Interleukin-1ß moderates the relationships between middle frontal-mACC/insular connectivity and depressive symptoms in bipolar II depression.

The functional alterations of the brain in bipolar II depression (BDII-D) and their clinical and inflammatory associations are understudied. We aim to investigate the functional brain alterations in BDII-D and their relationships with inflammation, childhood adversity, and psychiatric symptoms, and to examine the moderating effects among these factors. Using z-normalized amplitude of low-frequency fluctuation (zALFF), we assessed the whole-brain resting-state functional activity between 147 BDII-D individuals and 150 healthy controls (HCs). Differential ALFF regions were selected as seeds for functional connectivity analysis to observe brain connectivity alterations resulting from abnormal regional activity. Four inflammatory cytokines including interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) and five clinical scales including Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), Positive and Negative Syndrome Scale (PANSS), Columbia-Suicide Severity Rating Scale (C-SSRS), and Childhood Trauma Questionnaire (CTQ) were tested and assessed in BDII-D. Partial correlations with multiple comparison corrections identified relationships between brain function and inflammation, childhood adversity, and psychiatric symptoms. Moderation analysis was conducted based on correlation results and previous findings. Compared to HCs, BDII-D individuals displayed significantly lower zALFF in the superior and middle frontal gyri (SFG and MFG) and insula, but higher zALFF in the occipital-temporal area. Only the MFG and insula-related connectivity exhibited significant differences between groups. Within BDII-D, lower right insula zALFF value correlated with higher IL-6, CRP, and emotional adversity scores, while lower right MFG zALFF was related to higher CRP and physical abuse scores. Higher right MFG-mid-anterior cingulate cortex (mACC) connectivity was associated with higher IL-1ß. Moreover, IL-1ß moderated associations between higher right MFG-mACC/insula connectivity and greater depressive symptoms. This study reveals that abnormal functional alterations in the right MFG and right insula were associated with elevated inflammation, childhood adversity, and depressive symptoms in BDII-D. IL-1ß may moderate the relationship between MFG-related connectivity and depressive symptoms.

Understanding the needs of women undergoing breast ultrasound: Are male radiologists still needed?

INTRODUCTION: A trend towards less male radiologists specializing in breast ultrasound was observed. A common notion in the field of breast radiology is, that female patients feel more comfortable being treated by female radiologists. The aim of the study was to understand and report the needs of women undergoing breast ultrasound with regards to the sex of the radiologist performing the investigation. METHODS: Informed consent was obtained from all patients prior to inclusion in a prospective bi-center quality study. At center 1 (72 patients), the women were examined exclusively by female radiologists, at center 2 (100 patients) only by male radiologists. After the examination the patients were asked about their experiences and their wishes for the future. RESULTS: Overall, women made no distinction between female and male radiologists; 25% of them wanted a female radiologist and 1.2% wanted a male radiologist. The majority (74%) stated that it made no difference whether a female or male radiologist performed the examination. The majority of women in group 2, who were investigated exclusively by male radiologists, stated that they had no preferences with regard to the sex of the radiologist (93%); 5% of the women wished to be investigated solely by a female radiologist and 2% exclusively by a male radiologist. DISCUSSION: The majority of women undergoing breast ultrasound are unconcerned about the radiologist's sex. It would appear that women examined by male radiologists are less selective about the sex of the examining radiologist. TRIAL REGISTRATION: Written informed consent was obtained from all patients. All patient data were anonymized. The physicians had no access to any further personal data. National regulations did not require dedicated ethics approval with anonymized lists or retrospective questionnaires.

Cross-sectional study of retrospective self-reported childhood emotional neglect and inhibitory neurometabolite levels in the pregenual anterior cingulate cortex in adult humans.

High childhood emotional maltreatment (CM-EMO) is reported in mood and anxiety disorders. The associations with an increased risk for psychopathology are not fully understood. One potential factor may be through alterations in gamma-Aminobutyric acid (GABA). The pregenual anterior cingulate cortex (pgACC) is an important brain region for emotion processing and its' GABA levels were previously implicated in mood and anxiety disorders pathophysiology. We examined the association between the self-reported CM-EMO in adulthood and GABA + levels in the pgACC and in a control region, anterior mid cingulate cortex. GABA+ and total creatine (tCr) were measured in the pgACC and aMCC voxels in seventy-four healthy volunteers (32 (43%) women, ages 19-54, age [standard deviation] = 27.1 [6.5]) using proton magnetic resonance spectroscopy at 7 T. Childhood Trauma Questionnaire was completed by adult participants to measure retrospective self-reported experience of emotional neglect (CM-EMO-NEG) and emotional abuse (CM-EMO-AB) during childhood. Linear mixed models tested the interaction between the region and the two subscales, and GABA+/tCr ratios, with an adjusted alpha = 0.025. Following, linear models, including with covariates were tested. There was an interaction effect between region and CM-EMO-NEG (B = -0.007, p = 0.009), driven by a negative relationship between CM-EMO-NEG and GABA+/tCr in the pgACC (B = -0.004, p = 0.013). Results for CM-EMO-NEG were robust to inclusion of different covariates (ps < 0.035). There was no interaction effect for the CM-EMO-AB (B = 0.007, p = 0.4). Limitations include cross-sectional measurement and retrospective nature of the CTQ. The findings indicate preliminary importance of inhibitory neurometabolite concentrations in the pgACC for retrospective reporting of CM-EMO-NEG.

Peptide Receptor Radionuclide Therapy in Merkel Cell Carcinoma: A Comprehensive Review.

Merkel cell carcinoma is a rare, aggressive skin malignancy, also known as neuroendocrine carcinoma of the skin, with high rates of recurrence and distant metastasis. In refractory metastatic Merkel cell carcinoma (mMCC), besides immunotherapy, chemotherapy, and radiation, peptide receptor radionuclide therapy (PRRT) may be a viable option since this type of tumor can express somatostatin receptors. Methods: We performed a comprehensive review of the literature to evaluate the efficacy of PRRT in mMCC patients. Results: Thirty-seven patients with mMCC received PRRT (1-5 cycles) with 177Lu- or 90Y-labeled somatostatin analogs (cumulative activity, 1.5-30 GBq). Radiographic response was available for 19 of 28 patients who received PRRT alone. Six (31.6%) of 19 patients showed objective responses, from partial to complete, and no severe adverse events were reported. Conclusion: Our analysis supports the use of PRRT in mMCC with sufficient somatostatin receptor uptake, although the quality of the available evidence is low. Prospective clinical trials are already in development and have started accruing in some parts of the world.

The Potential Contribution of Hexavalent Chromium to the Carcinogenicity of Chrysotile Asbestos.

Chrysotile asbestos is a carcinogenic mineral that has abundantly been used in industrial and consumer applications. The carcinogenicity of the fibers is partly governed by reactive Fe surface sites that catalyze the generation of highly toxic hydroxyl radicals (HO•) from extracellular hydrogen peroxide (H2O2). Chrysotile also contains Cr, typically in the low mass permille range. In this study, we examined the leaching of Cr from fibers at the physiological lung pH of 7.4 in the presence and absence of H2O2. Furthermore, we investigated the potential of cells from typical asbestos-burdened tissues and cancers to take up Cr leached from chrysotile in PCR expression, immunoblot, and cellular Cr uptake experiments. Finally, the contribution of Cr to fiber-mediated H2O2 decomposition and HO• generation was studied. Chromium readily dissolved from chrysotile fibers in its genotoxic and carcinogenic hexavalent redox state upon oxidation by H2O2. Lung epithelial, mesothelial, lung carcinoma, and mesothelioma cells expressed membrane-bound Cr(VI) transporters and accumulated Cr up to 10-fold relative to the Cr(VI) concentration in the spiked medium. Conversely, anion transporter inhibitors decreased cellular Cr(VI) uptake up to 45-fold. Finally, chromium associated with chrysotile neither decomposed H2O2 nor contributed to fiber-mediated HO• generation. Altogether, our results support the hypothesis that Cr may leach from inhaled chrysotile in its hexavalent state and subsequently accumulate in cells of typically asbestos-burdened tissues, which could contribute to the carcinogenicity of chrysotile fibers. However, unlike Fe, Cr did not significantly contribute to the adverse radical production of chrysotile.

Somatostatin analogues in treatment-refractory meningioma: a systematic review with meta-analysis of individual patient data.

Treatment-refractory meningiomas have a dismal prognosis and limited treatment options. Meningiomas express high-densities of somatostatin receptors (SSTR), thus potentially susceptible to antitumorigenic effects of somatostatin analogues (SSA). Evidence for SSA in meningiomas is scarce, and it is unclear if published literature would either (1) support wider use of SSA, if (2) more evidence is desirable, or if (3) available evidence is sufficient to discard SSA. We addressed the need for more evidence with a systematic review and meta-analysis. We performed an individual patient data (IPD) meta-analysis. Main outcomes were toxicity, best radiological response, progression-free survival, and overall survival. We applied multivariable logistic regression models to estimate the effect of SSA on the probability of obtaining radiological disease control. The predictive performance was evaluated using area under the curve and Brier scores. We included 16 studies and compiled IPD from 8/9 of all previous cohorts. Quality of evidence was overall ranked "very low." Stable disease was reported in 58% of patients as best radiological response. Per 100 mg increase in total SSA dosage, the odds ratios for obtaining radiological disease control was 1.42 (1.11 to 1.81, P = 0.005) and 1.44 (1.00 to 2.08, P = 0.05) for patients treated with SSA as monodrug therapy vs SSA in combination with everolimus, respectively. Low quality of evidence impeded exact quantification of treatment efficacy, and the association between response and treatment may represent reverse causality. Yet, the SSA treatment was well tolerated, and beneficial effect cannot be disqualified. A prospective trial without bias from inconsistent study designs is warranted to assess SSA therapy for well-defined meningioma subgroups.

Characteristics and survival of patients with cancer with intended off-label use-a cohort study.

OBJECTIVE: To describe the characteristics and the survival of patients with cancer with intended off-label use (OLU) cancer treatment and reimbursement request. DESIGN: Cohort study using medical record data. SETTING: Three major cancer centres in Switzerland. PARTICIPANTS: 519 patients with cancer and a reimbursement request for OLU between January 2015 and July 2018. MAIN OUTCOMES: Characteristics of patients with cancer with and without access to intended OLU. Characteristics included the Glasgow prognostic score (GPS) which includes C reactive protein and albumin and discriminates prognostic groups. RESULTS: OLU was intended for 519 (17%) of 3046 patients with cancer, as first-line treatment in 51% (n=264) and second-line in 31% (n=162). Of the 519 patients, 63% (n=328) were male, 63% (n=329) had solid cancer and 21% (n=111) had a haematological malignancy. Their median overall survival was 23.6 months (95% CI: 19.0 to 32.5). Access to OLU had 389 (75%) patients who were compared with patients without access on average 4.9 years younger (mean; 95% CI: 1.9 to 7.9 years), had a better overall prognosis according to the GPS (51% with GPS of 0 vs 39%; OR: 1.62 (95% CI: 1.01 to 2.59)), had less frequently solid cancer (62% vs 71%; OR: 0.66 (95% CI: 0.41 to 1.05)) and advanced stage cancer (53% vs 70%; OR: 0.48 (95% CI: 0.30 to 0.75)), were more frequently treatment-naive (53% vs 43%; OR: 1.55 (95% CI 1.01 to 2.39)) and were more frequently in an adjuvant/neoadjuvant treatment setting (14% vs 5%; OR: 3.39 (95% CI: 1.45 to 9.93)). Patients with access to OLU had a median OS of 31.1 months versus 8.7 months for patients without access (unadjusted HR: 0.54; (95% CI: 0.41 to 0.70)). CONCLUSION: Contrary to the common assumption, OLU in oncology is typically not primarily intended for patients with exhausted treatment options. Patient characteristics largely differ between patients with and without access to intended OLU. More systematic evaluations of the benefits and harms of OLU in cancer care and the regulation of its access is warranted.

Soil-pH and cement influence the weathering kinetics of chrysotile asbestos in soils and its hydroxyl radical yield.

Chrysotile asbestos is a toxic and carcinogenic mineral that has been used in a variety of industrial and consumer applications. Much of the fiber- and cement-containing asbestos waste has ended up in terrestrial environments. Chrysotile weathering in soils and the potential for natural attenuation have, however, hardly been examined yet. Here we explored how soil properties influence the dissolution rate of chrysotile, the release of the carcinogenic metals chromium and nickel, and the hydroxyl radical (HO•) generation by chrysotile fibers. Chrysotile dissolution rates in soil suspensions decreased with increasing soil-pH and were lower than reported rates in soil-free systems. Dissolved organic carbon did not markedly accelerate dissolution at circumneutral pH, whereas cement mixed with soil inhibited dissolution because of its alkalinity. The HO•-yield of incubated fibers in non-amended soils eventually decreased by 60-75%. The decline was fastest in an acidic podzol soil, yet was followed by a small rebound. Cement amendment induced the largest HO•-yield reduction (∼90%), presumably due to surface coating of the fibers. Overall, this work demonstrates that the potential for natural attenuation of chrysotile asbestos in soils critically depends on soil chemical parameters and the presence of cement in association with the fibers.

Treatment for gastrointestinal and pancreatic neuroendocrine tumours: a network meta-analysis.

BACKGROUND: Several available therapies for neuroendocrine tumours (NETs) have demonstrated efficacy in randomised controlled trials. However, translation of these results into improved care faces several challenges, as a direct comparison of the most pertinent therapies is incomplete. OBJECTIVES: To evaluate the safety and efficacy of therapies for NETs, to guide clinical decision-making, and to provide estimates of relative efficiency of the different treatment options (including placebo) and rank the treatments according to their efficiency based on a network meta-analysis. SEARCH METHODS: We identified studies through systematic searches of the following bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (Ovid); and Embase from January 1947 to December 2020. In addition, we checked trial registries for ongoing or unpublished eligible trials and manually searched for abstracts from scientific and clinical meetings. SELECTION CRITERIA: We evaluated randomised controlled trials (RCTs) comparing two or more therapies in people with NETs (primarily gastrointestinal and pancreatic). DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data to a pre-designed data extraction form. Multi-arm studies were included in the network meta-analysis using the R-package netmeta. We separately analysed two different outcomes (disease control and progression-free survival) and two types of NET (gastrointestinal and pancreatic NET) in four network meta-analyses. A frequentist approach was used to compare the efficacy of therapies. MAIN RESULTS: We identified 55 studies in 90 records in the qualitative analysis, reporting 39 primary RCTs and 16 subgroup analyses. We included 22 RCTs, with 4299 participants, that reported disease control and/or progression-free survival in the network meta-analysis. Precision-of-treatment estimates and estimated heterogeneity were limited, although the risk of bias was predominantly low. The network meta-analysis of progression-free survival found nine therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.36 [95% CI, 0.28 to 0.46]), interferon plus somatostatin analogue (HR, 0.34 [95% CI, 0.14 to 0.80]), everolimus plus somatostatin analogue (HR, 0.38 [95% CI, 0.26 to 0.57]), bevacizumab plus somatostatin analogue (HR, 0.36 [95% CI, 0.15 to 0.89]), interferon (HR, 0.41 [95% CI, 0.18 to 0.94]), sunitinib (HR, 0.42 [95% CI, 0.26 to 0.67]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.48 [95% CI, 0.28 to 0.83]), surufatinib (HR, 0.49 [95% CI, 0.32 to 0.76]), and somatostatin analogue (HR, 0.51 [95% CI, 0.34 to 0.77]); and six therapies for gastrointestinal NETs: 177-Lu-DOTATATE plus somatostatin analogue (HR, 0.07 [95% CI, 0.02 to 0.26]), everolimus plus somatostatin analogue (HR, 0.12 [95%CI, 0.03 to 0.54]), bevacizumab plus somatostatin analogue (HR, 0.18 [95% CI, 0.04 to 0.94]), interferon plus somatostatin analogue (HR, 0.23 [95% CI, 0.06 to 0.93]), surufatinib (HR, 0.33 [95%CI, 0.12 to 0.88]), and somatostatin analogue (HR, 0.34 [95% CI, 0.16 to 0.76]), with higher efficacy than placebo. Besides everolimus for pancreatic NETs, the results suggested an overall superiority of combination therapies, including somatostatin analogues. The results indicate that NET therapies have a broad range of risk for adverse events and effects on quality of life, but these were reported inconsistently. Evidence from this network meta-analysis (and underlying RCTs) does not support any particular therapy (or combinations of therapies) with respect to patient-centred outcomes (e.g. overall survival and quality of life). AUTHORS' CONCLUSIONS: The findings from this study suggest that a range of efficient therapies with different safety profiles is available for people with NETs.

Unwillingly traumatizing: is there a psycho-traumatologic pathway from general surgery to postoperative maladaptation?

BACKGROUND: Surgery may possibly be undermined by psychologic, psychiatric and psychosomatic problems, as long as these problems interfere with a patient's capacity to cope with surgery adaptively. Recent studies have shown that interpersonal trauma, e.g. abuse or neglect, and its correlates are involved in the adaptation to surgery. This observation is heuristically coherent, given the respective traumatization is an interpersonal event occurring in a relationship. Notably, surgery inevitably leads to the violation of physical boundaries within a doctor-patient relationship. Based on the principles of psycho-traumatologic thinking, such a constellation is deemed qualified to activate posttraumatic symptoms in the traumatized. METHOD: The present topical review summarizes the respective findings which point to a subgroup of patients undergoing surgery, in whom difficulty bearing tension and confiding in others may cause adaptive problems relevant to surgery. Although this theorizing is empirically substantiated primarily with respect to total knee arthroplasty (TKA), a pubmed-research reveals psychopathologic distress to occur prior to surgery beyond TKA. Likewise, posttraumatic distress occurs in large numbers in the context of several operations, including cardiac, cancer and hernia surgery. CONCLUSION: Aspects of psychological trauma may be linked to the outcomes of general surgery, as well, e.g. biliary, hernia or appendix surgery. The mechanisms possibly involved in this process are outlined in terms of a hierarchical organization of specific anxiety and negative affect as well as in terms of psychodynamics which imply the unconscious action of psychologic defenses at their core. IMPLICATIONS: Not least, we encourage the screening for trauma and its correlates including defenses prior to general surgery in order to identify surgical candidates at risk of, e.g. chronic postoperative pain, before the operation.

Somatostatin Receptor-Targeted Radiopeptide Therapy in Treatment-Refractory Meningioma: Individual Patient Data Meta-analysis.

Somatostatin receptor (SSTR)-targeted peptide receptor radionuclide therapy (PRRT) represents a promising approach for treatment-refractory meningiomas. Methods: We performed an individual patient data meta-analysis, including all published data on meningioma patients treated with SSTR-targeted PRRT. The main outcomes were toxicity, response to treatment, progression-free survival (PFS), and overall survival (OS). We applied the Kaplan-Meier method to estimate survival probabilities and report incidence rates per 100 person-years. We applied Cox proportional hazards models to determine the effect of covariates. Results: We screened 537 papers and identified 6 eligible cohort studies. We included a total of 111 patients who had treatment-refractory meningioma and received SSTR-targeted PRRT. Disease control was achieved in 63% of patients. The 6-mo PFS rates were 94%, 48%, and 0% for World Health Organization grades I, II, and III, respectively. The risk of disease progression decreased by 13% per 1,000-MBq increase in the total applied activity. The 1-y OS rates were 88%, 71%, and 52% for World Health Organization grades I, II, and III, respectively. The risk of death decreased by 17% per 1,000-MBq increase in the total applied activity. The main side effects comprised transient hematotoxicity, such as anemia in 22% of patients, leukopenia in 13%, lymphocytopenia in 24%, and thrombocytopenia in 17%. Conclusion: To our knowledge, this individual patient data meta-analysis represents the most comprehensive analysis of the benefits of and adverse events associated with SSTR-targeted PRRT for treatment-refractory meningioma. The treatment was well tolerated, achieved disease control in most cases, and showed promising results regarding PFS and OS.

[68Ga]Ga-PSMA-11 in prostate cancer: a comprehensive review.

Imaging of the prostate-specific membrane antigen (PSMA) has become an important tool for managing patients with recurrent prostate cancer, and one of the most frequently employed radiopharmaceuticals is [68Ga]Ga-PSMA-11. Herein, we summarize the preclinical development and the clinical applications of [68Ga]Ga-PSMA-11 and present side-by-side comparisons with other radiopharmaceuticals or imaging modalities, in order to assist imagers and clinicians in recommending, performing, and interpreting the results of [68Ga]Ga-PSMA-11 PET scans in patients with prostate cancer.

Identifying the reactive sites of hydrogen peroxide decomposition and hydroxyl radical formation on chrysotile asbestos surfaces.

BACKGROUND: Fibrous chrysotile has been the most commonly applied asbestos mineral in a range of technical applications. However, it is toxic and carcinogenic upon inhalation. The chemical reactivity of chrysotile fiber surfaces contributes to its adverse health effects by catalyzing the formation of highly reactive hydroxyl radicals (HO•) from H2O2. In this Haber-Weiss cycle, Fe on the fiber surface acts as a catalyst: Fe3+ decomposes H2O2 to reductants that reduce surface Fe3+ to Fe2+, which is back-oxidized by H2O2 (Fenton-oxidation) to yield HO•. Chrysotile contains three structural Fe species: ferrous and ferric octahedral Fe and ferric tetrahedral Fe (Fe3+tet). Also, external Fe may adsorb or precipitate onto fiber surfaces. The goal of this study was to identify the Fe species on chrysotile surfaces that catalyze H2O2 decomposition and HO• generation. RESULTS: We demonstrate that at the physiological pH 7.4 Fe3+tet on chrysotile surfaces substantially contributes to H2O2 decomposition and is the key structural Fe species catalyzing HO• generation. After depleting Fe from fiber surfaces, a remnant fiber-related H2O2 decomposition mode was identified, which may involve magnetite impurities, remnant Fe or substituted redox-active transition metals other than Fe. Fe (hydr)oxide precipitates on chrysotile surfaces also contributed to H2O2 decomposition, but were per mole Fe substantially less efficient than surface Fe3+tet. Fe added to chrysotile fibers increased HO• generation only when it became incorporated and tetrahedrally coordinated into vacancy sites in the Si layer. CONCLUSIONS: Our results suggest that at the physiological pH 7.4, oxidative stress caused by chrysotile fibers largely results from radicals produced in the Haber-Weiss cycle that is catalyzed by Fe3+tet. The catalytic role of Fe3+tet in radical generation may also apply to other pathogenic silicates in which Fe3+tet is substituted, e.g. quartz, amphiboles and zeolites. However, even if these pathogenic minerals do not contain Fe, our results suggest that the mere presence of vacancy sites may pose a risk, as incorporation of external Fe into a tetrahedral coordination environment can lead to HO• generation.

Activation of artemisinin and heme degradation in Leishmania tarentolae promastigotes: A possible link.

Endoperoxides (EPs) appear to be promising drug candidates against protozoal diseases, including malaria and leishmaniasis. Previous studies have shown that these drugs need an intracellular activation to exert their pharmacological potential. The efficiency of these drugs is linked to the extensive iron demand of these intracellular protozoal parasites. An essential step of the activation mechanism of these drugs is the formation of radicals in Leishmania. Iron is a known trigger for intracellular radical formation. However, the activation of EPs by low molecular iron or by heme iron may strongly depend on the structure of the EPs themselves. In this study, we focused on the activation of artemisinin (Art) in Leishmania tarentolae promastigotes (LtP) in comparison to reference compounds. Viability assays in different media in the presence of different iron sources (hemin/fetal calf serum) showed that IC50 values of Art in LtP were modulated by assay conditions, but overall were within the low micromolar range. Low temperature electron paramagnetic resonance (EPR) spectroscopy of LtP showed that Art shifted the redox state of the labile iron pool less than the EP ascaridole questioning its role as a major activator of Art in LtP. Based on the high reactivity of Art with hemin in previous biomimetic experiments, we focused on putative heme-metabolizing enzymes in Leishmania, which were so far not well described. Inhibitors of mammalian heme oxygenase (HO; tin and chromium mesoporphyrin) acted antagonistically to Art in LtP and boosted its IC50 value for several magnitudes. By inductively coupled plasma methods (ICP-OES, ICP-MS) we showed that these inhibitors do not block iron (heme) accumulation, but are taken up and act within LtP. These inhibitors blocked the conversion of hemin to bilirubin in LtP homogenates, suggesting that an HO-like enzyme activity in LtP exists. NADPH-dependent degradation of Art and hemin was highest in the small granule and microsomal fractions of LtP. Photometric measurements in the model Art/hemin demonstrated that hemin requires reduction to heme and that subsequently an Art/heme complex (λmax 474 nm) is formed. EPR spin-trapping in the system Art/hemin revealed that NADPH, ascorbate and cysteine are suitable reductants and finally activate Art to acyl-carbon centered radicals. These findings suggest that heme is a major activator of Art in LtP either via HO-like enzyme activities and/or chemical interaction of heme with Art.

Radioisotope imaging for discriminating benign from malignant cytologically indeterminate thyroid nodules.

The risk of malignancy in thyroid nodules with indeterminate cytological classification (Bethesda III-IV) ranges from 10% to 40%, and early delineation is essential as delays in diagnosis can be associated with increased mortality. Several radioisotope imaging techniques are available for discriminating benign from malignant cytologically indeterminate thyroid nodules, and for supporting clinical decision-making. These techniques include iodine-123, technetium-99m-pertechnetate, technetium-99m-methoxy-isobutyl-isonitrile (technetium-99m-MIBI), and fluorine-18-fluorodeoxyglucose (fluorine-18-FDG). This review discusses the currently available radioisotope imaging techniques for evaluation of thyroid nodules, including the mechanism of radiotracer uptake and the indications for their use.

Association of Surgical Volume and Quality Management in Thyroid Surgery: A Two-Nation Multicenter Study.

BACKGROUND: High-volume caseload in thyroid surgery is associated with lower postoperative complication rates resulting to better outcomes. The aim of the present study was to investigate the correlation of the departments' annual number of thyroid surgeries on the adherence to consensus guidelines and on the implementation of measures for quality assurance. METHODS: In 2016, we sent an anonymous electronic survey with questions related to the perioperative management in thyroid surgery to all directors of departments in operative medicine in Switzerland and Austria. We compared the pre- and postoperative management with the summarized recommendations of the four most frequently used consensus guidelines. Analogously, we analyzed the implementation of six measures for quality assurance related to thyroid surgery for each participating department. Using logistic regression analysis, we evaluated the correlation of number of guidelines respected and number of measures for quality assurance with the departments' annual number of surgeries performed. Furthermore, we evaluated the number of departments providing thyroid cancer surgery and their experience in neck dissection. RESULTS: The management corresponded in 64.0% to the summarized recommendations. Adherence to the summarized recommendations and implementation of measures for quality assurance were significantly more likely with increasing numbers of surgeries performed (p = 0.049 and p < 0.001). Ninety-two departments provided thyroid cancer surgery, whereas 12/92 (13.0%) were not able to perform central and/or lateral neck dissection. CONCLUSION: Consensus guidelines are insufficiently implemented within thyroid surgery, and quality management is associated with surgical volume.

Therapeutic Options for Neuroendocrine Tumors: A Systematic Review and Network Meta-analysis.

IMPORTANCE: Multiple therapies are currently available for patients with neuroendocrine tumors (NETs), yet many therapies have not been compared head-to-head within randomized clinical trials (RCTs). OBJECTIVE: To assess the relative safety and efficacy of therapies for NETs. DATA SOURCES: PubMed, Embase, the Cochrane Central Register of Controlled Trials, trial registries, meeting abstracts, and reference lists from January 1, 1947, to March 2, 2018, were searched. Key search terms included neuroendocrine tumors, gastrointestinal neoplasms, therapy, and randomized controlled trial. STUDY SELECTION: Randomized clinical trials comparing 2 or more therapies in patients with NETs (primarily gastrointestinal and pancreatic) were evaluated. Thirty RCTs met the selection criteria. DATA EXTRACTION AND SYNTHESIS: Pairs of independent reviewers screened studies, extracted data, and assessed the risk of bias. A network meta-analysis with a frequentist approach was used to compare the efficacy of therapies; the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used. MAIN OUTCOMES AND MEASURES: Disease control, progression-free survival, overall survival, adverse events, and quality of life. RESULTS: The systematic review identified 30 relevant RCTs comprising 3895 patients (48.4% women) assigned to 22 different therapies for NETs. These therapies showed a broad range of risk for serious and nonserious adverse events. The network meta-analyses included 16 RCTs with predominantly a low risk of bias; nevertheless, precision-of-treatment estimates and estimated heterogeneity were limited. The network meta-analysis found 7 therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.35 [95% CI, 0.28-0.45]), everolimus plus somatostatin analogue (HR, 0.35 [95% CI, 0.25-0.51]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.44 [95% CI, 0.26-0.75]), interferon (HR, 0.37 [95% CI, 0.16-0.83]), interferon plus somatostatin analogue (HR, 0.31 [95% CI, 0.13-0.71]), somatostatin analogue (HR, 0.46 [95% CI, 0.33-0.66]), and sunitinib (HR, 0.42 [95% CI, 0.26-0.67]), and 5 therapies for gastrointestinal NETs: bevacizumab plus somatostatin analogue (HR, 0.22 [95% CI, 0.05-0.99]), everolimus plus somatostatin analogue (HR, 0.31 [95% CI, 0.11-0.90]), interferon plus somatostatin analogue (HR, 0.27 [95% CI, 0.07-0.96]), Lu 177-dotatate plus somatostatin analogue (HR, 0.08 [95% CI, 0.03-0.26], and somatostatin analogues (HR, 0.40 [95% CI, 0.21-0.78]) with higher efficacy than placebo and suggests an overall superiority of combination therapies. CONCLUSIONS AND RELEVANCE: The findings from this study suggest that a range of efficient therapies with different safety profiles is available for patients with NETs.

The Effect of pH and Biogenic Ligands on the Weathering of Chrysotile Asbestos: The Pivotal Role of Tetrahedral Fe in Dissolution Kinetics and Radical Formation.

Chrysotile asbestos is a soil pollutant in many countries. It is a carcinogenic mineral, partly due to its surface chemistry. In chrysotile, FeII and FeIII substitute Mg octahedra (Fe[6]), and FeIII substitutes Si tetrahedra (Fe[4]). Fe on fiber surfaces can generate hydroxyl radicals (HO. ) in Fenton reactions, which damage biomolecules. To better understand chrysotile weathering in soils, net Mg and Si dissolution rates over the pH range 3.0-11.5 were determined in the presence and absence of biogenic ligands. Also, HO. generation and Fe bulk speciation of pristine and weathered fibers were examined by EPR and Mössbauer spectroscopy. Dissolution rates were increased by ligands and inversely related to pH with complete inhibition at cement pH (11.5). Surface-exposed Mg layers readily dissolved at low pH, but only after days at neutral pH. On longer timescales, the slow dissolution of Si layers became rate-determining. In the absence of ligands, Fe[6] precipitated as Fenton-inactive Fe phases, whereas Fe[4] (7 % of bulk Fe) remained redox-active throughout two-week experiments and at pH 7.5 generated 50±10 % of the HO. yield of Fe[6] at pristine fiber surfaces. Ligand-promoted dissolution of Fe[4] (and potentially Al[4]) labilized exposed Si layers. This increased Si and Mg dissolution rates and lowered HO. generation to near-background level. It is concluded that Fe[4] surface species control long-term HO. generation and dissolution rates of chrysotile at natural soil pH.