Computational exploration and experimental validation to identify a dual inhibitor of cholinesterase and amyloid-beta for the treatment of Alzheimer's disease.

The cholinesterases are essential targets implicated in the pathogenesis of Alzheimer's disease (AD). In the present study, virtual screening and molecular docking are performed to identify the potential hits. Docking-post processing (DPP) and pose filtration protocols against AChE and BChE resulted in three hits (AW00308, HTS04089, and JFD03947). Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) and molecular dynamics simulation analysis affirmed the stability and binding pattern of the docked complex JFD03947, which was further synthesized and evaluated for in vitro cholinesterase inhibition (AChE, IC50 = 0.062 µM; BChE, IC50 = 1.482 µM) activity. The enzyme kinetics study of the JFD03947 against hAChE and hBChE suggested a mixed type of inhibition. The results of thioflavin T-assay also elicited anti-Aß aggregation activity by JFD03947. Further, biological evaluation of identified compound JFD03947 also showed neuroprotective ability against the SH-SY5Y neuroblastoma cell lines.

Design, synthesis, and evaluation of novel N-(4-phenoxybenzyl)aniline derivatives targeting acetylcholinesterase, ß-amyloid aggregation and oxidative stress to treat Alzheimer's disease.

Novel hybrids N-(4-phenoxybenzyl)aniline were designed, synthesized, and evaluated for their potential AChE inhibitory activity along with antioxidant potential. The inhibitory potential (IC50) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman's method. Among all the tested compounds, 42 with trimethoxybenzene substituent showed maximum hAChE inhibition with the competitive type of enzyme inhibition (IC50 = 1.32 µM; Ki = 0.879 µM). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed favorable BBB permeability by most of the synthesized compounds. Meanwhile, compound 42 also inhibited AChE-induced Aß aggregation (39.5-66.9%) in thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 42. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 42 in brain homogenates.

Design and development of novel N-(pyrimidin-2-yl)-1,3,4-oxadiazole hybrids to treat cognitive dysfunctions.

Novel hybrids bearing a 2-aminopyrimidine (2-AP) moiety linked to substituted 1,3,4-oxadiazoles were designed, synthesized and biologically evaluated. Among the developed compounds, 28 noncompetitively inhibited human acetylcholinesterase (hAChE; pIC50 = 6.52; Ki = 0.17 µM) and showed potential in vitro antioxidant activity (60.0%) when evaluated using the Ellman's and DPPH assays, respectively. Compound 28 competitively displaced propidium iodide (PI) from the peripheral anionic site (PAS) of hAChE (17.6%) and showed high blood-brain barrier (BBB) permeability, as observed in the PAMPA-BBB assay. Additionally, compound 28 inhibited hAChE-induced Aß aggregation in a concentration-dependent manner according to the thioflavin T assay and was devoid of neurotoxic liability towards SH-SY5Y cell lines, as demonstrated by the MTT assay. The behavioral studies of compound 28 in mice showed a significant reversal of scopolamine-induced amnesia, as observed in Y-maze and passive avoidance tests. Furthermore, compound 28 exhibited significant AChE inhibition in the brain in ex vivo studies. An evaluation of oxidative stress biomarkers revealed the antioxidant potential of 28. Moreover, in silico molecular docking and dynamics simulation studies were used as a computational tool to evaluate the interactions of compound 28 with the active site residues of hAChE.

Design and development of 1,3,4-oxadiazole derivatives as potential inhibitors of acetylcholinesterase to ameliorate scopolamine-induced cognitive dysfunctions.

The novel hybrids bearing 4-aminopyridine (4-AP) tethered with substituted 1,3,4-oxadiazole nucleus were designed, synthesized, and evaluated for their potential AChE inhibitory property along with significant antioxidant potential. The inhibitory potential (IC50) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman's method. Among all the compounds, 9 with 4-hydroxyl substituent showed maximum hAChE inhibition with the non-competitive type of enzyme inhibition (IC50 = 1.098 µM; Ki = 0.960 µM). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed significant BBB permeability in most of the synthesized compounds. Meanwhile, compound 9 also inhibited AChE-induced Aß aggregation (38.2-65.9%) by thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 9. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 9 in brain homogenates.

Biphenyl-3-oxo-1,2,4-triazine linked piperazine derivatives as potential cholinesterase inhibitors with anti-oxidant property to improve the learning and memory.

A series of novel piperazine tethered biphenyl-3-oxo-1,2,4-triazine derivatives were designed, and synthesized. Amongst the synthesized analogs, compound 6g showed significant non-competitive inhibitory potential against acetylcholinesterase (AChE, IC50; 0.2 ±â€¯0.01 µM) compared to standard donepezil (AChE, IC50: 0.1 ±â€¯0.002 µM). Compound 6g also exhibited significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE (22.22 ±â€¯1.11%) and showed good CNS permeability in PAMPA-BBB assay (Pe(exp), 6.93 ±â€¯0.46). The in vivo behavioral studies of compound 6g indicated significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. Further, ex vivo studies showed a significant AChE inhibition and reversal of the scopolamine-induced oxidative stress by compound 6g. Moreover, molecular docking and dynamics simulations of compound 6g showed a consensual binding affinity and active site interactions with the PAS and active catalytic site (CAS) residues of AChE.

Design and development of novel p-aminobenzoic acid derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer's disease.

Based on the quantitative structure-activity relationship (QSAR), some novel p-aminobenzoic acid derivatives as promising cholinesterase enzyme inhibitors were designed, synthesized, characterized and evaluated to enhance learning and memory. The in vitro enzyme kinetic study of the synthesized compounds revealed the type of inhibition on the respective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vivo studies of the synthesized compounds exhibited significant reversal of cognitive deficits in the animal models of amnesia as compared to standard drug donepezil. Further, the ex vivo studies in the specific brain regions like the hippocampus, hypothalamus, and prefrontal cortex regions also exhibited AChE inhibition comparable to standard donepezil. The in silico molecular docking and dynamics simulations studies of the most potent compound 22 revealed the consensual interactions at the active site pocket of the AChE.

Transition to international classification of disease version 10, clinical modification: the impact on internal medicine and internal medicine subspecialties.

BACKGROUND: The US health care system uses diagnostic codes for billing and reimbursement as well as quality assessment and measuring clinical outcomes. The US transitioned to the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) on October, 2015. Little is known about the impact of ICD-10-CM on internal medicine and medicine subspecialists. METHODS: We used a state-wide data set from Illinois Medicaid specified for Internal Medicine providers and subspecialists. A total of 3191 ICD-9-CM codes were used for 51,078 patient encounters, for a total cost of US $26,022,022 for all internal medicine. We categorized all of the ICD-9-CM codes based on the complexity of mapping to ICD-10-CM as codes with complex mapping could result in billing or administrative errors during the transition. Codes found to have complex mapping and frequently used codes (n = 295) were analyzed for clinical accuracy of mapping to ICD-10-CM. Each subspecialty was analyzed for complexity of codes used and proportion of reimbursement associated with complex codes. RESULTS: Twenty-five percent of internal medicine codes have convoluted mapping to ICD-10-CM, which represent 22% of Illinois Medicaid patients, and 30% of reimbursements. Rheumatology and Endocrinology had the greatest proportion of visits and reimbursement associated with complex codes. We found 14.5% of ICD-9-CM codes used by internists, when mapped to ICD-10-CM, resulted in potential clinical inaccuracies. CONCLUSIONS: We identified that 43% of diagnostic codes evaluated and used by internists and that account for 14% of internal medicine reimbursements are associated with codes which could result in administrative errors.

Design, synthesis, and biological evaluation of some novel indolizine derivatives as dual cyclooxygenase and lipoxygenase inhibitor for anti-inflammatory activity.

Some novel indolizine derivatives were synthesized by bioisosteric modification of imidazo[1,2-a]pyridine for anti-inflammatory activity. The physicochemical characterization and structure of compounds were elucidated by state of the art spectroscopic technique. Induced fit docking was performed for initial screening to elucidate the interactions with corresponding amino acids of cyclooxygenase (COX-1, COX-2) and lipoxygenase (LOX) enzymes. The target compounds 53-60 were then evaluated against in vivo carrageenan and arachidonic acid induced rat paw edema models for anti-inflammatory activity. Amongst all the synthesized derivatives, compound 56 showed the significant anti-inflammatory activity in both rat paw edema models with very less ulcerogenic liability in comparison to standard diclofenac, celecoxib, and zileuton. The compounds 56 was further assessed to observe in vitro enzyme inhibition assay on both cyclooxygenase and lipoxygenase enzyme where it showed a preferential and selective non-competitive enzyme inhibition towards the COX-2 (IC50=14.91µM, Ki=0.72µM) over COX-1 (IC50>50µM) and a significant non-competitive inhibition of soybean lipoxygenase enzyme (IC50=13.09µM, Ki=0.92µM). Thus, in silico, in vivo, and in vitro findings suggested that the synthesized indolizine compound 56 has a dual COX-2 and LOX inhibition characteristic and parallel in vivo anti-inflammatory activity in comparison to the standard drugs.

Design, synthesis and evaluation of some N-methylenebenzenamine derivatives as selective acetylcholinesterase (AChE) inhibitor and antioxidant to enhance learning and memory.

Series of some 3,5-dimethoxy-N-methylenebenzenamine and 4-(methyleneamino)benzoic acid derivatives comprising of N-methylenebenzenamine nucleus were designed, synthesized, characterized, and assessed for their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory, and antioxidant activity thereby improving learning and memory in rats. The IC50 values of all the compound along with standard were determined on AChE and BChE enzyme. The free radical scavenging activity was also assessed by in vitro DPPH (2,2-diphenyl-1-picryl-hydrazyl) and hydrogen peroxide radical scavenging assay. The selective inhibitions of all compounds were observed against AChE in comparison with standard donepezil. The enzyme kinetic study of the most active compound 4 indicated uncompetitive AChE inhibition. The docking studies of compound 4 exhibited the worthy interaction on active-site gorge residues Phe330 and Trp279 responsible for its high affinity towards AChE, whereas lacking of the BChE inhibition was observed due to a wider gorge binding site and absence of important aromatic amino acids interactions. The ex vivo study confirmed AChE inhibition abilities of compound 4 at brain site. Further, a considerable decrease in escape latency period of the compound was observed in comparison with standard donepezil through in vivo Spatial Reference Memory (SRM) and Spatial Working Memory (SWM) models which showed the cognition-enhancing potential of compound 4. The in vivo reduced glutathione (GSH) estimation on rat brain tissue homogenate was also performed to evaluate free radical scavenging activity substantiated the antioxidant activity in learning and memory.

Synthesis, anti-inflammatory, analgesic, 5-lipoxygenase (5-LOX) inhibition activities, and molecular docking study of 7-substituted coumarin derivatives.

In the present study, 7-subsituted coumarin derivatives were synthesized using various aromatic and heterocyclic amines, and evaluated in vivo for anti-inflammatory and analgesic activity, and for ulcerogenic risk. The most active compounds were evaluated in vitro for 5-lipoxygenase (5-LOX) inhibition. Docking study was performed to predict the binding affinity, and orientation at the active site of the enzyme. In vivo anti-inflammatory and analgesic activity, and in vitro 5-LOX enzyme inhibition study revealed that compound 33 and 35 are the most potent compounds in all the screening methods. In vitro kinetic study of 35 showed mixed or non-competitive type of inhibition with 5-LOX enzyme. Presence of OCH3 group in 35 and Cl in 33 at C6-position of benzothiazole ring were found very important substitutions for potent activity.

ACR Appropriateness Criteria® Liver Lesion-Initial Characterization.

Incidental liver masses are commonly identified on imaging performed for other indications. Since the prevalence of benign focal liver lesions in adults is high, even in patients with primary malignancy, accurate characterization of incidentally detected lesions is of paramount clinical importance. This document reviews utilization of various imaging modalities for characterization of incidentally detected liver lesions, discussed in the context of several clinical scenarios. For each clinical scenario, a summary of current evidence supporting the use of a given diagnostic modality is reported. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Pancreatic Cyst.

Incidental pancreatic cysts are increasingly detected on imaging studies performed for unrelated indications and may be incompletely characterized on these studies. Adequate morphological characterization is critical due to the small risk of malignant degeneration associated with neoplastic pancreatic cysts, as well as the risk of associated pancreatic adenocarcinoma. For all pancreatic cysts, both size and morphology determine management. Specifically, imaging detection of features, such as pancreatic ductal communication and presence or absence of worrisome features or high-risk stigmata, have important management implications. The recommendations in this publication determine the appropriate initial imaging study to further evaluate a pancreatic cyst that was incidentally detected on a nondedicated imaging study. The recommendations are designed to maximize the yield of diagnostic information in order to better risk-stratify pancreatic cysts and assist in guiding future management. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Chronic Liver Disease.

The liver fibrosis stage is the most important clinical determinate of morbidity and mortality in patients with chronic liver diseases. With newer therapies, liver fibrosis can be stabilized and possibly reversed, thus accurate diagnosis and staging of liver fibrosis are clinically important. Ultrasound, CT, and conventional MRI can be used to establish the diagnosis of advanced fibrosis/cirrhosis but have limited utility for assessing earlier stages of fibrosis. Elastography-based ultrasound and MRI techniques are more useful for assessment of precirrhotic hepatic fibrosis. In patients with advanced fibrosis at risk for hepatocellular carcinoma (HCC), ultrasound is the surveillance modality recommended by international guidelines in nearly all circumstances. However, in patients in whom ultrasound does not assess the liver well, including those with severe steatosis or obesity, multiphase CT or MRI may have a role in surveillance for HCC. Both multiphase CT and MRI can be used for continued surveillance in patients with a history of HCC, and contrast-enhanced ultrasound may have an emerging role in this setting. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Comprehensive review of mechanisms of pathogenesis involved in Alzheimer's disease and potential therapeutic strategies.

AD is a progressive neurodegenerative disorder and a leading cause of dementia in an aging population worldwide. The enormous challenge which AD possesses to global healthcare makes it as urgent as ever for the researchers to develop innovative treatment strategies to fight this disease. An in-depth analysis of the extensive available data associated with the AD is needed for a more comprehensive understanding of underlying molecular mechanisms and pathophysiological pathways associated with the onset and progression of the AD. The currently understood pathological and biochemical manifestations include cholinergic, Aß, tau, excitotoxicity, oxidative stress, ApoE, CREB signaling pathways, insulin resistance, etc. However, these hypotheses have been criticized with several conflicting reports for their involvement in the disease progression. Several issues need to be addressed such as benefits to cost ratio with cholinesterase therapy, the dilemma of AChE selectivity over BChE, BBB permeability of peptidic BACE-1 inhibitors, hurdles related to the implementation of vaccination and immunization therapy, and clinical failure of candidates related to newly available targets. The present review provides an insight to the different molecular mechanisms involved in the development and progression of the AD and potential therapeutic strategies, enlightening perceptions into structural information of conventional and novel targets along with the successful applications of computational approaches for the design of target-specific inhibitors.

Design and development of multitarget-directed N-Benzylpiperidine analogs as potential candidates for the treatment of Alzheimer's disease.

The multitarget-directed strategy offers an effective and promising paradigm to treat the complex neurodegenerative disorder, such as Alzheimer's disease (AD). Herein, a series of N-benzylpiperidine analogs (17-31 and 32-46) were designed and synthesized as multi-functional inhibitors of acetylcholinesterase (AChE) and ß-secretase-1 (BACE-1) with moderate to excellent inhibitory activities. Among the tested inhibitors, 25, 26, 40, and 41 presented the most significant and balanced inhibition against both the targets. Compounds 40 and 41 exhibited high brain permeability in the PAMPA-BBB assay, significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE, and were devoid of neurotoxicity towards SH-SY5Y neuroblastoma cell lines up to the maximum tested concentration of 80 µM. Meanwhile, both these compounds inhibited self- and AChE-induced Aß aggregation in thioflavin T assay, which was also re-affirmed by morphological characterization of Aß aggregates using atomic force microscopy (AFM). Moreover, 40 and 41 ameliorated the scopolamine-induced cognitive impairment in elevated plus and Y-maze experiments. Ex vivo and biochemical analysis established the brain AChE inhibitory potential and antioxidant properties of these compounds. Further, improvement in Aß1-42-induced cognitive impairment was also observed by compound 41 in the Morris water maze experiment with significant oral absorption characteristics ascertained by the pharmacokinetic studies.

Design and development of some phenyl benzoxazole derivatives as a potent acetylcholinesterase inhibitor with antioxidant property to enhance learning and memory.

Based on the Gaussian-based quantitative structure-activity relationship (QSAR) and virtual screening (VS) processes, some promising acetylcholinesterase inhibitors (AChEIs) having antioxidant potential were designed synthesized, characterized, and evaluated for their ability to enhance learning and memory. The synthesized phenyl benzoxazole derivatives exhibited significant antioxidant potential and AChE inhibitory activity, whereas the antioxidant potential of compound 34 (49.6%) was observed significantly better than standard donepezil (<10%) and parallel to ascorbic acid (56.6%). Enzyme kinetics study of most potent compound 34 (AChE IC50 = 0.363 ±â€¯0.017 µM; Ki = 0.19 ±â€¯0.03 µM) revealed the true nature and competitive type of inhibition on AChE. The compound 34 was further assessed for in vivo and ex vivo studies and the results showed the significant reversal of cognitive deficits and antioxidant potential at the dose of 5 mg/kg comparable to standard drug donepezil.

ACR Appropriateness Criteria® Jaundice.

Jaundice is the end result of myriad causes, which makes the role of imaging in this setting particularly challenging. In the United States, the most common causes of all types of jaundice fall into four categories including hepatitis, alcoholic liver disease, blockage of the common bile duct by a gallstone or tumor, and toxic reaction to a drug or medicinal herb. Clinically, differentiating between the various potential etiologies of jaundice requires a detailed history, targeted physical examination, and pertinent laboratory studies, the results of which allow the physician to categorize the type of jaundice into mechanical or nonmechanical causes. Imaging modalities used to evaluate the jaundiced patient (all etiologies) include abdominal ultrasound (US), CT, MR cholangiopancreatography, endoscopic retrograde cholangiopancreatography and endoscopic US. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Right Upper Quadrant Pain.

Although right upper quadrant pain is a very common clinical presentation, it can be nonspecific. However, acute cholecystitis is very often the diagnosis of exclusion. This review focuses on the recommended imaging evaluation in the most commonly encountered clinical scenarios presenting with right upper quadrant abdominal pain, including suspected biliary disease, suspected acute cholecystitis, and suspected acalculous cholecystitis. This document hopes to clarify the appropriate utilization of the many imaging procedures that are available and commonly employed in these clinical settings. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Design, Synthesis, Evaluation and Computational Studies of Nipecotic Acid-Acetonaphthone Hybrids as Potential Antiepileptic Agents.

BACKGROUND: Nipecotic acid is considered to be one of the most potent inhibitors of neuronal and glial γ-aminobutyric acid (GABA) uptake in vitro. However, nipecotic acid does not readily cross the blood-brain barrier (BBB) following peripheral administration, owing to its hydrophilic nature. OBJECTIVE: A series of substituted acetonaphthones tethered nipecotic acid derivatives were designed and synthesized with an aim to improve the lipophilicity and the blood-brain barrier (BBB) permeation. METHODS: Synthesized compounds were tested in mice models of PTZ, pilocarpine, and DMCM induced epilepsy, in vivo. The rota-rod test was performed to determine the acute neurotoxicity of the potential leads (4a, 4b, and 4i). These potential hybrids were also evaluated for their ability to cross the BBB by an in vitro parallel artificial membrane permeability BBB assay (PAMPA-BBB). The leads were subjected to in silico molecular docking and dynamics studies on homology modelled protein of human GABA (γ-amino butyric acid) transporter 1 (GAT1) and prediction of their pharmacokinetic properties. RESULT: Amongst the synthesized derivatives, compounds 3a, 3b, 3i, 4a, 4b, and 4i exhibited increased latency of seizures against subcutaneous pentylenetetrazole (scPTZ) induced seizures in mice. Derivatives 4a, 4b, 4i were more effective compared to nipecotic acid ester counterparts 3a, 3b and 3i placing the importance of the presence of free carboxyl group in the centre. The findings revealed that 4i was comparatively more permeable (Pe= 8.89) across BBB than the standard tiagabine (Pe= 7.86). In silico studies proved the consensual interactions of compound 4i with the active binding pocket. CONCLUSION: Some nipecotic acid-acetonaphthone hybrids with considerable anti-epileptic activity, drug like properties and the ability to permeate the BBB have been successfully synthesized.

ACR Appropriateness Criteria® Staging of Pancreatic Ductal Adenocarcinoma.

Pancreatic adenocarcinoma is associated with poor overall prognosis. Complete surgical resection is the only possible option for cure. As such, increasingly complex surgical techniques including sophisticated vascular reconstruction are being used. Continued advances in surgical techniques, in conjunction with use of combination systemic therapies, and radiation therapy have been suggested to improve outcomes. A key aspect to surgical success is reporting of pivotal findings beyond absence of distant metastases, such as tumor size, location, and degree of tumor involvement of specific vessels associated with potential perineural tumor spread. Multiphase contrast-enhanced multidetector CT and MRI are the imaging modalities of choice for pretreatment staging and presurgical determination of resectability. Imaging modalities such as endoscopic ultrasound and fluorine-18-2-fluoro-2-deoxy-D-glucose imaging with PET/CT are indicated for specific scenarios such as biopsy guidance and confirmation of distant metastases, respectively. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.