Intraductal Papillary Mucinous Neoplasm of the Pancreas in Young Patients: Tumor Biology,Clinical Features,and Survival Outcomes

Aim

The aim of this paper is to describe the characteristics of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas in young patients.

Methods

We evaluated 1693 patients from the Pancreatic Surgery Consortium who underwent resection for IPMN and classified them as younger or older than 50 years of age at the time of surgery. We assessed the relationship of age with clinical, radiological, pathological, and prognostic features.

Results

We identified 90 (5%) young patients. Age was not associated with differences in main pancreatic duct size (P = 0.323), presence of solid components (P = 0.805), or cyst size (P = 0.135). IPMNs from young patients were less likely to be of gastric type (37 vs. 57%, P = 0.005), and more likely to be of oncocytic (15 vs. 4%, P = 0.003) and intestinal types (44 vs. 26%, P = 0.004). Invasive carcinomas arising from IPMN were less common in young patients (17 vs. 27%, P = 0.044), and when present they were commonly of colloid type (47 vs. 31% in older patients, P = 0.261) and had better overall survival than older patients (5-year, 71 vs. 37%, log-rank P = 0.031).

Conclusion

Resection for IPMN is infrequent in young patients, but when they are resected, IPMNs from young patients demonstrate different epithelial subtypes from those in older patients and more favorable prognosis.

     

Design,Synthesis and Characterization of HIV-1 CA-Targeting Small Molecules: Conformational Restriction of PF74

Small molecules targeting the PF74 binding site of the HIV-1 capsid protein (CA) confer potent and mechanistically unique antiviral activities. Structural modifications of PF74 could further the understanding of ligand binding modes, diversify ligand chemical classes, and allow identification of new variants with balanced antiviral activity and metabolic stability. In the current work, we designed and synthesized three series of PF74-like analogs featuring conformational constraints at the aniline terminus or the phenylalanine carboxamide moiety, and characterized them using a biophysical thermal shift assay (TSA), cell-based antiviral and cytotoxicity assays, and in vitro metabolic stability assays in human and mouse liver microsomes. These studies showed that the two series with the phenylalanine carboxamide moiety replaced by a pyridine or imidazole ring can provide viable hits. Subsequent SAR identified an improved analog 15 which effectively inhibited HIV-1 (EC₅₀ = 0.31 μM), strongly stabilized CA hexamer (ΔTm = 8.7 °C), and exhibited substantially enhanced metabolic stability (t_1/2 = 27 min for 15 vs. 0.7 min for PF74). Metabolic profiles from the microsomal stability assay also indicate that blocking the C5 position of the indole ring could lead to increased resistance to oxidative metabolism.     

Glucosamine modulates chondrocyte proliferation, matrix synthesis, and gene expression

OBJECTIVE: To investigate the effects of glucosamine (GlcN) on chondrocyte proliferation, matrix production, and gene expression for providing insights into the biochemical basis of its reported beneficial effects in osteoarthritis (OA). METHODS: Dose-dependent effect of GlcN on cell morphology, proliferation, cartilage matrix production and gene expression was examined by incubating primary bovine chondrocytes with various amounts of GlcN in monolayers (2D) and in cell-laden hydrogels (3D constructs). Histology, immunofluorescent staining and biochemical analyses were used to determine the effect of GlcN on cartilage matrix production in 3D constructs. The impact of GlcN on gene expression was evaluated with real-time polymerase chain reaction (PCR). RESULTS: GlcN concentration and culture conditions significantly affected the cell behavior. Quantitative detection of matrix production in cell-laden hydrogels indicated a relatively narrow window of GlcN concentration that promotes matrix production (while limiting cellular proliferation, but not cell viability). Notably, GlcN enhanced cartilage specific matrix components, aggrecan and collagen type II, in a dose-dependent manner up to 2 mM but the effect was lost by 15 mM. Additionally, GlcN treatment up-regulated transforming growth factor-beta1 (TGF-beta1) mRNA levels. CONCLUSION: Results indicate that culture conditions play a significant role in determining the effect of GlcN on chondrocytes, explaining both the previously reported beneficial and deleterious effects of this sugar. The ability of GlcN to alter TGF-beta1 signaling provides a biochemical mechanism for GlcN activity on chondrocytes that up to now has remained elusive. The observed anabolic effect of optimal GlcN concentrations on chondrocytes may be useful in formulating effective cartilage repair strategies.     

A comparison of the efficacy and safety of iopamidol-370 and iodixanol-320 in patients undergoing multidetector-row computed tomography

OBJECTIVES: To prospectively compare the effects on heart rate (HR) and contrast enhancement efficacy of iopamidol-370 and iodixanol-320 in contrast-enhanced, multidetector-row computed tomography (CE-MDCT). METHODS: IMPACT is a multicenter, double-blind study involving 166 patients undergoing CE-MDCT of the liver (n = 121) or peripheral arteries (n = 45) randomized to receive equi-iodine doses (40 gI) of iopamidol-370 or iodixanol-320 intravenous at 4 mL/s. CE-MDCT was performed using 16-MDCT scanners according to predefined imaging protocols. HR was measured with the patient in the supine position before and continuously for 5 minutes after contrast medium administration. Mean and peak increases in HR and the proportion of subjects with predefined HR increases (>5 to <10, 10 to <15, 15 to <20, >20 bpm) were compared in the 2 populations. Liver images were assessed by 2 independent, blinded readers for contrast enhancement [Hounsfield unit (HU)], using predefined regions-of-interest during the arterial and portal-venous phase of enhancement. RESULTS: Effects on HR: Eighty-four subjects received iopamidol-370 whereas 82 received iodixanol-320. Mean age, gender distribution, weight, total iodine dose, dose/body weight, concomitant medications and use of beta-blockers were comparable in the 2 groups. Mean baseline HR was similar in the 2 groups (iopamidol-370: 72.3 +/- 12.5 bpm; iodixanol-320: 74.5 +/- 11.9 bpm). Mean changes from baseline to peak postdose were similar in the 2 groups (8.0 +/- 9.3 bpm after iopamidol-370 and 8.4 +/- 14.7 after iodixanol-320, P = 0.72). The proportion of subjects in each group having increases of <5, >5 to <10, 10 to <15, 15 to <20, or >20 bpm was comparable (P = 0.87). Two subjects experienced postcontrast tachycardia (HR increase >70 bpm, peak HR of 146 and 164 bpm), both in the iodixanol-320 group (2.4%). Contrast Enhancement: Of the 121 patients undergoing liver CT, 60 received iopamidol-370 whereas 61 received iodixanol-320. Mean age, gender distribution, weight, total iodine dose, and dose/body weight were comparable in the 2 groups. Iopamidol-370 provided significantly higher HU values in abdominal aorta during the arterial phase of enhancement for both readers [R1: 301.3 +/- 80.2 vs. 273.6 +/- 65.9 HU, 95% confidence interval (6.1-56.8), P = 0.02; R2: 302.0 +/- 73.6 vs. 275.1 +/- 62.9 HU, 95% confidence interval (2.3-51.3), P = 0.03]. No significant difference was observed between the 2 contrast medium during the portal venous phase of enhancement. CONCLUSIONS: When the same injection rate and iodine dose is used, the effects on HR of bolus intravenous injections of iopamidol-370 and iodixanol-320 were similar. Iopamidol-370 provides significantly greater enhancement during the arterial phase and similar enhancement during the portal venous phase compared with iodixanol-320.     

State-of-the-art cross-sectional imaging in bladder cancer

Advances in cross-sectional imaging have given radiology an increasingly significant role in the diagnosis, staging, and restaging of patients with bladder cancer. The primary role of computed tomography (CT) in bladder cancer is for tumor staging and screening for distant metastases. Multidetector-row CT may improve the evaluation of bladder tumors by overcoming the difficulties of previous generations of CT in detecting invasion of contiguous organs and nodal staging. Magnetic resonance imaging (MRI) however is still considered superior to CT for primary staging of bladder carcinoma. The multiplanar capability of MRI with its superior soft-tissue resolution offers improved evaluation of local staging of bladder tumors. Positron emission tomography/CT is emerging as a novel-imaging tool for the detection of distant metastases. In this review, we emphasize the value of current cross-sectional imaging and discuss the potential applications of novel imaging techniques in the management of patients with bladder cancer, predominantly transitional cell carcinoma.     

Dynamic-threshold level set method for volumetry of porcine kidney in CT images in vivo and ex vivo assessment of the accuracy of volume measurement

RATIONALE AND OBJECTIVE: We sought to assess the accuracy of a novel computerized volumetry method, called dynamic-thresholding (DT) level set, in determining the renal volume of pigs in CT images on the basis of in vivo and ex vivo reference standards. METHODS AND MATERIALS: Eight Yorkshire breed anesthetized pigs (weight range 45-50 kg) were scanned on a 64-slice multidetector CT scanner (Sensation 64; Siemens) after injection of an iodinated (300 mg I/ml) contrast agent through an IV cannula. The kidneys of the pigs were then surgically resected and scanned by CT in the same manner. Both in vivo and ex vivo CT images were subjected to our computerized volumetry using DT level set method. The resulting volumes of the kidneys were compared with in vivo and ex vivo reference standards: the former was established by manual contouring of the kidneys on the CT images by an experienced radiologist, and the latter was established as the water displacement volume of the resected kidney. RESULTS: The comparisons of the in vivo and ex vivo measurements by our volumetric scheme with the associated reference standards yielded a mean difference of 1.73 +/- 1.24% and 3.38 +/- 2.51%, respectively. The correlation coefficients were 0.981 and 0.973 for in vivo and ex vivo comparisons, respectively. The mean difference between in vivo and ex vivo reference standards was 5.79 +/- 4.26%, and the correlation coefficient between the two standards was 0.760. CONCLUSION: Our computerized volumetry using the DT level set method can provide accurate in vivo and ex vivo measurements of kidney volume, despite a large difference between the two reference standards. This technique can be employed in human subjects for the determination of renal volume for preoperative surgical planning and assessment of oncology treatment.     

Identification of a Novel Kindred with Familial Pancreatitis and Pancreatic Cancer

Background/Aims: Hereditary pancreatic cancer comprises about 10% of pancreatic cancer cases. Multiple causative mutations have been identified. Here we describe a pancreatitis/pancreatic cancer (P/PC) family, which demonstrates pancreatitis and pancreatic cancer resulting from an uncharacterized mutation. Methods: Family members completed evaluations to determine signs of mutation status. Select patients were screened for mutations associated with hereditary pancreatic diseases. Results: In generation II, 12 siblings exhibit 6 cases of pancreatitis, 3 pancreatic cancer, and 2 obligate carrier status. The average age at pancreatitis diagnosis of enrolled members is 32.5 years; average age at pancreatic cancer diagnosis is 59 years. There is no association with known cancer syndromes. Those affected generally present with mild epigastric pain, and CT scans demonstrate characteristic fatty infiltration of the pancreatic body and tail with sparing of the head and neck. Full sequenceanalysis of genes associated with hereditary pancreatic disease failed to dem- onstrate known mutations or polymorphisms. Conclusion: Based upon pedigree evaluation and preliminary DNA analysis, we believe that the family members with P/PC carry a novel genetic mutation resulting in hereditary pancreatitis. This mutation is autosomal dominant, expressed with high penetrance, and is part of a unique hereditary syndrome that significantly increases pancreatic cancer risk.     

Imaging angiogenesis: applications and potential for drug development

Recognition of the importance of angiogenesis to tumor growth and metastasis has led to efforts to develop new drugs that are targeted to angiogenic vasculature. Clinical trials of these agents are challenging, both because there is no agreed upon method of establishing the correct dosage for drugs whose mechanism of action is not primarily cytotoxic and because of the long time it takes to determine whether such drugs have a clinical effect. Therefore, there is a need for rapid and effective biomarkers to establish drug dosage and monitor clinical response. This review addresses the potential of imaging as a way to accurately and reliably assess changes in angiogenic vasculature in response to therapy. We describe the advantages and disadvantages of several imaging modalities, including positron emission tomography, x-ray computed tomography, magnetic resonance imaging, ultrasound, and optical imaging, for imaging angiogenic vasculature. We also discuss the analytic methods used to derive blood flow, blood volume, empirical semiquantitative hemodynamic parameters, and quantitative hemodynamic parameters from pharmacokinetic modeling. We examine the validity of these methods, citing studies that test correlations between data derived from imaging and data derived from other established methods, their reproducibility, and correlations between imaging-derived hemodynamic parameters and other pathologic indicators, such as microvessel density, pathology score, and disease outcome. Finally, we discuss which imaging methods are most likely to have the sensitivity and reliability required for monitoring responses to cancer therapy and describe ways in which imaging has been used in clinical trials to date.