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Previous protocol | A description of the assay can be found in a previously published article [ | PMC9927051 | ||
Cohort details of the earlier clinical trial | lung cancer, Lung cancer | LUNG CANCER, -11, LUNG CANCER | Subjects were enrolled between 2014-06-02 and 2017-11-16 in three medical centers. In all cases, the study received approval of Institutional Review Boards (IRB) in accordance with the Declaration of Helsinki, and subjects read and signed a dedicated consent form. Inclusion and exclusion criteria were applied as described in our previously published article [Lung cancer type distribution. Distribution of lung cancer types in the cohort of the earlier clinical trial. Subjects were enrolled between 2014-06-02 and 2017-11-16 in three medical centers. The 'Other' group includes lung cancer types other than non-small cells lung cancer and small cells lung cancer | PMC9927051 |
Cohort details of the later clinical trial | lung cancer, Lung cancer | LUNG CANCER, LUNG CANCER | Subjects were enrolled between 2019-03-24 and 2021-03-09 in three medical centers. In all cases, the study received IRB approval in accordance with Declaration of Helsinki, and subjects read and signed a dedicated consent form. The same inclusion and exclusion criteria were applied as described in our previous published article [Lung cancer type distribution. Distribution of lung cancer types in the cohort of the later clinical trial. Subjects were enrolled between 2019-03-24 and 2021-03-09 in three medical centers | PMC9927051 |
Data analysis | cancer stage, cancer, malignancy, lung cancer, Machine Learning | CANCER, LUNG CANCER, REGRESSION, SEPARATION, PATHOLOGY | Each subject was assigned a datasheet containing raw fluorescent readings of the plate wells as a function of time. The fluorescent readings were transformed into values which correlate with the acidity of the sample. We modeled the biological progression of the immunological response and extracted a set of informative features for use in our assay.Machine Learning (ML) models were trained using logistic regression implemented by the publicly available scikit-learn Python library. For cross-validation, a stratified fivefold split was used. Confidence interval (CI) was calculated using Wilson score interval. Each stage is displayed separately for sensitivity calculation. We determined the decision boundary by choosing the point on the ROC curve with the highest Euclidean distance from the main diagonal. For a measure of separation between lung cancer and control subjects, the area under the receiver operating characteristic curve (AUC) was chosen. Repeated evaluations with different random, cross validation train/test splits were performed to verify result stability. Our cancer reference method is based on the results from tissue biopsy pathology of lung nodules, which determines whether there is a malignancy, and the lung cancer type. The cancer stage is determined by a physician specialist based on defined medical criteria. | PMC9927051 |
Results | PMC9927051 | |||
Analytical sensitivity and specificity of the metabolic activity lung cancer test (MA-LC) | The Metabolic Activity test measures the change in acid concentration over time in reaction to exposure to a stimulant. We use 8-Hydroxypyrene-1,3,6-trisulfonic acid (HPTS)—a highly water-soluble, membrane-impermeant pH indicator (pH 6.6 to 8.0) that is added to each plate’s well. HPTS exhibits a pH-dependent adsorption shift that allows the performance of ratiometric pH measurements by using the excitation ratio of 403/455 nm (d) that correlates with acidity. Analytical sensitivity of the newly developed metabolic activity test represents the smallest amount of change over time of acidity in a sample that can be accurately measured by the MA test.To calculate the analytical sensitivity, we first determined the limit of blank (LOB). Our blank is PBMCs without a stimulant. We measure the highest result that is likely to be observed with a blank with certainty of 90% (z-score of 1.645 times the standard deviation of the repeats). Next, we’ve added to the LOB the lowest measurement result that is likely to be observed with PBMCs with a stimulant with certainty of 90%. The calculated lower limit of quantification (LLOQ) for metabolism activity based on the above calculations is 0.000119 (d/minute) in change of acidity over time. This points out the high sensitivity of the MA test to detect tiny changes in acid concentration over time.The MA test measures time-dependent changes in acid concentration of the extracellular fluid in a reaction that relates to the glycolysis metabolic cycle. We verified that the test specifically quantifies glycolysis by measuring the acidity (d) change over time. We use 2-deoxy-D-glucose (2-DG), a glucose analogue able to suppress glycolysis by competitively inhibiting hexokinase 2 (HK2). Adding a general stimulant (mitogen PHA, stimulates metabolic activity in a nonspecific manner) to PBMCs causes detectable extracellular acidification reaction resulting from the secretion of lactic acid, a product of the glycolysis pathway into the extracellular fluid (blue line—Fig. Acidity signal is related to glycolysis metabolic pathway (2DG suppresses acidification/glycolysis). The blue line shows acidity (d) changes over time of PBMCs together with a general stimulant (mitogen PHA). The orange line shows acidity (d) changes over time of PBMCs together with a general stimulant (mitogen PHA) and 2DG (10 mM/well)Oligomycin (OMC) is an inhibitor of the oxidative phosphorylation metabolic cycle. It is an Adenosine Triphosphate (ATP) synthase inhibitor that prevents phosphorylation of Adenosine Diphosphate (ADP) to ATP. Inhibition of ATP synthase via the oxidative phosphorylation metabolic cycle stimulates the increase of the glycolysis cycle in order to meet the energy production need of the cell. We verified that adding OMC (4 μM/well) together with PHA to PBMCs increased the glycolysis rate (orange line—Fig. Inhibition of oxidative phosphorylation metabolic pathway by OMC increases glycolysis. LThe orange line shows acidity (d) changes over time of PBMCs together with a general stimulant (mitogen PHA) and OMC. The blue line shows acidity (d) changes over time of PBMCs together with a general stimulant (mitogen PHA)These two experiments show that acidity changes over time in PBMCs extracellular fluid correlate with changes of the glycolysis metabolic cycle. | PMC9927051 | ||
Data analysis | lung cancer, cancer, malignancy, cancer stage | REGRESSION, CANCER, PATHOLOGY, LUNG CANCER | Each subject was assigned a datasheet containing raw fluorescent readings of the plate wells as a function of time. The fluorescent readings were transformed into values which correlate with the acidity of the sample. We modeled the biological progression of the immunological response and extracted a set of informative features for use in our assay. Machine Learning (ML) models were trained using logistic regression implemented by the publicly available scikit-learn Python library. For cross-validation, a stratified fivefold split was used. We determined the decision boundary by choosing the point on the receiver operating characteristic (ROC) curve with the highest Euclidean distance from the main diagonal. Repeated evaluations with different random, cross validation train/test splits were performed to verify result stability. Our cancer reference method is based on the results from tissue biopsy pathology of lung nodules, which determines whether there is a malignancy, and the lung cancer type. The cancer stage is determined by a physician specialist based on defined medical criteria. | PMC9927051 |
Discussion | tumor, allergy, lung cancer, early-stage lung cancer, TAA | VIRUS, TUMOR, DISEASE, ALLERGY, SENSITIVITY, LUNG CANCER, DISEASES | We describe an improved immunometabolism blood test that measures the function of the immune cells in response to LC antigenic stimuli based on enhancement of the glycolysis metabolic pathway of immune cells. Glycolysis enhancement is a marker for the rapid activation of most immune cells [This research article compares results from two clinical trials; in the earlier clinical trial an earlier MA-LC protocol was used and in the later clinical trial an improved protocol was used. Since the clinical benefits for early detection have been demonstrated, this current research focuses on early-stage lung cancer (stages I, II). Our results indicate that the MA-LC in its final version improves the test’s specificity from 81.7% (Table Sensitivity and specificity of MA-LC of the earlier clinical trialSensitivity and specificity of MA-LC of the later clinical trialThe sensitivity and specificity obtained by MA-LC in detecting early-stage lung cancer is much higher than the results reported for stages I, II in the literature by using only one method [Other biomarkers noninvasive tests focus on detecting circulating biomarkers, including tumor DNA, tumor antigens, tumor cells, exosomes, and extracellular vesicles. These biomarkers are released to peripheral blood primarily when the tumor reaches a certain size at a later stage of the disease.We have previously shown [The broad potential of this immunometabolism-based platform may also extend to other types of diseases, as well as to treatment monitoring and therapy selection. It could provide the cellular immune status of vaccinated people to SARS-COV-2 by using virus spike peptides, measure other cellular immune statuses to diseases such as allergy, autoimmune, immunodeficiency, antimicrobial immunity, follow up the effect of immunotherapy treatments, and measure drug efficacy.Liquid ImmunoBiopsy™ is a new, promising, and non-invasive platform that measures the metabolic state of the immune system as a direct indicator of cellular immune responses (primarily T and B cells) to antigenic stimuli. The MA-LC provides results within five hours of receiving the blood sample for MA-LC. The analytical sensitivity of the test is high with a lower limit of quantification (LLOQ) of 0.000119 (d/minute) in change of acidity over time. It specifically quantifies glycolysis which is a biomarker for the activation level of immune cells that are re-exposed in vitro to lung TAA stimulants.The present study has limitations. Not all control subjects received LDCT screening, nor were they followed-up after the blood draw, therefore, it is unknown whether lung cancer cases were already present and missed. Separately, cross validation is a widely used approach for assessment of classification performance and can address known individual confounders. However, cross-validation procedures do not control simultaneously for all confounders, and the use of an independent test set is needed to evaluate the generalizability of these results. Prospective studies are planned to validate classifier performance in an independent cohort and verify the generalization predictions from confounder-controlled CV.The MA-LC is, | PMC9927051 |
Conclusions | lung cancer, lung cancer stage, lung cancer stage II | LUNG CANCER | Data analysis of a clinical trial applying the improved protocol of the ImmunoBiopsy™ test shows test specificity and sensitivity of 94.0% and 97.3%, respectively in detecting lung cancer stage I, and test specificity and sensitivity of 94.0% and 100%, respectively in detecting lung cancer stage II. The sensitivity and specificity obtained by this test in detecting stage I and stage II lung cancer is significantly higher than the results reported for stage I and stage II in the literature that uses only one method. ImmunoBiopsy™ is a promising, and non-invasive test to help diagnose early stages of lung cancer with low material costs and fast results. Detecting lung cancer in its early stage is a critical component in raising the overall survival rate and prognosis for lung cancer. | PMC9927051 |
Acknowledgements | THORACIC | The authors are indebted to Dr. Ori Haberfeld, Dr. Yaron Saiet, Dr. Eran Gilad from Department of General Thoracic Surgery, Rambam Health Care Campus, Israel and to Dr. Yana Kogan, Dr. Einat Fireman Klain, Dr. Sonia Shneer and Dr. Raya Cohen from Pulmonary Division, Faculty of Medicine, Lady Davis Carmel Medical Center, Israel for their help in recruiting suitable subjects for the clinical study and explaining to them the research study and its risks and signing an informed consent form in accordance with the Helsinki Convention. The authors thank Gratzia Luzon, Irena Shahar and Mori Hay Levy for their help in coordinating the clinical studies. | PMC9927051 | |
Author contributions | ONCOLOGY, THORACIC | SS—Conceptualization, project administration, investigation, writing—original draft, review and editing. FP—Biochemistry expert, methodology. HD—Software, formal analysis, data curation, writing—original draft. ES—Resources, investigation, validation. ED—Formal analysis, funding acquisition, visualization. ST—Software, data curation. GD—Conceptualization, writing—review and editing, funding acquisition. NA—Oncology medical expert. Principal investigator of clinical trial site. AK—Thoracic surgery medical expert. Principal investigator of clinical trial site. YA—Pulmonary medical expert. Principal investigator of clinical trial site. All authors read and approved the final manuscript. | PMC9927051 | |
Funding | This work was supported by Savicell Diagnostics Ltd. | PMC9927051 | ||
Availability of data and materials | Available from the corresponding author on reasonable request. | PMC9927051 | ||
Declarations | PMC9927051 | |||
Ethics approval and consent to participate | All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committees and with the 1964 Helsinki declaration and its later amendments (subjects read and signed a dedicated consent form). Ethics committee approval numbers of the Institutional review board are: 0105-13-CMC for Carmel Medical Center, Haifa; 0274-15-RMB for Rambam Medical Center, Haifa; and 0009-13-TLV for Sourasky Medical Center, Tel Aviv. | PMC9927051 | ||
Consent for publication | Not applicable. | PMC9927051 | ||
Competing interests | Shafrira Shai, Hagai Drori, Eyal J. Scheinman, Eyal Davidovits, Giora Davidovits, Shoval Tirman, are employed by Savicell Diagnostics and own stock and/or options in Savicell Diagnostics’ parent company. Fernando Patolsky and Yochai Adir are consultants and own stock and/or options in Savicell Diagnostics’ parent company. Nadir Arber and Amit Katz: none to declare. | PMC9927051 | ||
References | PMC9927051 | |||
Methods | cancers, cancer testis antigen-specific immune | CANCERS | Forty-nine patients with CCR4-negative solid cancers were enrolled in the phase Ia and Ib trials on KW-0761. An integral analysis of safety, clinical responses, prognosis, blood laboratory data, and cancer testis antigen-specific immune responses was performed. | PMC10511099 |
Results | lung cancer | ADVERSE EVENTS, DISEASE, LUNG CANCER | Grade 3–4 treatment-related adverse events were reported in 21 (42.9%) out of 49 patients, all of which were manageable. A partial response and stable disease were observed in 1 and 9 patients, respectively. A durable clinical response was noted in 2 esophageal and 2 lung cancer patients. eTreg depletion in peripheral blood was confirmed in most patients, and eTreg depletion was sustained during the KW-0761 treatment. High lymphocyte levels at baseline and 2 weeks after the initiation of KW-0761 were associated with a favorable clinical outcome. | PMC10511099 |
Conclusions | A durable clinical response was noted in some patients, and high lymphocyte levels before treatment initiation may be a biomarker for the efficacy of KW-0761. The synergistic effect of KW-0761 for depleting Tregs and other immunotherapies is expected in the future. | PMC10511099 | ||
Data Availability | All relevant data are within the paper and its | PMC10511099 | ||
Introduction | Sezary Syndrome, various cancer, Cancer | MYCOSIS FUNGOIDES, SEZARY SYNDROME, CYTOTOXICITY, ADULT T-CELL LEUKEMIA-LYMPHOMA, CANCER | Cancer immunotherapy is now more frequently used in clinical practice and immune checkpoint inhibitors (ICIs) have improved the prognosis of patients with various cancer types; however, their efficacy is still insufficient [KW-0761 (mogamulizumab) is a humanized anti-C-C chemokine receptor type 4 (CCR4) IgG1 monoclonal antibody (mAb) with enhanced antibody-dependent cellular cytotoxicity. Since CCR4 is overexpressed in relapsed Adult T-cell leukemia-lymphoma, Mycosis Fungoides, and Sezary Syndrome [ | PMC10511099 |
Materials and methods | PMC10511099 | |||
Patients | cancer | CANCER | Patients were eligible if they had CCR4-negative advanced or recurrent solid cancer with target lesions. CCR4 expression was examined by immunohistochemistry (IHC) using an anti-CCR4 mAb (KM2160; Kyowa Kirin) and confirmed by a review committee with a central evaluation. The inclusion criteria were the same as those in previous studies [ | PMC10511099 |
Study design | DISEASE PROGRESSION | The present study was designed as multi-institutional, open-label, investigator-initiated phase Ia and Ib clinical trials on KW-0761 (mogamulizumab). The investigational drug KW-0761 was provided by Kyowa Kirin. Patients received 8 intravenous infusions of KW-0761 weekly followed by monthly infusions until disease progression or patient refusal. The phase Ia study consisted of a non-randomized 3+3 dose-escalation design with 0.1, 0.5, and 1.0 mg/kg of KW-0761, and the sample size was set using Fibonacci’s method ( | PMC10511099 | |
CONSORT diagram for trial. | Phase Ia (a) and Phase Ib (b) studies. | PMC10511099 | ||
Toxicity evaluation | Tumor, Toxicity, Cancer | ADVERSE EVENT, TUMOR, CANCER | Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The independent data monitoring committee chaired by Professor Ryuzo Ueda, Department of Tumor Immunology, Aichi Medical University School of Medicine evaluated the safety data for each dose level. | PMC10511099 |
Clinical response evaluation | Responses were evaluated 12 weeks after the first KW-0761 treatment or at the point of study discontinuation based on computed tomography (CT) scans according to RECIST (ver. 1.1) and immune-related RECIST [ | PMC10511099 | ||
Blood laboratory data | BLOOD | Peripheral blood sampling was performed at baseline and at every timepoint of KW-0761 infusions. Blood laboratory tests consisted of a blood count, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), phosphate, albumin, γ-glutamyltransferase (GGT), amylase and thyroid stimulating hormone (TSH). The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) were defined as the values of the neutrophil, platelet, and monocyte counts divided by the lymphocyte count, respectively. | PMC10511099 | |
Treg depletion effects on PBMCs | Treg depletion was assessed as previously described [ | PMC10511099 | ||
IHC | tumor | TUMOR | Archived or newly obtained tumor samples from patients were screened for the expression of CCR4, NY-ESO-1, and XAGE1 (GAGED2a) by IHC as previously described [ | PMC10511099 |
Enzyme-linked Immunosorbent Assay (ELISA) for NY-ESO-1 or XAGE1 antibodies | Serum samples were obtained at baseline, 4 and 8 weeks after the first KW-0761 treatment, and every 4 weeks during the continuous treatment until the point of study discontinuation. Recombinant NY-ESO-1 and the synthetic XAGE1 protein (1 μM) in ELISA Buffer kit (PeproTech, Rocky Hill, NJ) were adsorbed onto a 96-well ELISA plate (Nunc, Roskilde, Denmark) and incubated at 4°C overnight. Plates were washed with 0.05% Tween-20 in PBS and blocked with 1% BSA/PBS (200 μl/well) at room temperature for 1 hour. After washing, 100 μl of serially diluted serum was added to each well and incubated at room temperature for 2 hours. After washing, horseradish peroxidase-conjugated goat anti-human IgG (MBL, Nagoya, Japan) was added to the wells, and the plates were incubated at room temperature for 1 hour. After washing and development, absorbance was read at 490 nm [ | PMC10511099 | ||
Statistical analysis | Quantitative data without a normal distribution were analyzed using the 2-tailed non-parametric Mann-Whitney U test. The 2-tailed Fisher’s exact probability test was used for bivariate analyses. Cumulative survival was plotted using the Kaplan–Meier method, and differences were compared using the Log-rank test. Statistical analyses were performed using JMP Pro, version 16.0.0 (JMP, Tokyo). P values <0.05 were considered to be significant. | PMC10511099 | ||
Results | PMC10511099 | |||
Patient characteristics | cancer | CANCER | Between October 2013 and April 2016, 49 patients with CCR4-negative advanced solid cancer were assigned to receive the KW-0761 treatment at doses of 0.1 mg/kg (n = 23), 0.5 mg/kg (n = 3), and 1.0 mg/kg (n = 23) in the phase I study ( | PMC10511099 |
Adverse events (AEs) | All grade and grade 3–4 treatment-related AEs occurred in 46 (93.9%) and 21 (42.9%), respectively, out of 49 patients ( | PMC10511099 | ||
Reagent-related adverse events. | ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, Gamma-glutamyltransferase | PMC10511099 | ||
Clinical responses | PD, SD | DISEASE | Clinical responses were 1 partial response (PR), 9 stable disease (SD), and 39 PD ( | PMC10511099 |
Characteristics of clinical responses. | esophageal cancer, tumor, Tumor | TUMOR, METASTASIS, TUMOR, OESOPHAGEAL CANCER, ADVERSE EVENTS, TUMOR GROWTH | (a) A Waterfall plot for the best percentage change from baseline. A positive change in the tumor burden indicates tumor growth, while a negative change reflects a tumor reduction. The tumor type, presence or absence of adverse events, and presence or absence of NY-ESO-1 and XAGE1 antibody responses are annotated for each patient. (b) A Spaghetti plot for the percentage change in the target lesion tumor burden from baseline over time. Tumor burden was measured as the sum of the longest diameters of the target lesions by patients over time. The black triangle indicates the first occurrence of a new lesion. Horizontal dotted lines denote a 30% decrease and a 20% increase. 0.1 mg/ml (n = 23), blue bar; 0.5 mg/ml (n = 3), green bar; 1.0 mg/ml (n = 23), orange bar.Patient B-09 was a 64-year-old male with chemotherapy-resistant relapsed esophageal cancer metastasis in the pleura at the baseline ( | PMC10511099 |
Representative CT imaging in patients with a durable clinical response. | esophageal cancer, Multiple liver metastases, cancer, Esophageal cancer, pleural tumor | METASTASIS, OESOPHAGEAL CANCER, CANCER, PLEURAL METASTASIS, LYMPH NODE METASTASIS, ESOPHAGEAL CANCER, DISEASE PROGRESSION | (a) Esophageal cancer patient B-09. Pleural metastasis (yellow arrow) was observed on CT and FDG-PET at baseline. The pleural tumor was decreased in size by the KW-0761 treatment, which was also confirmed by a reduction in standardized uptake value-max (SUV-max) on FDG-PET. Although pleural metastasis shrank, abdominal lymph node metastasis (orange arrow) developed after 23 infusions, which was evaluated as a new lesion, leading to the discontinuation of treatment. (b) Esophageal cancer patient B-39. Multiple liver metastases (yellow arrow) were observed on CT at baseline. Disease progression and a new lesion in the liver (red arrow) were confirmed after the first 8 infusions; however, all lesions subsequently decreased in size. The objective feasible response was sustained until 36 weeks after the first treatment when abdominal lymph node metastasis developed (orange arrow).Patient B-39 was a 59-year-old female with chemotherapy-resistant relapsed metastasis in the liver from esophageal cancer (Although 2 patients with esophageal cancer showed a durable clinical response, there was no significant prognostic difference between patients with esophageal cancer and those with other cancer types ( | PMC10511099 |
FoxP3 | eTreg depletion in peripheral blood by KW-0761 was examined at baseline and during the KW-0761 treatment by flow cytometry. The percentage of eTregs in CD4 | PMC10511099 | ||
Blood laboratory data | The lymphocyte count, percent lymphocytes in leukocytes (% lymphocytes), NLR, MLR, and PLR were analyzed by blood laboratory tests at baseline and weekly after the initiation of KW-0761 until 8 infusions. The lymphocyte count and % lymphocytes markedly decreased immediately after the initiation of KW-0761, along with rapid increases in NLR, PLR, and MLR ( | PMC10511099 | ||
Changes in blood laboratory data and correlations for overall survival. | (a) The lymphocyte count (/μl), percent lymphocytes in leukocytes (% lymphocytes), NLR, MLR, and PLR were assessed by blood laboratory tests at baseline and weekly after the first KW-0761 treatment until 8 infusions. Kaplan-Meier curves of OS were analyzed between high and low groups divided by the median values of calculated parameters at baseline (b) and 2 weeks after the initiation of KW-0761 (c). Bar, median; *, p<0.05. | PMC10511099 | ||
Cancer-testis (CT) antigen-specific antibody responses | Serum NY-ESO-1 and XAGE1 antibodies at baseline and after the first 8 infusions or at the time of the discontinuation of treatment were analyzed by ELISA in patients with less than 8 infusions ( | PMC10511099 | ||
Discussion | cancer, peripheral T-cell lymphoma | NON-SMALL CELL LUNG CANCER, PERIPHERAL T-CELL LYMPHOMA, HTLV-1-ASSOCIATED MYELOPATHY-TROPICAL SPASTIC PARAPARESIS, CANCER, SOLID TUMORS, ADULT T-CELL LEUKEMIA/LYMPHOMA | We conducted phase Ia and Ib clinical trials on KW-0761 to examine the selective depletion of Tregs in 49 patients with CCR4-negative solid cancer [Strategies targeting Tregs to increase anti-tumor immunity, including antibodies against CTLA-4, OX40, 4-1BB, and ICOS, have attracted attention [Treg reductions by KW-0761 have been analyzed in trials on adult T-cell leukemia/lymphoma, primary peripheral T-cell lymphoma, and HTLV-1-associated myelopathy-tropical spastic paraparesis, in which a wide range of dosages (0.003–1.0 mg/kg) of KW-0761 were examined [CT antigens, such as NY-ESO-1 and XAGE1, are known to show unique expression patterns and induce spontaneous humoral and cellular immune responses in various cancer patients [Regarding predictive markers of treatment efficacy, our group previously reported that serum NY-ESO-1 and XAGE1 antibody responses predicted good clinical responses with an anti-PD-1 treatment for non-small cell lung cancer [In conclusion, 49 patients were enrolled in the KW-0761 phase I trial, in which KW-0761 was safely administered and eTregs in peripheral blood were depleted in most patients. A durable clinical response was observed in some patients, and high lymphocyte levels before treatment may be a biomarker for the efficacy of the KW-0761 treatment. A phase I clinical trial on preoperative combination therapy of KW-0761 plus an anti-PD-1 treatment in patients with advanced or recurrent solid tumors is currently underway. The synergistic effect of KW-0761 for depleting Tregs and other immunotherapies is expected in the future. | PMC10511099 |
Supporting information | PMC10511099 | |||
Clinical courses of patients. | cancer, PD | CANCER, DISEASE | Kaplan–Meier curves of OS and PFS for 49 CCR4-negative solid cancer patients were analyzed with doses of KW-0761 (a, b) and clinical responses (c, d). PD, progressive disease; SD, stable disease; PR, partial response.(TIF)Click here for additional data file. | PMC10511099 |
Characteristics of clinical responses and survival in esophageal cancer patients. | esophageal cancer, tumor, cancer, Esophageal cancer, non-esophageal cancer | ESOPHAGEAL CANCER, TUMOR, OESOPHAGEAL CANCER, CANCER, ESOPHAGEAL CANCER | (a) A Spaghetti plot for the percentage change in the target lesion tumor burden from baseline over time in esophageal cancer patients (n = 14, left) and non-esophageal cancer patients (n = 35, right). (b-c) Kaplan-Meier curves of OS and PFS for 49 CCR4-negative solid cancer patients were analyzed with or without esophageal cancer. Horizontal dotted lines denote a 30% decrease and a 20% increase. Esophageal cancer (n = 14), red line; non-esophageal cancer (n = 35), blue line.(TIF)Click here for additional data file. | PMC10511099 |
Effects of Treg depletion in peripheral blood. | Longitudinal changes in the percentage of eTregs in CD4(TIF)Click here for additional data file. | PMC10511099 | ||
Longitudinal changes in serological immune responses for NY-ESO-1 and XAGE-1. | Antibody responses in the phase Ib trial were analyzed for NY-ESO-1 (a) and XAGE-1 (b) in patients with positive antibody responses at baseline or during the KW-0761 treatment.(TIF)Click here for additional data file. | PMC10511099 | ||
Clinical courses of patients based on NY-ESO-1 and XAGE1 antibody responses. | tumor | TUMOR | Kaplan-Meier curves of OS and PFS were analyzed based on the presence or absence of tumor NY-ESO-1 or XAGE1 antigen expression (a, b), baseline serum NY-ESO-1 or XAGE1 antibody responses (c, d), and increased NY-ESO-1 or XAGE1 antibody responses after the KW-0761 treatment (e, f).(TIF)Click here for additional data file. | PMC10511099 |
Patient characteristics and serological immune response. | (DOCX)Click here for additional data file. | PMC10511099 | ||
CONSORT 2010 checklist of information to include when reporting a randomised trial*. | (DOC)Click here for additional data file. | PMC10511099 | ||
References | PMC10511099 | |||
Summary | Both authors contributed equally.ICON study group members are listed in the | PMC10755111 | ||
Background | CHRONIC CLUSTER HEADACHE | We demonstrated in the randomised controlled ICON study that 48-week treatment of medically intractable chronic cluster headache (MICCH) with occipital nerve stimulation (ONS) is safe and effective. In L-ICON we prospectively evaluate its long-term effectiveness and safety. | PMC10755111 | |
Methods | attack-frequency | ICON participants were enrolled in L-ICON immediately after completing ICON. Therefore, earlier ICON participants could be followed longer than later ones. L-ICON inclusion was stopped after the last ICON participant was enrolled in L-ICON and followed for ≥2 years by completing six-monthly questionnaires on attack frequency, side effects, subjective improvement and whether they would recommend ONS to others. Primary outcome was the change in mean weekly attack frequency 2 years after completion of the ICON study compared to baseline. Missing values for log-transformed attack-frequency were imputed for up to 5 years of follow-up. Descriptive analyses are presented as (pooled) geometric or arithmetic means and 95% confidence intervals. | PMC10755111 | |
Findings | ± | EVENTS | Of 103 eligible participants, 88 (85%) gave informed consent and 73 (83%) were followed for ≥2 year, 61 (69%) ≥ 3 year, 33 (38%) ≥ 5 years and 3 (3%) ≥ 8.5 years. Mean (±SD) follow-up was 4.2 ± 2.2 years for a total of 370 person years (84% of potentially 442 years). The pooled geometric mean (95% CI) weekly attack frequency remained considerably lower after one (4.2; 2.8–6.3), two (5.1; 3.5–7.6) and five years (4.1; 3.0–5.5) compared to baseline (16.2; 14.4–18.3). Of the 49/88 (56%) ICON ≥50% responders, 35/49 (71%) retained this response and 15/39 (38%) ICON non-responders still became a ≥50% responder for at least half the follow-up period. Most participants (69/88; 78% [0.68–0.86]) reported a subjective improvement from baseline at last follow-up and 70/88 (81% [0.70–0.87]) would recommend ONS to others. Hardware-related surgery was required in 44/88 (50%) participants in 112/122 (92%) events (0.35 person-year | PMC10755111 |
Interpretation | ONS is a safe, well-tolerated and long-term effective treatment for MICCH. | PMC10755111 | ||
Funding | The | PMC10755111 | ||
Keywords | PMC10755111 | |||
Research in context | PMC10755111 | |||
Evidence before this study | cluster headache, headache | ADVERSE EVENTS, CHRONIC CLUSTER HEADACHE, CLUSTER HEADACHE | We searched PubMed on November 13th, 2023, with the keywords “chronic cluster headache”, “cluster headache”, and “occipital nerve stimulation” (ONS), without restrictions to language or publication year. Of the 171 items, we excluded reviews and publications that did not report attack frequency at least 24 months after implantation. In publications combining different headache types, only data from patients with cluster headache were extracted. All publications only included data from retrospective or prospective long-term recordings of open-label assessment of the effect of ONS in case series. There were no prospective follow-up studies of the long-term effect of ONS in participants of a randomised controlled trial.We included 10 studies from 9 unique study populations of patients with medically intractable chronic cluster headache (MICCH) in this review. No formal meta-analysis was performed due to the large heterogeneity of the design, nature (retrospective versus prospective), outcome measures, follow-up time, inclusion criteria and results. Instead, balanced means and ranges across all studies are reported. In total, 293 unique participants are reported with a mean follow-up of 54 months (range 37–87).Most studies were small (<30 patients) and often there were methodological issues such as selection bias, uncertain length of the baseline period, incomplete or no formal statistical assessment at all of outcome and adverse events, little or no information on the number of participants that were lost to follow up and how these were statistically handled, and data reported only at the last follow-up with no information on effects at earlier intervals.All studies showed a reduction in attack frequency (mean 55%; median 50%, range 25%–95%). Detailed data on adverse events was lacking, but a mean of 58% (range 24%–80%) of participants experienced one or more (serious) adverse events during follow-up. | PMC10755111 |
Added value of this study | ± | ADVERSE EVENTS | This study provides a prospective detailed follow-up (range 2–8.5 years) of the long-term efficacy and safety of ONS in patients with MICCH who had participated in the only randomized, dose-controlled study of the effects of ONS in MICCH to date (ICON trial). Both participants who had improved at the end of the randomised trial and those who had not improved were included in the follow-up, providing important information on whether early improvement persisted and whether delayed improvement could occur with continued treatment. Moreover, compared to existing studies, this study had minimal selection bias, a long specified baseline of 3 months, full evaluation of outcome and adverse events at regular half-yearly intervals up to 8.5 years, and detailed information on the number of participants who were lost to follow up and why.The mean follow-up was 4.2 ± 2.2 years for a total of 370 person-years. Objective and subjective sustained efficacy were high. More than two-third of the ≥50% responders at the end of the ICON study retained this response. Moreover, during the follow-up period, more than one-third of the non-responders converted to a ≥50% responder for at least half the follow-up period. At the last follow-up, subjective improvement from baseline was reported by 78% of the participants and 81% would recommend ONS to other patients with MICCH. Hardware-related serious adverse events (SAE; formally defined as “serious” solely because short hospitalisations were required for replacements) occurred in 55% of participants with a SAE rate of 0.37 person-year. | PMC10755111 |
Implications of all the available evidence | ONS offers long-term and well-tolerated improvement in MICCH and may also be considered for patients with CCH who respond only sub-optimally to standard medical treatment but do not yet meet the strict criteria of MICCH. Improved ONS devices and stimulation protocols currently under development may confer even better effects but that remains to be demonstrated. | PMC10755111 | ||
Introduction | CHRONIC CLUSTER HEADACHE, CLUSTER HEADACHE | Medically intractable chronic cluster headache (MICCH) is the most extreme and disabling form of cluster headache, in which patients continue to have frequent, often daily, attacks despite a variety of standard prophylactic medication.We showed in the randomized double-blind ICON study that both 100% and 30% electrical dose occipital nerve stimulation (ONS) were safe, well tolerated and reduced attack frequency by an average of 50% in people with MICCH for at least 48 weeks.Previous retrospectiveIn this structured follow-up study, we prospectively and in detail evaluated the long-term effectiveness and safety of ONS for at least two years in 88 Dutch participants of the ICON trial (L-ICON). Most participants could be followed for much longer, some even for more than eight years. In particular, we evaluated: (i) whether responders remained responders over time; (ii) whether satisfied participants remained satisfied; and (iii) whether non-responders and/or dissatisfied participants could still become responder and/or satisfied. | PMC10755111 | |
Methods | PMC10755111 | |||
Ethics | Written informed consent was obtained from all participants and the study protocol was approved by the ethical committee of the LUMC (METC-LDD; Protocol number P10.016). | PMC10755111 | ||
ICON trial | paresthesia | PARESTHESIA | The parent study (ICON trial) was an investigator-initiated, international, multicentre, randomised, double-blind, phase 3, electrical dose-controlled clinical trial. After 12 weeks of baseline observation, participants were randomised to 24 weeks of occipital nerve stimulation at either 100% or 30% of the individually determined range between paresthesia threshold and near-discomfort (double-blind phase of the study). In weeks 25–48, participants received individually optimised open-label ONS.At the beginning of the ICON study, it was assumed that 30% stimulation was clinically ineffective, yet caused the same paresthesia as the 100% stimulation and thus was useful as a blinded sham/placebo comparison. At the end of the study, however, 30% stimulation was found to be as effective as 100% stimulation. Blinding remained throughout the first double-blind phase of the study. | PMC10755111 |
Patients and questionnaires | MOS, COMPLICATIONS | For logistic reasons, only Dutch patients who had completed the full 48-week ICON study were invited for prospective structured follow-up every 6 months for at least two years but if possible longer.ICON study participants were asked to participate and enrolled in the L-ICON follow-up study immediately after completion of the ICON study, 48 weeks after ONS implantation. Meanwhile, the ICON study continued to enrol new patients until 3 December 2017. Therefore, initial ICON participants could start earlier in L-ICON and be followed longer than ICON participants enrolled later in the ICON study. Inclusion for the L-ICON study was stopped after the last ICON participant was enrolled in L-ICON and followed for ≥2 years (i.e. ≥3 years after ONS implantation).Participants who consented had to complete two web-based questionnaires every six months. Unless they had explicitly withdrawn, the participants were reminded to complete the questionnaires six and two weeks before and two and six weeks after every six-month deadline. The six-monthly reminders were sent regardless of whether or not they had submitted the questionnaires six months earlier.One questionnaire included questions on: (i) neurostimulator use; (ii) side effects and complications; (iii) mean weekly attack frequency over the past six months; (iv) whether participants experienced improvement and if so, an estimated percentage of improvement; and (v) whether patients would recommend this treatment to a similar patient on a five-point scale. The other questionnaire consisted of the MOS | PMC10755111 | |
Statistics | REGRESSION, ADVERSE EVENT, EVENT, ADVERSE EVENTS | Because participants in the LICON follow-up study were each enrolled immediately after completion of the ICON study (i.e. 48 weeks after ONS implantation), while the ICON study was still recruiting new patients until December 3rd 2017, the initial LICON participants (who started the ICON study already in 2013) had a much longer (potential) follow-up than those enrolled later (e.g. only in 2016). We therefore calculated the maximal potential follow durations for each individual participant and the entire group. First we calculated the potential maximal follow-up duration for each individual participant from the time they were included for the L-ICON follow-up study (i.e. immediately after they completed the ICON study 48 weeks after ONS implantation) to the end of the L-ICON follow-up study. Then, we calculated the total potential follow-up duration for the entire group by summing all individual potential follow-up durations and adding them together for all participants.Descriptive analyses were used to visualize response after ONS implantation. Furthermore, missing values for attack frequency and three SF36 items (mental health sum score, general health and physical health sum score) were imputed until 5 years after completion of the ICON trial (after the end of the open label extension, i.e. 48 weeks after implantation). Variations in the imputed datasets were analysed and pooled data from five different imputed datasets was used. Age, body mass index (BMI), sex, weekly attack frequency, mental health sum score, physical health sum score and general health score were used as predictors with predictive mean matching. Because of the low number of data points from 5 years after ICON trial completion, data was imputed until 5 years after completion of the ICON trial. The distribution of the attack frequencies was skewed. Therefore, we used the logarithm of the weekly attack frequency in the analyses and the geometric mean for the representation of the pooled data. Data is depicted with a 95% confidence interval (CI) around the pooled geometric or arithmetic mean. A Kaplan Meier survival analysis was performed for time to first treatment success, defined as ≥ 50% or ≥30% reduction in attack frequency. Participants were censored if the event had not occurred 5 years after ICON trial completion. A binary logistic regression model was used to predict a yes/no ≥ 50% reduction in attack frequency at 2 years after ICON trial completion. Sex, restlessness during attacks and ≥50% response in week 1–4, after implantation were used as categorical predictors. Age, mean weekly attack frequency at baseline and number of autonomic symptoms were used as continuous predictors. Adverse events and serious adverse events were depicted using a rate point estimate with a 95% confidence interval. As in the ICON study, serious adverse events were defined according to EN ISO 14155-1, which implies that surgical interventions and hospital admissions labelled as serious adverse events, irrespective of the nature of the hospital admission. | PMC10755111 | |
Outcomes | ADVERSE EVENTS | The primary outcome was the change in mean weekly attack frequency 2 years after completion of the ICON study (i.e. 3 years after ONS implantation) compared to baseline (i.e. the three months before ONS implantation). Secondary outcomes were (i) Change in mean attack frequency from baseline after 1, 2 and 5 years (ii) whether non-responders (i.e. <50% or <30% reduction in attack frequency from baseline); at the end of the ICON study became responders during long-term follow up; (iii) occurrence of adverse events; (iv) mean SF-36 scores; (v) predictive capacity of sex, age, restlessness, mean weekly attack frequency at baseline, number of autonomic symptoms and ≥50% response in week 1–4 after implantation for efficacy at two years and (vi) subjective improvement and willingness to recommend this treatment to other patients. | PMC10755111 | |
Role of the funding source | The funders had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. | PMC10755111 | ||
Results | PMC10755111 | |||
Subjective response and satisfaction | Most participants (69/88; 78% [68%–86%]) reported a subjective improvement from baseline at their last follow-up; 9/88 (10% [5%–19%]) reported no change and 4/88 (5%) a worsening. The remaining 6 (7%) could not answer the question since they had a broken stimulator (n = 2) or the stimulator was turned off for varying reasons (no more attacks (n = 1), no effect (n = 1), unknown (n = 2)).Most participants would also recommend (70/88; 81% [70%–87%]) this treatment to other patients; the majority would even make a strong recommendation (52/70, 74% [48%–69%]). Only 2 (2%) participants would not recommend ONS and 14/88 (16%) did not have a (strong) opinion. | PMC10755111 | ||
Predictive factors for efficacy at 2 years | DISEASE | Sex, age, number of autonomic symptoms, disease duration, restlessness and attack frequency at baseline are presented in | PMC10755111 | |
Adverse events | ADVERSE EVENTS | From the end of the ICON trial to the last follow-up visit, N = 202 serious adverse events (SAE) occurred in 63/88 (72%) participants ( | PMC10755111 | |
Discussion | headache, attack-frequency, fracture, dislocation | ADVERSE EVENTS, THIGH DISEASE, CLUSTER HEADACHE, STAGGERED, EVENTS | In this study, we prospectively and structurally assessed the long-term effectiveness, safety and tolerability of ONS in 88 patients with MICCH who had initially completed the 48-week randomised, double-blind, electrically dose-controlled ICON trial. Both ICON responders and non-responders were followed for at least two years with a mean of four years and a total of 370 person-years which is 84% of a potential maximum total duration of 442 person years. After 3 years of follow-up, 60/88 (68%) participants were still active, and after five years, 32/88 (36%); three participants could be followed for 8.5 years. The majority of participants who were ≥50% responders at the end of the ICON study remained responder for most of the follow-up period, and more than one third of initial non-responders became ≥50% responders. Mean group attack-frequency and the SF-36 general health scores also remained improved for at least 5 years. Remarkably, most participants, even those in whom attack frequency did not significantly decrease, reported subjective improvement and would recommend ONS to other patients with MICCH. ONS was generally well-tolerated. Most SAEs were due to a short hospital stay for hardware replacement. The overall incidence per person-year for SAEs was 0.62, for hardware-related SAEs 0.37, for non-hardware-related SAEs 0.24, for additional hardware-related surgery 0.35 and for all non-serious AEs 1.83.ONS is a relatively new, minimally invasive and reversible prophylactic treatment for MICCH. Small open-label case seriesThe results are in good agreement with those of other retrospectiveIt was notable that even participants without an objective reduction in attack frequency reported subjective improvement and satisfaction, and continued ONS therapy. This was probably due to a reduction in attack severity and an improved response to acute and prophylactic medical treatment, as in the ICON study and other trials.As in other studies,In the ICON study, we used non-rechargeable implantable pulse generators (IPGs) and hardware originally developed for epidural spinal cord stimulation, which increased the risk of fracture or dislocation of the leads when used for ONS. However, for necessary replacements during follow-up, we were able to use (i) rechargeable IPGs, reducing the need for surgical battery replacement; (ii) new, more flexible electrodes that adapt better to the shape of the skull, reducing the risk of fracture; and (iii) tined leads, reducing the risk of dislocation. The number of hardware-related additional surgeries was 0.35 per person-year, which is similar to other ONS studies.We found no significant predictors of long-term response, consistent with previous studies.Important strengths of this follow up study include (i) the large sample size, with both responders and non-responders to 48 weeks ONS at the start of the follow up, minimising the risk of a large selection bias; and (ii) the long and structured prospective follow-up period with a high retention rate of 73/88 (83%) active participants at the end of the predetermined minimum follow-up of two years, i.e. three years after ONS implantation. In fact, the majority of participants in the L-ICON follow-up study were followed even longer than two years because they were included only after they had each completed the 48-week ICON study, the inclusion for the ICON study was spread over many years, and because the L-ICON follow-up took place in parallel with the ICON study. Of the 88 participants who started follow-up, 61 (69%) could be followed ≥3 years, 33 (38%) ≥5 years and 3 (3%) for as long as ≥8.5 years. Based on the actual, compared to the potential maximum duration of follow up–because not all participants started at the same time -, drop out accounted for only 16% of the total person years.Apart from drop-out and loss-to-follow-up, events that reflect everyday practice and are unavoidable in this type of study, other limitations should be considered. Not all participants in the ICON study took part in the L-ICON follow up. A total of 19 participants from the ICON trial who did not participate in the L-ICON were missing completely at random (i) N = 11 did not live in the Netherlands and thus were not approached to participate in L-ICON for logistical reasons; and (ii) N = 8 were not approached because these patients had started the ICON study very late and therefore would have ended the ICON study very late; inclusion of these 8 patients would have delayed the end of the L-ICON study by at least two years. Therefore, their missingness should not have biased the results. Furthermore, no differences were observed between participants and non-participants in key demographic and clinical characteristics at baseline. Moreover, response rates during the ICON study did not differ between L-ICON participants and non-participants. Finally, response rates in the ICON study did not correlate with the likelihood of participating in the L-ICON study.The main statistical analysis was performed for a follow-up of 5 years after completion of the ICON trial. Because of the research design (staggered inclusion), not everybody had an equally long follow-up, therefore missing data are unavoidable. The reasons for missingness should be considered very carefully as non-random missingness could bias the results. Most of the missing data after 5 years of follow-up is due to the fact that, because of the staggered inclusion, these participants had not yet reached 5 years of follow-up after completion of the ICON trial when the study ended (n = 24 cases, Moreover, in an effort to address these missing data and minimise selection bias and biased data loss, we used the full observations as a template for the incomplete observations by using multiple imputations that allowed us to use the data from all ICON trial participants, including those who showed no effect in or completed the ICON trial. By assuming that the missingness of the data is (completely at) random, it is reasonable to extrapolate the measurements. The assumption is that if measurements are stopped in a participant, the future data will behave similarly to the data of similar participants who did remain in the study. To illustrate the robustness of our data, we also performed an analysis without imputed data which showed similar data to those with imputations (As with all headache studies, we had to rely on self-reported data on attack frequency and adverse events. However, we believe the data are accurate and complete. Although prospective recording of attacks immediately after each attack using an electronic diary is considered the most optimal and reliable way to measure attack frequency, it is also the most burdensome for patients.Finally, all participants previously did not respond (sufficiently) to an optimal dose of, or were intolerant of and/or had a contraindication to verapamil and lithium, as well as at least one of the other recommended treatments for cluster headache: methysergide, topiramate or gabapentin. During the L-ICON follow-up study, all participants received individually optimised treatments and were allowed to use any prophylactic drug in addition to ONS. However, these drugs had previously proven ineffective for these patients and no new drugs had become available during the ICON and L-ICON studies. We therefore conclude that the observed effects were due to ONS and not to other concurrent prophylactic medications. Because of the extremely high disease burden, several neuromodulatory options with a wide range of targets such as sphenopalatine ganglion block and stimulation, vagal nerve stimulation, greater occipital nerve blocks and stimulation, and even deep brain stimulation (DBS) have been explored with mixed results. | PMC10755111 |
Contributors | Study design (conceptualization and methodology): LAW, JH, WM, FJPMH, EWZ, MDF, ICON study group; Data collection and curation: RBB, LAW, IFC; Data analysis and formal analysis: RBB, EWZ; Writing—original draft: RBB, MDF, RF; Writing—review and editing: RBB, LAW, IFC, JH, WM, FJPMH, EWZ, MDF, RF; Supervision: MDF, RF.RBB and EWZ have verified the underlying data. All authors commented on the manuscript and approved the final version of the manuscript. | PMC10755111 | ||
Data sharing statement | The data sets used and/or analysed during the present study are available from the corresponding author on reasonable request. | PMC10755111 | ||
Declaration of interests | BRAIN | WM reports honoraria from Novartis, Teva, AbbVie, Lundbeck and Lilly, and consultancy and lecture fees from Lilly; RF reports consultancy and lecture fees from Novartis, Lundbeck, AbbVie, Lilly and TEVA, and independent support from the Dutch Brain Foundation, Leiden University Fund and Innovation Fund Dutch Healthcare Providers; FH reports consultancy and lecture fees form ABBOTT, Saluda, Grunenthal and Pfizer; RB, EZ, LW, JH, IC and MF report no relevant conflict of interest. No funding was received for the ICON study group. | PMC10755111 | |
References | PMC10755111 | |||
Supplementary data | PMC10755111 | |||
Supplementary Figures and Tables | PMC10755111 | |||
Study protocol | PMC10755111 | |||
PubMed table | PMC10755111 | |||
ICON group | PMC10755111 | |||
Acknowledgements | This study was funded by the Supplementary data related to this article can be found at | PMC10755111 | ||
Background | PD, anorexia nervosa, purging disorder, bulimia nervosa | DISORDER, PATHOPHYSIOLOGY, DELAYED GASTRIC EMPTYING | Prior work supports delayed gastric emptying in anorexia nervosa and bulimia nervosa (BN) but not binge-eating disorder, suggesting that neither low body weight nor binge eating fully accounts for slowed gastric motility. Specifying a link between delayed gastric emptying and self-induced vomiting could offer new insights into the pathophysiology of purging disorder (PD). | PMC10106287 |
Methods | Women ( | PMC10106287 | ||
Results | gastrointestinal distress, Delayed gastric emptying | DELAYED GASTRIC EMPTYING, PURGING | Delayed gastric emptying was associated with purging with no main or moderating effects of binge eating in the placebo condition. Medication eliminated group differences in gastric emptying but did not alter group differences in reported gastrointestinal distress. Exploratory analyses revealed that medication caused increased postprandial PYY release, which predicted elevated gastrointestinal distress. | PMC10106287 |
Conclusions | Delayed gastric emptying, purging behaviors | DELAYED GASTRIC EMPTYING, PURGING | Delayed gastric emptying demonstrates a specific association with purging behaviors. However, correcting disruptions in gastric emptying may exacerbate disruptions in gut peptide responses specifically linked to the presence of purging after normal amounts of food. | PMC10106287 |
Key words | gastrointestinal diseases, nausea, nonpurging, postprandial gastrointestinal distress, postprandial fullness, non-eating disorder, Delayed gastric emptying, vomiting, PD, increases gastric motility | GASTROINTESTINAL DISEASES, DELAYED GASTRIC EMPTYING, PURGING | Delayed gastric emptying has been observed in numerous gastrointestinal diseases marked by increased postprandial fullness, nausea, and stomach discomfort (Hajishafiee, Bitarafan, & Feinle-Bisset, The current study examined gastric emptying in women with PD and BN who used vomiting as their primary purging method, women with nonpurging BN, and non-eating disorder controls to determine whether (i) gastric emptying is linked to binge eating, purging, or both, (ii) gastric emptying is associated with postprandial gastrointestinal distress, and (iii) a medication that increases gastric motility impacts differences in gastric emptying and postprandial gastrointestinal distress. Data from participants in the current study were included in prior analyses to examine whether postprandial peptide YY (PYY) and ghrelin responses contributed to differences in subjective responses to a fixed test meal (Keel et al., | PMC10106287 |
Methods | PMC10106287 | |||
Participants | Women (The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. This study was approved by the Human Subjects Committee of the IRB at both institutions where data were collected, and participants provided written informed consent prior to study participation. Participants were paid $75, $50, $100, and $100 across the four visits. | PMC10106287 | ||
Procedure | Axis I Disorders, Depression | SCID, MENDELSON | During their first visit, participants completed a medical exam, including pregnancy tests and tests of liver function, the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) (First, Spitzer, Gibbon, & Williams, Descriptive statistics for clinical measures and gastric emptying by groupBDI, Beck Depression Inventory (Beck, Ward, Mendelson, Mock, & Erbaugh, During the third and fourth visits, participants came to the lab between 7:30–8:00 h after an overnight fast to complete the standardized meal assessment used in our prior study (Keel et al., | PMC10106287 |
Gastric emptying assessment | Plasma acetaminophen concentrations were measured using a validated Liquid Chromatography-Mass Spectrometry (LCMS) method (Baliga & Kallury, | PMC10106287 | ||
Gut peptide assessment | Plasma samples for PYY were collected, stored, and assayed following instructions for a commercially available radioimmunoassay (RIA) kit (Millipore, St. Charles, MO, USA; PYYT-66HK), with a sensitivity of 10 pg/ml, and intra-assay and interassay CVs of 5.3% and 7.0%. | PMC10106287 | ||
Data analyses | gastrointestinal distress | Multi-level models captured within-subject levels and changes in acetaminophen concentrations, gastrointestinal distress, and postprandial PYY (Level 1) and whether group (Level 2) differed in these levels or changes, with random effects for intercept and slope (time) (Keel et al., | PMC10106287 |
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