Correlation of angiogenesis with 18F-FMT and 18F-FDG uptake in non-small cell lung cancer

L-[3-¹⁸F]-α-methyltyrosine (¹⁸F-FMT) is an amino-acid tracer for positron-emission tomography (PET). We have conducted a clinicopathologic study to elucidate the correlation of angiogenesis with ¹⁸F-FMT and 2-[¹⁸F]-fluoro-2-deoxy-D-glucose (¹⁸F-FDG) uptake in patients with non-small cell lung cancer (NSCLC). Thirty-seven NSCLC patients were enrolled in this study, and two PET studies with ¹⁸F-FMT and ¹⁸F-FDG were performed. Uptake of PET tracers was evaluated with standardized uptake value. Vascular endothelial growth factor (VEGF), CD31, CD34, L-type amino acid transporter 1 (LAT1) and Ki-67 labeling index of the resected tumors were analyzed by immunohistochemical staining, and correlated with the clinicopathologic variables and the uptake of PET tracers. The median VEGF rate was 45% (range, 10–78%). High expression was seen in 30 patients (81%, 30/37). VEGF expression was statistically associated with progressively growing microvessel count. VEGF showed a correlation with LAT1 expression ( P  = 0.04) and Ki-67 labeling index ( P  = 0.01). However, it showed no correlation with age, gender, disease stage, tumor size, and histology. Microvessel density (MVD) showed no correlation with any parameters. ¹⁸F-FMT and ¹⁸F-FDG uptake correlated significantly with VEGF ( P  < 0.0001, P  = 0.026, respectively), whereas the correlation of ¹⁸F-FMT and VEGF was more meaningful. The present study demonstrated that the metabolic activity of primary tumors as evaluated by PET study with ¹⁸F-FMT and ¹⁸F-FDG is related to tumor angiogenesis and the proliferative activity in NSCLC. ( Cancer Sci 2009; 100: 753–758)     

The effects of antifungal stewardship programs at a tertiary-care teaching hospital in Japan

Patients with invasive fungal diseases (IFDs) generally have a high mortality rate, and resistance to antifungal drugs and the high costs associated with it have led to recent problems, necessitating the appropriate use of antifungals. To this end, we launched Antifungal Stewardship Programs (AFSPs) in our hospital. Patients who were systemically administered antifungals from January 2011 to December 2016 were enrolled this study and divided into pre-intervention and intervention groups. No significant difference was observed in defined daily doses per 1000 patient-days (23.3 ± 8.0 vs 20.4 ± 10.8, p = 0.251) between the groups. The monthly average for the days of therapy per 1000 patient-days was significantly lower in the intervention group (15.1 ± 3.1 vs 12.7 ± 4.3, p = 0.009). The cost of the antifungals reduced over the 3-year period by $260,520 (13.5%). Furthermore, a decreasing trend was observed in both the 30-day mortality (40.9% vs 30.0%, p = 0.414) and in-hospital mortality (63.6% vs 36.7%, p = 0.054) in patients with candidemia. Our results indicate that AFSPs are efficacious and cost-effective approaches.     

Autoimmune Pancreatitis as a New Clinical Entity (Three Cases of Autoimmune Pancreatitis with Effective Steroid Therapy)

The most common forms of chronic pancreatitisare related to alcohol ingestion, whereas the entity ofnon-alcohol-associated (idiopathic) pancreatitis ispoorly understood. Autoimmunity has been suggested as a possible etiologic factor of idiopathicchronic pancreatitis. A total of 362 Japanese patientsunderwent endoscopic retrograde pancreatography (ERP)for suspected pancreatic disease, and 161 were diagnosed with chronic pancreatitis. Among them, we foundthree cases (1.86% incidence) of unique chronicpancreatitis, in which ERP revealed diffuse narrowing ofthe main pancreatic duct with an irregular wall. We diagnosed these three patients as havingpancreatitis associated with an autoimmune mechanismmorphologically and biochemically and started them onsteroid therapy. The characteristics of the these three patients were as follows:hypergammaglobulinemia, eosinophilia, ultrasonographyshowing hypoehoic diffuse swelling in the pancreas(sausage-like appearance), ERP showing diffuse narrowingof the main pancreatic duct with irregular like thumbprintlike marks,reversible exocrine insufficiency, and positiveanti-carbonic anhydrase II antibody. After one month ofthe treatment with steroids, pancreatitis dramatically improved morphologically and enzymatically.Here we describe these cases of the suspected autoimmunechronic pancreatitis. We must recognize the concept andthe features of autoimmune pancreatitis in order to avoid unnecessary surgery as pancreaticcancer.     

Ultrastructural analyses of pancreatic grafts preserved by the two-layer cold-storage method and by simple cold storage in University of Wisconsin solution

The two-layer cold storage method (TLM) using University of Wisconsin (UW) solution supplies sufficient oxygen to pancreatic grafts during preservation and extends pancreas preservation time to up to 96 h in the canine model. Simple cold storage in UW (UWM) on the other hand, preserves canine pancreas grafts for up to 72 h by preventing cell swelling, mainly because of its high osmotic pressure. The aim of this study is to analyze morphologically dog pancreatic grafts preserved by these two methods with their different mechanisms. Immediately after preservation of canine pancreata by TLM for 72 h and 96 h (group 1 and group 3, respectively), and by UWM for 72 h and 96 h (group 2 and group 4, respectively), tissue ATP levels were determined using high-performance liquid chromatography (HPLC), and detailed morphological analyses of intragraft components were performed using light- and electron microscopy. The mean areas of one mitochondrion and rough endoplasmic reticulum (RER) vacuolization were calculated by computer-graphic analyses using NIH image 1.62 f soft. The tissue ATP levels were significantly higher in groups 1 and 3 than groups 2 and 4 ( P < 0.05). Light microscopy demonstrated no marked difference among the 4 groups. By electron microscopy however, mitochondrial swelling and RER vacuolization were observed in acinar cells to various extents in the 4 groups. They were significantly more evident in group 2 than group 1 ( P < 0.05), and in group 4 than group 3 ( P < 0.05). In conclusion, TLM demonstrated excellent protection of intracellular organelles, mitochondria, and RER, up to 72-96 h. Well-maintained graft ATP levels in TLM groups may result in maintaining the integrity of intracellular organelle membranes as well as cellular membranes.     

Proteomics and phosphoproteomics reveal key regulators associated with cytostatic effect of amino acid transporter LAT1 inhibitor

L‐type amino acid transporter 1 (LAT1) is highly expressed in various cancers and plays important roles not only in the amino acid uptake necessary for cancer growth but also in cellular signaling. Recent research studies have reported anticancer effects of LAT1 inhibitors and demonstrated their potential for cancer therapy. Here, we characterized the proteome and phosphoproteome in LAT1‐inhibited cancer cells. We used JPH203, a selective LAT1 inhibitor, and performed tandem mass tag–based quantitative proteomics and phosphoproteomics on four biliary tract cancer cell lines sensitive to JPH203. Our analysis identified hundreds to thousands of differentially expressed proteins and phosphorylated sites, demonstrating the broad influence of LAT1 inhibition. Our findings showed various functional pathways altered by LAT1 inhibition, and provided possible regulators and key kinases in LAT1‐inhibited cells. Comparison of these changes among cell lines provides insights into general pathways and regulators associated with LAT1 inhibition and particularly suggests the importance of cell cycle–related pathways and kinases. Moreover, we evaluated the anticancer effects of the combinations of JPH203 with cell cycle–related kinase inhibitors and demonstrated their potential for cancer therapy. This is the first study providing the proteome‐wide scope of both protein expression and phosphorylation signaling perturbed by LAT1 inhibition in cancer cells.     

Radioimmunotherapy with an 211At-labeled anti–tissue factor antibody protected by sodium ascorbate

Tissue factor (TF), the trigger protein of the extrinsic blood coagulation cascade, is abundantly expressed in various cancers including gastric cancer. Anti-TF monoclonal antibodies (mAbs) capable of targeting cancers have been successfully applied to armed antibodies such as antibody-drug conjugates (ADCs) and molecular imaging probes. We prepared an anti-TF mAb, clone 1084, labeled with astatine-211 (²¹¹At), as a promising alpha emitter for cancer treatment. Alpha particles are characterized by high linear energy transfer and a range of 50-100 µm in tissue. Therefore, selective and efficient tumor accumulation of alpha emitters results in potent antitumor activities against cancer cells with minor effects on normal cells adjacent to the tumor. Although the ²¹¹At-conjugated clone 1084 (²¹¹At-anti-TF mAb) was disrupted by an ²¹¹At-induced radiochemical reaction, we demonstrated that astatinated anti-TF mAbs eluted in 0.6% or 1.2% sodium ascorbate (SA) solution were protected from antibody denaturation, which contributed to the maintenance of cellular binding activities and cytocidal effects of this immunoconjugate. Although body weight loss was observed in mice administered a 1.2% SA solution, the loss was transient and the radioprotectant seemed to be tolerable in vivo. In a high TF–expressing gastric cancer xenograft model, ²¹¹At-anti-TF mAb in 1.2% SA exerted a significantly greater antitumor effect than nonprotected ²¹¹At-anti-TF mAb. Moreover, the antitumor activities of the protected immunoconjugate in gastric cancer xenograft models were dependent on the level of TF in cancer cells. These findings suggest the clinical availability of the radioprotectant and applicability of clone 1084 to ²¹¹At-radioimmunotherapy.     

Reconsideration of frailty in relation to surgical indication

Given that an increasing number of elderly patients are undergoing surgical procedures for a diversity of indications, the concept of frailty is currently being examined in more depth in clinical medicine. Established surgical risk scores designed to predict mortality are mainly focused on general demographic information and clinical factors; however, these do not account for the frailty condition. With vulnerability and low resiliency in the frail elderly, these conventional scores are unable to accurately predict postoperative outcomes including adverse complications, disability, the need for additional rehabilitation, and prolonged length of hospitalization. Over the last decade, it has been demonstrated that frailty is an independent risk factor of surgery and strongly associated with adverse postoperative outcomes and mortality. It is essential today that surgeons assimilate the concept of frailty and the relationship between frailty and surgical outcomes. A preoperative frailty assessment can assist in determining surgical indication and optimal perioperative management, ultimately impacting the postoperative functional state and quality of life. Here we review the validity of preoperative frailty assessments for surgical intervention, possible treatments for frailty, and indicate future directions in this field.     

Suppressive effect of pitavastatin on aortic arch dilatation in acute stanford type B aortic dissection: analysis of STANP trial

Objectives

Medical therapy for patients with uncomplicated acute type B aortic dissection (ABAD) is essentially accepted for its excellent early outcome; however, long-term outcomes have not been satisfactory due to aorta-related complications. This trial was performed to investigate the efficacy of a statin as an additive that may enhance the effectiveness of conventional medical treatment in patients with ABAD.

Methods

This was a multi-center, prospective, and randomized comparative investigation of patients with uncomplicated ABAD. Fifty patients with ABAD compatible with inclusion criteria were randomly assigned to two groups and then received administration of pitavastatin (group P) or not (group C). We followed up the patients for 1 year from study onset.

Results

Two patients demised during the follow-up period (both were in group C). In addition, aorta-related interventions were performed in two patients (entry closure for aortic dissection by endovascular repair in one patient in each group). Aortic arch diameters at 1 year in group P tended to be smaller than in group C (P?=?0.17), and the rate of change of the aortic arch diameters from onset to 1 year was significantly lower in group P (P?=?0.046). Multivariate analysis identified patency of the false lumen was detected as a risk factor for aortic arch dilatation (P?=?0.02), and pitavastatin intake was a negative risk factor (P?=?0.03).

Conclusions

Pitavastatin treatment, in addition to the standard antihypertensive therapy, may have a suppressive effect on aortic arch dilatation in patients with ABAD.