Publications by authors named "Joud Hajjar"

33 Publications

Author response to Cunha .

J Immunother Cancer 2021 Jul;9(7)

Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

The need to identify biomarkers to predict immunotherapy response for rare cancers has been long overdue. We aimed to study this in our paper, 'Radiomics analysis for predicting pembrolizumab response in patients with advanced rare cancers'. In this response to the Letter to the Editor by Cunha , we explain and discuss the reasons behind choosing LASSO (Least Absolute Shrinkage and Selection Operator) and XGBoost (eXtreme Gradient Boosting) with LOOCV (Leave-One-Out Cross-Validation) as the feature selection and classifier method, respectively for our radiomics models. Also, we highlight what care was taken to avoid any overfitting on the models. Further, we checked for the multicollinearity of the features. Additionally, we performed 10-fold cross-validation instead of LOOCV to see the predictive performance of our radiomics models.
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http://dx.doi.org/10.1136/jitc-2021-003299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317086PMC
July 2021

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.

J Exp Med 2021 07 5;218(7). Epub 2021 May 5.

Department of Genetics, University of Alabama at Birmingham, Birmingham, AL.

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.
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http://dx.doi.org/10.1084/jem.20201750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105723PMC
July 2021

Radiomics analysis for predicting pembrolizumab response in patients with advanced rare cancers.

J Immunother Cancer 2021 04;9(4)

Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Background: We present a radiomics-based model for predicting response to pembrolizumab in patients with advanced rare cancers.

Methods: The study included 57 patients with advanced rare cancers who were enrolled in our phase II clinical trial of pembrolizumab. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related RECIST (irRECIST). Patients were categorized as 20 "controlled disease" (stable disease, partial response, or complete response) or 37 progressive disease). We used 3D-slicer to segment target lesions on standard-of-care, pretreatment contrast enhanced CT scans. We extracted 610 features (10 histogram-based features and 600 second-order texture features) from each volume of interest. Least absolute shrinkage and selection operator logistic regression was used to detect the most discriminatory features. Selected features were used to create a classification model, using XGBoost, for the prediction of tumor response to pembrolizumab. Leave-one-out cross-validation was performed to assess model performance.

Findings: The 10 most relevant radiomics features were selected; XGBoost-based classification successfully differentiated between controlled disease (complete response, partial response, stable disease) and progressive disease with high accuracy, sensitivity, and specificity in patients assessed by RECIST (94.7%, 97.3%, and 90%, respectively; p<0.001) and in patients assessed by irRECIST (94.7%, 93.9%, and 95.8%, respectively; p<0.001). Additionally, the common features of the RECIST and irRECIST groups also highly predicted pembrolizumab response with accuracy, sensitivity, specificity, and p value of 94.7%, 97%, 90%, p<0.001% and 96%, 96%, 95%, p<0.001, respectively.

Conclusion: Our radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer.

Interpretation: Our radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer.
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http://dx.doi.org/10.1136/jitc-2020-001752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051405PMC
April 2021

Associations between the gut microbiome and fatigue in cancer patients.

Sci Rep 2021 Mar 12;11(1):5847. Epub 2021 Mar 12.

Department of Investigational Cancer Therapeutics, Unit 0455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.

Fatigue is the most prevalent symptom of cancer and its treatments. Changes in the intestinal microbiome have been identified in chronic fatigue syndrome and other neuropsychiatric disorders, and cancer patients. However, the association between intestinal microbiome and fatigue in patients with advanced cancers has not been evaluated. Understanding the connection between intestinal microbiome and fatigue will provide interventional and therapeutic opportunities to manipulate the microbiome to improve fatigue and other patients' reported outcomes. In this project, we aimed to identify associations between microbiome composition and fatigue in advanced cancer patients. In this cross-sectional observational study at a tertiary cancer care center, we included 88 patients with advanced, metastatic, unresectable cancers who were in a washout period from chemotherapy. We measured fatigue using the MD Anderson Symptom Inventory-Immunotherapy fatigue score, and used 16srRNA to analyze intestinal microbiome. Using correlation analysis we found that Eubacterium hallii was negatively associated with fatigue severity scores (r = - 0.30, p = 0.005), whereas Cosenzaea was positively associated with fatigue scores (r = 0.33, p = 0.0002). We identified microbial species that exhibit distinct composition between high-fatigued and low-fatigued cancer patients. Further studies are warranted to investigate whether modulating the microbiome reduces cancer patients' fatigue severity and improves their quality of life.
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http://dx.doi.org/10.1038/s41598-021-84783-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954807PMC
March 2021

Strategies for improving the management of immune-related adverse events.

J Immunother Cancer 2020 12;8(2)

Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

With the advent of immunotherapeutic agents, durable and dramatic responses have been observed in several hard-to-treat malignancies, outlining a roadmap to conquering cancer. Immune checkpoint inhibitors (ICPi) are a class of immunotherapeutic agents that attack the tumor cells by reinvigorating the suppressed immune system. However, the unbridled T-cell activity disrupts the immune homeostasis and induces a unique spectrum of side effects called immune-related adverse events (irAEs) in a significant proportion of patients. These irAEs are distinct from the side effects produced by traditional chemotherapeutic agents. Although majority of irAEs are manageable with corticosteroids and other immunosuppressive agents, life-threatening and fatal events have been reported. In the absence of predictive biomarkers to identify patients at risk for irAEs and standardized approach to detect, report, and treat irAEs, management of irAEs has been challenging to the patients, caregivers and the healthcare providers alike. With increasing use of ICPis for treatment of various cancers, the incidence of irAEs will undoubtedly increase. There is a compelling need to develop measures to effectively manage irAEs, both in the community settings and in cancer centers alike. To this end, in this paper, we propose several strategies, such as providing patient education, harmonizing irAE management guidelines, standardizing reporting of irAEs, optimizing the choice of immunosuppressive agents, conducting preclinical, clinical and translational studies to better understand irAEs, including high-risk patients, incorporating diagnostic tools to personalize irAE management using wireless technology and digital health, providing a platform to hear the missing patient's voice, and sharing evolving data to improve the management of irAEs.
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http://dx.doi.org/10.1136/jitc-2020-001754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735083PMC
December 2020

T-cell agonists in cancer immunotherapy.

J Immunother Cancer 2020 10;8(2)

Section of Immunology, Department of Allergy & Rheumatology, Baylor College of Medicine, Texas and Texas Children's Hospital, Houston, Texas, USA.

Cancer cells can evade immune surveillance in the body. However, immune checkpoint inhibitors can interrupt this evasion and enhance the antitumor activity of T cells. Other mechanisms for promoting antitumor T-cell function are the targeting of costimulatory molecules expressed on the surface of T cells, such as 4-1BB, OX40, inducible T-cell costimulator and glucocorticoid-induced tumor necrosis factor receptor. In addition, CD40 targets the modulation of the activation of antigen-presenting cells, which ultimately leads to T-cell activation. Agonists of these costimulatory molecules have demonstrated promising results in preclinical and early-phase trials and are now being tested in ongoing clinical trials. In addition, researchers are conducting trials of combinations of such immune modulators with checkpoint blockade, radiotherapy and cytotoxic chemotherapeutic drugs in patients with advanced tumors. This review gives a comprehensive picture of the current knowledge of T-cell agonists based on their use in recent and ongoing clinical trials.
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http://dx.doi.org/10.1136/jitc-2020-000966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537335PMC
October 2020

The Natural History of X-Linked Lymphoproliferative Disease (XLP1): Lessons from a Long-Term Survivor.

Case Reports Immunol 2020 26;2020:8841571. Epub 2020 Aug 26.

Texas Children's Hospital and Baylor College of Medicine, Department of Pediatrics, Section of Immunology, Allergy and Retrovirology, Houston, TX, USA.

X-linked lymphoproliferative disease (XLP1) is a rare primary immunodeficiency characterized by EBV-triggered immune dysregulation, lymphoproliferation, dysgammaglobulinemia, and lymphoma. Early childhood mortality from overwhelming inflammation is expected in most patients. The only curative therapy is hematopoietic stem cell transplant (HSCT); however, whether to perform HSCT on an asymptomatic patient remains debatable. This uncertainty arises because the natural history of XLP1 patients without transplantation is not clear. In this case report, we present the natural history of XLP1 in a 43-year-old male patient who did not receive HSCT. We also review the literature on untransplanted XLP1 patients who lived into mid-adulthood. Despite surviving childhood presentations that are typically fatal, we found that these rare patients remain susceptible to manifestations of XLP1 decades later.
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http://dx.doi.org/10.1155/2020/8841571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474360PMC
August 2020

Are Cancer Patients at Higher Risk of Death With COVID-19?

J Immunother Precis Oncol 2020 May 17;3(2):49-51. Epub 2020 Mar 17.

Department of Medicine, Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, La Jolla, California, USA.

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http://dx.doi.org/10.4103/2666-2345.280883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442944PMC
May 2020

Decrease in tumor content assessed in biopsies is associated with improved treatment outcome response to pembrolizumab in patients with rare tumors.

J Immunother Cancer 2020 04;8(1)

Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Decreased tumor content (TC) in resection specimens after neoadjuvant therapy is used to predict prognosis. We investigated whether TC assessed in biopsy specimens or the shift in TC from baseline to on-treatment can be used accordingly to predict response in patients with rare tumors who were treated with pembrolizumab.

Methods: A total of 57 tumors (represented by 173 baseline and 179 on-treatment biopsies) from 57 patients with rare tumors participating in an ongoing phase II clinical trial of pembrolizumab were evaluated. TC was estimated on H&E-stained slides and tumors were dichotomized into low and high TC according to a cut-off of 10%. Necrosis, proliferative fibrosis (PF) and normal tissue were assessed in on-treatment biopsies. TC at baseline and on-treatment, as well as the shift in TC from baseline to on-treatment, was correlated with clinical response defined according to Response Evaluation Criteria in Solid Tumors.

Results: A decrease in TC was seen in 14% (n=8); no change in TC was seen in 75% (n=43); and an increase in TC from baseline to on-treatment was seen in 11% (n=6). Objective response was significantly associated with decrease in TC from baseline to on-treatment (38%, 3/8) compared with no change/increase in TC (6%, 3/49) (p=0.031). Patients with a decrease in TC had a significantly increased time to progression (TTP) (75% probability) compared with patients with an increase (20% probability) or no change in TC (19% probability) (p=0.0042). Low TC was seen in 23% (13/57) of the tumors at baseline and in 26% (15/57) on-treatment. High TC was seen in 77% (44/57) of tumors at baseline and in 74% (42/57) on-treatment. No significant associations with response were seen for necrosis, PF or normal tissue in on-treatment biopsies.

Conclusion: Patients with a decrease in TC from baseline to on-treatment had a significant improvement in objective response and a longer TTP. Our data suggest that the shift in TC might be used to predict response to pembrolizumab in rare tumors. However, further investigations in larger cohorts are needed to determine the clinical value of TC, the shift in TC and the cut-off of 10% assessed in biopsies.

Trial Registration Number: NCT02721732.
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http://dx.doi.org/10.1136/jitc-2020-000665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204618PMC
April 2020

Overview of Basic Immunology and Clinical Application.

Adv Exp Med Biol 2020 ;1244:1-36

Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.

Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells are found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and cross-talk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.
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http://dx.doi.org/10.1007/978-3-030-41008-7_1DOI Listing
July 2020

Phase 2 study of pembrolizumab in patients with advanced rare cancers.

J Immunother Cancer 2020 03;8(1)

Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Patients with advanced rare cancers have poor prognosis and few treatment options. As immunotherapy is effective across multiple cancer types, we aimed to assess pembrolizumab (programmed cell death 1 (PD-1) inhibitor) in patients with advanced rare cancers.

Methods: In this open-label, phase 2 trial, patients with advanced rare cancers whose tumors had progressed on standard therapies, if available, within the previous 6 months were enrolled in nine tumor-specific cohorts and a 10th cohort for other rare histologies. Pembrolizumab 200 mg was administered intravenously every 21 days. The primary endpoint was non-progression rate (NPR) at 27 weeks; secondary endpoints were safety and tolerability, objective response rate (ORR), and clinical benefit rate (CBR).

Results: A total of 127 patients treated between August 15, 2016 and July 27, 2018 were included in this analysis. At the time of data cut-off, the NPR at 27 weeks was 28% (95% CI, 19% to 37%). A confirmed objective response (OR) was seen in 15 of 110 (14%) evaluable patients (complete response in one and partial response in 14). CBR, defined as the percentage of patients with an OR or stable disease ≥4 months, was 38% (n=42). Treatment was ongoing in 11 of 15 patients with OR at last follow-up. In the cohort with squamous cell carcinoma (SCC) of the skin, the NPR at 27 weeks was 36%, ORR 31%, and CBR 38%. In patients with adrenocortical carcinoma (ACC), NPR at 27 weeks was 31%, ORR 15%, and CBR 54%. In the patients with carcinoma of unknown primary (CUP), NPR at 27 weeks was 33%, ORR 23%, and CBR 54%. In the paraganglioma-pheochromocytoma cohort, NPR at 27 weeks was 43%, ORR 0%, and CBR 75%. Treatment-related adverse events (TRAEs) occurred in 66 of 127 (52%) patients, and 12 (9%) had grade ≥3 TRAEs. The most common TRAEs were fatigue (n=25) and rash (n=17). There were six deaths, all of which were unrelated to the study drug.

Conclusions: The favorable toxicity profile and antitumor activity seen in patients with SCC of skin, ACC, CUP, and paraganglioma-pheochromocytoma supports further evaluation of pembrolizumab in this patient population.

Trial Registration Number: NCT02721732.
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http://dx.doi.org/10.1136/jitc-2019-000347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078933PMC
March 2020

Prophylactic Antibiotics Versus Immunoglobulin Replacement in Specific Antibody Deficiency.

J Clin Immunol 2020 01 22;40(1):158-164. Epub 2019 Nov 22.

Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Purpose: Prophylactic antibiotics (PA) and immunoglobulin replacement (IGRT) are commonly used in specific antibody deficiency (SAD); however, optimal treatment is not well-established. Our purpose is to compare treatment outcomes with IGRT and/or PA among SAD patients.

Methods: A retrospective chart review of SAD patients treated at two tertiary centers between January 2012 and May 2017 was performed. Clinical and laboratory data, and rates of infections prior to and after treatment with IGRT or PA were analyzed. Descriptive analyses, between-group comparisons of rates of infection after 1 year of treatment, and a stepwise logistic regression model were employed to explore factors contributing to treatment outcomes.

Results: We identified 65 SAD patients with mean age were 18 years (2-71 years). The baseline mean number of infections in the PA group and IGRT group was 4.71 (SD 3.15) and 7.73 (SD 6.65), respectively. Twenty-nine (44.6%) received IGRT, 7 (10.7%) received PA, 7 (10.7%) received both IGRT and PA, 15 (23.1%) failed PA and switched to IGRT, and 7 did not receive any specific treatment. After 1 year of treatment, the difference in the mean number of infections in PA vs. IGRT was not statistically significant [2.86 (2.73) vs. 4.44 (4.74), p = 0.27]. Reporting autoimmunity increased the odds for persistent infections (OR = 4.29; p = 0.047), while higher IgG levels decreased the odds for persistent infections (OR = 0.68, p = 0.018).

Conclusions: PA and IGRT are equally effective as first line in preventing infections in SAD patients. However, patients who fail PA would benefit from IGRT.
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http://dx.doi.org/10.1007/s10875-019-00716-2DOI Listing
January 2020

Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: A working group report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma & Immunology.

J Allergy Clin Immunol 2020 01 27;145(1):46-69. Epub 2019 Sep 27.

Departments of Pediatrics and Medicine, University of South Florida, St Petersburg, Fla; Division of Pediatric Allergy/Immunology, Johns Hopkins-All Children's Hospital, St Petersburg, Fla; Division of Pediatric Allergy Immunology, Massachusetts General Hospital, Boston, Mass.

Genetic testing has become an integral component of the diagnostic evaluation of patients with suspected primary immunodeficiency diseases. Results of genetic testing can have a profound effect on clinical management decisions. Therefore clinical providers must demonstrate proficiency in interpreting genetic data. Because of the need for increased knowledge regarding this practice, the American Academy of Allergy, Asthma & Immunology Primary Immunodeficiency Diseases Committee established a work group that reviewed and summarized information concerning appropriate methods, tools, and resources for evaluating variants identified by genetic testing. Strengths and limitations of tests frequently ordered by clinicians were examined. Summary statements and tables were then developed to guide the interpretation process. Finally, the need for research and collaboration was emphasized. Greater understanding of these important concepts will improve the diagnosis and management of patients with suspected primary immunodeficiency diseases.
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http://dx.doi.org/10.1016/j.jaci.2019.09.009DOI Listing
January 2020

Case 40-2018: A Woman with Recurrent Sinusitis, Cough, and Bronchiectasis.

N Engl J Med 2019 04;380(14):1383

Baylor College of Medicine, Houston TX

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http://dx.doi.org/10.1056/NEJMc1901268DOI Listing
April 2019

Overview of Basic Immunology and Translational Relevance for Clinical Investigators.

Adv Exp Med Biol 2018;995:1-41

Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.

Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells are found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and the crosstalk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.
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http://dx.doi.org/10.1007/978-3-030-02505-2_1DOI Listing
May 2019

Biomarkers of response to immune checkpoint blockade in cancer treatment.

Crit Rev Oncol Hematol 2018 Oct 3;130:108-120. Epub 2018 Aug 3.

Section of Immunology, Allergy and Rheumatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, United States. Electronic address:

Immune checkpoint inhibitors (ICPis) are emerging as the new corner stone of cancer treatment due to their ability to produce durable responses in patients with various cancers. But, objective responses to ICPis vary among each type of cancer. Further, treatment with ICPis is often associated with risk of developing immune-related adverse event, which are potentially life-threatening if untreated, indicating a need for patient selection. However, given the complexity of the tumor microenvironment and the dynamic interaction between tumor and immune cells, development of robust biomarkers to predict patients who are likely to respond to treatment with ICPis remains a challenge. In this review we present an overview of the immune monitoring strategies that are currently in use to enable appropriate patient selection.
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http://dx.doi.org/10.1016/j.critrevonc.2018.07.010DOI Listing
October 2018

Improved diagnostic clarity in shrimp allergic non-dust-mite sensitized patients.

Allergy Asthma Proc 2018 Sep;39(5):377-383

From the Section of Immunology, Allergy and Rheumatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.

Background: Allergen specific immunoglobulin E (sIgE) levels predictive of shrimp allergy have not been identified, but these may be helpful in identifying patients at risk for shrimp-induced allergic reactions.

Objective: This study sought to identify component resolved diagnostic tests useful for diagnosis of shrimp allergy in patients with or without house-dust mite (HDM) sensitization to the major allergen cysteine protease (Der p 1).

Methods: Patients with positive skin-prick test (SPT) results and/or sIgE values were recruited. Shrimp allergy was classified by oral food challenge (OFC) or by a clear history of anaphylaxis after shrimp ingestion. Patients with shrimp allergy and patients who were tolerant were further classified based on HDM sensitivity (Der p 1 > 0.35 kUA/L). Testing for sIgE to total shrimp, and shrimp and HDM components was performed. The Fisher exact test, Wilcoxon sum rank test, and receiver operating characteristics analyses were used to compare sIgE levels in patients with allergy and patients who were tolerant.

Results: Of 79 patients recruited, 12 patients with shrimp allergy (7 with positive OFC results and 5 with a history of anaphylaxis) and 18 patients who were shrimp tolerant were enrolled. Of the patients not HDM sensitized, sIgE levels to shrimp (10.5 kUA/L, p = 0.012) and Der p 10 (4.09 kUA/L, p = 0.035) were higher in patients with shrimp allergy. Shrimp sIgE of ≥3.55 kUA/L had 100% diagnostic sensitivity and 85.7% specificity (receiver operating characteristic 0.94 [0.81, 1.0] 95% CI) and Der p 10 sIgE levels of ≥3.98 kUA/L had a diagnostic sensitivity of 80% and specificity of 100% (receiver operating characteristic 0.86 [0.57, 1.0] 95% CI) for prediction of clinical reactivity.

Conclusion: HDM sensitization influences shrimp and HDM component sIgE levels and, consequently, their diagnostic accuracy in shrimp allergy. In our series, in the patients who were non-HDM sensitized, a shrimp sIgE level of >3.55 kUA/L showed 100% sensitivity and, Der p 10 sIgE of >3.98 kUA/L showed 100% specificity for the diagnosis of shrimp allergy. These levels may not be applicable to every patient and, therefore, may not obviate the need for OFC.
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http://dx.doi.org/10.2500/aap.2018.39.4148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122289PMC
September 2018

Questioning the accuracy of currently available pneumococcal antibody testing.

J Allergy Clin Immunol 2018 10 21;142(4):1358-1360. Epub 2018 Jun 21.

Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY.

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http://dx.doi.org/10.1016/j.jaci.2018.06.013DOI Listing
October 2018

Correction to: Use of Genetic Testing for Primary Immunodeficiency Patients.

J Clin Immunol 2018 May;38(4):540-541

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

The original version of this article unfortunately contained mistakes in some of the author names and affiliations. The correct list of author names and affiliations is below, with the corrections in bold.
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http://dx.doi.org/10.1007/s10875-018-0510-2DOI Listing
May 2018

Use of Genetic Testing for Primary Immunodeficiency Patients.

J Clin Immunol 2018 04 19;38(3):320-329. Epub 2018 Apr 19.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Genetic testing plays a critical role in diagnosis for many primary immunodeficiency diseases. The goals of this report are to outline some of the challenges that clinical immunologists face routinely in the use of genetic testing for patient care. In addition, we provide a review of the types of genetic testing used in the diagnosis of PID, including their strengths and limitations. We describe the strengths and limitations of different genetic testing approaches for specific clinical contexts that raise concern for specific PID disorders in light of the challenges reported by the clinical immunologist members of the CIS in a recent membership survey. Finally, we delineate the CIS's recommendations for the use of genetic testing in light of these issues.
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http://dx.doi.org/10.1007/s10875-018-0489-8DOI Listing
April 2018

Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience.

Invest New Drugs 2018 08 21;36(4):638-646. Epub 2017 Nov 21.

Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.

Background Immunotherapy is emerging as the cornerstone for treatment of patients with advanced cancer, but significant toxicity (immune-related adverse events [irAEs]) associated with unbridled T cell activity remains a concern. Patients and methods A retrospective review of the electronic medical records of 290 patients with advanced cancer treated on an immunotherapy-based clinical trial in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center between February 2010 and September 2015 was performed. Clinical and laboratory parameters were collected to determine the incidence of irAEs, risk factors, and their association with treatment outcomes. Results Ninety eight of 290 patients (34%) experienced any grade irAEs. Among the 15 (5.2%) patients with grade ≥ 3 irAEs, the most common irAEs were dermatitis and enterocolitis. Although 80% of the patients with grade ≥ 3 irAEs required systemic corticosteroids, all the 15 patients recovered from the irAEs. On re-challenge, 4 of the 5 patients who had received systemic corticosteroids for irAE continued to respond. There were no irAE-related deaths. Importantly, patients with grade ≥ 3 irAEs had improved overall response rate (25 vs. 6%; p = 0.039) and longer median time to progression (30 weeks vs. 10 weeks; p = 0.0040) when compared to those without grade ≥ 3 irAEs. Conclusion Incidence of irAEs with immunotherapeutic agents indicates an active immune status, suggestive of potential clinical benefit to the patient. Further validation of this association in a large prospective study is warranted.
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http://dx.doi.org/10.1007/s10637-017-0534-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962379PMC
August 2018

Radiomics to predict immunotherapy-induced pneumonitis: proof of concept.

Invest New Drugs 2018 08 27;36(4):601-607. Epub 2017 Oct 27.

Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030-4004, USA.

We present the first reported work that explores the potential of radiomics to predict patients who are at risk for developing immunotherapy-induced pneumonitis. Despite promising results with immunotherapies, immune-related adverse events (irAEs) are challenging. Although less common, pneumonitis is a potentially fatal irAE. Thus, early detection is critical for improving treatment outcomes; an urgent need to identify biomarkers that predict patients at risk for pneumonitis exists. Radiomics, an emerging field, is the automated extraction of high fidelity, high-dimensional imaging features from standard medical images and allows for comprehensive visualization and characterization of the tissue of interest and corresponding microenvironment. In this pilot study, we sought to determine whether radiomics has the potential to predict development of pneumonitis. We performed radiomic analyses using baseline chest computed tomography images of patients who did (N = 2) and did not (N = 30) develop immunotherapy-induced pneumonitis. We extracted 1860 radiomic features in each patient. Maximum relevance and minimum redundancy feature selection method, anomaly detection algorithm, and leave-one-out cross-validation identified radiomic features that were significantly different and predicted subsequent immunotherapy-induced pneumonitis (accuracy, 100% [p = 0.0033]). This study suggests that radiomic features can classify and predict those patients at baseline who will subsequently develop immunotherapy-induced pneumonitis, further enabling risk-stratification that will ultimately lead to better treatment outcomes.
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http://dx.doi.org/10.1007/s10637-017-0524-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924418PMC
August 2018

Multiple Brain Abscesses Caused by Trichosporon inkin in a Patient with X-Linked Chronic Granulomatous Disease (CGD) Successfully Treated with Antifungal Therapy.

J Clin Immunol 2017 08 11;37(6):519-523. Epub 2017 Jul 11.

The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, 78229-3900, TX, USA.

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http://dx.doi.org/10.1007/s10875-017-0419-1DOI Listing
August 2017

Health-Related Quality of Life in Adult Patients with Common Variable Immunodeficiency Disorders and Impact of Treatment.

J Clin Immunol 2017 Jul 23;37(5):461-475. Epub 2017 May 23.

Texas Children's Hospital and Baylor College of Medicine, 1102 Bates St, Houston, TX, 77030, USA.

Purpose: Common variable immunodeficiency disorder (CVID) is a primary immunodeficiency disease (PIDD) often associated with severe and chronic infections. Patients commonly receive immunoglobulin (Ig) treatment to reduce the cycle of recurrent infection and improve physical functioning. However, how Ig treatment in CVID affects quality of life (QOL) has not been thoroughly evaluated. The purpose of a recent Immune Deficiency Foundation (IDF) mail survey was to assess the factors that are associated with QOL in patients with CVID receiving Ig treatment.

Methods: A 75-question survey developed by the IDF and a 12-item Short Form Health Survey (SF-12) to assess QOL were mailed to adults with CVID. Mean SF-12 scores were compared between patients with CVID and the general US adult population normative sample.

Results: Overall, 945 patients with CVID completed the surveys. More than half of the patients (54.9%) received intravenous Ig and 44.9% received subcutaneous Ig treatment. Patients with CVID had significantly lower SF-12 scores compared with the general US population regardless of sex or age (p < 0.05). Route of IgG replacement did not dramatically improve QOL. SF-12 scores were highest in patients with CVID who have well-controlled PIDD, lacked physical impairments, were not bothered by treatment, and received Ig infusions at home.

Conclusion: These data provide insight into what factors are most associated with physical and mental health, which can serve to improve QOL in patients in this population. Improvements in QOL can result from early detection of disease, limiting digestive system disease, attention to fatigue, and implementation of an individual treatment plan for the patient.
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http://dx.doi.org/10.1007/s10875-017-0404-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489588PMC
July 2017

Overview of Basic Immunology for Clinical Investigators.

Adv Exp Med Biol 2017 ;995:1-31

Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.

Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells are found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and the cross talk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.
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http://dx.doi.org/10.1007/978-3-319-53156-4_1DOI Listing
September 2017

Increased Incidence of Fatigue in Patients with Primary Immunodeficiency Disorders: Prevalence and Associations Within the US Immunodeficiency Network Registry.

J Clin Immunol 2017 Feb 26;37(2):153-165. Epub 2017 Jan 26.

Section of Immunology, Allergy and Rheumatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Introduction: Patients with primary immunodeficiency (PID) often report fatigue, yet this symptom has not been studied in PID. Fatigue affects 6-7.5% of healthy adults. The goal of this study is to estimate the prevalence of fatigue in patients with PID and investigate its associated factors.

Methods: We analyzed 2537 PID patients registered in USIDNET to determine responses to the field "fatigue" in the core registry form. Demographics, immune phenotypes, and comorbid conditions were compared between fatigued and non-fatigued patients to identify relevant associations and potential drivers. A focused analysis was performed for patients with predominantly antibody deficiency disorders (PADs).

Results: Fatigue was reported in 25.9% (95% CI 23.7-28.3) of PAD patients, compared to 6.4% (95% CI 4.9-8.2) of non-PAD. Patients with common variable immunodeficiency (CVID) had the highest prevalence of fatigue (p < 0.001) among all PID diagnoses. Other factors that were associated with a higher rate of fatigue among PAD patients included female sex, higher BMI, depression, bronchiectasis, and autoimmunity. Additionally, fatigued PAD patients had lower absolute lymphocyte, CD3, CD4, and CD8 counts compared to non-fatigued patients.

Conclusion: Our findings suggest that fatigue is overrepresented in PAD patients. Prospective studies to estimate prevalence, risk factors, and fatigue etiology in PID are warranted, so therapeutic interventions can be considered.
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http://dx.doi.org/10.1007/s10875-016-0367-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326589PMC
February 2017

Gastric Adenocarcinoma in a Patient with X-Linked Agammaglobulinemia and HIV: Case Report and Review of the Literature.

Front Pediatr 2016 23;4:100. Epub 2016 Sep 23.

Section of Immunology, Allergy and Rheumatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine , Houston, TX , USA.

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http://dx.doi.org/10.3389/fped.2016.00100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033959PMC
September 2016

Incidence of infusion reactions to anti-neoplastic agents in early phase clinical trials: The MD Anderson Cancer Center experience.

Invest New Drugs 2017 02 29;35(1):59-67. Epub 2016 Sep 29.

Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.

Infusion reactions (IRs) to anti-neoplastic agents require prompt recognition and immediate treatment to avert significant complications. We conducted a retrospective review of the medical records of consecutive patients who received anti-neoplastic therapy in the outpatient treatment center of the Department of Investigational Cancer Therapeutics from January 1, 2013 to November 30, 2013. Of the 597 patients who received treatment, 9 (1.5 %) had IRs (all ≤ grade 2). The most common IRs observed on first occurrence were chills (n = 5), itching, rash, and facial flushing (n = 3 each). There were no IR-related deaths. All the IRs were reversible with appropriate symptomatic treatment and the therapy was completed after temporary cessation of infusion in 7 of the 9 patients. The infusion was stopped in 2 patients due to symptoms suggestive of IgE-mediated allergic reaction and cytokine storm. Five of the 8 patients who were re-challenged with the same therapy developed a similar reaction. However, the infusion was completed in 4 of the 5 patients after administration of intravenous diphenhydramine and/or hydrocortisone, or slowing the rate of infusion. And, subsequent cycles with the same agents were uneventful. IRs to anti-neoplastic agents are rare. Though the clinical presentations are overlapping, most IRs are not IgE-mediated allergic reactions. Appropriate premedication and slow rate of infusion facilitates uneventful administration of the anti-neoplastic agents in subsequent cycles. Further study in a larger cohort of patients to identify biomarkers of hypersensitivity is warranted.
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http://dx.doi.org/10.1007/s10637-016-0395-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896759PMC
February 2017

Development and Initial Validation of a Questionnaire to Measure Health-Related Quality of Life of Adults with Common Variable Immune Deficiency: The CVID_QoL Questionnaire.

J Allergy Clin Immunol Pract 2016 Nov - Dec;4(6):1169-1179.e4. Epub 2016 Sep 21.

Link srl, Rome, Italy.

Background: Generic health status quality of life (QoL) instruments have been used in patients with common variable immune deficiency (CVID). However, by their nature, these tools may over- or underestimate the impact of diseases on an individual's QoL.

Objective: The objective of this study was to develop and validate a questionnaire to measure specific-health-related QoL for adults with CVID (CVID_QoL).

Methods: The 32-item content of the CVID_QoL questionnaire was developed using focus groups and individual patient interviews. Validation studies included 118 adults with CVID who completed Short Form-36, Saint George Respiratory Questionnaire, General Health Questionnaire-12, and EuroQol-5D questionnaire in a single session. Principal component and factor analysis solutions identified 3 scores to be similar in number and content for each solution. Validation of 3 factor scores was performed by construct validity. Reproducibility, reliability, convergent validity, and discriminant validity were evaluated. Matrices consisting of correlations between the 32 items in the CVID_QOL were calculated.

Results: Factor analysis identified 3 dimensions: emotional functioning (EF), relational functioning (RF), and gastrointestinal and skin symptoms (GSS). The instrument had good internal consistency (Cronbach's alpha, min. 0.74 for GSS, max. 0.84 for RF, n = 118) and high reproducibility (intraclass correlation coefficient, min. 0.79 for RF, max 0.90 for EF, n = 27). EF and RF scores showed good convergent validity correlating with conceptually similar dimensions of other study scales. Acute and relapsing infections had a significant impact on EF and RF.

Conclusions: This study provides evidence of the reliability and construct validity of the CVID_QoL to identify QoL issues in patients with CVID that may not be addressed by generic instruments.
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http://dx.doi.org/10.1016/j.jaip.2016.07.012DOI Listing
October 2017

Targeting the indoleamine 2,3-dioxygenase pathway in cancer.

J Immunother Cancer 2015 15;3:51. Epub 2015 Dec 15.

Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 455, Houston, TX 77030 USA.

Tumor cells escape the immune surveillance system of the host through a process called immune tolerance. Immunotherapy targets molecules that serve as checks and balances in the regulation of immune response. Indoleamine-2,3-dioxygenase (IDO) is an intracellular enzyme, which through the process of tryptophan depletion exerts an immunosuppressive effect, facilitating immune escape of tumors. This review summarizes our current knowledge on IDO expression in malignancies, the IDO inhibitors that are currently available and those under clinical development.
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http://dx.doi.org/10.1186/s40425-015-0094-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678703PMC
December 2015
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