Granzyme B PET Imaging for Assessment of Disease Activity in Inflammatory Bowel Disease.

Developing a noninvasive imaging method to detect immune system activation with a high temporal resolution is key to improving inflammatory bowel disease (IBD) management. In this study, granzyme B (GZMB), typically released from cytotoxic T and natural killer cells, was targeted using PET with 68Ga-NOTA-GZP (where GZP is ß-Ala-Gly-Gly-Ile-Glu-Phe-Asp-CHO) to detect early intestinal inflammation in murine models of colitis. Methods: Bioinformatic analysis was used to assess the potential of GZMB as a biomarker for detecting IBD and predicting response to treatment. Human active and quiescent Crohn disease and ulcerative colitis tissues were stained for GZMB. We used IL-10-/- mice treated with dextran sulfate sodium (DSS) as an IBD model, wild-type C57BL/6J mice as a control, and anti-tumor necrosis factor as therapy. We used a murine GZMB-binding peptide conjugated to a NOTA chelator (NOTA-GZP) labeled with 68Ga as the PET tracer. PET imaging was conducted at 1, 3, and 4 wk after colitis induction to evaluate temporal changes. Results: Bioinformatic analysis showed that GZMB gene expression is significantly upregulated in human ulcerative colitis and Crohn disease compared with the noninflamed bowel by 2.98-fold and 1.92-fold, respectively; its expression is lower by 2.16-fold in treatment responders than in nonresponders. Immunofluorescence staining of human tissues demonstrated a significantly higher GZMB in patients with active than with quiescent IBD (P = 0.032).68Ga-NOTA-GZP PET imaging showed significantly increased bowel uptake in IL-10-/- mice with DSS-induced colitis compared with vehicle-treated IL-10-/- mice (SUVmean, 0.75 vs. 0.24; P < 0.001) and both vehicle- and DSS-treated wild-type mice (SUVmean, 0.26 and 0.37; P < 0.001). In the IL-10-/- DSS-induced colitis model, the bowel PET probe uptake decreased in response to treatment with tumor necrosis factor-α (SUVmean, 0.32; P < 0.001). There was a 4-fold increase in colonic uptake of 68Ga-NOTA-GZP in the colitis model compared with the control 1 wk after colitis induction. The uptake gradually decreased to approximately 2-fold by 4 wk after IBD induction; however, the inflamed bowel uptake remained significantly higher than control at all time points (week 4 SUVmean, 0.23 vs. 0.08; P = 0.001). Conclusion: GZMB is a promising biomarker to detect active IBD and predict response to treatment. This study provides compelling evidence to translate GZMB PET for imaging IBD activity in clinical settings.

Allysine-Targeted Molecular MRI Enables Early Prediction of Chemotherapy Response in Pancreatic Cancer.

Neoadjuvant therapy (NAT) is routinely used in pancreatic ductal adenocarcinoma (PDAC), but not all tumors respond to this treatment. Current clinical imaging techniques are not able to precisely evaluate and predict the response to neoadjuvant therapies over several weeks. A strong fibrotic reaction is a hallmark of a positive response, and during fibrogenesis allysine residues are formed on collagen proteins by the action of lysyl oxidases (LOX). Here we report the application of an allysine-targeted molecular magnetic resonance imaging (MRI) probe, MnL3, to provide an early, noninvasive assessment of treatment response in PDAC. Allysine increased 2- to 3-fold after one dose of NAT with FOLFIRINOX in sensitive human PDAC xenografts in mice. Molecular MRI with MnL3 could specifically detect and quantify fibrogenesis in PDAC xenografts. Comparing the MnL3 signal before and 3 days after one dose of FOLFIRINOX predicted subsequent treatment response. The MnL3 tumor signal increased by 70% from day 0 to day 3 in mice that responded to subsequent doses of FOLFIRINOX, while no signal increase was observed in FOLFIRINOX-resistant tumors. This study indicates the promise of allysine-targeted molecular MRI as a noninvasive tool to predict chemotherapy outcomes.

International Medical Graduates in Radiology Residencies: Demographics, Performance, and Visa Issues.

RATIONALE AND OBJECTIVES: The number of international medical graduates (IMG) in radiology residencies has varied from year to year even as the number of candidates continues to grow. It is unclear from which countries the IMGs are arriving and what visas are being used to accommodate them. MATERIALS AND METHODS: We sent a survey to 195 program directors (PD) in diagnostic radiology (DR) inquiring about the number and nationality of IMG residents in their program, their attitudes about IMG candidates, the performance of their IMG trainees, and the visas that are offered. RESULTS: We received responses from 121 of 195 (62.1%) DR programs (121/149 =81.2% of actionable emails). 80/121 (66.1%) had at least one IMG in their DR residency program and the countries of origin included India (36), Iran (30), Saudi Arabia (24), Egypt (16), Canada (14), Brazil (14), and Pakistan (9), as the most common. While most programs (76/104, 73.1%) offered J1 visas, 23/99 (23.2%) provided H-1B visas to trainees. IMG DR residents overall performed as well as American graduates, with an equal number of PDs saying IMGs performed better and worse than American graduates. PDs' issues with IMGs centered on visas: (1) expense, (2) lack of familiarity, (3) Educational Commission for Foreign Medical Graduates regulations, and (4) time commitment in submitting paperwork. CONCLUSION: Most radiology IMG residents originate from India and Middle Eastern countries. Once enrolled, IMG residents perform similarly to US graduates. However, adding IMG candidates to the training program requires overcoming bureaucratic and monetary hurdles around visas. SUMMARY SENTENCE: Most DR international medical graduate residents are from India or the Middle East. Although their performance is the same as American graduates in general, PDs note the monetary and bureaucratic hassles accompanying their recruitment.

HER3 PET Imaging Predicts Response to Pan Receptor Tyrosine Kinase Inhibition Therapy in Gastric Cancer.

PURPOSE: New generation of receptor tyrosine kinase inhibitors (RTKIs) have shown to improve survival in many solid tumors. However, an imaging biomarker is needed for patient selection and prediction of treatment response. This study evaluates the use of quantitative changes of HER3 on 68 Ga-NOTA-HER3P1 PET/MRI for prediction of early response to pan-RTKIs in gastric cancer (GCa). PROCEDURES: GCa cell lines were evaluated for expression of RTKs, and downstream signaling pathways (AKT and MAPK). Cell viability was assessed following 24-72 h of treatment with 0.01-1 µmol/L of afatinib, a pan-RTKI. HER3-expressing afatinib-sensitive (NCI-N87) and resistant cells (SNU16) were selected for evaluation of changes in RTKs expression and downstream pathways, with 24-72 h of 0.1 µmol/L afatinib treatment. 68 Ga-NOTA-HER3P1 PET/MRI was performed in subcutaneous NCI-N87 and SNU16 xenografts (nu:nu, n = 12/group) at baseline and 4 days after afatinib treatment (10 mg/kg, PO, daily). Temporal changes in PET measures were correlated to HER3 expression in tumors, tumor growth rate, and treatment response. RESULTS: With afatinib therapy, NCI-N87 cells showed increased total HER3 expression, and reduction of other RTKs and downstream nodes within 72 h, while SNU16 cells showed no significant change in total HER3 and downstream nodes. 68 Ga-HER3P1 PET/MRI showed increased uptake in NCI-N87 and no significant change in SNU16 tumors (day 4 vs. baseline SUVmean: 3.8 ± 0.7 vs. 1.6 ± 0.6, p < 0.05 in NCI-N87, and 1.5 ± 0.7 vs. 1.7 ± 0.7, p > 0.05 in SNU16). These findings were in concordance with HER3 expression in histopathological analyses and tumor growth over 3 weeks of treatment (mean tumor volume in treated vs. control: 11 ± 17 mm3 vs. 293 ± 79 mm3, p < 0.001 in NCI-N87, and 238 ± 91 mm3 vs. 282 ± 35 mm3, p > 0.05 in SNU16). CONCLUSIONS: Quantitative changes in HER3 PET could be used to predict response to pan-RTKI within few days after initiation of treatment and can help with personalizing GCa management.

ImmunoPET: Antibody-Based PET Imaging in Solid Tumors.

Immuno-positron emission tomography (immunoPET) is a molecular imaging modality combining the high sensitivity of PET with the specific targeting ability of monoclonal antibodies. Various radioimmunotracers have been successfully developed to target a broad spectrum of molecules expressed by malignant cells or tumor microenvironments. Only a few are translated into clinical studies and barely into clinical practices. Some drawbacks include slow radioimmunotracer kinetics, high physiologic uptake in lymphoid organs, and heterogeneous activity in tumoral lesions. Measures are taken to overcome the disadvantages, and new tracers are being developed. In this review, we aim to mention the fundamental components of immunoPET imaging, explore the groundbreaking success achieved using this new technique, and review different radioimmunotracers employed in various solid tumors to elaborate on this relatively new imaging modality.

Immune Checkpoint Inhibitor-Mediated Cancer Theranostics with Radiolabeled Anti-Granzyme B Peptide.

Although immune checkpoint inhibitors (ICI) have revolutionized cancer management, patient response can be heterogeneous, and the development of ICI resistance is increasingly reported. Novel treatment strategies are necessary not only to expand the use of ICI to previously unresponsive tumor types but also to overcome resistance. Targeted radionuclide therapy may synergize well with ICIs since it can promote a pro-inflammatory tumor microenvironment. We investigated the use of a granzyme B targeted peptide (GZP) as a cancer theranostic agent, radiolabeled with 68Ga (68Ga-GZP) as a PET imaging agent and radiolabeled with 90Y (90Y-GZP) as a targeted radionuclide therapy agent for combinational therapy with ICI in murine models of colon cancer. Our results demonstrate that GZP increasingly accumulates in tumor tissue after ICI and that the combination of ICI with 90Y-GZP promotes a dose-dependent response, achieving curative response in some settings and increased overall survival.

Peroxidasin Deficiency Re-programs Macrophages Toward Pro-fibrolysis Function and Promotes Collagen Resolution in Liver.

BACKGROUND & AIMS: During liver fibrosis, tissue repair mechanisms replace necrotic tissue with highly stabilized extracellular matrix proteins. Extracellular matrix stabilization influences the speed of tissue recovery. Here, we studied the expression and function of peroxidasin (PXDN), a peroxidase that uses hydrogen peroxide to cross-link collagen IV during liver fibrosis progression and regression. METHODS: Mouse models of liver fibrosis and cirrhosis patients were analyzed for the expression of PXDN in liver and serum. Pxdn-/- and Pxdn+/+ mice were either treated with carbon tetrachloride for 6 weeks to generate toxin-induced fibrosis or fed with a choline-deficient L-amino acid-defined high-fat diet for 16 weeks to create nonalcoholic fatty liver disease fibrosis. Liver histology, quantitative real-time polymerase chain reaction, collagen content, flowcytometry and immunostaining of immune cells, RNA-sequencing, and liver function tests were analyzed. In vivo imaging of liver reactive oxygen species (ROS) was performed using a redox-active iron complex, Fe-PyC3A. RESULTS: In human and mouse cirrhotic tissue, PXDN is expressed by stellate cells and is secreted into fibrotic areas. In patients with nonalcoholic fatty liver disease, serum levels of PXDN increased significantly. In both mouse models of liver fibrosis, PXDN deficiency resulted in elevated monocyte and pro-fibrolysis macrophage recruitment into fibrotic bands and caused decreased accumulation of cross-linked collagens. In Pxdn-/- mice, collagen fibers were loosely organized, an atypical phenotype that is reversible upon macrophage depletion. Elevated ROS in Pxdn-/- livers was observed, which can result in activation of hypoxic signaling cascades and may affect signaling pathways involved in macrophage polarization such as TNF-a via NF-kB. Fibrosis resolution in Pxdn-/- mice was associated with significant decrease in collagen content and improved liver function. CONCLUSION: PXDN deficiency is associated with increased ROS levels and a hypoxic liver microenvironment that can regulate recruitment and programming of pro-resolution macrophages. Our data implicate the importance of the liver microenvironment in macrophage programming during liver fibrosis and suggest a novel pathway that is involved in the resolution of scar tissue.

Artificial Intelligence and the Future of Diagnostic and Therapeutic Radiopharmaceutical Development:: In Silico Smart Molecular Design.

Novel diagnostic and therapeutic radiopharmaceuticals are increasingly becoming a central part of personalized medicine. Continued innovation in the development of new radiopharmaceuticals is key to sustained growth and advancement of precision medicine. Artificial intelligence has been used in multiple fields of medicine to develop and validate better tools for patient diagnosis and therapy, including in radiopharmaceutical design. In this review, we first discuss common in silico approaches and focus on their usefulness and challenges in radiopharmaceutical development. Next, we discuss the practical applications of in silico modeling in design of radiopharmaceuticals in various diseases.

Non-invasive Detection of Immunotherapy-Induced Adverse Events.

PURPOSE: Cancer immunotherapy has markedly improved the prognosis of patients with a broad variety of malignancies. However, benefits are weighed against unique toxicities, with immune-related adverse events (irAE) that are frequent and potentially life-threatening. The diagnosis and management of these events are challenging due to heterogeneity of timing onset, multiplicity of affected organs, and lack of non-invasive monitoring techniques. We demonstrate the use of a granzyme B-targeted PET imaging agent (GZP) for irAE identification in a murine model. EXPERIMENTAL DESIGN: We generated a model of immunotherapy-induced adverse events in Foxp3-DTR-GFP mice bearing MC38 tumors. GZP PET imaging was performed to evaluate organs non-invasively. We validated imaging with ex vivo analysis, correlating the establishment of these events with the presence of immune infiltrates and granzyme B upregulation in tissue. To demonstrate the clinical relevance of our findings, the presence of granzyme B was identified through immunofluorescence staining in tissue samples of patients with confirmed checkpoint inhibitor-associated adverse events. RESULTS: GZP PET imaging revealed differential uptake in organs affected by irAEs, such as colon, spleen, and kidney, which significantly diminished after administration of the immunosuppressor dexamethasone. The presence of granzyme B and immune infiltrates were confirmed histologically and correlated with significantly higher uptake in PET imaging. The presence of granzyme B was also confirmed in samples from patients that presented with clinical irAEs. CONCLUSIONS: We demonstrate an interconnection between the establishment of irAEs and granzyme B presence and, for the first time, the visualization of those events through PET imaging.

National and Subnational Incidence, Mortality, and Years of Life Lost Due to Breast Cancer in Iran: Trends and Age-Period-Cohort Analysis Since 1990.

Breast cancer is the most common cancer among women, causing considerable burden and mortality. Demographic and lifestyle transitions in low and low-middle income countries have given rise to its increased incidence. The successful management of cancer relies on evidence-based policies taking into account national epidemiologic settings. We aimed to report the national and subnational trends of breast cancer incidence, mortality, years of life lost (YLL) and mortality to incidence ratio (MIR) since 1990. As part of the National and Subnational Burden of Diseases project, we estimated incidence, mortality and YLL of breast cancer by sex, age, province, and year using a two-stage spatio-temporal model, based on the primary dataset of national cancer and death registry. MIR was calculated as a quality of care indicator. Age-period-cohort analysis was used to distinguish the effects of these three collinear factors. A significant threefold increase in age-specific incidence at national and subnational levels along with a twofold extension of provincial disparity was observed. Although mortality has slightly decreased since 2000, a positive mortality annual percent change was detected in patients aged 25-34 years, leading to raised YLLs. A significant declining pattern of MIR and lower provincial MIR disparity was observed. We observed a secular increase of breast cancer incidence. Further evaluation of risk factors and developing national screening policies is recommended. A descending pattern of mortality, YLL and MIR at national and subnational levels reflects improved quality of care, even though mortality among younger age groups should be specifically addressed.

Impact of 18F-FDG PET/MR based tumor delineation in radiotherapy planning for cholangiocarcinoma.

PURPOSE: Radiation therapy (RT) is an effective treatment for unresectable cholangiocarcinoma (CC). Accurate tumor volume delineation is critical in achieving high rates of local control while minimizing treatment-related toxicity. This study compares 18F-FDG PET/MR to MR and CT for target volume delineation for RT planning. METHODS: We retrospectively included 22 patients with newly diagnosed unresectable primary CC who underwent 18F-FDG PET/MR for initial staging. Gross tumor volume (GTV) of the primary mass (GTVM) and lymph nodes (GTVLN) were contoured on CT images, MR images, and PET/MR fused images and compared among modalities. The dice similarity coefficient (DSC) was calculated to assess spatial coverage between different modalities. RESULTS: GTV MPET/MR (median: 94 ml, range 16-655 ml) was significantly greater than GTV MMR (69 ml, 11-635 ml) (p = 0.0001) and GTV MCT (96 ml, 4-564 ml) (p = 0.035). There was no significant difference between GTV MCT and GTV MMR (p = 0.078). Subgroup analysis of intrahepatic and extrahepatic tumors showed that the median GTV MPET/MR was significantly greater than GTV MMR in both groups (117.5 ml, 22-655 ml vs. 102.5 ml, 22-635 ml, p = 0.004 and 37 ml, 16-303 ml vs. 34 ml, 11-207 ml, p = 0.042, respectively). The GTV LNPET/MR (8.5 ml, 1-27 ml) was significantly higher than GTV LNCT (5 ml, 4-16 ml) (p = 0.026). GTVPET/MR had the highest similarity to the GTVMR, i.e., DSCPET/MR-MR (0.82, 0.25-1.00), compared to DSC PET/MR-CT of 0.58 (0.22-0.87) and DSCMR-CT of 0.58 (0.03-0.83). CONCLUSION: 18F-FDG PET/MR-based CC delineation yields greater GTVs and detected a higher number of positive lymph nodes compared to CT or MR, potentially improving RT planning by reducing the risk of geographic misses.

Bone Marrow Aspiration/Biopsy in the Evaluation of Fever of Unknown Origin in Patients with AIDS.

BACKGROUND: HIV can interrupt the normal development of bone marrow cell lines. Bone marrow aspiration/biopsy (BMA/B) has been described as a diagnostic tool in AIDS patients with fever of unknown origin (FUO). In this review, we aimed to study patients with AIDS who had undergone a BMA/B to investigate FUO and describe the pathologies diagnosed in the biopsy. METHODS: Thirty-four BMA/B samples were collected from AIDS patients admitted for work-up of FUO to the infectious disease ward of a tertiary referral HIV center in Tehran, Iran, between September 2014 and September 2015. Data including age, sex, duration of disease, CD4 cell counts, hepatitis B (HBV) and C (HCV) coinfection, the primary presentation of AIDS, and the treatment history were retrieved and analyzed. Patients underwent BMA/B. An expert pathologist reviewed the BMA/B specimens. RESULTS: The mean age of the patients was 37.5 years (range, 26-56), and 27 (79%) were men. Twenty-seven (79%) patients contracted HIV from injection drug use, and 7 (21%) via sexual transmission. Only 3 (9%) of the BMA/B examinations were normal. Hypocellular bone marrow was diagnosed in 22 (65%) patients. Other pathologies included granulomas in 6 (18%), hematologic malignancies in 2 (6%), and leishmaniasis Aspergillosis, each in 1 (3%) patient. Six (17%) of the specimens were found to have tuberculosis infections. CONCLUSION: Hypocellular bone marrow was the most common pathology on BMA/B examinations, followed by the presence of granulomas. Tuberculosis, Aspergillosis, and Leishmaniasis the opportunistic infections diagnosed on BMA/B specimens. Our results support BMA/B as an appropriate diagnostic tool for early diagnosis of opportunistic infections and malignancies in AIDS. BMA/B is indispensable in the armament of diagnostic tools of the physicians managing AIDS patients.

Ultrasound for Intubation Confirmation: A Randomized Controlled Study among Emergency Medicine Residents.

Confirmation of endotracheal tube (ETT) placement during intubation is a critical skill for emergency medicine (EM) residents; airway ultrasonography has been suggested as an accessible and accurate method of ETT confirmation. Here, we investigated the accuracy with which EM residents could identify ETT location in cadavers using different ultrasound modes. EM attendings intubated either the trachea or the esophagus of a cadaver, and blinded residents identified ETT position using either B-mode or B-mode plus color Doppler. Residents correctly identified ETT location in 1075 of 1203 trials (89.4%); performance improved with post-graduate year (residents in post-graduate year 3 had 97.8% accurate identifications). There were 556 (91.7%) correct identifications made with B-mode and 519 (86.9%) with B-mode plus color Doppler (p value = 0.007); thus, accuracy did not improve with addition of color Doppler to B-mode. Further research is needed on the efficacy of different ultrasound modes in confirming ETT placement in live intubations.

HER3 Differentiates Basal From Claudin Type Triple Negative Breast Cancer and Contributes to Drug and Microenvironmental Induced Resistance.

Triple Negative Breast Cancer (TNBC) is an aggressive form of Breast Cancer (BC). Numerous kinase inhibitors (KI) targeting different pathway nodes have shown limited benefit in the clinical setting. In this study, we aim to characterize the extent of HER3 reliance and to define the effect of Neuregulin (NRG) isoforms in TNBCs. Basal and Claudin type TNBC cell lines were treated with a range of small molecule inhibitors, in the presence or absence of the HER3 ligand NRG. Single agent and combination therapy was also evaluated in human cancer cell lines through viability and biochemical assessment of the AKT/MAPK signaling pathway. We show that Basal (BT20, HCC-70, and MDA-MB-468) and Claudin type (MDA-MB-231, BT-549) TNBC cell lines displayed differential reliance on the HER family of receptors. Expression and dynamic HER3 upregulation was predominant in the Basal TNBC subtype. Furthermore, the presence of the natural ligand NRG showed potent signaling through the HER3-AKT pathway, significantly diminishing the efficacy of the AKT and PI3K inhibitors tested. We report that NRG augments the HER3 feedback mechanism for continued cell survival in TNBC. We demonstrate that combination strategies to effectively block the EGFR-HER3-AKT pathway are necessary to overcome compensatory mechanisms to NRG dependent and independent resistance mechanisms. Our findings suggests that the EGFR-HER3 heterodimer forms a major signaling hub and is a key player in tumorigenesis in Basal but not Claudin type TNBC tested. Thus, HER3 could potentially serve as a biomarker for identifying patients in which targeted therapy against the EGFR-HER3-AKT axis would be most valuable.

Targeted Palliative Radionuclide Therapy for Metastatic Bone Pain.

Bone metastasis develops in multiple malignancies with a wide range of incidence. The presence of multiple bone metastases, leading to a multitude of complications and poorer prognosis. The corresponding refractory bone pain is still a challenging issue managed through multidisciplinary approaches to enhance the quality of life. Radiopharmaceuticals are mainly used in the latest courses of the disease. Bone-pain palliation with easy-to-administer radionuclides offers advantages, including simultaneous treatment of multiple metastatic foci, the repeatability and also the combination with other therapies. Several ߯- and α-emitters as well as pharmaceuticals, from the very first [89Sr]strontium-dichloride to recently introduced [223Ra]radium-dichloride, are investigated to identify an optimum agent. In addition, the combination of bone-seeking radiopharmaceuticals with chemotherapy or radiotherapy has been employed to enhance the outcome. Radiopharmaceuticals demonstrate an acceptable response rate in pain relief. Nevertheless, survival benefits have been documented in only a limited number of studies. In this review, we provide an overview of bone-seeking radiopharmaceuticals used for bone-pain palliation, their effectiveness and toxicity, as well as the results of the combination with other therapies. Bone-pain palliation with radiopharmaceuticals has been employed for eight decades. However, there are still new aspects yet to be established.

Comparison of HIV Indicators after the Implementation of a New Model for TB and HIV Management in an Iranian Prison.

OBJECTIVES: A new national clinical guideline for the management of tuberculosis and HIV in Iranian prisons was released in 2011. The aim of this study was to compare HIV indicators in the case and control prisons after implementation of the new guideline. METHODS: This report examines outcomes observed during the pilot phase of its implementation at a case prison from October 2013 to June 2014 compared to a control prison that had not yet implemented the guideline. The case prison included incarcerated individuals in the Great Tehran Prison. A prison in Alborz province was considered as a control group. Pearson's Chi-squared, two-sample t-test, paired t-test and Kruskal-Wallis were used for the analysis. RESULTS: The intervention significantly increased the total number of inmates tested for HIV and of diagnoses of HIV-positive inmates in the case prison compared to the control prison (P<0.001). Moreover, coverage of antiretroviral therapy was higher in the case prison compared to the control prison (P=0.015). CONCLUSION: We recommend the implementation of this guideline in all Iranian prisons.

Molecular imaging of bone metastases using tumor-targeted tracers.

Bone metastasis is a disastrous manifestation of most malignancies, especially in breast, prostate and lung cancers. Since asymptomatic bone metastases are not uncommon, early detection, precise assessment, and localization of them are very important. Various imaging modalities have been employed in the setting of diagnosis of bone metastasis, from plain radiography and bone scintigraphy to SPECT, SPECT/CT, PET/CT, MRI. However, each modality showed its own limitation providing accurate diagnostic performance. In this regard, various tumor-targeted radiotracers have been introduced for molecular imaging of bone metastases using modern hybrid modalities. In this article we review the strength of different cancer-specific radiopharmaceuticals in the detection of bone metastases. As shown in the literature, among various tumor-targeted tracers, 68Ga DOTA-conjugated-peptides, 68Ga PSMA, 18F DOPA, 18F galacto-RGD integrin, 18F FDG, 11C/18F acetate, 11C/18F choline, 111In octreotide, 123/131I MIBG, 99mTc MIBI, and 201Tl have acceptable capabilities in detecting bone metastases depending on the cancer type. However, different study designs and gold standards among reviewed articles should be taken into consideration.

Successful palliative peptide receptor radionuclide therapy for impending compression of vena cava due to unresectable liver metastasis of neuroendocrine tumor.

We present the case of a 77 year old male patient with metastatic pancreatic neuroendocrine tumor (NET). The patient was initially treated by extensive surgical resection that however, led to severe complications with delayed recovery. During follow-up, a number of new liver metastases were detected, one of which was in segment I with impending compression of the inferior vena cava. Due to age and general condition of the patient, instead of further surgical treatment, the patient received four cycles of 177Lu-DOTATOC resulting in an overall partial response with successful tumor reduction in liver segment I, resolving an impending compression of vena cava.

Anti-inflammatory cytokines in autism spectrum disorders: A systematic review and meta-analysis.

BACKGROUND: In the search for the causes of autism spectrum disorders (ASD), inflammatory markers have emerged as potential candidates. The present meta-analysis was performed on studies examining circulating concentrations of anti-inflammatory cytokines in people with ASD compared with control subjects without ASD. METHODS: We identified potentially eligible studies by systematically searching electronic databases from inception to February 2018. RESULTS: Twenty-five studies with a total of 1754 participants (1022 patients with ASD and 732 control subjects) were included in the mate-analysis; 4 for interferon (IFN)-α, 9 for interleukin (IL)-1 receptor antagonist (Ra), 9 for IL-4, 6 for IL-5, 3 for IL-9, 14 for IL-10, 7 for IL-13, and 6 for transforming growth factor (TGF)-ß. We found a moderate decrease in plasma levels of IL-10 (SMD = -0.59) and a small decrease in serum levels of IL-1Ra (SMD = -0.25) in patients with ASD. On the contrary, serum IL-5 levels were slightly increased (SMD = 0.26) in these patients. We conducted meta-regression analyses to investigate the possible effect of moderatos on the effect size (ES) of difference in mean levels of IL-10. Difference in the mean age between patients and controls showed a negative influence on the ES and was able to explain about 0.4 of total between-study variance. In contrast, latitude exerted a positive effect on the ES and explained a lower proportion (0.1) of total between-study variance. CONCLUSIONS: This meta-analysis provides evidence for the lower concentration of anti-inflammatory cytokines IL-10 and IL-1Ra in autistic patients compared with control subjects. Also, meta-regression analyses point to the interaction of latitude, age, and gender with peripheral alterations of associated anti-inflammatory cytokines.

A meta-analysis of pro-inflammatory cytokines in autism spectrum disorders: Effects of age, gender, and latitude.

BACKGROUND: Autism spectrum disorders (ASD) occur in 1.5% of the general population worldwide. Studies suggest that ASD might have more costs than diabetes and attention deficit and hyperactivity disorder by 2025. Dysregulation of the cytokine system is well-documented in ASD. We conducted a meta-analysis of studies providing data on circulating concentrations of pro-inflammatory cytokines in people with ASD compared with control subjects without ASD. METHODS: We identified potentially eligible studies by systematically searching electronic databases from inception to February 2018. RESULTS: Thirty-eight studies with total of 2487 participants (1393 patients with ASD and 1094 control subjects) were included in the meta-analysis; 13 for interferon (IFN)-γ, 17 for interleukin (IL)-1ß, 22 for IL-6, 19 for tumor necrosis factor (TNF)-α, 4 for IL-1α, 6 for IL-2, 4 for IL-7, 8 for IL-8, 14 for IL-12, 3 for IL-15, 12 for IL-17, 3 for IL-18, 3 for IL-2 receptor, 3 for TNF-ß, and 3 for IL-23. We found medium increases in levels of plasma IFN-γ (standardized mean difference, SMD = 0.53) and serum IL-1ß (SMD = 0.56) and small increases in levels of blood IL-1ß (SMD = 0.35), serum IL-6 (SMD = 0.30) and serum TNF-α (SMD = 0.31) for patients with ASD. Meta-regression analyses identified latitude as a negative moderator of the effect size (ES) of difference in mean levels of IFN-γ (R2 = 0.26) and TNF-α (R2 = 0.74). Also, difference in the mean age between patients and controls had a negative interaction with the ES of difference in mean levels of IL-1ß. In contrast, there was a positive effect of the moderator of difference in the proportion of male subjects between patients and controls on the ES of difference in mean levels of IL-1ß. We found no significant alterations in peripheral levels of other pro-inflammatory cytokines including IL-1α, IL-2, IL-2R, IL-3, IL-7, IL-8, IL-12, IL-12p40, IL-12p70, IL-15, IL-17, IL-18, IL-23, TBF-ß, and TNFRI/II in patients with ASD. CONCLUSIONS: This meta-analysis provides evidence for higher concentration of pro-inflammatory cytokines IFN-γ, IL-1ß, IL-6, and TNF-α in autistic patents compared with control subjects. Also, meta-regression analyses point to the interaction of latitude, age, and gender with peripheral alterations of associated pro-inflammatory cytokines.