of randomized controlled trials.

BACKGROUND: A relationship between baseline tumor-infiltrating lymphocytes (TIL) and outcomes has been described in HER2-positive breast cancer. Nevertheless, the magnitude of this association and whether this effect differs based on the type of anti-HER2 agent remain controversial. This meta-analysis investigated the association between baseline TIL and pathologic complete response (pCR) rates in HER2-positive breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab and lapatinib either alone or in combination. METHODS: A literature search covering PubMed, Embase and the Cochrane library up to October 31, 2016 identified randomized, controlled trials investigating neoadjuvant chemotherapy plus trastuzumab and lapatinib either alone or in combination where published data for pCR based on pre-treatment TIL scores were available. Two subgroups were considered: high baseline TIL vs. non-high TIL, according to each study definition. Summary risk estimates (odds ratio) and 95% confidence intervals (CI) were calculated for pCR using pre-treatment TIL levels for each trial. Pooled analyses were conducted using random and fixed effects models. Interaction P-values were computed using a Monte Carlo permutation test. RESULTS: A total of 5 studies (N=1256 patients) were included. Overall, high TIL subgroup was associated with a significantly increased pCR rate (OR 2.46; 95% CI 1.36-4.43; P=0.003). No interaction was observed between TIL subgroup (high vs. non-high TIL) and response to anti-HER2 agent(s) (trastuzumab vs. lapatinib vs. their combination; P=0.747) and chemotherapy (anthracycline and taxanes vs. taxanes only; P=0.201). A stronger association between high TIL subgroup and pCR rates was observed when examining only the 4 studies using anthracycline- and taxane- based neoadjuvant chemotherapy and the 60% cut-off for high TIL (N=869, NeoALTTO excluded) with an OR of 2.88 (95% CI 2.03-4.08; P<0.001). CONCLUSIONS: In HER2-positive breast cancer, high baseline TIL are associated with increased pCR probability irrespective of neoadjuvant anti-HER2 agent(s) and chemotherapy regimens used.

Cystic echinococcosis in Sardinia: farmers' knowledge and dog infection in sheep farms.

Cystic Echinococcosis (CE) is one of the most widespread parasitic diseases in Sardinia, the second largest Mediterranean island where almost 3,558,000 milk sheep were raised extensively. The aim of this survey was to evaluate the level of farmers' knowledge on CE transmission, focusing on the role of human to facilitate the persistence of this zoonosis in Sardinia after 14 years after the last campaign against CE. The other goal of the survey is to update on presence of Echinococcus granulosus in its definitive hosts through three ELISA coproantigen tests. An interview was carried out with 172 farmers. The questionnaire was designed to include possible factors associated with the transmission of Echinococcosis: ownership and number of dogs, the use of anthelmintic drugs against dog cestode, frequency of anthelmintic treatment in dogs, home slaughtering and offal disposal. Individual faecal samples were retrieved from 300 dogs, and after a preliminary macroscopic examination to discover adult worms and/or proglottids, was submitted to copromicroscopic examination. Coproantigens were then extracted according to the protocol described by Allan et al. (1992), and subsequently stored at -20°C until use. Faecal soluble antigens from E. granulosus were detected using three different ELISA coproantigen assays: (a) the commercially produced Chekit Echinotest (Bommeli, Bern, CH) based on polyclonal antibodies against adult excretory/secretory (E/S) antigens; (b) a sandwich ELISA that uses rabbit polyclonal antibodies against adult E/S antigens and biotinylated monoclonal antibody EmA9 produced against adult Echinococcus multilocularis somatic extract (Malgor et al., 1997); and (c) a sandwich assay that uses monoclonal antibody EgC3 produced by immunization with adult E. granulosus E/S products (Casaravilla et al., 2005). Questionnaire results reveal that on all farms home-slaughtering was done, and offal was used as dog meal raw (17%) or after boiling (37%), discarded in the trash (23%), or buried superficially (15%). Most farmers (69%) declared to deworm their dogs, but only 10% used cestodicidal drugs. The coprological survey of 300 farm dogs using sedimentation, flotation and three different coproantigen (CA) ELISAs resulted in a faecal prevalence of 8.3% for taeniid eggs, while the CA tests gave prevalences of 3% (Chekit Echinotest, Bommeli), 6% (EmA9 sandwich ELISA) and 10% (EgC3 sandwich ELISA). Our results show that this is not only an educational problem, but also an economic one, stressing the need that future control plans should follow an integrative approach including veterinary and medical services, farmers, breeders' associations and the Government.

Intraoperative phrenic nerve monitoring in cardiac surgery.

BACKGROUND: Left hemidiaphragmatic paralysis due to phrenic nerve lesion is a frequent complication of hypothermic cardiopulmonary bypass. Although this is believed to be caused by cold injury to the phrenic nerve, its exact cause is still not clear. STUDY OBJECTIVE: To assess feasibility, safety, and usefulness of intraoperative phrenic nerve function monitoring. SETTING: Elective cardiac surgery in a university hospital. PATIENTS: Consenting patients scheduled for myocardial revascularization surgery with the use of the left internal mammary artery. DESIGN: Intraoperative monitoring of compound diaphragmatic action potentials (CDAPs) through transcutaneous stimulation of phrenic nerves. INTERVENTIONS: Patients were divided in two groups. Group 1 received intracoronary cold St. Thomas's solution as the only cardioplegic method. Group 2 received topical cardiac cooling with ice-cold solutions in addition to intracoronary cardioplegia. RESULTS: In all group 1 patients, function of phrenic nerves was maintained throughout the surgical procedure. Group 2: in two patients, bilateral, and in one patient, left phrenic nerve conduction was abolished after submersion of the heart in ice-cold solution. In two of them, the action potential of the left hemidiaphragm was absent by the end of surgery. In one, nerve conduction recovered with rewarming of the patient. DISCUSSION: Intraoperative monitoring of CDAP was safe and easily obtained in the intraoperative setting. It allowed us to observe changes in phrenic nerve conduction occurring during surgery and as a result of cold cardioplegia. Cryogenic lesion of phrenic nerve might explain our findings. However, nerve ischemia cannot be ruled out and it may worsen axonal damage or delay its recovery. COMMENT: This monitoring method allowed us to predict postoperative diaphragmatic dysfunction. Also, surgeons can be warned of the damaging effects of excessive cooling of the pericardium and surrounding structures; thus, preventive measures can be taken.

Ketanserin in the treatment of protamine-induced pulmonary hypertension.

The reversal of heparin by protamine may cause severe hemodynamic deterioration, characterized by systemic hypotension, pulmonary hypertension, and bronchoconstriction. A case report is presented concerning the administration of ketanserin in the treatment of pulmonary vasoconstriction and right ventricular failure following the infusion of protamine in a patient undergoing coronary artery bypass surgery and mitral valve replacement. The potential role of serotonin in the development of this serious complication is discussed.