Elevated Alkaline Phosphatase Prior to Transarterial Chemoembolization for Neuroendocrine Tumors Predicts Worse Outcomes

Introduction

We hypothesized that an elevated preoperative alkaline phosphatase (AP) predicted worse outcomes for patients undergoing transarterial chemoembolization (TACE) for neuroendocrine tumor (NET) liver metastases.

Methods

We reviewed all patients who underwent TACE for metastatic NET between 2009 and 2013. Survival was evaluated using preprocedure variables.

Results

One hundred and nine patients underwent 210 TACE procedures. The average age was 57.7 years (range 20–78). Primary sites included pancreas (N?=?20), other gastrointestinal (N?=?52), lung (N?=?9), and unknown (N?=?28). The tumor was grade 1 in 68 (62 %), grade 2 in 21 (19 %), and grade 3 in 3 (3 %). Extrahepatic disease was present in 54 (50 %) and greater than 50 % hepatic tumor burden by imaging in 63 (58 %). Elevated bilirubin occurred in 8 (7 %), elevated AP in 22 (20 %), elevated ALT in 21 (19 %), and elevated AST in 41 (38 %). Univariate predictors included tumor grade (43 vs 27 vs 21 months, p?=?0.015), hepatic tumor burden (59 vs 37 months, p?=?0.009), and elevated AP (59 vs 23 months, p?<?0.001). On multivariate analysis, only elevated AP (p?=?0.001) predicted worse survival.

Conclusions

Elevated AP prior to TACE for metastatic NET portends a worse survival outcome, even more so than tumor grade or extent of hepatic disease.

     

Extensive cross-reactive neutralizing antibody response in Indian patients with limited genetic diversity of HIV-1

Genome sequence analysis of HIV-1 subtype C viruses from India shows monophyletic lineage and relatively limited genetic diversity. To understand its immunological implication, cross-reactivity of neutralizing antibody response was investigated. In primary screening, neutralizing antibody response to single heterologous primary HIV-1 subtype C isolate was assessed in plasma samples from 235 HIV-1 infected, anti-retroviral treatment naive individuals from Pune, India. Plasma samples that showed > or =90% neutralization and two randomly selected plasma samples that showed 50-60% neutralization were tested against a panel of primary HIV-1 subtype C isolates obtained from epidemiologically unlinked individuals from India. The neutralizing antibody response showed extensive cross-neutralization, suggesting presence of shared neutralization determinants among circulating HIV-1 subtype C viruses in India.     

Kidney retransplantation after anti–programmed cell death‐1 (PD‐1)–related allograft rejection

In this report, we describe the first kidney retransplantation performed after anti–programmed cell death‐1 (PD‐1)–related allograft rejection. In 2014, we administered pembrolizumab (anti–PD‐1) for ~9 months to a 57‐year‐old kidney transplant recipient with metastatic cutaneous squamous cell carcinoma (CSCC). The patient experienced both a complete antitumor response and T cell–mediated allograft rejection requiring reinitiation of hemodialysis. Four‐and‐a‐half years after initiating pembrolizumab, the patient remained without evidence of CSCC relapse and received a kidney transplant from a living‐unrelated donor. Ten‐and‐a‐half months after kidney retransplantation, the allograft is functioning well and the patient's CSCC remains in remission. This case illustrates the potential for PD‐1 blockade to bring about durable immune‐mediated tumor control in chronically immunosuppressed patients, and begins to address the feasibility of kidney retransplantation in patients who have previously received immune checkpoint inhibitor therapy for cancer. Results from this and future cases may help elucidate mechanisms of antitumor immunity and allograft tolerance, and inform updates to transplant decision models. Our report also underscores the need for clinical trials testing novel immunotherapy combinations in solid organ transplant recipients designed to uncouple antitumor and anti‐allograft immunity.     

Surgical stress and cytoskeletal changes in lens epithelial cells following manual and femtosecond laser-assisted capsulotomy

AIM: To study the effect of mechanical stress on the cytoskeleton in lens epithelial cells following conventional phacoemulsification surgery (CPS) and femtosecond laser-assisted cataract surgery (FLACS). METHODS: The cytoskeleton of the epithelial cells of the anterior lens capsules (ALC) removed by CPS and FLACS was examined by immunohistochemistry. Expression of the intermediate filament, glial fibrillary acidic protein (GFAP), and glutamine synthetase (GS) immunoreactivity were detected. In order to map the actin network of cells, fluorescently labeled phalloidin was used. The samples were examined using confocal laser scanning microscopy. RESULTS: GFAP expression was visible in a larger number of the epithelial cells after CPS compared to FLACS. In CPS sample’s epithelial cells, GFAP immunoreactivity indicated robust morphological change. Regarding the actin filaments, the presence of tubular elements connecting epithelial cells, regular actin pattern and marked cortical network after CPS were found. Following FLACS, the actin cytoskeleton of the epithelial cells remained densely structured, and the tubular elements were undetectable, however, the above-mentioned regular actin pattern and the marked cortical network were visible. CONCLUSION: The conventional removal of the ALC induces more robust changes of the cytoskeleton of the lens epithelial cells.     

Molecular docking studies on N-hydroxyindole derivatives as potent inhibitors of human lactate dehydrogenase isoform 5 against cancer cell proliferation

Most metastatic cancer cells show a metabolic switch from normal oxidative phosphorylation to an increased rate of glycolysis named as the “Warburg effect.” Thus, even under hypoxic environments, Warburg effect provides a sufficient supply of energy from glucose. Isoform 5 of human lactate dehydrogenase (hLDH5) catalyzes the final step in the glycolysis (pyruvate to lactate) and constitutes a new anticancer target. In silico methods were employed to study the inhibitory property of the N-Hydroxyindole-based compounds against hLDH5. The compound ligands are subjected to Standard Precision (SP) docking and Extra Precision (XP) docking in GLIDE against the target protein hLDH5 [PDB ID: 1I10] each at the active site and at the cofactor binding site. Based on the docking score, glide energy, and hydrogen bonding interactions, six best compounds are selected and further subjected to Induced Fit Docking. Absorption, distribution, metabolism, and excretion (ADME) properties of the ligands are analyzed using QikProp. All computational methods are performed using Schrödinger suite 2009 USA. Compound 3m (6-[4-(2-carboxyethyl)phenyl]-1-hydroxy-1H-indole-2-carboxylic acid) showed the best conformational fit compared to the reference inhibitors.