Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer.

Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/phage (AAVP) particles in mice bearing MDA-PCa-118b, a patient-derived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicide-inducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, ligand-directed theranostics for translational applications in AVPC.

Clopidogrel IBS Patients Have Higher Incidence of Gastrointestinal Symptoms Influenced by Age and Gender.

BACKGROUND: Clopidogrel is an irreversible antagonist of P2Y12 receptors (P2Y12Rs) used as an antiplatelet drug to reduce risk of thrombosis. P2Y12Rs are expressed in gastrointestinal (GI) tract where they might regulate GI function. AIM: To evaluate if blockade of P2Y12Rs by clopidogrel is associated with higher incidence of GI symptoms in patients with irritable bowel syndrome (IBS). METHODS: A retrospective analysis of our institutional database was conducted for a 13-year period. IBS patients were identified, and their demographics, GI symptoms and clopidogrel therapy were collected. Logistic regression models were used to characterize symptoms in clopidogrel versus no-clopidogrel IBS-groups, adjusting for Age and Sex differences. An additional study characterized the P2Y12R distribution in human gut. RESULTS: The search identified 7217 IBS patients (6761 no-clopidogrel/456 clopidogrel). There were a higher proportion of patients with GI symptoms on clopidogrel (68%) compared to controls (60%, p = 0.0011) that were Females (70 vs. 60%, p = 0.0003) not Males (61 vs. 60%; p = 0.8312). In Females, clopidogrel was associated with higher incidence of GI symptoms (Age adjusted; p < 0.0001) for pain, constipation, gastroparesis (p ≤ 0.0001) and psychogenic pain (p = 0.0006). Age or Sex (adjusted models) influenced one or more GI symptoms (i.e., pain, p < 0.0001; constipation, p < 0.0001/p = 0.008; diarrhea, flatulence, p = 0.01). P2Y12R immunoreactivity was abundant in human ENS; glial-to-neuron ratio of P2Y12Rs expressed in Females â‰« Males. CONCLUSIONS: Irreversible blockade of P2Y12R by clopidogrel is associated with higher incidence of GI symptoms in Female IBS patients, although Age or Sex alone contributes to symptomatology. Prospective studies can determine clinical implications of P2Y12Rs in IBS.

Non-opioid anesthetic drug abuse among anesthesia care providers: a narrative review.

PURPOSE: The objective of this narrative review is to provide an overview of the problem of non-opioid anesthetic drug abuse among anesthesia care providers (ACPs) and to describe current approaches to screening, therapy, and rehabilitation of ACPs suffering from non-opioid anesthetic drug abuse. SOURCE: We first performed a search of all literature available on PubMed prior to April 11, 2016. The search was limited to articles published in Spanish and English, and the following key words were used: anesthesiology, anesthesia personnel, AND substance-related disorders. We also searched Ovid MEDLINE® databases from 1946-April 11, 2016 using the following search terms: anesthesiology OR anesthesia, OR nurse anesthetist OR anesthesia care provider OR perioperative nursing AND substance-related disorders. PRINCIPAL FINDINGS: Despite an increased awareness of drug abuse among ACPs and improvements in preventive measures, the problem of non-opioid anesthetic drug abuse remains significant. While opioids are the most commonly abused anesthesia medications among ACPs, the abuse of non-opioid anesthetics is a significant cause of morbidity, mortality, and professional demise. CONCLUSION: Early detection, effective therapy, and long-term follow-up help ACPs cope more effectively with the problem and, when possible, resume their professional activities. There is insufficient evidence to determine the ability of ACPs to return safely to anesthesia practice after rehabilitation, though awareness of the issue and ongoing treatment are necessary to minimize patient risk from potentially related clinical errors.

Remifentanil-acute opioid tolerance and opioid-induced hyperalgesia: a systematic review.

The use of opioids may seem to be a double-edged sword; they provide straight analgesic and antihyperalgesic effects initially, but subsequently are associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) that have been reported in experimental studies and clinical observations. It has been suggested that opioids can induce an acute tolerance and hyperalgesia in dose- and/or time-dependent manners even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management in clinical anesthesia and in the intensive care units because of its rapid onset and offset. We reviewed articles analyzing AOT and/or OIH by remifentanil and focused on the following issues: (1) evidence of remifentanil inducing AOT and/or OIH and (2) importance of AOT and/or OIH in considering the reduction of remifentanil dosage or adopting preventive modulations. Twenty-four experimental and clinical studies were identified using electronic searches of MEDLINE (PubMed, Ovid, Springer, and Elsevier). However, the development of AOT and OIH by remifentanil administration remains controversial. There is no sufficient evidence to support or refute the existence of OIH in humans.

Molecular imaging of active mutant L858R EGF receptor (EGFR) kinase-expressing nonsmall cell lung carcinomas using PET/CT.

The importance of the EGF receptor (EGFR) signaling pathway in the development and progression of nonsmall cell lung carcinomas (NSCLC) is widely recognized. Gene sequencing studies revealed that a majority of tumors responding to EGFR kinase inhibitors harbor activating mutations in the EGFR kinase domain. This underscores the need for novel biomarkers and diagnostic imaging approaches to identify patients who may benefit from particular therapeutic agents and approaches with improved efficacy and safety profiles. To this goal, we developed 4-[(3-iodophenyl)amino]-7-{2-[2-{2-(2-[2-{2-([(18)F]fluoroethoxy)-ethoxy}-ethoxy]-ethoxy)-ethoxy}-ethoxy]-quinazoline-6-yl-acrylamide ([(18)F]F-PEG6-IPQA), a radiotracer with increased selectivity and irreversible binding to the active mutant L858R EGFR kinase. We show that PET with [(18)F]F-PEG6-IPQA in tumor-bearing mice discriminates H3255 NSCLC xenografts expressing L858R mutant EGFR from H441 and PC14 xenografts expressing EGFR or H1975 xenografts with L858R/T790M dual mutation in EGFR kinase domain, which confers resistance to EGFR inhibitors (i.e., gefitinib). The T790M mutation precludes the [(18)F]F-PEG6-IPQA from irreversible binding to EGFR. These results suggest that PET with [(18)F]F-PEG6-IPQA could be used for the selection of NSCLC patients for individualized therapy with small molecular inhibitors of EGFR kinase that are currently used in the clinic and have a similar structure (i.e., iressa, gefitinib, and erlotinib).

Imaging epigenetic regulation by histone deacetylases in the brain using PET/MRI with ¹8F-FAHA.

Epigenetic modifications mediated by histone deacetylases (HDACs) play important roles in the mechanisms of different neurologic diseases and HDAC inhibitors (HDACIs) have shown promise in therapy. However, pharmacodynamic profiles of many HDACIs in the brain remain largely unknown due to the lack of validated methods for noninvasive imaging of HDAC expression-activity. In this study, dynamic PET/CT imaging was performed in 4 rhesus macaques using [(18)F]FAHA, a novel HDAC substrate, and [(18)F]fluoroacetate, the major radio-metabolite of [(18)F]FAHA, and fused with corresponding MR images of the brain. Quantification of [(18)F]FAHA accumulation in the brain was performed using a customized dual-tracer pharmacokinetic model. Immunohistochemical analyses of brain tissue revealed the heterogeneity of expression of individual HDACs in different brain structures and cell types and confirmed that PET/CT/MRI with [(18)F]FAHA reflects the level of expression-activity of HDAC class IIa enzymes. Furthermore, PET/CT/MRI with [(18)F]FAHA enabled non-invasive, quantitative assessment of pharmacodynamics of HDAC inhibitor SAHA in the brain.

Postoperative sore throat: prophylaxis and treatment.

Postoperative sore throat (POST) is one of the most reported complications after general anesthesia with an incidence of as high as 60% which may impact patient satisfaction and increase the cost of treatment. The aim of this review is to summarize the currently accepted approaches and new trends intended to reduce the risk and increase the treatment efficacy of POST. Difficult intubation, traumatic intubation, and several other factors contribute to the development of POST. Endotracheal intubation using a stylet-loaded tube exerts excessive pressure on the anterior tracheal wall predisposing to mucosal trauma and contributing to development of POST. Pharmacological interventions are aimed at prevention, amelioration of symptoms, and treatment of POST. Medications suggested for this purpose include corticosteroids, topical sprays and creams, non-steroidal anti-inflammatory drugs (NSAID), and N-methyl-D-aspartate (NMDA) receptor antagonists. The use of video-laryngoscopes (VL) for endotracheal intubation improves the glottic view and increases the success rates with less force required to ensure adequate laryngoscopic view. Nevertheless, despite advances in laryngoscopic devices, the incidence of POST remains high. A novel intubation technique with endotracheal tube (ETT) rotation 180 degrees (ETT 180°) has been suggested to overcome stylet related injury and, possibly, decrease the POST. To date, no clinical trials have been conducted to test the efficacy of ETT 180° in reducing the incidence of POST. Undoubtedly, the suggested method deserves further investigation to determine its role in patient care.

Human CD34+ cells in experimental myocardial infarction: long-term survival, sustained functional improvement, and mechanism of action.

RATIONALE: Human CD34(+) cells have been used in clinical trials for treatment of myocardial infarction (MI). However, it is unknown how long the CD34(+) cells persist in hearts, whether the improvement in cardiac function is sustained, or what are the underlying mechanisms. OBJECTIVE: We sought to track the fate of injected human CD34(+) cells in the hearts of severe combined immune deficiency (SCID) mice after experimental MI and to determine the mechanisms of action. METHODS AND RESULTS: We used multimodality molecular imaging to track the fate of injected human CD34(+) cells in the hearts of SCID mice after experimental MI, and used selective antibody blocking to determine the mechanisms of action. Bioluminescence imaging showed that injected CD34(+) cells survived in the hearts for longer than 12 months. The PET signal from the injected cells was detected in the wall of the left ventricle. Cardiac MRI showed that left ventricular ejection fraction was significantly improved in the treated mice compared to the control mice for up to 52 weeks (P<0.05). Furthermore, treatment with anti-alpha4beta1 showed that generation of human-derived cardiomyocytes was inhibited, whereas anti-vascular endothelial growth factor (VEGF) treatment blocked the production of human-derived endothelial cells. However, the improvement in cardiac function was abolished only in the anti-VEGF, but not anti-alpha4beta1, treated group. CONCLUSIONS: Angiogenesis and/or paracrine effect, but not myogenesis, is responsible for functional improvement following CD34(+) cells therapy.

A preclinical model for predicting drug response in soft-tissue sarcoma with targeted AAVP molecular imaging.

Human sarcomas are rare but diverse malignant tumors derived from mesenchymal tissue. Clinical response to therapy is currently determined by the modified World Health Organization (WHO) criteria or the Response Evaluation Criteria in Solid Tumors (RECIST), but these standards correlate poorly with sarcoma patient outcome. We introduced ligand-directed particles with elements of AAV and phage (AAVP) to enable integration of tumor targeting to molecular imaging. We report drug-response monitoring and prediction in a nude rat model of human sarcoma by AAVP imaging. As a proof-of-concept, we imaged Herpes simplex thymidine kinase in a clinic-ready setting with PET to show that one can a priori predict tumor response to a systemic cytotoxic. Given the target expression in patient-derived sarcomas, this platform may be translated in clinical applications. Sarcoma-specific ligands and promoters may ultimately lead to an imaging transcriptome.

Case Report: Post-operative Angioedema After a Laryngeal Mask Airway Application.

Angioedema with macroglossia is a rare complication of anesthesia. We present a clinical case of post-operative development of angioedema presenting as macroglossia in a patient receiving chronic therapy with lisinopril, who developed symptoms in the early post-operative period following surgery in a lateral position, when a laryngeal mask airway was used. Possible mechanisms of angioedema and macroglossia development in our patient are discussed along with potential underlying predisposing mechanisms and available therapeutic approaches.

The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects.

Hypoxia inducible factor-1 (HIF-1) promotes tumor cell adaptation to microenvironmental stress. HIF-1 is up-regulated in irradiated tumors and serves as a promising target for radiosensitization. We initially confirmed that the orally bioavailable HIF-1 inhibitor PX-478 reduces HIF-1 protein levels and signaling in vitro in a dose-dependent manner and provides direct radiosensitization of hypoxic cancer cells in clonogenic survival assays using C6 glioma, HN5 and UMSCCa10 squamous cells, and Panc-1 pancreatic adenocarcinoma cell lines. However, PX-478 yields striking in vivo tumor sensitization to single-dose irradiation, which cannot be explained by incremental improvement in direct tumor cell killing. We show that PX-478 prevents postradiation HIF-1 signaling and abrogates downstream stromal adaptation in C6 and HN5 reporter xenografts as measured by serial ultrasound, vascular magnetic resonance imaging, and hypoxia response element-specific micro-positron emission tomography imaging. The primacy of indirect PX-478 in vivo effects was corroborated by our findings that (a) either concurrent or early postradiation sequencing of PX-478 provides roughly equivalent sensitization and (b) constitutive vascular endothelial growth factor expression maintains refractory tumor vessel function and progression following combined radiation and PX-478. These results confirm that disruption of postradiation adaptive HIF-1 signaling by PX-478 imparts increased therapeutic efficacy through blockade of HIF-1-dependent reconstitution of tumor stromal function. Successful translation of targeted HIF-1 radiosensitization to the clinical setting will require specific consideration of tumor microenvironmental effects and mechanisms.

The Effects of Patient Positioning on the Outcome During Posterior Cranial Fossa and Pineal Region Surgery.

Background: Surgery on posterior cranial fossa (PCF) and pineal region (PR) carries the risks of intraoperative trauma to the brainstem structures, blood loss, venous air embolism (VAE), cardiovascular instability, and other complications. Success in surgery, among other factors, depends on selecting the optimal patient position. Our objective was to find associations between patient positioning, incidence of intraoperative complications, neurological recovery, and the extent of surgery. Methods: This observational study was conducted in two medical centers: The Ohio State University Wexner Medical Center (USA) and The Burdenko Neurosurgical Institute (Russian Federation). Patients were distributed in two groups based on the surgical position: sitting position (SP) or horizontal position (HP). The inclusion criteria were adult patients with space-occupying or vascular lesions requiring an open PCF or PR surgery. Perioperative variables were recorded and summarized using descriptive statistics. The post-treatment survival, functional outcome, and patient satisfaction were assessed at 3 months. Results: A total of 109 patients were included in the study: 53 in SP and 56 in HP. A higher proportion of patients in the HP patients had >300 mL intraoperative blood loss compared to the SP group (32 vs. 13%; p = 0.0250). Intraoperative VAE was diagnosed in 40% of SP patients vs. 0% in the HP group (p < 0.0001). However, trans-esophageal echocardiographic (TEE) monitoring was more common in the SP group. Intraoperative hypotension was documented in 28% of SP patients compared to 9% in HP group (p = 0.0126). A higher proportion of SP patients experienced a new neurological symptom compared to the HP group (49 vs. 29%; p = 0.0281). The extent of tumor resection, postoperative 3-months survival, functional outcome, and patient satisfaction were not different in the groups. Conclusions: The SP was associated with, less intraoperative bleeding, increased intraoperative hypotension, VAE, and postoperative neurological deficit. More HP patients experienced macroglossia and increased blood loss. At 3 months, there was no difference of parameters between the two groups. Clinical Trial Registration: ClinicalTrials.gov: registration number NCT03364283.

N(3)-Substituted thymidine analogues V: synthesis and preliminary PET imaging of N(3)-[(18)F]fluoroethyl thymidine and N(3)-[(18)F]fluoropropyl thymidine.

INTRODUCTION: [(18)F]-Labeled analogues of thymidine have demonstrated efficacy for PET imaging of cellular proliferation. We have synthesized two [(18)F]-labeled N(3)-substituted thymidine analogues, N(3)-[(18)F]fluoroethyl thymidine (N(3)-[(18)F]-FET) and N(3)-[(18)F]fluoropropyl thymidine (N(3)-[(18)F]-FPrT), and performed preliminary PET imaging studies in tumor-bearing mice. METHODS: Thymidine was converted to its 3',5'-O-bis-tetrahydropyranyl ether, which was then converted to the N(3)-ethyl and propyl-substituted mesylate precursors. Reactions of these mesylate precursors with n-Bu(4)N[(18)F] or K[(18)F]/kryptofix followed by acid hydrolysis and HPLC purification yielded N(3)-[(18)F]-FET and N(3)-[(18)F]-FPrT, respectively. Subcutaneous (sc) xenografts of H441 human non-small cell lung cancer were established in two groups of mice (each n=6). Micro-PET images of the tumor-bearing animals were acquired after intravenous injection of N(3)-[(18)F]-FET or N(3)-[(18)F]-FPrT (3700 KBq/animal). RESULTS: The radiochemical yields were 2-12% (d.c.) for N(3)-[(18)F]-FET and 30-38% (d.c.) for N(3)-[(18)F]-FPrT. Radiochemical purity was >99% and calculated specific activity was >74 GBq/mumol at the end of synthesis. The accumulation of N(3)-[(18)F]-FET and N(3)-[(18)F]-FPrT in the tumor tissue at 2 h postinjection was 1.81+/-0.78 and 2.95+/-1.14 percent injected dose per gram (%ID/g), respectively; tumor/muscle ratios were 5.57+/-0.82 and 7.69+/-2.18, respectively; the unidirectional influx rates (K(i)) were 0.013 and 0.018 ml/g per minute, respectively. CONCLUSION: Two novel [(18)F]- N(3)-substituted thymidine analogues have been synthesized in good yields, high purity and high specific activity. Preliminary in vivo studies demonstrated the efficacy of these [(18)F]- N(3)-substituted thymidine analogues for PET imaging of tumors.

Perioperative Management of Subarachnoid Hemorrhage in a Patient with Alagille Syndrome and Unrepaired Tetralogy of Fallot: Case Report.

Alagille syndrome (ALGS) is a genetic disorder associated with multisystem dysfunction involving the hepatic, cardiovascular, and neurologic systems. Tetralogy of Fallot (TOF), a congenital cardiac anomaly, is commonly found in these patients. Patients with ALGS may also have an increased risk of cerebrovascular abnormalities and bleeding. Ruptured cerebral aneurysm and subarachnoid hemorrhage (SAH) may be developed, increasing the incidence of morbidity and mortality. Advances in neuroimaging and neurosurgery have allowed early identification and treatment of such vascular abnormalities, improving patients' outcomes and reducing life-threatening complications such as intracranial bleeding. Authors describe the perioperative management of a patient with ALGS and TOF who was admitted to the emergency department due a ruptured intracranial aneurysm with concomitant SAH. Surgical treatment included diagnostic cerebral arteriography with coil embolization of a left posterior communicating artery aneurysm, and placement of right external ventricular drain (EVD). The combination of neuroprotective anesthetic techniques, fast emergence from anesthesia, and maintenance of intraoperative hemodynamic stability led to a successful perioperative management. A multidisciplinary approach in specialized centers is essential for the treatment of patients with SAH, especially in patients with ALGS and complex congenital heart disease such as TOF.

The Role of Simulation in Planning Intraoperative Magnetic Resonance Imaging-Guided Neurosurgical Procedures: A Case Report.

Simulation of the actual procedure is a simple and yet effective method of increasing patient safety and reducing the rate of unexpected adverse effects. We present our experience with 2 cases of preprocedural simulation on healthy volunteers that were performed in the intraoperative magnetic resonance imaging suite. During one of the cases, we also simulated a scenario of sudden cardiac arrest. Such an approach helped us to refine the procedures and coordinate the work of different teams within the intraoperative magnetic resonance imaging suite as well as improve the quality of patient management.

The Role of Permissive and Induced Hypotension in Current Neuroanesthesia Practice.

BACKGROUND: Induced hypotension (IH) had been used for decades in neurosurgery to reduce the risk for intraoperative blood loss and decrease blood replacement. More recently, this method fell out of favor because of concerns for cerebral and other end-organ ischemia and worse treatment outcomes. Other contributing factors to the decline in its popularity include improvements in microsurgical technique, widespread use of endovascular procedures, and advances in blood conservation and transfusion protocols. Permissive hypotension (PH) is still being used occasionally in neurosurgery; however, its role in current anesthesia practice remains unclear. Our objective was to describe contemporary utilization of IH and PH (collectively called PH) in clinical practice among members of the Society for Neuroscience in Anesthesiology and Critical Care (SNACC). METHODS: A questionnaire was developed and distributed among SNACC members that addressed practice patterns related to the use of PH. The responses were analyzed based on the number of individuals who responded to each specific question. RESULTS: Of 72 respondents, 67.6% reported over 10 years of clinical experience, while 15.5% reported 5-10 years of post-training experience. The respondents admitted to providing anesthesia for 300 (median) neurosurgical cases per year. PH was applied most commonly during open interventions on cerebral aneurysms (50.8%) and arteriovenous malformations (46%). Seventy-three percent of respondents were not aware of any complications in their practice attributable to PH. CONCLUSION: PH is still being used in neuroanesthesia practice by some providers. Further research is justified to clarify the risks and benefits of PH in modern neuroanesthesia practice.

Massive blood loss in elective spinal and orthopedic surgery: Retrospective review of intraoperative transfusion strategy.

OBJECTIVE: To evaluate the perioperative dynamics of hematologic changes and transfusion ratio in patients undergoing a major spinal surgery accompanied with massive bleeding defined as blood loss >5 liters. DESIGN: Retrospective cohort study. SETTING: Operating room of a university-affiliated hospital. PATIENTS: Adult patients who underwent elective neurosurgical, orthopedic, or combined spinal surgical procedure between 2008 and 2012. METHODS: Patients who underwent a major spinal or orthopedic surgery and who experienced major bleeding (>5 L) during surgery were identified and selected for final analysis. The following information was analyzed: demographics, clinical diagnoses, hematologic parameters, estimated intraoperative blood loss, blood product transfusions, and survival 1 year after surgery. RESULTS: During the study period, 25 patients, who underwent 28 spinal procedures, experienced intraoperative blood loss >5 L. Mean patient age was 50.5 years and 56.4% were males. The majority of patients underwent procedures to manage spinal metastases. Median estimated intraoperative blood loss was 11.25 L (IQR 6.35-22 L) and median number of units (U) transfused was 24.5 U (IQR 14.0-32.5 U) of packed red blood cells (RBCs), 24.5 U (IQR 14.0-34.0 U) of fresh frozen plasma (FFP), and 4.5 U (IQR 3.0-11.5 U) of platelets (PLTs). The blood product transfusion ratio was 1 and 4 for RBC:FFP, and RBC:PLT, respectively. Hematocrit, hemoglobin, PLTs, partial thromboplastin, prothrombin time, INR, and, fibrinogen varied significantly throughout the procedures. However, acid-base status did not change significantly during surgery. Patients' survival at 1 year was 79.17%. CONCLUSION: Our results indicate that a 1:1 RBC:FFP and 4:1 RBC:PLT transfusion ratio was associated with significant intraoperative variations in coagulation variables but stable intraoperative acid-base parameters. This transfusion ratio helped clinicians to achieve postoperative coagulation parameters not significantly different to those at baseline. Future studies should assess if more liberal transfusion strategies or point of care monitoring might be warranted in patients undergoing spinal surgery at risk of major blood loss.