Clinical Manifestations of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third coronavirus causing an outbreak in the twenty-first century. It is related to a contagious coronavirus disease (COVID-19), which its high pace of spreading allowed it to lie to the whole world and be turned into a pandemic only a few months after the identification of the first case. Currently, the reverse transcription-polymerase chain reaction (RT-PCR) test of throat swap is the gold standard of diagnosis; however, several studies have reported false-negative results with non-ideal sensitivity. Because this pandemic constitutes a significant burden on global healthcare systems and due to the high transmission rate of the virus, an accurate diagnosis algorithm is needed to reduce the missing case number. A comprehensive clinical examination and taking a history of all systems (not just limited to the respiratory system) combined with hematologic laboratory tests and chest imaging can lead to a sensitive diagnosis, severity assessment, and RT-PCT test interpretation. This chapter focuses on clinical characteristics, hematologic laboratory, and chest imaging features in COVID-19.

Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical and Genetic Features of 32 Iranian Patients.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare congenital condition characterized by a selective predisposition to infections caused by weakly virulent mycobacteria and other types of intra-macrophagic pathogens. The 16 genes associated with MSMD display a considerable level of allelic heterogeneity, accounting for 31 distinct disorders with variable clinical presentations and prognosis. Most of MSMD deficiencies are isolated, referred to as selective susceptibility to mycobacterial diseases. However, other deficiencies are syndromic MSMD, defined by the combination of the mycobacterial infection with another, equally common, infectious, specific phenotypes. Herein, we described a series of 32 Iranian MSMD cases identified with seven distinct types of molecular defects, all of which are involved in the interferon gamma (IFNγ) immunity, including interleukin IL-12 receptor-ß1 (IL-12Rß1) deficiency (fifteen cases), IL-12p40 deficiency (ten cases), and IL-23R deficiency (three cases), as well as IFNγ receptor 1 (IFNγR1) deficiency, IFNγ receptor 2 (IFNγR2) deficiency, interferon-stimulated gene 15 (ISG15) deficiency, and tyrosine kinase 2 (TYK2) deficiency each in one case. Since the first report of two MSMD patients in our center, we identified 30 other affected patients with similar clinical manifestations. As the number of reported Iranian cases with MSMD diagnosis has increased in recent years and according to the national vaccination protocol, all Iranian newborns receive BCG vaccination at birth, early diagnosis, and therapeutic intervention which are required for a better outcome and also prevention of similar birth defects. Therefore, we investigated the clinical and molecular features of these 32 patients. The current report also defined novel classes of pathological mutations, further expanding our knowledge of the MSMD molecular basis and associated clinical manifestations.

The effect of insomnia on development of Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia and a neurodegenerative disorder characterized by memory deficits especially forgetting recent information, recall ability impairment, and loss of time tracking, problem-solving, language, and recognition difficulties. AD is also a globally important health issue but despite all scientific efforts, the treatment of AD is still a challenge. Sleep has important roles in learning and memory consolidation. Studies have shown that sleep deprivation (SD) and insomnia are associated with the pathogenesis of Alzheimer's disease and may have an impact on the symptoms and development. Thus, sleep disorders have decisive effects on AD; this association deserves more attention in research, diagnostics, and treatment, and knowing this relation also can help to prevent AD through screening and proper management of sleep disorders. This study aimed to show the potential role of SD and insomnia in the pathogenesis and progression of AD.

Effect of blood glucose level on standardized uptake value (SUV) in 18F- FDG PET-scan: a systematic review and meta-analysis of 20,807 individual SUV measurements.

OBJECTIVES: To evaluate the effect of pre-scan blood glucose levels (BGL) on standardized uptake value (SUV) in 18F-FDG-PET scan. METHODS: A literature review was performed in the MEDLINE, Embase, and Cochrane library databases. Multivariate regression analysis was performed on individual datum to investigate the correlation of BGL with SUVmax and SUVmean adjusting for sex, age, body mass index (BMI), diabetes mellitus diagnosis, 18F-FDG injected dose, and time interval. The ANOVA test was done to evaluate differences in SUVmax or SUVmean among five different BGL groups (< 110, 110-125, 125-150, 150-200, and > 200 mg/dl). RESULTS: Individual data for a total of 20,807 SUVmax and SUVmean measurements from 29 studies with 8380 patients was included in the analysis. Increased BGL is significantly correlated with decreased SUVmax and SUVmean in brain (p < 0.001, p < 0.001,) and muscle (p < 0.001, p < 0.001) and increased SUVmax and SUVmean in liver (p = 0.001, p = 0004) and blood pool (p = 0.008, p < 0.001). No significant correlation was found between BGL and SUVmax or SUVmean in tumors. In the ANOVA test, all hyperglycemic groups had significantly lower SUVs compared with the euglycemic group in brain and muscle, and significantly higher SUVs in liver and blood pool. However, in tumors only the hyperglycemic group with BGL of > 200 mg/dl had significantly lower SUVmax. CONCLUSION: If BGL is lower than 200 mg/dl no interventions are needed for lowering BGL, unless the liver is the organ of interest. Future studies are needed to evaluate sensitivity and specificity of FDG-PET scan in diagnosis of malignant lesions in hyperglycemia.

Basic understanding and therapeutic approaches to target toll-like receptors in cancerous microenvironment and metastasis.

Toll-like receptors (TLRs) are transmembrane components that sense danger signals, like damage- and pathogen-associated molecular pattern molecules, as receptors, and maintain homeostasis in tissues. They are mainly involved in immune system activation through a variety of mediators, which either carry out (1) elimination of pathogenic threats and redressing homeostatic imbalances or (2) contribution to the initiation and worsening of pathological conditions, including cancers. Under physiological conditions, TLRs coordinate the innate and adaptive immunity, and inhibit autoimmune disorders. In pathological conditions, such as cancer, they can present both tumor and receptor-specific roles. Although the roles of individual TLRs in various cancers have been described, the effects of targeting TLRs to treat cancer and prevent metastasis are still controversial. A growing body of literature has suggested contribution of both activators and inhibitors of TLR signaling pathway for cancer treatment, dependent on several context-specific factors. In short, TLRs can play dual roles with contradictory outcomes in neoplastic conditions. This hampers the development of TLR-based therapeutic interventions. A better understanding of the interwoven TLR pathways in cancerous microenvironment is necessary to design TLR-based therapies. In this review, we consider the molecular mechanisms of TLRs signaling and their involvement in tumor progression. Therapeutic modalities targeting TLRs for cancer treatment are discussed as well.

Concordance of MRI With Pathology for Primary Staging of Rectal Cancer in Routine Clinical Practice: A Single Institution Experience.

PURPOSE: MRI is the preferred imaging modality for primary staging of rectal cancer, used to guide treatment. Patients identified with clinical stage I disease receive upfront surgical resection; those with clinical stage II or greater undergo upfront neoadjuvant therapy. Although clinical under-/over-staging may have consequences for patients and presents opportunities for organ preservation, the correlation between clinical and pathologic staging in routine clinical practice within a single institute has not been fully established. METHODS: This retrospective, Institutional Review Board-approved study, conducted at a National Cancer Institute-Designated Comprehensive Cancer Center with a multi-disciplinary rectal cancer disease center, included patients undergoing rectal MRI for primary staging January 1, 2018-August 30, 2020. Data collection included patient demographics, initial clinical stage via MRI report, pathologic diagnosis, pathologic stage, and treatment. The primary outcome was concordance of overall clinical and pathologic staging. Secondary outcomes included reasons for mismatched staging. RESULTS: A total 105 rectal adenocarcinoma patients (64 males, mean age 57 ± 12.7 years) had staging MRI followed by surgical resection. A total of 28 patients (27%) had mismatched under-/over- staging. Ten patients (10%) were understaged with mismatched T stage group (clinical stage I, pathologic stage II), five (5%) were understaged with mismatched N stage group (clinical stage I, pathologic stage III), and 13 (12%) were overstaged (clinical stage II-III, pathologic stage 0-I). Treatment matched concordance between clinical and pathologic stages was 86%. CONCLUSION: MRI for primary rectal cancer staging has high concordance with pathology. Future studies to assess strategies for reducing clinically relevant understaging would be beneficial.

Prospective Validation of a Prediction Model for the Diagnosis of Acute Pancreatitis.

Importance: While most patients with acute pancreatitis (AP) fulfill diagnostic criteria with characteristic abdominal pain and serum lipase levels of at least 3 times the upper limit of normal (reference range) at presentation, early imaging is often used for confirmation. A prior prediction model and corresponding point-based score were developed using nonimaging parameters to diagnose AP in patients presenting to the emergency department (ED). Objective: To evaluate the performance of the prediction model to diagnose AP in a prospective patient cohort. Design, Setting, and Participants: This prospective diagnostic study included consecutive adult patients presenting to the ED between January 1, 2020, and March 9, 2021, at 2 large academic medical centers in the northeastern US with serum lipase levels at least 3 times the upper limit of normal. Patients transferred from outside institutions or with malignant disease and established intra-abdominal metastases, acute trauma, or altered mentation were excluded. Data were analyzed from October 15 to October 23, 2023. Exposures: Participants were assigned scores for initial serum lipase level, number of prior AP episodes, prior cholelithiasis, abdominal surgery within 2 months, presence of epigastric pain, pain of worsening severity, duration from pain onset to presentation, and pain level at ED presentation. Main Outcome and Measures: A final diagnosis of AP, established by expert review of hospitalization records. Results: Prospective scores in 349 participants (mean [SD] age, 53.0 [18.8] years; 184 women [52.7%]; 66 Black [18.9%]; 199 White [57.0%]) demonstrated an area under the receiver operating characteristics curve of 0.91. A score of at least 6 points achieved highest accuracy (F score, 82.0), corresponding to a sensitivity of 81.5%, specificity of 85.9%, positive predictive value of 82.6%, and negative predictive value of 85.1% for AP diagnosis. Early computed tomography or magnetic resonance imaging was performed more often in participants predicted to have AP (116 of 155 [74.8%] with a score ≥6 vs 111 of 194 [57.2%] with a score <6; P < .001). Early imaging revealed an alternative diagnosis in 8 of 116 participants (6.9%) with scores of at least 6 points, 1 of 93 (1.1%) with scores of at least 7 points, and 1 of 73 (1.4%) with scores of at least 8 points. Conclusions and Relevance: In this multicenter diagnostic study, the prediction model demonstrated excellent AP diagnostic accuracy. Its application may be used to avoid unnecessary confirmatory imaging.

Machine Learning Model Drift: Predicting Diagnostic Imaging Follow-Up as a Case Example.

OBJECTIVE: Address model drift in a machine learning (ML) model for predicting diagnostic imaging follow-up using data augmentation with more recent data versus retraining new predictive models. METHODS: This institutional review board-approved retrospective study was conducted January 1, 2016, to December 31, 2020, at a large academic institution. A previously trained ML model was trained on 1,000 radiology reports from 2016 (old data). An additional 1,385 randomly selected reports from 2019 to 2020 (new data) were annotated for follow-up recommendations and randomly divided into two sets: training (n = 900) and testing (n = 485). Support vector machine and random forest (RF) algorithms were constructed and trained using 900 new data reports plus old data (augmented data, new models) and using only new data (new data, new models). The 2016 baseline model was used as comparator as is and trained with augmented data. Recall was compared with baseline using McNemar's test. RESULTS: Follow-up recommendations were contained in 11.3% of reports (157 or 1,385). The baseline model retrained with new data had precision = 0.83 and recall = 0.54; none significantly different from baseline. A new RF model trained with augmented data had significantly better recall versus the baseline model (0.80 versus 0.66, P = .04) and comparable precision (0.90 versus 0.86). DISCUSSION: ML methods for monitoring follow-up recommendations in radiology reports suffer model drift over time. A newly developed RF model achieved better recall with comparable precision versus simply retraining a previously trained original model with augmented data. Thus, regularly assessing and updating these models is necessary using more recent historical data.

Representing narrative evidence as clinical evidence logic statements.

Objective: Clinical evidence logic statements (CELS) are shareable knowledge artifacts in a semistructured "If-Then" format that can be used for clinical decision support systems. This project aimed to assess factors facilitating CELS representation. Materials and Methods: We described CELS representation of clinical evidence. We assessed factors that facilitate representation, including authoring instruction, evidence structure, and educational level of CELS authors. Five researchers were tasked with representing CELS from published evidence. Represented CELS were compared with the formal representation. After an authoring instruction intervention, the same researchers were asked to represent the same CELS and accuracy was compared with that preintervention using McNemar's test. Moreover, CELS representation accuracy was compared between evidence that is structured versus semistructured, and between CELS authored by specialty-trained versus nonspecialty-trained researchers, using χ2 analysis. Results: 261 CELS were represented from 10 different pieces of published evidence by the researchers pre- and postintervention. CELS representation accuracy significantly increased post-intervention, from 20/261 (8%) to 63/261 (24%, P value < .00001). More CELS were assigned for representation with 379 total CELS subsequently included in the analysis (278 structured and 101 semistructured) postintervention. Representing CELS from structured evidence was associated with significantly higher CELS representation accuracy (P = .002), as well as CELS representation by specialty-trained authors (P = .0004). Discussion: CELS represented from structured evidence had a higher representation accuracy compared with semistructured evidence. Similarly, specialty-trained authors had higher accuracy when representing structured evidence. Conclusion: Authoring instructions significantly improved CELS representation with a 3-fold increase in accuracy. However, CELS representation remains a challenging task.

Immune checkpoint inhibition in classical hodgkin lymphoma.

Introduction: Hodgkin lymphoma (HL) accounts for 10% of lymphoma cases every year. HL is often curable by conventional chemotherapy and radiotherapy. However, in case of relapsed or refractory HL (r/r HL) after autologous hematopoietic stem cell transplantation (ASCT), few treatment options are currently available. Blockade of the immune checkpoint receptors, programmed death receptor-1 (PD-1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expressed on T-cells, and their ligands expressed on tumor-associated antigen-presenting cells (APCs), and Hodgkin and Reed/Sternberg (HRS) cells can remove inhibitory signals from anti-tumor T cells. Checkpoint blockade using monoclonal antibodies could be a potential treatment. Nivolumab and pembrolizumab are approved antibodies for the treatment of r/r HL.Areas covered: This paper provides a comprehensive discussion of checkpoint inhibitors in HL treatment, including the most important clinical trials with mono- or combination therapies as a first or second-line treatment of HL.Expert opinion: Relatively high response rates and an acceptable safety profile of checkpoint inhibitors make them an effective therapy for HL. The combination of checkpoint inhibition with other conventional cancer treatments and identifying the mechanisms responsible for resistance to checkpoint inhibition may improve the efficacy and safety of this immunotherapy, and enhance patient quality of life.

A review of neurotoxicities associated with immunotherapy and a framework for evaluation.

Immuno-oncology agents, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T (CAR-T) cell therapies, are increasing in use for a growing list of oncologic indications. While harnessing the immune system against cancer cells has a potent anti-tumor effect, it can also cause widespread autoimmune toxicities that limit therapeutic potential. Neurologic toxicities have unique presentations and can progress rapidly, necessitating prompt recognition. In this article, we review the spectrum of central and peripheral neurologic immune-related adverse events (irAEs) associated with ICI therapies, emphasizing a diagnostic framework that includes consideration of the therapy regimen, timing of symptom onset, presence of non-neurologic irAEs, pre-existing neurologic disease, and syndrome specific features. In addition, we review the immune effector cell-associated neurotoxicity syndrome (ICANS) associated with CAR-T cell therapy and address diagnostic challenges specific to patients with brain metastases. As immunotherapy use grows, so too will the number of patients affected by neurotoxicity. There is an urgent need to understand pathogenic mechanisms, predictors, and optimal treatments of these toxicities, so that we can manage them without sacrificing anti-tumor efficacy.

Variation in Radiologists' Follow-Up Imaging Recommendations for Small Cystic Pancreatic Lesions.

OBJECTIVE: This study aimed to determine the incidence, identify imaging and patient factors, and measure individual radiologist variation associated with follow-up recommendations for small focal cystic pancreatic lesions (FCPLs), a common incidental imaging finding. METHODS: This institutional review board-approved retrospective study analyzed 146,709 reports from abdominal CTs and MRIs performed in a large academic hospital from July 1, 2016, to June 30, 2018. A trained natural language processing tool identified 4,345 reports with FCPLs, which were manually reviewed to identify those containing one or more <1.5-cm pancreatic cysts. For these patients, patient, lesion, and radiologist features and follow-up recommendations for FCPL were extracted. A nonlinear random-effects model estimated degree of variation in follow-up recommendations across radiologists at department and division levels. RESULTS: Of 2,872 reports with FCPLs < 1.5 cm, 708 (24.7%) had FCPL-related follow-up recommendations. Average patient age was 67 years (SD ± 11). In all, 1,721 (60.0%) reports were for female patients; 59.3% of patients had only one cyst. In multivariable analysis, older patients had slightly lower follow-up recommendation rates (odds ratio [OR]: 0.98 [0.98-1.00] per additional year), and lesions associated with main duct dilatation and septation were more likely to have a follow-up recommendation (ORs: 1.93 [1.11-3.36] and 2.88 [1.89-4.38], respectively). Radiologist years in practice (P = .51), trainee presence (P = .21), and radiologist gender (P = .52) were not associated with increased follow-up recommendations. There was significant interradiologist variation in the Abdominal Imaging Division (P = .04), but not in Emergency Radiology (P = .31) or Cancer Imaging Divisions (P = .29). DISCUSSION: Interradiologist variation significantly contributes to variability in follow-up imaging recommendations for FCPLs.

Interleukin 9 serum level and single nucleotide polymorphism in patients with asthma.

BACKGROUND: Asthma is a chronic inflammatory disease of airways which accounts for a huge economic, morbidity and mortality burden. There are different cytokines that contribute to asthma pathophysiology. Learning about these cytokines leads to attaining novel anti-inflammatory treatments for asthma control. OBJECTIVES: The objective of this study is to investigate the association between interleukin-9 serum level and gene polymorphism with asthma susceptibility. METHODS: This was a case-control study of 70 asthmatic patients and 77 healthy control adults aged 18-60. Asthma diagnosis and severity were based on physician diagnosis, pulmonary function test (PFT) and 2016 guild line of Global Initiative for Asthma (GINA). Interleukin 9(IL -9) serum level was measured using sandwich enzyme linked immunosorbent assay.  IL9 promoter single nucleotide polymorphism (SNP) (rs2069882) was also assessed using Real-Time PCR System. RESULTS: There was no significant association between IL-9 SNP polymorphism and asthma. IL-9 serum level was significantly associated with asthma susceptibility (p value= 0.016) and absolute eosinophil count (AEC) (P value=0.033) however its corelation with atopic asthma type, asthma sivierity and Immunoglubin E serum level were not statistically significant. CONCLUSION: Although there was no association between IL-9 SNP and asthma, but IL-9 serum level was significantly correlated with asthma susceptibility and AEC.

Roles of Myeloid-Derived Suppressor Cells in Cancer Metastasis: Immunosuppression and Beyond.

Metastasis is the direst face of cancer, and it is not a feature solely dependent on cancer cells; however, a complex interaction between cancer cells and host causes this process. Investigating the mechanisms of metastasis can lead to its control. Myeloid-derived suppressor cells (MDSCs) are key components of tumor microenvironment that favor cancer progression. These cells result from altered myelopoiesis in response to the presence of tumor. The most recognized function of MDSCs is suppressing anti-tumor immune responses. Strikingly, these cells are among important players in cancer dissemination and metastasis. They can exert their effect on metastatic process by affecting anti-cancer immunity, epithelial-mesenchymal transition, cancer stem cell formation, angiogenesis, establishing premetastatic niche, and supporting cancer cell survival and growth in metastatic sites. In this article, we review and discuss the mechanisms by which MDSCs contribute to cancer metastasis.

Novel Methods to Improve the Efficiency of Radioimmunotherapy for Non-Hodgkin Lymphoma.

Radioimmunotherapy (RIT) is a novel strategy for treating non-Hodgkin lymphoma (NHL). Several studies have shown the promising results of using RIT in NHL, which have led to FDA approval for two RIT agents in treating low grade NHL. In spite of these favorable results in low-grade NHL, most of the aggressive or relapsed/refractory NHL subjects experience relapses following RIT. Although more aggressive treatments such as myeloablative doses of RIT followed by stem cell transplantation appear to be able to provide a longer survival for some patients these approaches are associated with significant treatment-related adverse events and challenging to deliver in most centers. Therefore, it seems reasonable to develop treatment approaches that enhance the efficiency of RIT, while reducing its toxicity. In this paper, novel methods that improve the efficiency of RIT and reduce its toxicity through various mechanisms are reviewed. Further clinical development of these methods could expand the NHL patient groups eligible for receiving RIT, and even extend the use of RIT to new indications and disease groups in future.

Neurological recovery following traumatic spinal cord injury: a systematic review and meta-analysis.

OBJECTIVEPredicting neurological recovery following traumatic spinal cord injury (TSCI) is a complex task considering the heterogeneous nature of injury and the inconsistency of individual studies. This study aims to summarize the current evidence on neurological recovery following TSCI by use of a meta-analytical approach, and to identify injury, treatment, and study variables with prognostic significance.METHODSA literature search in MEDLINE and EMBASE was performed, and studies reporting follow-up changes in American Spinal Injury Association (ASIA) Impairment Scale (AIS) or Frankel or ASIA motor score (AMS) scales were included in the meta-analysis. The proportion of patients with at least 1 grade of AIS/Frankel improvement, and point changes in AMS were calculated using random pooled effect analysis. The potential effect of severity, level and mechanism of injury, type of treatment, time and country of study, and follow-up duration were evaluated using meta-regression analysis.RESULTSA total of 114 studies were included, reporting AIS/Frankel changes in 19,913 patients and AMS changes in 6920 patients. Overall, the quality of evidence was poor. The AIS/Frankel conversion rate was 19.3% (95% CI 16.2-22.6) for patients with grade A, 73.8% (95% CI 69.0-78.4) for those with grade B, 87.3% (95% CI 77.9-94.8) for those with grade C, and 46.5% (95% CI 38.2-54.9) for those with grade D. Neurological recovery was significantly different between all grades of SCI severity in the following order: C > B > D > A. Level of injury was a significant predictor of recovery; recovery rates followed this pattern: lumbar > cervical and thoracolumbar > thoracic. Thoracic SCI and penetrating SCI were significantly more likely to result in complete injury. Penetrating TSCI had a significantly lower recovery rate compared to blunt injury (OR 0.76, 95% CI 0.62-0.92; p = 0.006). Recovery rate was positively correlated with longer follow-up duration (p = 0.001). Studies with follow-up durations of approximately 6 months or less reported significantly lower recovery rates for incomplete SCI compared to studies with long-term (3-5 years) follow-ups.CONCLUSIONSThe authors' meta-analysis provides an overall quantitative description of neurological outcomes associated with TSCI. Moreover, they demonstrated how neurological recovery after TSCI is significantly dependent on injury factors (i.e., severity, level, and mechanism of injury), but is not associated with type of treatment or country of origin. Based on these results, a minimum follow-up of 12 months is recommended for TSCI studies that include patients with neurologically incomplete injury.

Radioimmunotherapy-based conditioning regimen prior to autologous stem cell transplantation in non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy and the sixth cause of death from cancer in the USA. Autologous stem cell transplantation (ASCT) is a potentially curative therapeutic option for many NHL patients. Choosing the most effective conditioning regimen prior to ASCT can lead to longer survival in these patients, and, as in many cases of high risk NHL, the only potentially curative option is stem cell transplantation. Radioimmunotherapy (RIT) is based on using radiolabeled monoclonal antibodies against tumoral antigens. Since lymphoma cells are sensitive to radiation, RIT has become a potential approach in treating NHL. In this review, we have discussed the efficacy and safety of RIT as an alternative conditioning regimen prior to ASCT.

Radioimmunotherapy as the first line of treatment in non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy. The estimated deaths and new cases of NHL in the USA in 2018 have reached 19,910 and 74,680, respectively, with 5-year survival rate of 71%. Therapeutic interventions for NHL consist of chemotherapy, radiation therapy and immunotherapy. Radioimmunotherapy (RIT) is a potential alternative treatment for NHL that is currently used in different lines of treatment. Studies show that nuclear medicine physicians and radiation oncologists are not yet certain about the proper line for administration of RIT. Herein, we have reviewed the efficiency and toxicity of RIT as the first line of treatment, and discussed potential novel indications, and strategies such as modifying induction therapy and using rituximab maintenance to optimize the efficiency of RIT as the first line of treatment. Our review indicates that it is more logical to postpone conventional therapies to the second or third lines of treatment instead of RIT.

Monoclonal Antibodies for Treatment of Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus affecting both children and adults, with debilitating and progressive symptoms. EoE has shown an explosive epidemiological rise in the past few decades. Many patients experience a poor level of disease control despite maximal use of available guideline-based therapies, which seriously hampers their quality of life. Diet restrictions and systemic and topical corticosteroids are the current mainstays of EoE therapy, but are associated with significant efficacy, treatment compliance, and safety issues such as oral or esophageal candidiasis, growth retardation, osteopenia, osteoporosis, glucose intolerance, and cataract formation. As EoE is a chronic inflammatory disease, immune cells and cytokines are responsible for the inflammatory response and symptoms. Monoclonal antibodies specifically targeting these pathophysiologic effectors offer more potent relief of histologic and clinical disease features while keeping off-target adverse effects to a minimum. Herein, we have reviewed the current evidence regarding efficacy and safety of monoclonal antibodies including mepolizumab (anti-IL-5), reslizumab (anti-IL-5), QAX576 (anti-IL-13), omalizumab (anti-immunoglobulin-E), and infliximab (anti-TNF-α) in treatment of EoE. Our review indicates that although the use of monoclonal antibodies for EoE treatment is safe with limited and reversible adverse events, however, it is not yet possible to reach a final verdict on the efficacy of mAbs in EoE. Future well-designed studies are needed to clarify the exact role of mAbs in EoE.

Mitogen-activated protein kinases as therapeutic targets for asthma.

Corticosteroid-resistant asthmatics, although comprising only a portion of the asthma population, account for most of the morbidity, mortality and economic burden associated with asthma. Moreover, corticosteroids are not effective inhibitors of airway remodeling changes, and their long-term use is associated with debilitating systemic side effects. Therefore, potent and safe novel therapeutic alternatives, targeting basic pathophysiological mechanisms responsible for the severe asthmatic phenotype are urgently needed. Mitogen-activated protein kinases (MAPKs) are ubiquitously expressed signaling enzymes that are involved in almost all aspects of the asthmatic inflammatory network; as such, they represent an emerging target for the treatment of asthma. This paper provides a rationale for targeting MAPKs in the treatment of asthma by reviewing the in vitro evidence of its relevance to asthma pathogenesis. This is followed by discussing the results of MAPK inhibition in pre-clinical models of asthma. Finally, the potential safety concerns regarding MAPK inhibition in human disease, as well as the future prospects for its clinical development are explored. In conclusion, this review underlines the promising results of MAPK inhibition in animal asthma models especially in restoring corticosteroid sensitivity, as well as recent clinical safety and efficacy evidence obtained from trials in similar disease areas such as COPD, and of course, the paucity of clinical evidence for targeting MAPKs in asthma. Based on this review, a more rigorous effort for clinical development of MAPK inhibitors in asthma is justified.