Baboon‐Like Syndrome in Children

Baboon syndrome is a combination of diffuse symmetrical erythema on the major flexural areas and V‐shaped erythema on both upper anteromedial thighs. Infectious agents have been described as possible triggers. We describe for the first time baboon syndrome in a child induced by a coinfection with Epstein‐Barr virus and cytomegalovirus.     

When is injury potentially reversible in a lung ischemia–reperfusion model?

ObjectiveTo verify the impact of ischemic time on lung cell viability in an experimental model of lung ischemia–reperfusion (IR) injury and its repercussion on lung performance after reperfusion.MethodsTwenty-four animals were subjected to selective clamping of the left pulmonary artery and divided into four groups (n = 6) according to ischemic time: 15 (IR15), 30 (IR30), 45 (IR45), and 60 min (IR60). All animals were observed for 120 min after reperfusion. The hemodynamics, arterial blood gases measurements, and histologic changes were analyzed. Immunofluorescence assays for caspase 3 and annexin V were performed. Lipid peroxidation was assessed by thiobarbituric acid–reactive substances, and caspase 3 activity was assessed by colorimetric extract.ResultsThe partial pressure of arterial oxygen significantly decreased at the end of the observation period in the IR30, IR45, and IR60 groups (P < 0.05). The final mean arterial pressure significantly decreased in the IR60 group (P < 0.05). We observed a significant increase in caspase 3 activity and caspase 3–positive cells by immunofluorescence in the IR45 group compared with the other groups (P < 0.05). Additionally, there was an increase in necrotic cells assessed by annexin V in the IR60 group. The histologic score did not show differences among the different groups.ConclusionsThe degree of cell damage had a negative impact on lung performance. Sixty minutes of lung ischemia and posterior reperfusion resulted in an increased number of necrotic cells, suggesting that these cells may not be able to reverse the effects of the IR injury because of the lack of viable cells.     

Dopamine-induced migrating myoelectrical complex-like activity in human duodenum

The effect of dopamine on human gastric and small intestinal interdigestive motility was investigated in 12 subjects. Intestinal motility was recorded by means of a four-lumen polyvinyl probe with four open tips located 15 cm apart, continuously perfused with distilled water. In each subject during the same study, after recording two consecutive spontaneous phase III of migrating myoelectrical complexes and when a phase II appeared, dopamine was infused intravenously twice in a dose of 5 g/kg/min for 15 min with an interval of 20 min between each infusion. In six subjects, the second dopamine infusion was preceded by a treatment with sulpiride (10 mg, intravenously, as bolus) or domperidone (10 mg, intravenously, as bolus), each considered a highly selective dopamine antagonist. The results show that dopamine stimulates duodenal motility producing a pattern similar to that observed in phase III of spontaneously occurring migrating myoelectrical complexes. The second dopamine infusion reproduced in all cases the same pattern of motility as observed during the first infusion. Sulpiride and domperidone prevented the effect of dopamine in all cases. It is therefore suggested that dopamine-induced duodenal motility may involve specific dopaminergic receptors.     

An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications

We describe the development of OncoFAP, an ultra-high-affinity ligand of fibroblast activation protein (FAP) for targeting applications with pan-tumoral potential. OncoFAP binds to human FAP with affinity in the subnanomolar concentration range and cross-reacts with the murine isoform of the protein. We generated various fluorescent and radiolabeled derivatives of OncoFAP in order to study biodistribution properties and tumor-targeting performance in preclinical models. Fluorescent derivatives selectively localized in FAP-positive tumors implanted in nude mice with a rapid and homogeneous penetration within the neoplastic tissue. Quantitative in vivo biodistribution studies with a lutetium-177–labeled derivative of OncoFAP revealed a preferential localization in tumors at doses of up to 1,000 nmol/kg. More than 30% of the injected dose had already accumulated in 1 g of tumor 10 min after intravenous injection and persisted for at least 3 h with excellent tumor-to-organ ratios. OncoFAP also served as a modular component for the generation of nonradioactive therapeutic products. A fluorescein conjugate mediated a potent and FAP-dependent tumor cell killing activity in combination with chimeric antigen receptor (CAR) T cells specific to fluorescein. Similarly, a conjugate of OncoFAP with the monomethyl auristatin E-based Vedotin payload was well tolerated and cured tumor-bearing mice in combination with a clinical-stage antibody-interleukin-2 fusion. Collectively, these data support the development of OncoFAP-based products for tumor-targeting applications in patients with cancer.

Small organic ligands which selectively bind with high affinity to tumor-associated antigens are increasingly applied as targeting delivery vehicles of small payloads such as radionuclides (1, 2), drugs (3–5), and fluorophores (6, 7) to tumor sites. In principle, the use of small ligands for targeting applications offers several advantages compared to intact immunoglobulins, including superior penetration of solid neoplastic lesions (8), lower immunogenicity (9), and a reduced cost of goods (10). Low molecular weight compounds may reach their target in vivo in a matter of seconds, thanks to rapid extravasation after intravenous administration (8). A strikingly selective accumulation of small ligands in neoplastic masses has been demonstrated for a small number of targets including somatostatin receptor type 2 (SSTR-2) (11), prostate-specific membrane antigen (PSMA) (12), and carbonic anhydrase IX (CAIX) (13), for which high-affinity small organic ligands are available. Those ligands are typically specific for defined tumor entities, such as neuroendocrine tumors (11), prostate cancer (3), and clear cell renal cell carcinoma (2).¹⁷⁷Lu-DOTATATE (Lutathera), a small-molecule product targeting SSTR-2, has been approved based on phase III data in which a clinically meaningful 82% reduction in the risk of disease progression or death was demonstrated in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) (14). Similar data are expected from the currently ongoing phase III VISION trial for ¹⁷⁷Lu-PSMA-617 (clinical trial no. {"type":"clinical-trial","attrs":{"text":"NCT03511664","term_id":"NCT03511664"}}NCT03511664), a radiolabeled small molecule that binds with high affinity to PSMA and that enables targeted beta particle therapy in metastatic castration-resistant prostate cancer patients (15). PHC-102, a ^99mTc-labeled small-molecule derivative targeting CAIX, exhibited favorable uptake in primary and metastatic lesions in patients with renal cell carcinoma (RCC) (2). In light of the promising performance of small organic ligands, it would be desirable to discover and develop small molecules with a broader tumor-targeting potential, therefore covering multiple cancer types.Fibroblast activation protein (FAP) is a type II integral membrane serine protease which is abundantly expressed in the stroma of more than 90% of the epithelial cancers, including malignant breast, colorectal, skin, prostate, and pancreatic cancers (16, 17), while exhibiting a restricted expression in normal adult tissues (18, 19). Haberkorn and coworkers (1, 20, 21) have recently described a series of FAP ligands capable of selective accumulation in FAP-positive tumors in mice and in patients. One of these products (named FAPI-04) showed impressive tumor to background ratios at early time points (i.e., few hours after administration) in a broad range of different cancer types in patients. More than 28 tumor types including breast, lung, pancreatic, head and neck, esophagus, and colorectal cancer presented a remarkably high uptake of a FAP-targeted small molecule labeled with gallium-68 (1, 20, 21). For this reason, FAP has recently been dubbed as “the next billion-dollar target for theranostic products” (22).Here, we describe how the chemical modification of a quinoline moiety in position 8 led to the discovery of OncoFAP, a small organic FAP ligand with a dissociation constant in the subnanomolar concentration range. OncoFAP exhibited a strikingly selective and efficient tumor-targeting performance when equipped with various types of payloads, including radionuclides, fluorophores, and cytotoxic drugs. The targeting delivery of radionuclides to solid tumors is rapidly gaining in popularity, as it may open theranostic opportunities, associated with the use of gallium-68 for positron emission tomography (PET) imaging and of lutetium-177 for therapeutic applications (23). The delivery of fluorescein to tumors enables the conditional activation of chimeric antigen receptor (CAR) T cells, which display a potent biocidal activity only in the presence of fluorescein-labeled adaptor molecules specific to a tumor antigen (24, 25). Finally, small-molecule–drug conjugates (SMDCs) promise to represent a valid alternative to antibody–drug conjugates for cancer therapy, with better tumor penetration and a lower cost of goods (8, 26, 27).     

Reoperations in patients with patent left internal mammary artery.

In the past decade the rate of reoperative coronary bypass grafting has averaged 8%. In these patients adequate myocardial protection is often difficult because delivery of cardioplegia is frequently suboptimal when the internal mammary artery graft is patent. We describe a simple technique for performing cardiac reoperation in patients with a patent left internal mammary artery graft through a balloon catheter used for angioplasty and positioned in the left internal mammary artery graft. Our study included 3 patients and there were no operative deaths and complications.     

Hb Southern Italy: coexistence of two missence mutations (the Hb Sun Prairie alpha2 130 Ala --> Pro and Hb Caserta alpha2 26 Ala --> Thr) in a single HBA2 gene

This study describes a new molecular condition in the alpha(2)-globin gene (HBA2) found in six unrelated families from Southern Italy (Campania and Sicily). This new double mutant form of haemoglobin is called Hb Southern Italy and originated from the coexistence of two known mutations occurring in the same globin gene, HBA2 26 G-->A (Hb Caserta) and HBA2 130 G-->C (Hb Sun Prairie). Hb Sun Prairie was originally observed in Indian patients in either the homozygous state, with severe hemolytic anemia, and in the heterozygous state with microcytosis, or in asymptomatic cases as an alpha-thalassemia carrier phenotype. Hb Caserta was observed for the first time in a Casertian family (South Italy) that displayed a slowmigrating haemoglobin upon investigation. We report the clinical phenotype and molecular study of this new double mutant form of haemoglobin in heterozygous and homozygous subjects, as well as in association with alpha degrees delectional thalassemia.     

Anti-IL6 treatment of serious COVID-19 disease: A monocentric retrospective experience

COVID-19 is causing a high influx of patients suffering from serious respiratory complications leading the necessity to find effective therapies. These patients seem to present with cytokine perturbation and high levels of IL6. Tocilizumab and sarilumab could be effective in this condition.We retrospectively collected data about 112 consecutive hospitalized in a single center.Fifty (IL6 group) treated with tocilizumab (8 mg/kg intravenously [IV], 2 infusions 12 hours apart) or sarilumab 400 mg IV once and 62 treated with the standard of care but not anti-cytokine drugs (CONTROL group).To determine whether anti-IL6 drugs are effective in improving prognosis and reducing hospitalization times and mortality in COVID-19 pneumonia.To date 84% (42/50) of IL6 group patients have already been discharged and only 2/50 are still recovered and intubated in intensive care. Six/fifty patients (12%) died: 5/6 due to severe respiratory failure within a framework of severe acute respiratory distress syndrome (ARDS), 1 suffered an acute myocardial infarction, and 1 died of massive pulmonary thromboembolism. There were no adverse treatment events or infectious complications. Compared to the CONTROL group they showed a lower mortality rate (12% versus 43%), for the same number of complications and days of hospitalization.Anti-IL6 drugs seem to be effective in the treatment of medium to severe forms of COVID-19 pneumonia reducing the risk of mortality due to multi-organ failure, acting at the systemic level and reducing inflammation levels and therefore microvascular complications. However, it is essential to identify the best time for treatment, which, if delayed, is rendered useless as well as counterproductive. Further studies and ongoing clinical trials will help us to better define patients eligible as candidates for more aggressive intervention.