Downstaging of Hepatocellular Carcinoma Prior to Liver Transplant: Is There a Role for Adjuvant Sorafenib in Locoregional Therapy?

Hepatocellular carcinoma (HCC) remains a common cause of mortality worldwide. Liver transplantation has emerged as the optimal treatment for cirrhotic patients with HCC; however, the shortage of donor organs leaves waitlisted patients at risk for disease progression beyond transplant criteria. Prevention of waitlist dropout has fueled investigation into a wide array of locoregional therapies for the management of HCC in candidates awaiting liver transplantation. We present a patient with HCC who underwent treatment with sorafenib, which resulted in a remarkable reduction in tumor burden to allow for liver transplant listing

BRAF and PIK3CA genes are somatically mutated in hepatocellular carcinoma among patients from South Italy

Poor data have been previously reported about the mutation rates in K-RAS, BRAF, and PIK3CA genes among patients with hepatocellular carcinoma (HCC). Here we further elucidated the role of these genes in pathogenesis of primary hepatic malignancies. Archival tumour tissue from 65 HCC patients originating from South Italy were screened for mutations in these candidate genes by direct sequencing. Overall, oncogenic mutations were detected in 15 (23%) patients for BRAF gene, 18 (28%) for PIK3CA gene, and 1 (2%) for K-RAS gene. Using statistical analysis, BRAF mutations were significantly correlated with the presence of either multiple HCC nodules (P=0.021) or higher proliferation rates (P=0.034). Although further extensive screenings are awaited in HCC patients among different populations, our findings clearly indicated that mutational activation of both BRAF and PIK3CA genes does contribute to hepatocellular tumorigenesis at somatic level in Southern Italian population

Safety and Efficacy of Intermittent High-Dose Liposomal Amphotericin B Antifungal Prophylaxis in Haemato-Oncology: An Eight-Year Single-Centre Experience and Review of the Literature.

Triazoles remain first-line agents for antifungal prophylaxis in high-risk haemato-oncology patients, but their use is increasingly contraindicated due to drug-drug interactions and additive toxicities with novel treatments. In this retrospective, single-centre, observational study, we present our eight-year experience of antifungal prophylaxis using intermittent high-dose liposomal Amphotericin B (L-AmB). All adults identified through our Antifungal Stewardship Programme as receiving L-AmB prophylaxis at 7.5 mg/kg once-weekly between February 2012 and January 2020 were included. Adverse reactions, including infusion reactions, electrolyte loss, and nephrotoxicity, were recorded. 'Breakthrough' invasive fungal infection (IFI) occurring within four weeks of L-AmB was classified using European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. Moreover, 114 courses of intermittent high-dose L-AmB prophylaxis administered to 92 unique patients were analysed. Hypokalaemia was the most common grade 3-4 adverse event, with 26 (23%) courses. Grade 3 nephrotoxicity occurred in 8 (7%) and reversed in all six patients surviving to 90 days. There were two (1.8%) episodes of breakthrough IFI, one 'probable' and one 'possible'. In this study, the largest evaluation of intermittent high-dose L-AmB prophylaxis conducted to date, toxicity was manageable and reversible and breakthrough IFI was rare. L-AmB prophylaxis represents a viable alternative for patients with a contraindication to triazoles

Effects of implantation of bone marrow cells on cytokine levels in the ischemic heart tissue. An experimental study

<p>Abstract</p> <p>Background</p> <p>In order to achieve a safe and persistent angiogenic effect, we investigated the potential of bone marrow cells implantation to enhance angiogenesis of ischemic hearts in a rat model, and also we have investigated growth factors accompanying and intermediating the angiogenesis, and the changes occurring in the levels of cytokines and their relations with angiogenesis.</p> <p>Methods</p> <p>30 adult male Wistar albino rats from the same colony were used. After anterior myocardial infarction induced by occlusion of the left anterior descending artery, they were divided into two groups (Group I and Group II). 2 × 10⁷bone marrow cells suspended in 0.1 ml phosphate-buffered saline solution and 0.1 ml phosphate-buffered saline solution were injected at six points in the infarcted area in Group I and Group II respectively. Changes in the vascular density and, vascular endothelial growth factor, vascular cell adhesion molecule and cytokine levels in the infarcted myocardium after bone marrow cells implantation were examined.</p> <p>Results</p> <p>The implantation assay showed that bone marrow cells induced angiogenesis. Light microscopic analysis of the vascular density in the ischemic area showed that, angiogenesis had been induced to higher in Group I than Group II. Levels of vascular endothelial growth factor, vascular cell adhesion molecule and the inflammatory cytokines such as interleukin-1 and tumor necrosis factor-α in Group I were significantly elevated compared with those in Group II.</p> <p>Conclusion</p> <p>Bone marrow cells implantation induced angiogenesis in a rat ischemic heart model as a result of increase of the levels of vascular endothelial growth factor, vascular cell adhesion molecule, interleukin-1, and tumor necrosis factor-α.</p

Acute occlusion of the celiac axis and its branches with perforation of gastric fundus and splenic infarction, findings on spiral computed tomography: a case report

We present the contrast-enhanced spiral CT findings in a case of acute celiac artery occlusion with gastric perforation and total splenic infarction. Spiral CT depicted thrombus in the celiac axis and its branches, stenosis of the superior mesenteric artery, splenic infarction and lack of enhancement of the gastric wall with a large necrotic gap. Spiral CT enabled prompt diagnosis and therapy in this rare condition in a patient with suspicion of acute mesenteric ischemia

Options for early breast cancer follow-up in primary and secondary care : a systematic review

Background Both incidence of breast cancer and survival have increased in recent years and there is a need to review follow up strategies. This study aims to assess the evidence for benefits of follow-up in different settings for women who have had treatment for early breast cancer. Method A systematic review to identify key criteria for follow up and then address research questions. Key criteria were: 1) Risk of second breast cancer over time - incidence compared to general population. 2) Incidence and method of detection of local recurrence and second ipsi and contra-lateral breast cancer. 3) Level 1–4 evidence of the benefits of hospital or alternative setting follow-up for survival and well-being. Data sources to identify criteria were MEDLINE, EMBASE, AMED, CINAHL, PSYCHINFO, ZETOC, Health Management Information Consortium, Science Direct. For the systematic review to address research questions searches were performed using MEDLINE (2011). Studies included were population studies using cancer registry data for incidence of new cancers, cohort studies with long term follow up for recurrence and detection of new primaries and RCTs not restricted to special populations for trials of alternative follow up and lifestyle interventions. Results Women who have had breast cancer have an increased risk of a second primary breast cancer for at least 20 years compared to the general population. Mammographically detected local recurrences or those detected by women themselves gave better survival than those detected by clinical examination. Follow up in alternative settings to the specialist clinic is acceptable to women but trials are underpowered for survival. Conclusions Long term support, surveillance mammography and fast access to medical treatment at point of need may be better than hospital based surveillance limited to five years but further large, randomised controlled trials are needed

TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML

Somatic TP53 mutations and 17p deletions with genomic loss of TP53 occur in 37% to 46% of acute myeloid leukemia (AML) with adverse-risk cytogenetics and correlate with primary induction failure, high risk of relapse, and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53-mutated AML and determine whether TP53 abnormalities identify a patient subgroup that may benefit from immunotherapy with flotetuzumab, an investigational CD123 × CD3 bispecific dual-affinity retargeting antibody (DART) molecule. The NanoString PanCancer IO360 assay was used to profile 64 diagnostic bone marrow (BM) samples from patients with TP53-mutated (n = 42) and TP53-wild-type (TP53-WT) AML (n = 22) and 45 BM samples from patients who received flotetuzumab for relapsed/refractory (R/R) AML (15 cases with TP53 mutations and/or 17p deletion). The comparison between TP53-mutated and TP53-WT primary BM samples showed higher expression of IFNG, FOXP3, immune checkpoints, markers of immune senescence, and phosphatidylinositol 3-kinase-Akt and NF-κB signaling intermediates in the former cohort and allowed the discovery of a 34-gene immune classifier prognostic for survival in independent validation series. Finally, 7 out of 15 patients (47%) with R/R AML and TP53 abnormalities showed complete responses to flotetuzumab (less than 5% BM blasts) on the CP-MGD006-01 clinical trial (NCT #02152956) and had significantly higher tumor inflammation signature, FOXP3, CD8, inflammatory chemokine, and PD1 gene expression scores at baseline compared with nonresponders. Patients with TP53 abnormalities who achieved a complete response experienced prolonged survival (median, 10.3 months; range, 3.3-21.3 months). These results encourage further study of flotetuzumab immunotherapy in patients with TP53-mutated AML

Integration of aqueous (micellar) two-phase systems on the proteins separation

A two-step approach combining an aqueous two-phase system (ATPS) and an aqueous micellar two-phase system (AMTPS), both based on the thermo-responsive copolymer Pluronic L-35, is here proposed for the purification of proteins and tested on the sequential separation of three model proteins, cytochrome c, ovalbumin and azocasein. Phase diagrams were established for the ATPS, as well as co-existence curves for the AMTPS. Then, by scanning and choosing the most promising systems, the separation of the three model proteins was performed. The aqueous systems based on Pluronic L-35 and potassium phosphate buffer (pH = 6.6) proved to be the most selective platform to separate the proteins (SAzo/Cyt = 1667; SOva/Cyt = 5.33 e SAzo/Ova = 1676). The consecutive fractionation of these proteins as well as their isolation from the aqueous phases was proposed, envisaging the industrial application of this downstream strategy. The environmental impact of this downstream process was studied, considering the carbon footprint as the final output. The main contribution to the total carbon footprint comes from the ultrafiltration (~ 49%) and the acid precipitation (~ 33%) due to the energy consumption in the centrifugation. The ATPS step contributes to ~ 17% while the AMTPS only accounts for 0.30% of the total carbon footprint.publishe

Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor

Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. In this study, we used human hippocampal progenitor cells to investigate the molecular pathways involved in the antidepressant-induced modulation of neurogenesis. Because our previous studies have shown that antidepressants regulate glucocorticoid receptor (GR) function, we specifically tested whether the GR may be involved in the effects of these drugs on neurogenesis. We found that treatment (for 3–10 days) with the antidepressant, sertraline, increased neuronal differentiation via a GR-dependent mechanism. Specifically, sertraline increased both immature, doublecortin (Dcx)-positive neuroblasts (+16%) and mature, microtubulin-associated protein-2 (MAP2)-positive neurons (+26%). This effect was abolished by the GR-antagonist, RU486. Interestingly, progenitor cell proliferation, as investigated by 5′-bromodeoxyuridine (BrdU) incorporation, was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone, (+14%) an effect which was also abolished by RU486. Furthermore, the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram, enhanced the effects of sertraline, whereas the protein kinase A (PKA)-inhibitor, H89, suppressed the effects of sertraline. Indeed, sertraline increased GR transactivation, modified GR phosphorylation and increased expression of the GR-regulated cyclin-dependent kinase-2 (CDK2) inhibitors, p27Kip1 and p57Kip2. In conclusion, our data suggest that the antidepressant, sertraline, increases human hippocampal neurogenesis via a GR-dependent mechanism that requires PKA signaling, GR phosphorylation and activation of a specific set of genes. Our data point toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans

Sarcopenic obesity and risk of new onset depressive symptoms in older adults: English Longitudinal Study of Ageing

We examined the role of sarcopenic obesity as a risk factor for new-onset depressive symptoms over 6-year follow-up in a large sample of older adults