Neonatal severe COVID-19 infection complicated by Staphilococcus aureus could be misinterpreted as MIS-C?: case report and review of literature.

At 23 days of life a neonate presented to the emergency room with crying and decreased oral intake. His parents were positive to SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), but he turned out negative. After one week he was admitted to NICU (neonatal intensive care unit) for respiratory failure, and nasopharyngeal swab (PCR test: polymerase chain reaction test) was positive for SARS-CoV-2. On examination the child had fever, tachy-dyspnea, reduced oxygen saturation, tachycardia, abdominal distension and tenderness, irritability and hypertonia. Blood exam showed respiratory acidosis, lymphocytopenia, hypoalbuminemia and coagulopathy; CRP (C reactive protein), procalcitonin, D-dimer, ferritin and NT-proBNP (N-terminal prohormone of brain natriuretic peptide) were elevated. Chest X-ray revealed bilateral interstitial infi ltration and abdomen ultrasound a thin fl uid effusion; echocardiography was normal. SARS-CoV-2 PCR tests on CSF (cerebrospinal fluid) and stool were also positive. He was started on non-invasive intermittent positive pressure respiratory ventilation, treated with antibiotic therapy, methylprednisolone, intravenous immunoglobulins, and antiplatelet therapy. Rapid clinical improvement was seen with remission of fever after eight days. The child complicated with bacterial super-infection presenting as pleural empyema. As presented in our case, it is not always easy to differentiate between severe forms of COVID-19 and MIS-C. Due to the rarity of these presentations in neonates, multicentric collaboration is needed to identify the specifi c characteristics of the two forms, better defi ne diagnostic criteria, and treatment options.

Early-onset fulminant neonatal sepsis caused by Multi-Drug Resistant and ESBL producing E. coli (CTX-M gene) in a late-preterm neonate: case report and literature review.

Neonatal sepsis is a systemic condition characterized by haemodynamic changes and other clinical manifestations due to a presence of pathogenic microorganisms (bacteria, viruses, or fungi) in nor- mally sterile fluid that occurs in an infant younger than 90 days old. Neonatal sepsis may be divided into two types: early-onset neonatal sepsis (EOS) and late-onset neonatal sepsis (LOS). Gram-posi- tive microorganisms are the etiological agents in 62% of EOS, and in 43% of the total the identified microorganism is GBS. Gram-negative microorganisms comprise 37% of the etiological agents of EOS, of which 29% are caused by Escherichia coli. ESBL-producing Enterobacteriaceae represent a major worldwide threat among drug-resistant bacteria in both hospital and community settings. ESBLs are often located on large plasmids that also harbour genes resistant to other antimicrobial classes, resulting in multidrug-resistant isolates. Plasmid-encoded ESBLs of the CTX-M-type are increasingly reported worldwide in Gram-negative rods and now account for most of the ESBLs found in Enterobacteriaceae. We present one case of EOS by Multi Drug Resistant (MDR) and ESBL producing E. coli (CTX-M gene) in a neonate born to a mother recently immigrated from Africa. Maternal blood culture grew the same bacteria.

Perfusion Index and Pulse Oximetry Screening for Congenital Heart Defects.

OBJECTIVE: To evaluate the efficacy of combined pulse oximetry (POX) and perfusion index (PI) neonatal screening for severe congenital heart defects (sCHD) and assess different impacts of screening in tertiary and nontertiary hospitals. STUDY DESIGN: A multicenter, prospective study in 10 tertiary and 6 nontertiary maternity hospitals. A total of 42 169 asymptomatic newborns from among 50 244 neonates were screened; exclusion criteria were antenatal sCHD diagnosis, postnatal clinically suspected sCHD, and neonatal intensive care unit admission. Eligible infants underwent pre- and postductal POX and PI screening after routine discharge examination. Targeted sCHD were anatomically defined. Positivity was defined as postductal oxygen saturation (SpO2) ≤95%, prepostductal SpO2 gradient >3%, or PI <0.90. Confirmed positive cases underwent echocardiography for definitive diagnosis. Missed cases were identified by consulting clinical registries at 6 regional pediatric heart centers. Main outcomes were incidence of unexpected sCHD; proportion of undetected sCHD after discharge in tertiary and nontertiary hospitals; and specificity, sensitivity, positive predictive value, and negative predictive value of combined screening. RESULTS: One hundred forty-two sCHD were detected prenatally. Prevalence of unexpected sCHD was 1 in 1115 live births, similar in tertiary and nontertiary hospitals. Screening identified 3 sCHD (low SpO2, 2; coarctation for low PI, 1). Four cases were missed. In tertiary hospitals, 95% of unsuspected sCHDs were identified clinically, whereas only 28% in nontertiary units; in nontertiary units PI-POX screening increased the detection rate to 71%. CONCLUSIONS: PI-POX predischarge screening provided benefits in nontertiary units, where clinical recognition rate was low. PI can help identify coarctation cases missed by POX but requires further evaluation in populations with higher rates of missed cases.

Transient Exposure of Endothelial Cells to Doxorubicin Leads to Long-Lasting Vascular Endothelial Growth Factor Receptor 2 Downregulation.

Doxorubicin (Dox) is an effective antineoplastic drug with serious cardiotoxic side effects that persist after drug withdrawal and can lead to heart failure. Dysregulation of vascular endothelium has been linked to the development of Dox-induced cardiotoxicity, but it is unclear whether and how transient exposure to Dox leads to long-term downregulation of Endothelial Vascular Endothelial Growth Factor Receptor type2 (VEGFR2), essential for endothelial cells function. Using an in vitro model devised to study the long-lasting effects of brief endothelial cells exposure to Dox, we show that Dox leads to sustained protein synthesis inhibition and VEGFR2 downregulation. Transient Dox treatment led to the development of long-term senescence associated with a reduction in VEGFR2 levels that persisted days after drug withdrawal. By analyzing VEGFR2 turnover, we ruled out that its downregulation was depended on Dox-induced autophagy. Conversely, Dox induced p53 expression, reduced mTOR-dependent translation, and inhibited global protein synthesis. Our data contribute to a mechanistic basis to the permanent damage caused to endothelial cells by short-term Dox treatment.

Use of paclitaxel carried in lipid core nanoparticles in patients with late-stage solid cancers with bone metastases: Lack of toxicity and therapeutic benefits.

Patients with heavily pretreated, late-stage cancer and bone metastasis are usually poor candidates for further chemotherapy. Previously, we showed that association to lipid nanoparticles (LDE) drastically decreases the toxicity of anti-cancer drugs. Here, we tested the hypothesis that paclitaxel (PTX) carried in LDE could benefit end-of-life patients with painful bone metastases that had been previously treated with conventional PTX. Methods: Eighteen consecutive patients with late-stage cancer, 8 with breast, 5 with prostate and 5 with lung carcinoma, aged 59±9 years, were included in this study. All were receiving opioid medication. LDE-PTX was administered at 175 mg/m 2 every 3 weeks until disease progression. Clinical imaging examinations and serum biochemistry determinations were performed to monitor disease progression. Intensity of bone pain, use of opioid medications and occurrence of pathological bone fractures were also evaluated. Results: In total, 104 chemotherapy cycles were performed and none of the patients showed clinical and laboratorial toxicities or pathological bone fractures. In all patients, pain was reduced so as to allow substitution of non-opioid for opioid medication. Median progression-free survival (PFS) was four months (95% CI 2.4-5.5), but in five patients PFS was longer than 6 months. Conclusions: Absence of observable clinical and laboratorial toxicities from LDE-PTX treatment, improvement of bone pain and the possible effect on PFS in some patients, despite previous use of conventional PTX, suggest that LDEPTX merits further clinical investigation .

Generalized Arterial Calcification of Infancy Type 1 (GACI1): Identification of a Novel Pathogenic Variant (c.1715T>C (p.Leu572Ser)).

Generalized Arterial Calcification of Infancy (GACI) is a rare disease inherited in a recessive manner, with severe and diffuse early onset of calcifications along the internal elastic lamina in large and medium size arteries. The diagnosis results are from clinical manifestations, imaging, histopathologic exams, and genetic tests. GACI is predominantly caused by biallelic pathogenic variant in the ENPP1 gene (GACI1, OMIM#208000) and, to a lesser extent, by pathogenic variants in the ABCC6 gene (GACI2, OMIM#614473). We present a novel variation in the ENPP1 gene identified in a patient clinically diagnosed with GACI and confirmed by genetic investigation and autopsy as GACI type 1. The sequence analysis of the patient's ENPP1 gene detected two heterozygous variants c.1412A>G (p.Tyr471Cys) and c.1715T>C (p.Leu572Ser). The variant c.1715T>C (p.Leu572Ser) has not been described yet in the literature and in mutation databases. A genetic analysis was also carried out for the parents of the newborn; the heterozygous pathogenic variant c.1412A>G (p.Tyr471Cys) was detected in the mother's ENPP1 gene, and a sequence analysis of the father's ENPP1 gene revealed the novel heterozygous variant c.1715T>C (p.Leu572Ser). Our results showed that the variant c.1715T>C (p.Leu572Ser) may have a pathogenic role in the development of GACI type1 (GACI1, OMIM#208000), at least when associated with the pathogenic c.1412A>G (p.Tyr471Cys) variant. The identification of novel mutations potentially enabled genotype/phenotype associations that will ultimately have an impact on clinical management and prognosis for the disease.

Development of a Perinatal Palliative Care Model at a Level II Perinatal Center Supported by a Pediatric Palliative Care Network.

Objective: To describe the model build up to take care of fetuses and newborns eligible to perinatal palliative care (PnPC) followed in an Italian II level perinatal center. Methods: Retrospective chart review of all fetuses and newborn infants eligible to PnPC admitted to level II perinatal center within a 4 years period. Results: Forty-five of 848 infants (0.5%) referred to II level NICU were eligible to PnPC. Twenty-seven percentage had fetal diagnosis. Twenty percentage were preterm infants at the limit of viability, 35% were newborns with life limiting or life threatening disease diagnosed in utero or at the postnatal ward, 45% were newborns not responding to intensive care intervention with high health care needs or medical complexity. Fifty-seven percentage of neonates admitted to NICU died before discharge, while 16 (35% of population considered) were discharged home. Median age at death was 4 days after birth, and delivery room death immediately after birth occurred in six patients (13%). Conclusions: Despite the paucity of our population and the high variability in disease trajectories the perinatal palliative care program build up in our region provides a reproducible method for a structured taking in charge of fetuses and neonates eligible to PnPC and their families, from the time of diagnosis to bereavement, in both outpatient and inpatient settings.

Impact of cancer-related symptom synergisms on health-related quality of life and performance status.

To identify the impact of multiple symptoms and their co-occurrence on health-related quality of life (HRQOL) dimensions and performance status (PS), 115 outpatients with cancer, who were not receiving active cancer treatment and were recruited from a university hospital in Sao Paulo, Brazil completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30, the Beck Depression Inventory, and the Brief Pain Inventory. Karnofsky Performance Status scores also were completed. Application of TwoStep Cluster analysis resulted in two distinct patient subgroups based on 113 patient experiences with pain, depression, fatigue, insomnia, constipation, lack of appetite, dyspnea, nausea, vomiting, and diarrhea. One group had multiple and severe symptom subgroup and another had less symptoms and with lower severity. Multiple and severe symptoms had worse PS, role functioning, and physical, emotional, cognitive, social, and overall HRQOL. Multiple and severe symptom subgroup was also six times as likely as lower severity to have poor role functioning; five times more likely to have poor emotional; four times more likely to have poor PS, physical, and overall HRQOL; and three times as likely to have poor cognitive and social HRQOL, independent of gender, age, level of education, and economic condition. Classification and Regression Tree analyses were undertaken to identify which co-occurring symptoms would best determine reduction in HRQOL and PS. Pain and fatigue were identified as indicators of reduction on physical HRQOL and PS. Fatigue and insomnia were associated with reduction in cognitive; depression and pain in social; and fatigue and constipation in role functioning. Only depression was associated with reduction in overall HRQOL. These data demonstrate that there is a synergic effect among distinct cancer symptoms that result in reduction in HRQOL dimensions and PS.

Pharmacokinetics and tumor uptake of a derivatized form of paclitaxel associated to a cholesterol-rich nanoemulsion (LDE) in patients with gynecologic cancers.

OBJECTIVE: A cholesterol-rich nanoemulsion termed LDE concentrates in cancer tissues after injection into the bloodstream. The association of a derivatized paclitaxel to LDE showed lower toxicity and increased antitumoral activity as tested in a B16 melanoma murine model. Here, the pharmacokinetics of LDE-paclitaxel oleate and the ability of LDE to concentrate the drug in the tumor were investigated in patients with gynecologic cancers. METHODS: Either LDE-paclitaxel oleate doubly labeled with [(14)C]-cholesteryl oleate and [(3)H]-paclitaxel oleate or [(3)H]-paclitaxel-cremophor was intravenously injected into eight patients. Blood samples were collected over 24 h to determine the plasma decay curves. Fractional clearance rate (FCR) and pharmacokinetic parameters were calculated by compartmental analysis. Also, specimens of tumors and the corresponding normal tissues were excised during the surgery for radioactivity measurement. RESULTS: The LDE and paclitaxel oleate FCR were similar (0.092 +/- 0.039 and 0.069 +/- 0.027 h(-1), respectively, n = 5, P = 0.390). FCR of paclitaxel oleate associated to LDE was smaller than that of paclitaxel-cremophor (0.231 +/- 0.128 h(-1), P = 0.028). Paclitaxel oleate T (1/2 )and AUC were greater than those of paclitaxel-cremophor (T (1/2 )=( )14.51 +/- 3.23 and 6.62 +/- 2.05 h and AUC = 2.49 +/- 0.35 and 1.26 +/- 0.40, respectively, P = 0.009, P = 0.004). The amount of paclitaxel and LDE-radioactive labels in the tumor was 3.5 times greater than in the normal tissues. CONCLUSION: Paclitaxel oleate associated to LDE is stable in the bloodstream and has greater plasma half-life and AUC than those for paclitaxel-cremophor. LDE concentrates 3.5 times more paclitaxel in malignant tissues than in normal tissues. Therefore, association to LDE is an interesting strategy for using paclitaxel to treat gynecologic cancers.

Clinical experience with drug delivery systems as tools to decrease the toxicity of anticancer chemotherapeutic agents.

INTRODUCTION: The toxicity of chemotherapeutic agents, resulting from their low pharmacological index, introduces considerable discomfort and risk to cancer patients. Among several strategies to reduce the toxicity of chemotherapeutic agents, targeted drug delivery is the most promising one. Areas covered: Liposomes, micelles, albumin-based, polymeric, dendritic and lipid core nanoparticles have been used as carriers to concentrate anticancer drugs in neoplastic tissues, and clinical studies of those preparations are reviewed. In most clinical studies, drug delivery systems reduced drug toxicity. Lipid core nanoparticles (LDE) that bind to cell lipoprotein receptors have the ability to concentrate in neoplastic tissues and were the first artificial non-liposomal system shown in in vivo studies to possess targeting properties. The toxicity reduction achieved by LDE as vehicle of carmustine, etoposide and paclitaxel was singularly strong. Expert opinion: The reduced toxicity offered by drug delivery systems has expanded treatment population that may benefit from chemotherapy including feeble, overtreated and elderly patients that would otherwise be offered palliative therapy. Drug delivery systems may either prolong the duration of treatments or allow increases in drug dose.

Phase II study of paclitaxel associated with lipid core nanoparticles (LDE) as third-line treatment of patients with epithelial ovarian carcinoma.

Ovarian cancer is often diagnosed at advanced stages, when poorly responsive to standard treatment. First-line treatment consists in schemes including cytoreductive surgery followed by adjuvant chemotherapy schemes with platinum and taxane derivatives. Second-line regimens are based on gemcitabine and liposomal doxorubicin. Third line is often not worthwhile because of the high toxicity with poor response to treatment. Previously, we showed that paclitaxel (PTX) carried in non-protein lipid core nanoparticles (LDE) resembling the chemical structure of LDL has remarkably reduced toxicity. Here, the hypothesis was tested whether PTX-LDE could safely benefit patients in third-line treatment setting. Fourteen women unresponsive to second-line chemotherapy for ovarian cancer, aged 61 ± 10 years, clinical stage IV and TqNqM1, were included. PTX-LDE was administered at 175 mg/m2, 3/3 week dose. Patients were submitted to clinical examinations before each chemotherapy cycle. Serum biochemistry and imaging examinations to monitor disease progression were performed. In total, 74 cycles of chemotherapy were done and, in all cycles, clinical or laboratorial toxicities were not observed. Median progression-free survival (PFS) was 3.0 months (95% CI 2.0-3.9). In four patients, PFS was >6 months and in 2 > 1 year. The unpreceded, striking absence of toxicity and consistently long PFS, compared to previous results, indicate that at least 4 among 14 patients had tumor arrest by the treatment and clear benefit of PTX-LDE at third-line setting. The absence of observable toxicity allows dose escalating to improve response to treatment, as perspective to be tested in the ensuing studies.

Association of carmustine with a lipid emulsion: in vitro, in vivo and preliminary studies in cancer patients.

PURPOSE: We had previously shown in acute leukemia and in breast and ovary carcinoma patients that a cholesterol-rich emulsion (LDE) that binds to receptors for low-density lipoprotein (LDL) may concentrate in neoplastic tissues. In this study, the potential of LDE as a carrier for anticancer drugs was investigated. METHODS: LDE was associated with carmustine, and the cytotoxicity of the LDE-carmustine complex was studied in a neoplastic cell line and its biodistribution was studied in mice. The plasma kinetics of the complex and its uptake by tumor and normal tissue were determined in cancer patients. Finally, an exploratory clinical study to determine the toxicity profile of LDE-carmustine at escalating dose levels was conducted in 42 advanced cancer patients refractory to conventional chemotherapy. RESULTS: Carmustine formed a stable association with LDE. The pharmacological action of carmustine, as tested in cancer cells, was not diminished by association with LDE compared with the free drug and was indeed mediated by the LDL receptor. The biodistribution in mice and plasma kinetics in patients of the emulsion were not changed by association of the drug. The uptake of LDE-carmustine by tumor was severalfold greater than the uptake by the corresponding normal tissue. Finally, patients treated with LDE-carmustine showed negligible side effects even at very high dose levels. CONCLUSIONS: Association with LDE preserves the cytotoxicity of carmustine and markedly diminishes its side effects.

Use of cholesterol-rich nanoparticles that bind to lipoprotein receptors as a vehicle to paclitaxel in the treatment of breast cancer: pharmacokinetics, tumor uptake and a pilot clinical study.

PURPOSE: In animal experiments paclitaxel oleate associated with a cholesterol-rich nanoemulsion concentrated in the neoplastic tissues and showed reduced toxicity and increased antitumor activity compared with paclitaxel-Cremophor EL. Here, a clinical study was performed in breast cancer patients to evaluate the tumoral uptake, pharmacokinetics and toxicity of paclitaxel associated to nanoemulsions. METHODS: Twenty-four hours before mastectomy [(3)H]-paclitaxel oleate associated with [(14)C]-cholesteryl oleate-nanoemulsion or [(3)H]-paclitaxel in Cremophor EL were injected into five patients for collection of blood samples and fragments of tumor and normal breast tissue. A pilot clinical study of paclitaxel-nanoemulsion administered at 3-week intervals was performed in four breast cancer patients with refractory advanced disease at 175 and 220 mg/m(2) dose levels. RESULTS: T (1/2) of paclitaxel oleate associated to the nanoemulsion was greater than that of paclitaxel (t (1/2) = 15.4 +/- 4.7 and 3.5 +/- 0.80 h). Uptake of the [(14)C]-cholesteryl ester nanoemulsion and [(3)H]-paclitaxel oleate by breast malignant tissue was threefold greater than the normal breast tissue and toxicity was minimal at the two dose levels. CONCLUSIONS: Our results suggest that the paclitaxel-nanoemulsion preparation can be advantageous for use in the treatment of breast cancer because the pharmacokinetic parameters are improved, the drug is concentrated in the neoplastic tissue and the toxicity of paclitaxel is reduced.

Uptake of a cholesterol-rich emulsion by breast cancer.

OBJECTIVE: Overexpression of low-density lipoprotein (LDL) receptors occurs in several cancer cell lines and offers a unique strategy for drug targeting by using LDL as vehicle. However, the native lipoprotein is difficult to obtain and handle. Previously, we showed that a lipidic emulsion (LDE) similar to the lipid structure of native LDL may bind to LDL receptors and be taken up by acute myelocytic leukemia cells. We also showed that LDE can also concentrate in ovarian cancer tissue. In this study, we tested whether LDE is taken up by breast carcinoma. METHODS: LDE labeled with (99m)Tc was injected into 18 breast cancer patients, and nuclear medicine images of the tumor and metastatic sites were acquired. Subsequently, LDE labeled with [3H]cholesteryl oleate was intravenously injected into 14 breast cancer patients 24-30 h before total mastectomy procedure. Fragments of normal and of breast cancer tissue excised during surgery were lipid extracted with chloroform/methanol and their radioactivity was measured in a scintillation solution. RESULTS: (99m)Tc-LDE images of the primary tumor and of metastasis sites were obtained in all 18 breast cancer patients. As directly measured in the tumor and in the normal mammary tissue, the amount of the emulsion radioactive label in the tumor was 4.5 times greater than in the normal tissue (range 1.2- to 8.8-fold). CONCLUSION: LDE concentrates much more in malignant breast tumor tissue than in the normal tissue. Thus it has potential to carry drugs or radionuclides directed against mammary carcinoma cells for diagnostic or therapeutic purposes.

Uso de uma microemulsão lipídica como veículo de quimioterápicos no tratamento do câncer de mama metastático / Use of a lipidic microemulsion as chemotherapic excipient in metastatic breast cancer

Em estudos anteriores demonstramos que em pacientes portadores de Leucemia Não Linfocítica Aguda e Carcinoma de Mama a microemulsão lipídica se liga a receptores de LDL, sugerindo que a LDE pudesse ser utilizada como carreador de quimiterápicos. Posteriormente, mostramos que o quimioterápico carmustina apresenta bom índice de incorporação à LDE. Foi demonstrado que o complexo é estável quimicamente e que a incorporação ao quimioterápico não altera as propriedades da emulsão. Com base nesses dados, o objetivo do presente estudo foi avaliar a toxicidade clínica e laboratorial do complexo carmustina-LDE dose de 300 mg/m² de superfície corpórea, administrada por via endovenosa a cada 4 semanas, em 18 pacientes portadoras de neoplasia primária de mama e refratária ao tratamento quimioterápico convencional. Esta dose é 20 por cento superior à máxima de carmustina prescrita na quimioterapia convencional, enquanto o intervalo entre as dose é menor...