Sacituzumab Govitecan for the treatment of advanced triple negative breast cancer patients: a multi-center real-world analysis.

Objective: The objective of this multicenter, observational, retrospective analysis was to evaluate the safety and efficacy of sacituzumab govitecan in metastatic triple-negative breast cancer (mTNBC) patients managed according to common clinical practice in Italy. Methods: Data were retrieved by 7 sites. Triple-negative BC was defined by the lack of expression of estrogen receptor (ER <1%), progesterone receptor (PgR <1%) and human-epidermal growth factor receptor-2 (HER2 0, 1+, 2+ ISH-not amplified) according to standard ASCO-CAP criteria. Demographic and clinical characteristics were collected. Premedication, dose modifications and treatment schedule were based on the approved label of the product. Adverse events (AEs) were assessed according to NCI-CTCAE v5.0. Results: Fifty-seven eligible patients who received sacituzumab govitecan for mTNBC were included. Median age was 53 years (range 25-75). Approximately 70% of patients had an initial diagnosis of TNBC. Median time from the diagnosis of metastatic BC to start of sacituzumab govitecan was 17 months (range 0-97) and median number of previous therapies was 3 (range 1-7). The most common sites of metastasis were lymph nodes (63.1% of patients), lung (57.9%), bone (50.8%) and liver (38.6%). Eight (14.0%) patients had a disease-free interval ≤12 months. A total of 32 (56.1%) deaths were observed and the median overall survival (OS) was 12.43 months (95% CI, 7.97 months-not reached). At a median follow-up of 10.6 months, 45 patients (78.9%) had progression and the median progression-free survival (PFS) was 4.9 months (95% CI, 3.7-7.1 months). Partial tumour response was observed in 19 patients (33.3%), stable disease in 16 (28.1%) and disease progression in 22 patients (38.6%). The most common treatment-related AEs were anemia (66.6% of patients), alopecia (66.6%), neutropenia (59.6%), nausea (42.1%) and diarrhea (38.6%). Neutropenia was the most common serious treatment-related AE: 21.0% and 8.7% of patients experienced grade 3 or 4 neutropenia, respectively. Twenty-two patients (38.6%) reduced the dose and 5.3% permanently discontinued treatment. Conclusion: The results of this real-world analysis showed that both safety and efficacy of sacituzumab govitecan in mTNBC patients are consistent with that previously reported in regulatory trials. The use of premedication and supportive measures was associated with a satisfactory toxicity profile.

Estrogen deprivation effects of endocrine therapy in breast cancer patients: Incidence, management and outcome.

Endocrine therapy is one of the standard adjuvant treatments to reduce the risk of recurrence and mortality in patients with hormone receptor positive early breast cancer. Despite its proven efficacy, ET side effects, which persist over time even if low grade, may deteriorate quality of life. During follow-up visits, emphasis is generally placed on the risk of disease recurrence, while the topic of ET side effects is commonly neglected and discussed only briefly. This could lead to poor adherence to therapy and early treatment discontinuation, resulting in worse survival outcomes. The aim of this review is to provide an overview of the available evidence on the incidence and reporting of ET-related side effects (including vasomotor symptoms, musculoskeletal disorders and genitourinary syndrome of menopause, as well as fatigue, psychological and ocular disorders, dysmetabolic effects and loss of bone density) and of the pharmacological and non-pharmacological strategies available to mitigate symptom burden.

Neratinib as adjuvant therapy in patients with HER2 positive breast cancer: expert opinion.

Neratinib is a tyrosine kinase receptor inhibitor used in the extended adjuvant therapy of early-stage breast cancer. After adjuvant trastuzumab therapy, neratinib reduces the risk of recurrence and, if taken within 1 year from trastuzumab, significantly improves the invasive disease-free survival of patients with early-stage human epidermal growth factor receptor-2 positive (HER2+) breast cancer with no increased risk of long-term toxicity. Diarrhea, the most common adverse event associated with neratinib use, deters some clinicians from prescribing this drug. However, neratinib-related toxicity is predictable, short-lived, mostly limited to the first month of treatment and can be managed with dose-escalation and prophylactic strategies. Thus, close surveillance and prompt management, relying on supportive care and administration schedule modification, allows discontinuation of treatment to be avoided.

Impaired Seroconversion After Severe Acute Respiratory Syndrome Coronavirus 2 mRNA Vaccine in Patients With Thymic Epithelial Tumors.

INTRODUCTION: Thymic epithelial tumors (TETs) are rare malignancies associated with dysregulation of the immune system and humoral- and cell-mediated immunity abnormalities. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine is effective in preventing coronavirus disease 2019 morbidity and mortality. The aim of this study was to evaluate the seroconversion in patients with TET after two doses of mRNA vaccine. METHODS: This is a prospective study in which consecutive patients with TET were enrolled before receiving the first dose of SARS-CoV-2 mRNA vaccine (BNT162b2 by Pfizer-BioNTech). SARS-CoV-2 spike-binding immunoglobulin (Ig)G antibody serologic levels were analyzed at different time points, including before first vaccine dose (T0), 1 month after the second dose (T2), and 3 months after the second dose (T3). RESULTS: Overall, 39 patients were included in the analysis. All patients had negative antibody titer results at T0. There were 19 patients (48.7%) in the follow-up with no residual tumor lesion/s (referred as no evidence of disease), and 20 (51.3%) had evidence of disease (ED) and were receiving systemic treatment. Dysregulations of the immune system were diagnosed in 29 patients (74.4%) with Good syndrome (GS) being the most frequent immune disorder (48.7%). At univariate analysis, lack of seroconversion at T2 was significantly associated with ED (p < 0.001) and with GS (p = 0.043). A significant association with impaired seroconversion was confirmed at multivariate analysis for ED (p = 0.00101) but not for GS (p = 0.625). CONCLUSIONS: Our data revealed that patients with TET with ED had substantially higher probability of impaired seroconversion after SARS-CoV-2 mRNA vaccine as compared with patients with no evidence of disease.

Resistivity Technique for the Evaluation of the Integrity of Buccal and Esophageal Epithelium Mucosa for In Vitro Permeation Studies: Swine Buccal and Esophageal Mucosa Barrier Models.

Permeation assays are important for the development of topical formulations applied on buccal mucosa. Swine buccal and esophageal epithelia are usually used as barriers for these assays, while frozen epithelia have been used to optimize the experimental setup. However, there is no consensus on these methods. In transdermal studies, barrier integrity has been evaluated by measuring electrical resistance (ER) across the skin, which has been demonstrated to be a simple, fast, safe, and cost-effective method. Therefore, the aims here were to investigate whether ER might also be an effective method to evaluate buccal and esophageal epithelium mucosa integrity for in vitro permeation studies, and to establish a cut-off ER value for each epithelium mucosa model. We further investigated whether buccal epithelium could be substituted by esophageal epithelium in transbuccal permeation studies, and whether their permeability and integrity were affected by freezing at -20 °C for 3 weeks. Fresh and frozen swine buccal and esophageal epithelia were mounted in Franz diffusion cells and were then submitted to ER measurement. Permeation assays were performed using lidocaine hydrochloride as a hydrophilic drug model. ER was shown to be a reliable method for evaluating esophageal and buccal epithelia. The esophageal epithelium presented higher permeability compared to the buccal epithelium. For both epithelia, freezing and storage led to decreased electrical resistivity and increased permeability. We conclude that ER may be safely used to confirm tissue integrity when it is equal to or above 3 kΩ for fresh esophageal mucosa, but not for buccal epithelium mucosa. However, the use of esophageal epithelium in in vitro transmucosal studies could overestimate the absorption of hydrophilic drugs. In addition, fresh samples are recommended for these experiments, especially when hydrophilic drugs are involved.

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors.

Deregulation of cell cycle, via cyclin D/CDK/pRb pathway, is frequently observed in breast cancer lending support to the development of drugs targeting the cell cycle control machinery, like the inhibitors of the cycline-dependent kinases (CDK) 4 and 6. Up to now, three CDK4/6 inhibitors have been approved by FDA for the treatment of hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. These agents have been effective in improving the clinical outcomes, but the development of intrinsic or acquired resistance can limit the efficacy of these treatments. Clinical and translational research is now focused on investigation of the mechanism of sensitivity/resistance to CDK4/6 inhibition and novel therapeutic strategies aimed to improve clinical outcomes. This review summarizes the available knowledge regarding CDK4/6 inhibitor, the discovery of new biomarkers of response, and the biological rationale for new combination strategies of treatment.

Red nacional para la atención de niños/as con fisuras orales: organización, funcionamiento y primeros resultados / National Health Care Network for children with oral clefts: organization, functioning, and preliminary outcomes

Introducción. Las fisuras orales son anomalías congénitas mayores que comprometen la integridad del labio y/o paladar, y pueden también afectar la nariz y las fosas nasales. La prevalencia enArgentina esde, aproximadamente, 15 afectados cada 10 000 nacimientos. El Ministerio de Salud de la Nación implemento, a partir del año 2015, una red nacional para la atención de niños/as con fisuras orales en Argentina a través de un trabajo conjunto entre la Red Nacional de Anomalías Congénitas (RENAC) (centro coordinador de la red nacional) y el Programa SUMAR. El objetivo de este trabajo es describir la red de atención y sus primeros resultados. Población y métodos. Se identificaron y acreditaron 61 instituciones que realizaban el tratamiento de fisuras orales de manera integral o articuladamente con otras instituciones. Se conectaron las maternidades con las instituciones tratantes, que se agruparon en nodos de la red de atención. Resultados. En el período entre marzo de 2015 y febrero de 2016, se identificaron 550 recién nacidos con cobertura exclusiva del sector público de salud. De ellos, un 18% presentó fisura de labio; 62%, fisura de labio y paladar; y 20%, fisura de paladar únicamente; en un 75% se presentaron de forma aislada y, en un 25%, asociadas a otras anomalías congénitas. Conclusión. Un 70% de los niños fue evaluado por una institución tratante acreditada y se encuentran en tratamiento. Se busca mejorar la sistematización de los datos, incorporar mayor cantidad de instituciones, fortalecer el trabajo interdisciplinario de los equipos y promover estándares de calidad para los tratamientos.

Introduction. Oral clefts are major congenital anomalies that may affect the lip and/or palate, and that may also involve the nose and nostrils. In Argentina, their prevalence is approximately 15 per 10 000 births. In 2015, the Ministry of Health of Argentina created a national health care network for children with oral clefts in Argentina through the joint work with the National Registry of Congenital Anomalies (Red Nacional de Anomalías Congénitas, RENAC) (coordinating center for the national network) and the SUMAR Program. The objective of this study was to describe the health care network and its preliminary outcomes. Population and methods. A total of 61 centers that provided a comprehensive treatment for oral clefts or in collaboration with other centers were identified and accredited. Maternity centers were connected with treating centers grouped in health care network nodes. Results. In the period between March 2015 and February 2016, 550 newborn infants who were exclusively covered by the public health care system were identified. Among these, 18% had a cleft lip; 62%, cleft lip and palate; and 20%, cleft palate only; 75% were isolated cases and 25%, in association with other congenital anomalies. Conclusion. Approximately 70% of children were assessed by a certified treating institution and are receiving treatment. The network seeks to improve data systematization, include the largest number of centers possible, strengthen interdisciplinary team work, and promote high-quality standards for treatments.

National Health Care Network for children with oral clefts: organization, functioning, and preliminary outcomes. / Red nacional para la atención de niños/as con fisuras orales: organización, funcionamiento y primeros resultados.

INTRODUCTION: Oral clefts are major congenital anomalies that may affect the lip and/or palate, and that may also involve the nose and nostrils. In Argentina, their prevalence is approximately 15 per 10 000 births. In 2015, the Ministry of Health of Argentina created a national health care network for children with oral clefts in Argentina through the joint work with the National Registry of Congenital Anomalies (Red Nacional de Anomalías Congénitas, RENAC) (coordinating center for the national network) and the SUMAR Program. The objective of this study was to describe the health care network and its preliminary outcomes. POPULATION AND METHODS: A total of 61 centers that provided a comprehensive treatment for oral clefts or in collaboration with other centers were identified and accredited. Maternity centers were connected with treating centers grouped in health care network nodes. RESULTS: In the period between March 2015 and February 2016, 550 newborn infants who were exclusively covered by the public health care system were identified. Among these, 18% had a cleft lip; 62%, cleft lip and palate; and 20%, cleft palate only; 75% were isolated cases and 25%, in association with other congenital anomalies. CONCLUSION: Approximately 70% of children were assessed by a certified treating institution and are receiving treatment. The network seeks to improve data systematization, include the largest number of centers possible, strengthen interdisciplinary team work, and promote high-quality standards for treatments.

INTRODUCCIÓN: Las fisuras orales son anomalías congénitas mayores que comprometen la integridad del labio y/o paladar, y pueden también afectar la nariz y las fosas nasales. La prevalencia enArgentina esde, aproximadamente, 15 afectados cada 10 000 nacimientos. El Ministerio de Salud de la Nación implemento, a partir del año 2015, una red nacional para la atención de niños/as con fisuras orales en Argentina a través de un trabajo conjunto entre la Red Nacional de Anomalías Congénitas (RENAC) (centro coordinador de la red nacional) y el Programa SUMAR. El objetivo de este trabajo es describir la red de atención y sus primeros resultados. POBLACIÓN Y MÉTODOS: Se identificaron y acreditaron 61 instituciones que realizaban el tratamiento de fisuras orales de manera integral o articuladamente con otras instituciones. Se conectaron las maternidades con las instituciones tratantes, que se agruparon en nodos de la red de atención. RESULTADOS: En el período entre marzo de 2015 y febrero de 2016, se identificaron 550 recién nacidos con cobertura exclusiva del sector público de salud. De ellos, un 18% presentó fisura de labio; 62%, fisura de labio y paladar; y 20%, fisura de paladar únicamente; en un 75% se presentaron de forma aislada y, en un 25%, asociadas a otras anomalías congénitas. CONCLUSIÓN: Un 70% de los niños fue evaluado por una institución tratante acreditada y se encuentran en tratamiento. Se busca mejorar la sistematización de los datos, incorporar mayor cantidad de instituciones, fortalecer el trabajo interdisciplinario de los equipos y promover estándares de calidad para los tratamientos.

Evaluation of different pig oral mucosa sites as permeability barrier models for drug permeation studies.

The objective of the present study was to investigate the influence of preparation and storage conditions on the histology and permeability of different parts of porcine oral mucosa used for in vitro studies of transbuccal formulations. Fresh and frozen (-20°C and -80°C, with or without cryoprotectant) epithelia of porcine palatal, gingival, dorsum of the tongue, and buccal mucosa were submitted for histological analyses to determine the effects of storage conditions on barrier integrity. Permeation of lidocaine hydrochloride (used as a hydrophilic model drug) across fresh and previously frozen oral epithelium was measured in order to evaluate the barrier function. Histological evaluation demonstrated that the oral epithelium was successfully separated from the connective tissue, except for gingival mucosa. After storage under different conditions, all tissues presented desquamation of superficial layers and spherical spaces induced by the freezing process. The permeability of lidocaine hydrochloride varied among the fresh oral mucosa and generally increased after freezing. In conclusion, fresh epithelium from the buccal and dorsum of the tongue mucosa should be used for in vitro studies investigating hydrophilic drug transport when these are the desired clinical application sites. However, when the palate is the target site, both fresh and frozen (for up to 4weeks, without addition of cryoprotectant) samples could be used. The addition of glycerol as a cryoprotectant should be avoided due to increased lidocaine hydrochloride permeability.

Hepatocyte growth factor (HGF) and hemodialysis: physiopathology and clinical implications.

Hepatocyte growth factor (HGF) is a pleiotropic cytokine which exerts a variety of effects on several cells, being involved in the regulation of many biological processes, such as inflammation, tissue repair, morphogenesis, angiogenesis, tumour propagation, immunomodulation of viral infections and cardio-metabolic activities. Patients undergoing regular hemodialysis (HD) present elevated levels of HGF, mainly due to the leukocyte activation associated with HD treatment. High HGF levels might account for specific clinical features of HD patients, i.e. mild liver damage in course of HCV-infection and high cardiovascular risk profile. Moreover, in patients with acute kidney injury, the induction of HGF may represent a crucial step to promote renal recovery, which can have important prognostic consequences in the short and long-term. In this review we discuss the mechanisms underlying HGF production in HD patients, the role of HGF in this particular patient population and the potential clinical implications derived from the study of HGF in HD patients.

Sirolimus vs cyclosporine after induction with basiliximab does not promote regulatory T cell expansion in de novo kidney transplantation: Results from a single-center randomized trial.

Regulatory T cells (Tregs), defined as CD4+CD25+highFoxP3+CD127- cells, could promote tolerance in renal transplantation (Tx). In an open-label, randomized, controlled trial 62 de-novo Tx recipients received induction with basiliximab and cyclosporine A (CsA) for the first month after Tx and then were assigned to treatment with sirolimus (SRL) or CsA and followed up for 2 years. The primary endpoint was to evaluate the effects of induction and maintenance treatments on circulating Tregs, while the secondary endpoint was the assessment of Treg renal infiltration and the relationship between Treg count and clinical outcomes. There were no significant differences in either circulating or tissue Treg number between the two groups. At 1 month post-Tx, all patients presented a profound Treg depletion, followed by a significant increase in Tregs that resulted stable during the follow-up. The same trend was also observed for non-activated Tregs (CD69-) and for other immunocompetent cells (CD4+ and CD8+ T cells, B cells and NK cells). Moreover, the Treg count did not correlate either with renal function or with acute rejection and graft loss. Initial immunosuppression is crucial to regulate circulating Tregs, regardless of subsequent immunosuppressive maintenance regimens. Strategies aiming to promote tolerance should consider the effects of different induction regimens.

[Heparin-induced trombocytopenia: pathogenesis, clinical manifestations and management in hemodialysis]. / Piastrinopenia indotta da eparina: patogenesi, manifestazioni cliniche e management in emodialisi.

Heparin has remained the most commonly used anticoagulant in hemodialysis patients (HD). Its use is usually safe but, in some cases, important adverse effects can occur. Heparin-induced thrombocytopenia (HIT) is an immuno-mediated condition due to the formation of PF4/heparin/IgG complex leading to the activation of platelets and coagulative cascade. The consequent prothrombotic hypercoagulable state may cause venous or arterial thrombosis, skin gangrene and acute platelet activation syndrome. Clinical and laboratory findings may be suggestive for HIT, but formal diagnosis requires the demonstration of the presence of circulating antibodies. Clinical management is complex including the withdrawal of any form of heparin and the administration of anticoagulants. In addition, since anticoagulation is routinely required to prevent clotting of the dialysis lines and membranes, in HD patients presenting HIT it is mandatory to establish heparin-free anticoagulation strategies. Thus, the use of citrate, direct thrombin inhibitors or eparinods have been proposed as alternative anticoagulation approaches in HIT. Here, we review the most important pathogenic factors and clinical features of HIT occurring in HD patients.

Ethnobiology of snappers (Lutjanidae): target species and suggestions for management.

In this study, we sought to investigate the biology (diet and reproduction) and ethnobiology (fishers knowledge and fishing spots used to catch snappers) of five species of snappers (Lutjanidae), including Lutjanus analis, Lutjanus synagris, Lutjanus vivanus, Ocyurus chrysurus, and Romboplites saliens at five sites along the northeast (Riacho Doce, Maceió in Alagoas State, and Porto do Sauípe, Entre Rios at Bahia State) and the southeast (SE) Brazilian coast (Paraty and Rio de Janeiro cities at Rio de Janeiro State, and Bertioga, at São Paulo State.).We collected 288 snappers and interviewed 86 fishermen. The stomach contents of each fish were examined and macroscopic gonad analysis was performed. Snappers are very important for the fisheries of NE Brazil, and our results indicated that some populations, such as mutton snapper (L. analis) and lane snapper (L. synagris), are being caught when they are too young, at early juvenile stages.Local knowledge has been shown to be a powerful tool for determining appropriate policies regarding management of target species, and artisanal fishermen can be included in management processes. Other suggestions for managing the fisheries are discussed, including proposals that could provide motivation for artisanal fishermen to participate in programs to conserve resources, such as co-management approaches that utilize local knowledge, the establishment of fishing seasons, and compensation of fishermen, through 'payment for environmental services'. These suggestions may enhance the participation of local artisanal fishermen in moving to a more realistic and less top-down management approach of the fish population.