What is the appropriate intravenous dose of vitamin E for very-low-birth-weight infants?

The Committee on Fetus and Newborn of the American Academy of Pediatrics (AAP) has endorsed 1 to 2 mg/dl as the normal range of serum tocopherol level. Our Cochrane review has shown that vitamin E supplementation resulting in levels >3.5 mg/dl, but not < or =3.5 mg/dl, significantly reduces the risk for severe retinopathy among very-low-birth-weight (VLBW) infants examined but increases the risks of sepsis and of necrotizing enterocolitis among infants treated for >1 week. As a fixed daily intravenous dose of vitamin E results in an inverse relationship between serum level and birth weight and is a risk for both low and high serum tocopherol levels, a dose adjusted for current weight appears more judicious than a fixed dose per day. Based on currently available data the AAP and the American Society for Clinical Nutrition currently recommend a routine intake of 2 ml/kg/day of MVI Pediatric (2.8 IU/kg/day) in VLBW infants (maximum of 5 ml/day or 7 IU/day).     

Pak and Rac GTPases promote oncogenic KIT–induced neoplasms

An acquired somatic mutation at codon 816 in the KIT receptor tyrosine kinase is associated with poor prognosis in patients with systemic mastocytosis and acute myeloid leukemia (AML). Treatment of leukemic cells bearing this mutation with an allosteric inhibitor of p21–activated kinase (Pak) or its genetic inactivation results in growth repression due to enhanced apoptosis. Inhibition of the upstream effector Rac abrogates the oncogene-induced growth and activity of Pak. Although both Rac1 and Rac2 are constitutively activated via the guanine nucleotide exchange factor (GEF) Vav1, loss of Rac1 or Rac2 alone moderately corrected the growth of KIT-bearing leukemic cells, whereas the combined loss resulted in 75% growth repression. In vivo, the inhibition of Vav or Rac or Pak delayed the onset of myeloproliferative neoplasms (MPNs) and corrected the associated pathology in mice. To assess the role of Rac GEFs in oncogene-induced transformation, we used an inhibitor of Rac, EHop-016, which specifically targets Vav1 and found that EHop-016 was a potent inhibitor of human and murine leukemic cell growth. These studies identify Pak and Rac GTPases, including Vav1, as potential therapeutic targets in MPN and AML involving an oncogenic form of KIT.     

PET‐CT vs contrast‐enhanced CT: What is the role for each after chemoradiation for advanced oropharyngeal cancer?

PURPOSE: The aim of our study was to assess the utility of positron emission tomography (PET) and 2 fluoro-2-deoxy-D-glucose coupled with neck CT compared with contrast-enhanced CT in predicting persistent cancer either at the primary site or cervical lymphatics in patients with oropharyngeal cancer treated with concurrent chemoradiation METHODS: Thirty consecutive patients underwent clinical examination, PET-CT, and contrast-enhanced CT to assess response after the completion of the treatment. The outcome variable was positive tissue diagnosis or negative disease at 6 months. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for the primary site as well as cervical disease. RESULTS: Contrast-enhanced CT alone showed the best accuracy in detecting disease at the primary site after treatment (85.7%). Accuracy in evaluating residual tumor in the cervical lymphatics for contrast-enhanced CT and PET-CT was 59.3% and 74.1%, respectively. For evaluating the neck, PET-CT and contrast-enhanced CT demonstrated 100% NPV, but the PPV was 36.3% and 26.6%, respectively. CONCLUSIONS: In this preliminary study, PET-CT seems to be superior to contrast-enhanced CT in predicting persistent disease in the neck after chemoradiation for oropharyngeal or unknown primary cancer, but not at the primary site. However, the possibility of a false-positive result in the neck remains high, and thus overtreatment may result. Even more concerning are the false-negative results. Larger, prospective studies will be important in defining the role of PET-CT in obviating the need for salvage neck dissections after chemoradiation.     

Fine Needle Aspiration cytology versus Fine Needle Sampling without aspiration. A prospective study of 200 cases

In the present prospective study of 200 patients with superficial swelling of various sites, FNS followed by FNA were performed. Fifteen cases were excluded due to inadequate material. In the 80 lymph node cases, FNS was diagnostic in 85% cases as compared to FNA in 87.5%. The diagnostic accuracy was higher for FNA (87.5%) than for FNS (81.25%). However FNS smears were much superior qualitatively than FNA smears and for the diagnosis of malignant conditions FNS was found to be much better. Regarding the 68 thyroid swellings, FNS obtained a diagnosis in 82.4% cases while FNA got it in 77.9%. The diagnostic accuracy with FNS (89%) was much better compared to FNA (75%). Of the 27 breast cases FNS yielded diagnostic material in 70.38% cases while FNA was diagnostic in 85.19%, thus establishing definite superiority. However FNS seemed to be better for diagnosing malignant lesions while FNA appeared better for diagnosing benign ones. In the 5 salivary gland lesions and 5 miscellaneous lesions both FNS and FNA fared equally well. On the whole FNS technique was much more patient friendly and gave high class "text book" quality smears while FNA smears gave quantitatively more adequate material. Both the techniques therefore would be complementary to each other.     

Management Guidelines for Infection After ACL Reconstruction: Expert Opinion Statement Based on the Modified Delphi Survey of Indian Arthroscopy Surgeons

AimInfection after anterior cruciate ligament (ACL) reconstruction, though rare, is a potentially devastating complication and the evidence-based recommendation on the various topics in its management is limited. The purpose of this study was to develop recommendations for the prevention and management of infections in ACL reconstruction surgery by performing a structured expert consensus survey using Delphi methodology.Materials and Methods22 topics of relevance in the prevention and management of infection following ACL reconstruction were chosen from an extensive literature review. 30 panelists were requested to respond to a three-round survey, with feedback, to develop a consensus statement on the topics.ResultsConsensus statements could be prepared in eleven out of twenty-two topics including: the graft is retained at the first arthroscopic debridement, the graft is removed when repeated debridement are needed, and revision ACL reconstruction is needed only if the patient develops instability. Concurrence could be obtained in the topics including: longer duration of antibiotics is needed in immunocompromised patients, soaking graft in antibiotic solution reduces infection risk, and knee swelling without warmth does not suggest infection.ConclusionsA proper skin preparation, a longer course of antibiotics in immunocompromised patients, and soaking the graft in antibiotics reduces the risk of infection. In case of infection, a healthy-looking graft must be retained at the first debridement and if the graft must be removed, revision ACL reconstruction is advised only if the patient develops instability.Supplementary InformationThe online version contains supplementary material available at 10.1007/s43465-021-00363-z.     

Ras-Mek-Erk Signaling Regulates Nf1 Heterozygous Neointima Formation

Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor-suppressor gene, which encodes neurofibromin, a negative regulator of diverse Ras signaling cascades. Arterial stenosis is a nonneoplastic manifestation of NF1 that predisposes some patients to debilitating morbidity and sudden death. Recent murine studies demonstrate that Nf1 heterozygosity (Nf1^+/−) in monocytes/macrophages significantly enhances intimal proliferation after arterial injury. However, the downstream Ras effector pathway responsible for this phenotype is unknown. Based on in vitro assays demonstrating enhanced extracellular signal-related kinase (Erk) signaling in Nf1^+/− macrophages and vascular smooth muscle cells and in vivo evidence of Erk amplification without alteration of phosphatidylinositol 3-kinase signaling in Nf1^+/− neointimas, we tested the hypothesis that Ras-Erk signaling regulates intimal proliferation in a murine model of NF1 arterial stenosis. By using a well-established in vivo model of inflammatory cell migration and standard cell culture, neurofibromin-deficient macrophages demonstrate enhanced sensitivity to growth factor stimulation in vivo and in vitro, which is significantly diminished in the presence of PD0325901, a specific inhibitor of Ras-Erk signaling in phase 2 clinical trials for cancer. After carotid artery injury, Nf1^+/− mice demonstrated increased intimal proliferation compared with wild-type mice. Daily administration of PD0325901 significantly reduced Nf1^+/− neointima formation to levels of wild-type mice. These studies identify the Ras-Erk pathway in neurofibromin-deficient macrophages as the aberrant pathway responsible for enhanced neointima formation.Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor-suppressor gene, which encodes the protein neurofibromin. Neurofibromin negatively regulates Ras activity in multiple cell types by accelerating the hydrolysis of active Ras-GTP to its inactive diphosphate conformation.¹ These loss-of-function mutations accelerate Ras signaling and sensitize vessel wall cells and circulating hematopoietic cells, particularly myeloid progenitors and their differentiated progeny, to growth factors implicated in maintaining vascular wall homeostasis and disease pathogenesis.^1–4 Some patients with NF1 are predisposed to intimal proliferation, termed neointima, leading to debilitating arterial stenosis and tissue ischemia that contribute significantly to the premature mortality observed in this population.⁵Nf1 heterozygous (Nf1^+/−) mice display increased neointima formation, characterized by proliferating vascular smooth muscle cells (VSMCs) and infiltration of bone marrow–derived macrophages after arterial ligation, which is reminiscent of patients with NF1.^5,6 Neurofibromin-deficient endothelial cells, VSMCs, and bone marrow–derived myeloid cells demonstrate preferential activation of the Ras-Erk signaling pathway, without corresponding alterations in Ras–phosphatidylinositol 3-kinase signaling, in response to multiple growth factors in vitro.^2–4,7 This is an interesting observation because lineage-restricted inactivation of a single Nf1 gene in endothelial cells and/or VSMCs does not replicate the striking neointima observed in Nf1 heterozygous mice. However, we recently demonstrated that lineage-specific inactivation of a single Nf1 gene copy in monocytes/macrophages is sufficient to reproduce the enhanced neointima formation observed in Nf1 heterozygous mice compared with wild-type (WT) mice.⁸Based on these observations, we used in vitro and in vivo systems of macrophage function to test the hypothesis that Nf1 heterozygous macrophage function and mobilization to sites of inflammation are directly controlled by Ras-Erk signaling and that use of a specific and long-acting inhibitor of Ras-Erk signaling, under evaluation in multiple phase 1 and 2 clinical trials for cancer and preclinical models of NF1 malignancy,^1,9–12 will reduce neointima formation after mechanical injury.     

Pilot Evaluation of Anti-1-amino-2-[18F] fluorocyclopentane-1-carboxylic acid (anti-2-[18F] FACPC) PET-CT in Recurrent Prostate Carcinoma

Molecular Imaging and Biology - Anti-1-amino-2-[18F]fluorocyclopentane-1-carboxylic acid (anti-2-[18F]FACPC) is an unnatural alicyclic amino acid radiotracer with high uptake in the DU-145 prostate...