Regional therapies for the treatment of primary and metastatic hepatic tumors: A disease-based review of techniques and critical appraisal of current evidence.

The practice of hepatic surgery has become increasingly complex as additional therapeutic options emerge to treat both primary and metastatic tumors of the liver. Liver-directed therapy options include selective internal radiation therapy (SIRT), stereotactic body radiation therapy, chemoembolization, bland embolization, hepatic artery infusion chemotherapy (HAIC), and ablative techniques such as microwave or radiofrequency ablation. Hepatocellular carcinoma has been treated with many of these therapies for palliation of symptoms, definitive treatment, and as a bridge to transplantation. Intrahepatic cholangiocarcinoma, particularly patients with unresectable disease, have demonstrated clinical responses to both SIRT as well as HAIC. Colorectal liver metastases have been treated with all of these techniques with varying degrees of success depending on the clinical scenario. A detailed understanding of these technologies and the evidence supporting their use is essential for the modern hepatic surgeon to properly sequence therapies and provide salvage options when first-line treatment has failed. This review describes these techniques and their appropriate usage based on the disease of interest and the respective evidence currently available.

Delineating Pro-Angiogenic Myeloid Cells in Cancer Therapy.

Recent evidence suggests that myeloid cells are critical in cancer development and therapy resistance processes. Pharmacological targeting of tumor-associated myeloid cells is an emerging approach among upcoming immune therapies. Surprisingly, myeloid cells are heterogeneous, including a subset of the myeloid cell displaying angiogenic properties in solid tumors. There is an urgent need to delineate angiogenic myeloid cell populations in order to facilitate specific targeting of protumor myeloid cells among heterogeneous pool. This review article is intended to compile all the relevant information in the literature for improved understanding of angiogenic myeloid cells and their role in tumor refractoriness to cancer therapy.

Nitric oxide releasing vascular catheters for eradicating bacterial infection.

The interaction of blood proteins with an implant surface is not only a fundamental phenomenon but is also key to several important medical complications. Plasma proteins binding on the surface of intravascular catheters can promote bacterial adhesion leading to the risk of local and systemic complications such as catheter-related blood infections (CRBIs). The incidences of CRBIs in the United States amount to more than 250,000 cases/year with an attributable mortality of up to 35% and an annual healthcare expenditure of $2.3 billion approximately. This demands the development of truly nonthrombogenic and antimicrobial catheters. In the present study, catheters were fabricated by incorporating a nitric oxide (NO) donor molecule, S-nitroso-N-acetyl-penicillamine (SNAP) in a hydrophobic medical grade polymer, Elasteon-E2As. NO offers antithrombotic and antibacterial attributes without promoting drug resistance and cytotoxicity. E2As-SNAP catheters were first coated with fibrinogen, a blood plasma protein plays a key role in clot formation and eventual bacterial adhesion to the implant surface. The suitability of the catheters for biomedical applications was tested in vitro for contact angle, NO release kinetics, inhibition of bacteria, and absence of cytotoxicity toward mammalian cells. The highly hydrophobic catheters released NO in the physiological range that inhibited >99% bacterial viability on fibrinogen-coated catheters in a 24 h study. No toxic response of E2As-SNAP catheters leachate was observed using a standard cytotoxicity assay with mouse fibroblast cells. Overall, the results showed that the E2As-SNAP catheters can inhibit viable bacteria even in the presence of blood proteins without causing a cytotoxic response. The fundamentals of this study are applicable to other blood-contacting medical devices as well. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2849-2857, 2018.

Marine oxygen production and open water supported an active nitrogen cycle during the Marinoan Snowball Earth.

The Neoproterozoic Earth was punctuated by two low-latitude Snowball Earth glaciations. Models permit oceans with either total ice cover or substantial areas of open water. Total ice cover would make an anoxic ocean likely, and would be a formidable barrier to biologic survival. However, there are no direct data constraining either the redox state of the ocean or marine biological productivity during the glacials. Here we present iron-speciation, redox-sensitive trace element, and nitrogen isotope data from a Neoproterozoic (Marinoan) glacial episode. Iron-speciation indicates deeper waters were anoxic and Fe-rich, while trace element concentrations indicate surface waters were in contact with an oxygenated atmosphere. Furthermore, synglacial sedimentary nitrogen is isotopically heavier than the modern atmosphere, requiring a biologic cycle with nitrogen fixation, nitrification and denitrification. Our results indicate significant regions of open marine water and active biologic productivity throughout one of the harshest glaciations in Earth history.

Combat-related facial burns: analysis of strategic pitfalls.

PURPOSE: Burns constitute approximately 10% of all combat-related injuries to the head and neck region. We postulated that the combat environment presents unique challenges not commonly encountered among civilian injuries. The purpose of the present study was to determine the features commonly seen among combat facial burns that will result in therapeutic challenges and might contribute to undesired outcomes. MATERIALS AND METHODS: The present study was a retrospective study performed using a query of the Burn Registry at the US Army Institute of Surgical Research Burn Center for all active duty facial burn admissions from October 2001 to February 2011. The demographic data, total body surface area of the burn, facial region body surface area involvement, and dates of injury, first operation, and first facial operation were tabulated and compared. A subset analysis of severe facial burns, defined by a greater than 7% facial region body surface area, was performed with a thorough medical record review to determine the presence of associated injuries. RESULTS: Of all the military burn injuries, 67.1% (n = 558) involved the face. Of these, 81.3% (n = 454) were combat related. The combat facial burns had a mean total body surface area of 21.4% and a mean facial region body surface area of 3.2%. The interval from the date of the injury to the first operative encounter was 6.6 ± 0.8 days and was 19.8 ± 2.0 days to the first facial operation. A subset analysis of the severe facial burns revealed that the first facial operation and the definitive coverage operation was performed at 13.45 ± 2.6 days and 31.9 ± 4.1 days after the injury, respectively. The mortality rate for this subset of patients was 32% (n = 10), with a high rate of associated inhalational injuries (61%, n = 19), limb amputations (29%, n = 9), and facial allograft usage (48%, n = 15) and a mean facial autograft thickness of 10.5/1,000th in. CONCLUSIONS: Combat-related facial burns present multiple challenges, which can contribute to suboptimal long-term outcomes. These challenges include prolonged transport to the burn center, delayed initial intervention and definitive coverage, and a lack of available high-quality color-matched donor skin. These gaps all highlight the need for novel anti-inflammatory and skin replacement strategies to more adequately address these unique combat-related obstacles.

Opioid guidelines in the management of chronic non-cancer pain.

BACKGROUND: Opioid abuse has increased at an alarming rate. However, available evidence suggests a wide variance in the use of opioids, as documented by different medical specialties, medical boards, advocacy groups, and the Drug Enforcement Administration (DEA). OBJECTIVES: The objective of these opioid guidelines by the American Society of Interventional Pain Physicians (ASIPP) is to provide guidance for the use of opioids for the treatment of chronic non-cancer pain, to bring consistency in opioid philosophy among the many diverse groups involved, to improve the treatment of chronic non-cancer pain, and to reduce the incidence of drug diversion. DESIGN: A policy committee evaluated a systematic review of the available literature regarding opioid use in managing chronic non-cancer pain. This resulted in the formulation of the essentials of guidelines, a series of potential evidence linkages representing conclusions, followed by statements regarding relationships between clinical interventions and outcomes. METHODS: Consistent with the Agency for Healthcare Research and Quality (AHRQ) hierarchical and comprehensive standards, the elements of the guideline preparation process included literature searches, literature synthesis, systematic review, consensus evaluation, open forum presentations, formal endorsement by the Board of Directors of the American Society of Interventional Pain Physicians (ASIPP), and blinded peer review. Evidence was designated based on scientific merit as Level I (conclusive), Level II (strong), Level III (moderate), Level IV (limited), or Level V (indeterminate). RESULTS: After an extensive review and analysis of the literature, the authors utilized two systematic reviews, two narrative reviews, 32 studies included in prior systematic reviews, and 10 additional studies in the synthesis of evidence. The evidence was limited. CONCLUSION: These guidelines evaluated the evidence for the use of opioids in the management of chronic non-cancer pain and recommendations for management. These guidelines are based on the best available scientific evidence and do not constitute inflexible treatment recommendations. Because of the changing body of evidence, this document is not intended to be a "standard of care."

Central neurochemical ultradian variability in depression.

UNLABELLED: Depression is characterized by blunted behavior and neuroendocrine function that generally improve with antidepressant treatment. This study examined intrinsic variability in brain neurotransmitter function, since it may be a source of blunted behavior and neuroendocrine function in depression and a marker for the illness, and has not previously been analyzed using wavelet decomposition. To measure variability in monoamine metabolites, lumbar cerebrospinal fluid (CSF) was collected in serial samples in depressed patients before and after treatment. We hypothesized that changes in variability would be observed after treatment. Mechanisms that control such variability may be critical to the pathophysiology of depression. METHOD: Time series data was obtained from serial ten-min sampling over a 24-hr period (N=144) from thirteen depressed patients, with a repeat collection after 5 weeks of antidepressant (sertraline or bupropion) treatment. Concentrations of tryptophan (TRP), the monoamine metabolites 5-HIAA (metabolite of serotonin) and HVA (metabolite of dopamine), and the HVA:5HIAA ratio were transformed to examine power in slowly (160 min/cycle) to rapidly (20 min/cycle) occurring events. Power, the sum of the squares of the coefficients in each d (detail) wavelet, reflects variability within a limited frequency bandwidth for that wavelet. Pre-treatment to post-treatment comparisons were conducted with repeated measures ANOVA. RESULTS: Antidepressant treatment was associated with increased power in the d2 wavelet from the HVA (p=0.03) and the HVA:5-HIAA ratio (p=0.03) series. The d1 and d3 wavelets showed increased power following antidepressant treatment for the ratio series (d1, p=0.01; d3, p=0.05). Significant changes in power were not observed for the 5-HIAA data series. Power differences among analytes suggest that the findings are specific to each system. CONCLUSION: The wavelet transform analysis shows changes in neurochemical signal variability following antidepressant treatment. Patterns or degrees of variability may be as important as, or possibly more important than, the mean levels of monoamine transmitters. Studies of variability observed in healthy individuals and a larger depressed sample will be needed to verify a relationship with mood and treatment response. Neurochemical measures of time-variability may be a pivotal marker in depression.

Treatment enhances ultradian rhythms of CSF monoamine metabolites in patients with major depressive episodes.

Unipolar and bipolar depressions show abnormal behavioral manifestations of ultradian (less than 24 h) rhythms, but abnormal rhythms of the central neurotransmitters thought to be important for depression pathophysiology (eg dopamine (DA) and serotonin (5-HT)) have not been shown in this time frame. Since antidepressant treatments normalize disrupted rhythms in depression (eg rapid-eye-movement sleep and hormonal rhythms), we hypothesized that depression-related changes in ultradian oscillations of DA and 5-HT might be revealed during antidepressant treatment. Cerebrospinal fluid (CSF) samples collected q10 min for 24 h in 13 patients experiencing major depressive episodes (MDE) before and after treatment for 5 weeks with sertraline or bupropion were assayed for levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), and their ratio was calculated. Data were analyzed in the frequency domain using Fourier transforms and multivariate permutation testing. Antidepressant treatments were associated with decreased variance for 5-HIAA, increased variance for HVA, and markedly increased variance for the HVA : 5-HIAA ratio (p<0.05, p<0.02, and p<0.003, respectively). With treatment, the correlations between 5-HIAA and HVA weakened (p=0.06). Power spectral density (PSD-the Fourier magnitude squared) of the 5-HIAA signals at periods of 1.75 and 3.7 h (both p<0.05) decreased, while circadian cycling of HVA levels (p<0.05) and of the ratio (p<0.005) increased after treatment. The PSD of the full-length HVA : 5-HIAA ratio series after treatment increased in rapid variability (20-103 min periods, p<0.05). Spectrographic windowing demonstrated a focal span of enhanced HVA : 5-HIAA ratio variability following antidepressant treatment, in an approximately 84-min period through the evening (p<0.05). Periodic neurotransmitter relationships in depressed patients were altered by treatment in this analysis of a small data set. This may represent a baseline abnormality in the regulation of periodic functions involved in the depression pathophysiology, but it could also be due to an unrelated antidepressant effect. Further studies including comparisons with healthy subject data are in progress.

Association of a critical CSF tryptophan threshold level with depressive relapse.

This work studies association between relapse during acute tryptophan depletion (ATD) and CSF level of tryptophan (TRP) in remitted depressives treated with sertraline or bupropion. Eight medication-responding depressives ingested an ATD amino acid mixture during 48-h continuous CSF sampling before and after treatment. Mood rating scores were compared with nadir levels of TRP in CSF. CSF TRP nadirs averaged 8.7% of am baselines in remitted patients. Mood relapsed whenever the CSF nadir was below 40 nmol/l TRP in remitted patients, and never when above (Fisher's exact test, P=0.029). Relapsing medication responders also showed very low preantidepressant ATD-induced nadirs. ATD-induced relapses were associated with low CSF TRP levels. Individual susceptibility to depletion may be independent of antidepressant treatment, mood state, or treatment status. Resistance to relapse may invoke an undefined, protective CNS mechanism against extremely low CSF levels of TRP during ATD.

Are we training future pain specialists?

The purpose of this study was to determine whether pain practices in Tennessee are training future pain specialists. Following IRB approval, a questionnaire designed for the study was administered to members of the TN Pain Society. Results indicate that none of the subjects are training residents at their pain practice and the majority are not training pain fellows. Few attendings reported having trained in a pain fellowship themselves and the majority are reportedly not engaged in continuing pain management education through national or international organizations, such as the American Pain Society (APS) or the International Association for the Study of Pain (IASP). Of concern is whether or not this sample reflects the nature of pain practices throughout the country. If so, will there be a shortage of pain residents and fellows in the near future? Will pain practices be opened and operated by those who are not trained to treat chronic pain?

Serial cerebrospinal fluid tryptophan and 5-hydroxy indoleacetic acid concentrations in healthy human subjects.

The role of the serotonergic system in the pathogenesis of behavioral disorders such as depression, alcoholism, obsessive-compulsive disorder, and violence is not completely understood. Measurement of the concentration of neurotransmitters and their metabolites in cerebrospinal fluid (CSF) is considered among the most valid, albeit indirect, methods of assessing central nervous system function in man. However, most studies in humans have measured lumbar CSF concentrations only at single time points, thus not taking into account rhythmic or episodic variations in levels of neurotransmitters, precursors, or metabolites. We have continuously sampled lumbar CSF via subarachnoid catheter in 12 healthy volunteers, aged 20-65 years. One ml (every 10 min) CSF samples were collected at a rate of 0.1ml/min for 24-hour (h), and the levels of tryptophan (TRP) and 5-hydroxy indoleacetic acid (5-HIAA) were measured. Variability across all 12 subjects was significantly greater (P < 0.0001) than the variability seen in repeated analysis of a reference CSF sample for both 5-HIAA (32.0% vs 7.9%) and TRP (25.4% vs 7.0%), confirming the presence of significant biological variability during the 24-hr period examined. This variability could not be explained solely by meal related effects. Cosinor analysis of the 24-hr TRP concentrations from all subjects revealed a significant diurnal pattern in CSF TRP levels, whereas the 5-HIAA data were less consistent. These studies indicate that long-term serial CSF sampling reveals diurnal and biological variability not evident in studies based on single CSF samples.