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Abstract | Current address for D.C. Cho: New York Medical College, Westchester Medical Center, Valhalla, New York; and current address for S. O'Day: Agenus, Lexington, Massachusetts. | PMC10729644 | ||
Purpose: | This phase Ib open-label, multicenter, platform study (NCT02646748) explored safety, tolerability, and preliminary activity of itacitinib (Janus kinase 1 inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ inhibitor) in combination with pembrolizumab [programmed death-1 (PD-1) inhibitor]. | PMC10729644 | ||
Experimental Design: | DISEASE PROGRESSION, SOLID TUMORS | Patients with advanced or metastatic solid tumors with disease progression following all available therapies were enrolled and received itacitinib (Part 1 initially 300 mg once daily) or parsaclisib (Part 1 initially 10 mg once daily; Part 2 all patients 0.3 mg once daily) plus pembrolizumab (200 mg every 3 weeks). | PMC10729644 | |
Results: | A total of 159 patients were enrolled in the study and treated with itacitinib (Part 1, | PMC10729644 | ||
Conclusions: | SOLID TUMORS | Although combination of itacitinib or parsaclisib with pembrolizumab showed modest clinical activity in this study, the overall response rates observed did not support continued development in patients with solid tumors. | PMC10729644 | |
Significance: | T-cell infiltration, tumor | TUMOR, SOLID TUMORS | PD-1 blockade combined with targeted therapies have demonstrated encouraging preclinical activity. In this phase I study, patients with advanced solid tumors treated with pembrolizumab (PD-1 inhibitor) and either itacitinib (JAK1 inhibitor) or parsaclisib (PI3Kδ inhibitor) experienced limited clinical activity beyond that expected with checkpoint inhibition alone and showed little effect on T-cell infiltration in the tumor. These results do not support continued development of these combinations. | PMC10729644 |
Introduction | Janus kinase-signal transducer, tumor | TUMOR, SOLID TUMORS | Immune checkpoint receptors are expressed on tumor, stromal, and immune cells, and negatively regulate the immune response in the tumor microenvironment (TME; ref. Excessive Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling within the TME may reduce antitumor responses, suggesting JAK enzymes could be potential therapeutic targets (PI3Kδ is enriched in hematopoietic cells, including lymphocytes and myeloid cells (We conducted a phase Ib platform study to explore the clinical safety and tolerability of increasing doses of either itacitinib or parsaclisib in combination with established dosing of the PD-1 inhibitor pembrolizumab in patients with solid tumors. Paired biomarker analysis of treatments and changes within the TME were also examined to provide insight on incorporating JAK1 or PI3Kδ inhibition. | PMC10729644 |
Materials and Methods | PMC10729644 | |||
Study Design | NSCLC, SCLC, pembrolizumab, PAD, toxicity, UC | SCLC, SOLID TUMORS, SMALL CELL LUNG CANCER, PAD, NSCLC | This phase Ib, multicenter, open-label, platform study (ClinicalTrials.gov identifier: NCT02646748) was conducted in the United States. The study evaluated combination of itacitinib or parsaclisib plus pembrolizumab in two parts: Part 1 consisted of Part 1a dose-escalation (enrolling all solid tumors) and Part 1b safety-expansion (focused on selected solid tumors); and Part 2 evaluated parsaclisib plus pembrolizumab in patients with small cell lung cancer (SCLC), NSCLC, and UC (Study design. Note: As of Protocol Amendment 8, enrollment was closed before reaching the planned number of patients. Dose-escalation (Part 1a) was performed using a 3+3 design to evaluate the MTD or pharmacologically active dose (PAD) for itacitinib or parsaclisib, in combination with a fixed dose of pembrolizumab (200 mg intravenously every 3 weeks). The highest dose at which less than one-third of patients experienced a dose-limiting toxicity (DLT) was defined as the MTD. Initial combination doses were based on previous results with itacitinib plus nab-paclitaxel and gemcitabine in advanced solid tumors (In Part 2 (parsaclisib plus pembrolizumab), PD-(L)1 treatment-naïve patients were enrolled and received parsaclisib (0.3 mg once daily) plus pembrolizumab (200 mg every 3 weeks) combination (If pembrolizumab treatment was discontinued, treatment with itacitinib or parsaclisib was also discontinued and the patient entered follow-up. If itacitinib or parsaclisib treatment was discontinued, treatment with pembrolizumab could continue after consultation with the sponsor. | PMC10729644 |
Patient Inclusion and Exclusion Criteria | NSCLC, SCLC, tumor, colorectal cancer, pneumonitis, melanoma, hepatitis B, toxicities, HNSCC, renal cell carcinoma, UC, infection, tumors | CARCINOMATOUS MENINGITIS, TUMOR, MELANOMA, TRIPLE-NEGATIVE BREAST CANCER, CENTRAL NERVOUS SYSTEM METASTASES, SURGICAL COMPLICATIONS, JC VIRUS INFECTION, ONCOLOGY, AUTOIMMUNE DISEASE, PANCREATIC DUCTAL ADENOCARCINOMA, COLORECTAL CANCER, SCLC, INTERSTITIAL LUNG DISEASE, GASTRIC CANCER, HEPATITIS B, ADVERSE EVENTS, METASTATIC ENDOMETRIAL CANCER, INFECTION, DISEASE PROGRESSION, PNEUMONITIS, DISEASE, SOLID TUMORS, HUMAN IMMUNODEFICIENCY VIRUS INFECTION, NSCLC, TRANSITIONAL CELL CARCINOMA, TUMORS | The study enrolled men and women ≥18 years of age with an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1, who were willing to provide a baseline and on-treatment tumor biopsy specimen, and had measurable disease based on RECIST v1.1. In Part 1a, enrolled patients had histologically or cytologically confirmed advanced or metastatic solid tumors that progressed after previous standard therapy. In Part 1b, patients enrolled were PD-(L)1 treatment-naïve or had disease progression on prior PD-(L)1–targeted therapy, and had histologically or cytologically confirmed advanced or metastatic endometrial cancer, gastric cancer, melanoma, microsatellite unstable colorectal cancer or other mismatch repair–deficient tumors, NSCLC, HNSCC, renal cell carcinoma, triple-negative breast cancer, genitourinary tract transitional cell carcinoma, or pancreatic ductal adenocarcinoma. In Part 2, patients who were PD-(L)1 treatment-naïve with histologically or cytologically confirmed advanced or metastatic SCLC, NSCLC, or UC were enrolled.Key exclusion criteria were serum creatinine >1.5 × institutional upper limit of normal (ULN), alkaline phosphatase, aspartate and/or alanine aminotransferase ≥2.5 × ULN, or total bilirubin ≥1.5 × ULN, persistent grade >1 toxic effects from prior therapy, or received live vaccine within 30 days. Additional exclusion criteria included having active infection (requiring systemic therapy), autoimmune disease, or central nervous system metastases and/or carcinomatous meningitis; current or history of pneumonitis; abnormal electrocardiogram; history of interstitial lung disease; history of human immunodeficiency virus infection; or evidence of hepatitis B or C virus infection or risk of reactivation. Patients who presented with unresolved (grade ≥2) toxicities from previous therapy and/or surgical complications were excluded from the study. All suspected immune-related adverse events (AE) during the study were treated with appropriate supportive care measures as determined by the treating investigator. | PMC10729644 |
Study Endpoints and Assessments | tumor | ADVERSE EVENT, TUMOR, DISEASE, EVENT, ADVERSE EVENT | The primary study endpoint was safety and tolerability in Part 1, assessed by monitoring the frequency, duration, and severity of AEs. A treatment-emergent adverse event (TEAE) was defined as an AE either reported for the first time or worsening of a preexisting event after first dose of study drug. AEs were classified into system organ class and Medical Dictionary for Regulatory Activities preferred term, and severity of AEs was assessed using Common Terminology Criteria for Adverse Events (v4.03). Secondary endpoints in Part 1 and 2 were ORR determined by radiographic disease assessments per RECIST v1.1, and change in the number of tumor-infiltrating lymphocytes (TIL) and ratio of CD8Exploratory study endpoints in Part 1 and 2 were pharmacokinetics of itacitinib and parsaclisib, and biomarker effects in plasma and tumor tissue after treatment with itacitinib or parsaclisib in combination with pembrolizumab. Plasma samples for pharmacokinetic analysis were collected predose on cycle 1 day 1, day 8 (±3 days), day 15 (±3 days), and cycle 2 day 1 (±3 days). On day 1 of cycle 1 and 2, plasma samples were also collected at 60 (±10) minutes, 2 (±0.5) hours, 4 (±0.5) hours, and 6 (±1) hours postdose. Plasma concentrations of itacitinib or parsaclisib were determined using validated LC/MS-MS method (Incyte Research Corporation; refs. | PMC10729644 |
Translational Biomarker Analyses | nontumor, tumor | TUMOR | Changes in TILs and the ratio of Teff to Tregs (CD8In Part 1, a single-color, Singleplex chromogenic assay (Indivumed) was used to quantify cells in the combined tumor plus stromal (nontumor) regions in baseline and on-treatment biopsy samples. In Part 2, a five-color, Multiplex IHC assay (Indivumed) was used to quantify cell densities separately in the tumor and stromal regions, in addition to a composite of the total tissue section from baseline and on-treatment biopsy samples. The Multiplex assay measured CD3 | PMC10729644 |
Plasma Protein Analysis | To further evaluate the pharmacodynamic effects and potential association with clinical response to study treatment, the presence of immune and nonimmune plasma proteins was determined using a Multiplex Proximity Extension Assay by Olink Proteomics. In this assay, each biomarker is identified by a matched pair of antibodies coupled to unique, partially complementary oligonucleotides and measured by qRT-PCR, with more than 1,100 plasma analytes evaluated per sample. | PMC10729644 | ||
Statistical Analysis | NSCLC, SCLC, tumor, DLTs, toxicity, UC | NSCLC, TUMOR, SCLC, EVENT | All patients enrolled in the study who received ≥1 dose of study drug (pembrolizumab, itacitinib, or parsaclisib) comprised the safety analysis population and the full analysis set (FAS) for baseline demographic and efficacy analyses. Descriptive statistics were used to summarize continuous and categorical variables. The exact method for binomial distributions was used to calculate the 95% confidence interval (CI) of ORR. The Kaplan–Meier method was used to estimate duration of response and progression-free survival, including median value and 95% CI.The pharmacokinetic and pharmacodynamic evaluable population included all patients in the FAS who provided at ≥1 plasma sample (≥1 pharmacokinetic or pharmacodynamic measurement). Summary statistics were calculated for pharmacokinetic parameters of itacitinib and parsaclisib, and analysis of pharmacodynamic data. The Wilcoxon matched-pairs signed-rank test (GraphPad Prism v7.02, GraphPad Software) was used to compare baseline and on-treatment tumor biopsy samples, with changes in TILs deemed significant at In Part 1a, 3 to 6 patients were enrolled in each dose level depending on the occurrence of DLTs. In Part 1b, with a planned enrollment of 60 patients [30 patients per expansion cohort A-1/A-2 (itacitinib plus pembrolizumab) and B-1/B-2 (parsaclisib plus pembrolizumab)], there was a ≥90% chance of observing a toxicity with a true event rate of >7.4%. In Part 2, with planned enrollment of a total of 10–29 patients with SCLC in a Simon two-stage design, and 28 patients with NSCLC and 36 patients with UC in a Simon one-stage design, the cohorts were to be terminated for lack of efficacy if there were one or fewer SCLC in stage 1 or five or fewer SCLC total in stage 1 and 2, seven or fewer NSCLC, or ≤13 patients with UC responded to treatment. This was an exploratory study and no formal statistical tests were performed.Effects of treatment on plasma protein biomarkers were determined by paired | PMC10729644 |
Data Availability Statement | Access to individual patient-level data is not available for this study. | PMC10729644 | ||
Ethics Statement | The study was performed in accordance with the International Council for Harmonisation Guideline for Good Clinical Practice, the principles of the Declaration of Helsinki, and other applicable local ethical and legal requirements. The study protocol and its amendments were reviewed and approved by institutional review boards or independent ethics committees, and patients provided written informed consent before enrollment. | PMC10729644 | ||
Results | PMC10729644 | |||
Patient Characteristics and Disposition | head and neck squamous cell carcinoma, SCLC, NSCLC, PD | COLORECTAL CANCER, SCLC, PROGRESSIVE DISEASE, UROTHELIAL CARCINOMA, SMALL CELL LUNG CANCER, NSCLC, ONCOLOGY, RENAL CELL CARCINOMA, RCC | At the data cut-off date (March 10, 2020), a total of 159 patients had been enrolled at 11 study sites and were included in both the safety population and FAS. Forty-nine patients were included in all of Part 1/Group A [itacitinib plus pembrolizumab; Patient demographics and baseline characteristics are summarized in Summary of demographic and baseline characteristicsAbbreviations: CRC, colorectal cancer; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HNSCC, head and neck squamous cell carcinoma; NSCLC, non–small cell lung cancer; PD-L1, programmed death-ligand 1; Q3W, every 3 weeks; QD, once daily; RCC, renal cell carcinoma; SCLC, small cell lung cancer; UC, urothelial carcinoma.
All 49 patients in Part 1a/Group A and Part 1b/Groups A-1/A-2 (itacitinib plus pembrolizumab), 74 (89.2%) patients in Part 1a/Group B and Part 1b/Groups B-1/B-2 (parsaclisib plus pembrolizumab), and 26 (96.3%) patients in Part 2 (parsaclisib plus pembrolizumab) discontinued treatment. Progressive disease (PD) was the most common reason for discontinuation in Part 1a/Group A [6 (75%)] and B [16 (47.1%)], Part 1b/Group A-1/A-2 [29 (70.7%)] and B-1/B-2 [30 (61.2%)], and Part 2 [13 (48.1%)]. AEs were also a common reason for treatment discontinuation of pembrolizumab in Part 1a/Group B [14 (41.2%)]. No patients remain on the study. Detailed patient disposition for each dose level evaluated in different treatment groups in Parts 1 and 2 are provided in | PMC10729644 |
Safety | Itacitinib 300 mg once daily was selected as the MTD in dose-escalation Part 1a/Group A and used in safety-expansion Part 1b/Group A-1 [PD-(L)1 treatment-experienced] and A-2 [PD-(L)1 treatment-naïve]. Parsaclisib 30 mg once daily was selected as the MTD/PAD in dose-escalation Part 1a/Group B, and parsaclisib 20 mg once daily and 30 mg once daily were selected for safety-expansion Part 1b/Group B-1 [PD-(L)1 treatment-experienced] and B-2 [PD-(L)1 treatment-naïve]. Taking into consideration that higher doses of parsaclisib (20 or 30 mg once daily) required prophylaxis for | PMC10729644 | ||
Part 1: Itacitinib plus Pembrolizumab | NSCLC, SCLC, primary pancreatic carcinoma, TEAEs, pain, pyrexia, chills | NON-SMALL CELL LUNG CANCER, SCLC, UROTHELIAL CARCINOMA, MALIGNANT NEOPLASM PROGRESSION, SMALL CELL LUNG CANCER, DRUG-INDUCED LIVER INJURY, ADVERSE EVENT, NSCLC | No patient in Part 1a/Group A, or Part 1b/Group A-1 [PD-(L)1 treatment-experienced] or A-2 [PD-(L)1 treatment-naïve] experienced a DLT. All patients in Part 1 treated with itacitinib experienced ≥1 TEAE (Summary of itacitinib and parsaclisib treatment-related TEAEs by MedDRA preferred term (≥5% of patients in the safety population)Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities; NSCLC, non-small cell lung cancer; Q3W, every 3 weeks; QD, once daily; SCLC, small cell lung cancer; TEAE, treatment-emergent adverse event; UC, urothelial carcinoma.
A total of 26 patients experienced ≥1 serious TEAE [6 (75.0%)] in Part 1a/Group A, and 20 (48.8%) in Part 1b/Group A-1/A-2 (Serious TRAEs considered related to pembrolizumab were reported in one patient in Part 1b/Group A-1 [chills and pyrexia (each 2.4%)], and considered related to itacitinib were reported in 2 patients in Part 1b/Group A-1/A-2 [pyrexia in 2 (4.9%) patients, and chills in 1 (2.4%) patient]. No serious TEAE reported in Part 1a/Group A were considered related to either pembrolizumab or itacitinib. Two patients in Part 1b/Group A-2 [PD-(L)1 treatment-naïve] had TEAEs of special interest, with laboratory results that met the criteria for potential drug-induced liver injury; neither patient met Hy’s Law criteria. TEAEs of grade ≥3 were reported in 7 patients (87.5%) in Part 1a/Group A and in 27 (65.9%) of patients in Part 1b/Group A-1/A2.Treatment was discontinued in 1 patient (12.5%) in Part 1a/Group A because of a TEAE of back pain. Both itacitinib and pembrolizumab were discontinued in 10 patients (24.4%) in Part 1b (2 patients in Group A-1 and 8 patients in Group A-2) because of TEAEs; 4 of the 10 patients discontinued because of malignant neoplasm progression. In Part 1b/Group A-2, 1 patient had itacitinib discontinued on day 153 (because of pyrexia), and pembrolizumab discontinued on day 184 (because of bilateral pulmonary emboli associated with progression of primary pancreatic carcinoma). | PMC10729644 |
Part 1: Parsaclisib plus Pembrolizumab | NSCLC, pneumonitis, DLTs, TEAEs, depressed, oliguria | PNEUMONITIS, NSCLC, OLIGURIA | One 72-year-old patient with NSCLC in Part 1a/Group B (receiving parsaclisib 2.5 mg once daily plus pembrolizumab) experienced two grade 4 DLTs of pneumonitis (day 12, considered related to pembrolizumab and parsaclisib; not resolved) and oliguria (day 14, considered related to parsaclisib; fatal). No patient in Part 1b/Group B-1 [PD-(L)1 treatment-experienced] or B-2 [PD-(L)1 treatment-naïve] experienced a DLT. All patients in Part 1 treated with parsaclisib experienced ≥1 TEAE (A total of 50 patients experienced ≥1 serious TEAE [23 (67.6%) in Part 1a/Group B, 27 (55.1%) in Part 1b/Group B-1/B-2] (Fifteen patients (44.1%) in Part 1a/Group B experienced TEAEs leading to discontinuation of parsaclisib, and 14 patients (41.2%) had TEAEs leading to discontinuation of pembrolizumab. TEAEs leading to treatment discontinuation occurred in 1 (2.9%) patient each except for increased alanine aminotransferase, increased aspartate aminotransferase, and depressed level of consciousness [each 2 (5.9%)]. Nine patients (18.4%) in Part 1b/Group B-1/B-2 experienced TEAEs leading to discontinuation of parsaclisib, and 8 patients (16.3%) had TEAEs leading to discontinuation of pembrolizumab. | PMC10729644 |
Part 2: Parsaclisib plus Pembrolizumab | DLTs, TEAEs | No DLTs were reported in patients enrolled in Part 2. All patients experienced ≥1 TEAE (Nine patients (33.3%) in Part 2 experienced TEAEs leading to discontinuation of parsaclisib, and 8 patients (29.6%) had TEAEs leading to discontinuation of pembrolizumab. | PMC10729644 | |
Efficacy | NSCLC, SCLC, SD, Tumor | SCLC, TUMOR, DISEASE, UROTHELIAL CARCINOMA, SMALL CELL LUNG CANCER, NSCLC | Of patients receiving itacitinib plus pembrolizumab in Part 1, 4 (8.2%) had partial response (PR) and 19 (38.8%) had stable disease (SD; Tumor response by RECIST (full analysis set)Abbreviations: CI, confidence interval; NSCLC, non–small cell lung cancer; ORR, objective response rate; Q3W, every 3 weeks; QD, once daily; SCLC, small cell lung cancer; UC, urothelial carcinoma.
Of patients receiving parsaclisib plus pembrolizumab in Part 1, 5 (6.0%) had complete response (CR), 9 (10.8%) had PR, and 21 (25.3%) had SD (Of patients receiving parsaclisib plus pembrolizumab in Part 2 of the study, 5 (18.5%) had PR and 6 (22.2%) had SD ( | PMC10729644 |
Pharmacokinetics | Itacitinib exposures were higher in patients receiving 300 mg compared with 400 mg once daily (Parsaclisib exposures increased with higher doses ( | PMC10729644 | ||
Tumor Lymphocyte IHC | NSCLC, SCLC, tumor, UC | TUMOR, EVALUABLE, SCLC, NSCLC | Representative Singleplex and Multiplex IHC images are shown in IHC analysis of paired screening and on-treatment (week 5–6) tumor biopsies, from patients receiving itacitinib or parsaclisib in combination with pembrolizumab. Because doses of parsaclisib examined in Part 1/Group B-1/B-2 (20–30 mg once daily) may also inhibit Teff function, in Part 2, a lower dose of parsaclisib (0.3 mg once daily) was evaluated in combination with pembrolizumab in PD-(L)1 treatment-naïve patients with SCLC, NSCLC, or UC. Evaluable paired biopsy samples were available for 9 patients in Part 2 (PR, | PMC10729644 |
Plasma Proteomics | HEAT | Plasma proteomic heat map analyses (Heat map of plasma proteins significantly changed (logNine unique proteins were significantly changed between cycle 1 and 2 in the itacitinib plus pembrolizumab combination groups (A-1/A-2; Twenty-seven unique proteins were differentially expressed between cycle 1 and 2 across the parsaclisib plus pembrolizumab combination groups (B-1/B-2, Part 2; | PMC10729644 | |
Discussion | NSCLC, tumor, T-cell, pembrolizumab | TUMOR, INFILTRATION, GROUP B, ENDOMETRIAL ADENOCARCINOMA, MINOR, SOLID TUMORS, OF LUNG ADENOCARCINOMA, SECONDARY, ADENOCARCINOMA, NSCLC, CHOLANGIOCARCINOMA | This phase Ib platform study evaluated the safety, efficacy, and pharmacodynamics of itacitinib (JAK1 inhibitor) or parsaclisib (PI3Kδ inhibitor) in combination with pembrolizumab (anti-PD-1) in patients with advanced or metastatic solid tumors. The study primary objective was to define a preliminary safety profile of itacitinib or parsaclisib in combination with pembrolizumab, and results were consistent with previously reported data (The study secondary objective was to investigate clinical efficacy and correlative pharmacodynamics. In Part 1a/Group B (parsaclisib 0.3–30 mg once daily or 2.5 mg every other day plus pembrolizumab 200 mg every 3 weeks), one patient achieved a CR (NSCLC) and 6 patients had a PR (adenocarcinoma, endometrial adenocarcinoma, NSCLC, cholangiocarcinoma, Analysis of tumor biopsies demonstrated that itacitinib in combination with pembrolizumab had no consistent effect on immune-cell infiltration into the tumor or stroma. The combination of itacitinib plus pembrolizumab resulted in only minor changes in a small number (nine) of plasma proteins. Notably, IFN-inducible proteins, such as CXCL9 and CXCL10, which are hallmark markers of anti-PD-(L)1 treatment, were not induced in patients treated with itacitinib, suggesting that coadministration of a JAK1 inhibitor with pembrolizumab blocks activation of the IFN pathway, which is required for T-cell activation. Moreover, in Part 1b/Groups A-1/A-2, 4 patients achieved a PR with no remarkable efficacy observed in any one tumor type treated with itacitinib plus pembrolizumab. In a database analysis study of lung adenocarcinoma transcriptome profiles, JAK1 expression was positively correlated with immune-cell infiltration, suggesting a potential role of JAK1 in the immune response (Pharmacodynamic evaluation of samples collected in Part 1 (Group B, B-1/B-2) demonstrated an increase in CD8Although a T-cell inflamed preclinical model demonstrated PI3Kδ inhibition together with PD-L1 blockade resulted in enhanced antitumor efficacy (In conclusion, PD-1 blockade in combination with either JAK1 or PI3Kδ inhibition in our study did not demonstrate significant clinical efficacy beyond that anticipated with pembrolizumab alone, despite encouraging preclinical activity in mouse models ( | PMC10729644 |
Supplementary Material | GROUP B | Supplementary Figure 1. Singleplex and Multiplex immunohistochemistry examples.Supplementary Table 1. Summary of patient disposition (Part 1a Group A) (Full Analysis Set)Supplementary Table 2. Summary of patient disposition (Part 1a Group B) (Full Analysis Set)Supplementary Table 3. Summary of patient disposition (Part 1b Expansion Group A-1/A-2) (Full Analysis Set)Summary of patient disposition (Part 1b Expansion Group B-1/B-2) (Full Analysis Set).Summary of patient disposition (Part 2) (Full Analysis Set)Summary of TEAEs by MedDRA preferred term [at least two patients (Part 1a Group A) or ≥10% of patients (Part 1a Group B, Part 1b, Part 2) in the safety population]Supplementary Table 7. Serious TEAE ≥5% of patients by MedDRA preferred term (safety population).Supplementary Table 8. Summary of steady state itacitinib pharmacokinetic parameters (cycle 2 day 1).Supplementary Table 9. Summary of steady state parsaclisib pharmacokinetic parameters (cycle 2 day 1).Supplementary Table 10. Plasma proteins differentially expressed between cycle 1 day 1 and cycle 2 day 1 with (A) itacitinib plus pembrolizumab (Part 1b Group A-1), or (B) parsaclisib plus pembrolizumab treatment (Part 1b Group B-1/B-2, and Part 2). | PMC10729644 | |
Acknowledgments | Funding for this study was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., and Incyte Corporation. The authors wish to thank the patients, investigators, and site personnel who participated in this study. Pharmacokinetic analysis was performed by April M. Barbour of Incyte Corporation. Medical writing assistance was provided by Matthew Bidgood, of Envision Pharma Group, and funded by Incyte Corporation.
| PMC10729644 | ||
Authors’ Disclosures | Melanoma, cancers, Tumor, P., Lyell | MELANOMA, DISORDERS, CANCERS, TUMOR, LYELL | P. Munster reports grants from Amgen, Pfizer, AstraZeneca, GSK, Novartis, Oric, Revolution Medicine, Aevinas, Cyteir, Tempest, Arch, and H3Bio during the conduct of the study; personal fees and other from Alessa and Janssen, Atlas, RasCal; non-financial support from Hap10; personal fees from Parthenon outside the submitted work. L.C. Villaruz reports personal fees from Takeda, Sanofi, Jannsen, InterVenn Biosciences, Daichi Sankyo, Jazz, and BMS outside the submitted work. G.T. Gibney reports other from Incyte during the conduct of the study; personal fees from Merck, Bristol Myers Squibb, Novartis, Huyabio, Incyte, Immunocore, Lyell, Iovance, Eisai, Regeneron, Sapience Therapeutics, Genentech, and Exicure; other from Exelixis outside the submitted work. F.S. Hodi reports personal fees and other from Incyte during the conduct of the study; grants from Bristol Myers Squibb; grants and personal fees from Novartis; personal fees from Merck, Aduro, Amgen, 7 hills Pharma, Apricity, Bicara, Bioentre, Catalym, Checkpoint Therapeutics, Compass Therapeutics, Genentech, Gossamer, Immunocore, Iovance, Merck, Pieris Pharmaceutical, Surface, Trillium, AstraZeneca, Corner Therapeutics, and Zumutor outside the submitted work; in addition, F.S. Hodi has a patent to Methods for Treating MICA-Related Disorders (#20100111973) pending and with royalties paid, a patent to Tumor antigens and uses thereof (#7250291) issued, a patent to Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response (#20170248603) pending, a patent to Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms (#20160340407) pending, a patent to Therapeutic peptides (#20160046716) pending, a patent to METHODS OF USING PEMBROLIZUMAB AND TREBANANIB pending, a patent to Vaccine compositions and methods for restoring NKG2D pathway function against cancers Patent number: 10279021 issued and with royalties paid, a patent to Antibodies that bind to MHC class I polypeptide-related sequence A Patent number: 10106611 issued and with royalties paid, and a patent to ANTI-GALECTIN ANTIBODY BIOMARKERS PREDICTIVE OF ANTI-IMMUNE CHECKPOINT AND ANTI-ANGIOGENESIS RESPONSES Publication number: 20170343552 pending. N.B. Mettu reports other from Mereo Biopharma, Erytech Pharma, Repare Therapeutics, Syros Pharmaceuticals, Merck Sharpe & Dohme, AstraZeneca, LP, Incyte, Compass Therapeutics, Biomed Valley Discoveries, Aravive, Inc., Nucana, and Genentech; grants from Leap Therapeutics outside the submitted work. M. Jones reports other from Incyte during the conduct of the study. M. Smith reports non-financial support from Envision Pharma Group during the conduct of the study; and employment and stock ownership with Incyte Corporation. No disclosures were reported by the other authors. | PMC10729644 |
Authors’ Contributions | PMC10729644 | |||
References | PMC10729644 | |||
2. Materials and Methods | PMC10146641 | |||
2.1. Compliance with Ethical Standards | After receiving permission from Zonguldak Bülent Ecevit University Clinical Research Ethics Committee (protocol No: 2019-96-12/06, ClinicalTrials.gov Identifier: NCT05499754), this prospective randomized study was conducted in Zonguldak Bülent Ecevit University Hospital, Turkey, between July 2019 and 2020. Informed written consent was obtained from all patients. The flow diagram according to CONSORT guidelines is provided as | PMC10146641 | ||
2.2. Patient Population | cerebral edema, glaucoma, SAD | CEREBRAL EDEMA, UNCONTROLLED HYPERTENSION, DIABETIC NEUROPATHY, GLAUCOMA | Ninety patients (aged 18–65 years) in the American Society of Anesthesiologists (ASA) class I–II who were scheduled for elective non-ophthalmic procedures that would last 1–2 h under general anesthesia in the supine position were included in this study. The sample of the study excluded patients with Mallampati and those in ASA class ≥III, and those with a history or suspicion of a difficult airway, more than three SAD placements, past intracranial/ocular surgery, diabetic neuropathy, cerebral edema or elevated ICP, glaucoma, potentially full stomachs, uncontrolled hypertension, obstetric conditions, and a lack of agreement to participate in the study. The demographic data, Mallampati scores, and ASA classes of all patients were recorded. | PMC10146641 |
2.3. Application of General Anesthesia and Monitoring | All patients were instructed to fast for at least 8 h before surgery. No premedication was given. When the patient was in the anesthesia room, their head was placed on a soft, 7 cm high pillow before the induction of anesthesia, with their neck flexed and head extended. The patients were connected to electrocardiography, noninvasive blood pressure measurement, peripheral pulse oximeter, end-tidal carbon dioxide (EtCOEach patient was randomly assigned to one of three groups, Group P (pLMA, | PMC10146641 | ||
2.4. Data Management | The ONSD values were measured by an experienced anesthesiologist who was not informed about the study using an Esaote MyLab 30 GOLDThe mean arterial pressure (MAP), HR, and ONSD values of the patients were recorded before induction (T0), 1 min after SAD placement (T1), 5 min after SAD placement (T5), and 10 min after SAD placement (T10). The same observer, who did not have any information about the study, recorded all the parameters that were examined in the study. | PMC10146641 | ||
2.5. Statistical Analysis | The planned sample size required to detect 95.9% test power (1 − β), 95% confidence (1 − α) and effect size d = 1.16 was 10 people per group. We included 30 patients in each group to compensate for patient dropouts [ | PMC10146641 | ||
3. Results | Clinical and Demographic CharacteristicsNinety patients were included in the study, and ninety completed the study (Whereas there was no significant difference among the HR values of the groups (Likewise, whereas there was no significant difference among the MAP values of the groups (An increase in ONSD was seen in all groups at measurement time T1 right after the insertion of the SADs, whereas there was no significant difference among the groups ( | PMC10146641 | ||
4. Discussion | neurological deficits, ONSD, SAD | COMPLICATION, COMPLICATIONS | In our study, when they were inserted into adult patients with normal airways, the effects of the pLMA, sLMA, and I-gel on hemodynamic responses and ONSD values were similar. In all three groups, the HR and MAP values measured 1 min after SAD insertion were similar to each other, and in the intragroup comparisons, these values were higher than those measured at the other measurement times. In the intragroup comparisons, it was also observed that ONSD values had a tendency to increase 1 min after SAD insertion in all three groups and return to baseline values afterward.In recent years, noninvasive ICP monitoring methods have become more popular. This is because they have fewer complications compared with invasive methods, are cost-effective, and reduce the need for certain factors, such as expertise in neurosurgery, that require some invasive measurement methods. Ideally, a noninvasive ICP assessment method must be accurate, reliable, pathology-independent, and capable of working in a heterogeneous patient population; use instantly available equipment; and be robust in relation to methodical variations, such as the experience of the operator [The ONSD measurement is subject to error and variation because it is observer dependent. Nevertheless, as the measurement methodology is well-standardized, and the results are repeatable, the variability in ONSD measurement can be minimized [In recent years, ONSD measurements have also been included in anesthesiology practices [Supraglottic airway devices are easy to use and atraumatic, and they create minimal somatic and autonomic responses. HR and MAP values increase during insertion and removal, but these differences are lower compared with those in tracheal intubation and extubation [For the immobilization of patients, their hemodynamic stability, and the early diagnosis and treatment of neurological deficits in endovascular treatments (EVT), practitioners have started to use SADs in anesthesia management. It has been stated that these devices, which are used in EVT to prevent hemodynamic instabilities associated with intubation and extubation, can be a safe alternative in anesthesia management, and there is no complication associated with their usage [The literature on SADs is vast, and varying results have been reported on their insertion success rates and times. The main factors that could have affected these results in the methodologies of previous studies have been reported as the experience levels of practitioners and differences in the use of muscle relaxants [ | PMC10146641 |
5. Limitations | intracranial pathologies, SAD | CEREBRAL ISCHEMIA, CARDIOVASCULAR DISEASES | There were some limitations to this study. One of the most important was that it was not technically possible for the person who recorded the data to be unaware of the airway device being used. Furthermore, as patients with normal airways were included in this study, the results may not be applicable to patients with difficult airways or extended LMA insertion durations. Third, this study was conducted with patients who had low ASA scores, and studies involving those with underlying cardiovascular diseases may provide different results. Another limitation is that we did not measure the ONSD optic nerve sheath diameter just before and after SAD insertion. Finally, the effects of SADs on ICP among patients with intracranial pathologies were not examined. Different results in terms of ONSD may be observed in patients who have a history of elevated ICP or cerebral ischemia. | PMC10146641 |
Author Contributions | Conceptualization, R.D.O. and G.K.; Data curation, G.K., B.G.K., and Ö.P.; Formal analysis, R.D.O. and H.A.; Investigation, R.D.O., G.K., and B.G.K.; Methodology, R.D.O., G.K., and B.G.K.; Resources, R.D.O. and G.K.; Visualization, H.A. and Ö.P.; Writing—original draft, R.D.O., G.K., and B.G.K.; Writing—review & editing, R.D.O., G.K., B.G.K., and H.A. All authors have read and agreed to the published version of the manuscript. | PMC10146641 | ||
Institutional Review Board Statement | The study was approved by the institute ethics committee (protocol No: 2019-96-12/06, ClinicalTrials.gov identifier: NCT05499754). | PMC10146641 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10146641 | ||
Data Availability Statement | The data used and/or analyzed during the current study are available from the corresponding author. | PMC10146641 | ||
Conflicts of Interest | The authors declare no competing interests and no conflict of interest. | PMC10146641 | ||
Objective | obesity, cardiometabolic diseases | OBESITY | Human brown adipose tissue (BAT) has gained considerable attention as a potential therapeutic target for obesity and its related cardiometabolic diseases; however, whether the gut microbiota might be an efficient stimulus to activate BAT metabolism remains to be ascertained. We aimed to investigate the association of fecal microbiota composition with BAT volume and activity and mean radiodensity in young adults. | PMC9938059 |
Methods | 82 young adults (58 women, 21.8 ± 2.2 years old) participated in this cross-sectional study. DNA was extracted from fecal samples and 16S rRNA sequencing was performed to analyse the fecal microbiota composition. BAT was determined via a static | PMC9938059 | ||
Results | The relative abundance of | PMC9938059 | ||
Conclusion | Our results suggest that fecal microbiota composition is involved in the regulation of BAT and glucose uptake by other tissues in young adults. Further studies are needed to confirm these findings. | PMC9938059 | ||
Clinical trial information | ClinicalTrials.gov no. NCT02365129 (registered 18 February 2015). | PMC9938059 | ||
Supplementary Information | The online version contains supplementary material available at 10.1007/s40618-022-01936-x. | PMC9938059 | ||
Keywords | / CBUA | Funding for open access charge: Universidad de Granada / CBUA | PMC9938059 | |
Introduction | obesity, cardiometabolic diseases, Eukarya | OBESITY, BROWN | Brown adipose tissue (BAT) is a tissue that dissipates energy through the action of the uncoupling protein-1 (UCP1) in rodents and in humans [The human gut harbours a vast array of microorganisms such as Eukarya, Archaea, fungi, and mainly bacteria [We hypothesized that the relative abundance of gut bacteria previously reported to improve obesity and cardiometabolic diseases, such as | PMC9938059 |
Material and methods | PMC9938059 | |||
Design study and participants | This cross-sectional study was carried out within the framework of the ACTIBATE study [ | PMC9938059 | ||
Body composition assessment | We measured the participants’ weight and height while being barefoot and wearing light clothing, using a SECA scale and stadiometer (model 799, Electronic Column Scale, Hamburg, Germany). Lean body mass and body fat mass were determined by Dual Energy X-ray Absorptiometry (Hologic Discovery Wi, Marlborough, MA, USA). Body mass index (BMI), lean mass index and fat mass index were calculated as weight, lean body mass and body fat mass in kg divided by height in meters square (m | PMC9938059 | ||
Fecal microbiota composition analyses | PMC9938059 | |||
Stool collection and DNA extraction | STERILE, LYSIS | The participants collected a fecal sample (50–60 g) 3 ± 7 days [mean ± standard deviation] prior to the positron emission tomography/computed tomography (PET/CT). They transported the fecal sample in plastic sterile containers inside a portable cooler until arrival at the research centre. Fecal samples were stored at −80 °C until the extraction of deoxyribonucleic acid (DNA). A QIAamp DNA Stool Mini Kit (QIAGEN, Barcelona, Spain) was utilized to extract DNA following the manufacturer’s instructions, and samples were incubated at 95 ºC to ensure lysis of both Gram-positive and Gram-negative bacteria. The quantification of DNA was performed using a NanoDrop ND1000 spectrophotometer (Thermo Fisher Scientific, DE, USA). We measured absorbance spectrophotometrically at A260/280 nm and A260/230 nm ratios for determining DNA purity. The A260/280 ratio is used to determine protein contamination [ | PMC9938059 | |
Sequencing analysis | We amplified DNA extracted by polymerase chain reaction (PCR) with primer pairs, 16S Amplicon PCR Forward Primer: 5’CCTACGGGNGGCWGCAG, and 16S Amplicon PCR Reverse Primer: 5’GACTACHVGGGTATCTAATCC targeting the V3 and V4 hypervariable regions of the bacterial 16S rRNA gene [ | PMC9938059 | ||
Bioinformatics analyses | “Dada2” [Taxonomic affiliation of phylotypes was assigned using the “classifier” function from Ribosomal Database Project (RDP), based on the naive Bayesian classification [ | PMC9938059 | ||
Brown adipose tissue measurements | PMC9938059 | |||
Shivering threshold test | To personalize the cooling protocol used to activate human BAT, subjects underwent a cooling test 48–72 h before the | PMC9938059 | ||
Personalized cooling protocol prior to positron emission tomography/computed tomography scan | shivering | After 48–72 h of the shivering threshold test, the participants went to the | PMC9938059 | |
Brown adipose tissue quantification | All PET/CT images were examined using the Beth Israel plug-in for FIJI software ( | PMC9938059 | ||
Statistical analysis | Data are presented as means ± standard deviations unless otherwise stated. All variables were tested for normality using D’Agostino and Pearson omnibus. Most of the variables displayed a non-normal distribution and, thus, non-parametric tests were used for all analyses. We did not detect any sex interaction across the variables studied (Fig. S1 and Table S1), nor differences between the status of BMI (data not shown); therefore, all main data for men and women, as well as the status of BMI, were pooled together. Partial Spearman correlations were used to investigate the correlation of fecal microbiota composition with BAT volume, | PMC9938059 | ||
Results | PMC9938059 | |||
Relationship between fecal microbiota composition and cold-induced BAT variables | We observed that the relative abundance of the Partial Spearman correlation of fecal microbiota composition with BAT volume, SUVmean, SUVpeak, and mean radiodensity adjusted for the PET/CT scan date. Boxes represent the statistically significant (Next, we investigated whether the relative abundance of specific genera within the above-mentioned taxonomic groups was associated with BAT-related variables (Fig. Partial Spearman correlations of relative abundance of | PMC9938059 | ||
Relationship of fecal microbiota composition with cold-induced uptake of | The relative abundance of Partial Spearman correlation of fecal microbiota composition with tissues related to | PMC9938059 | ||
Discussion | This study shows, for the first time, that the relative abundance of The role of gut microbiota composition in BAT activation and metabolism has been investigated in mouse models [We also observed a positive correlation of the relative abundance of | PMC9938059 | ||
Limitations and strengths | comorbidity | DISEASE | The cross-sectional design of this study precluded us from establishing cause-effect relationships. Our study population includes young adults without relevant disease or comorbidity; thus, our results cannot be extrapolated to older or unhealthier populations. Importantly, SCFAs were not measured and could be of interest for future studies. Further, although BAT takes up glucose from circulation, intracellular fatty acids are the main substrate of brown adipocytes in humans [ | PMC9938059 |
Conclusions | This is the first study showing a negative correlation of the relative abundance of | PMC9938059 | ||
Acknowledgements | This study is part of a PhD thesis conducted within the Biomedicine Doctoral Studies Program of the University of Granada, Spain. | PMC9938059 | ||
Author contributions | L.O-A, F.M.A and B.M-T and J.R.R: designed the research. L.O-A, F.M.A, and B.M-T: conducted the research. G.S-D., R.V-V, A.L, J.P-D, J.M.L, A.G, I.L, and P.C.N.R: provided essential reagents or materials. L.O-A, H.X, F.M.A, and B.M-T: analysed data or performed the statistical analysis. L.O-A, F.M.A, and B.M-T: wrote the paper. J.R.R and B.M-T: had primary responsibility for the final content. All authors critically reviewed and approved the final manuscript. | PMC9938059 | ||
Funding | RVV, AiA | DEL | Funding for open access charge: Universidad de Granada / CBUA. The study was supported by the Spanish Ministry of Economy and Competitiveness via Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI13/01393) and PTA 12264-I, Retos de la Sociedad (DEP2016- 79512-R), and European Regional Development Funds (ERDF), by the Spanish Ministry of Education (FPU13/04365, FPU16/05159 and FPU17/01523), the Fundación Iberoamericana de Nutrición (FINUT), the Redes Temáticas De Investigación Cooperativa RETIC (Red SAMID RD16/0022), InFLAMES Flagship Programme of the Academy of Finland (decision number: 337530), Fundación Alfonso Martin Escudero and NextGenerationEU (Maria Zambrano fellowship: RR_C_2021_04). AstraZeneca HealthCare Foundation, the University of Granada Plan Propio de Investigación 2016-Excellence actions: Unit of Excellence on Exercise and Health (UCEES), and by the Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades (ERDF, SOMM17/6107/UGR). AL and RVV are supported by the funds of the European Commission through the “European funds for regional development” (EFRE) as well as by the regional Ministry of Economy, Science and Digitalization of Saxony-Anhalt as part of the “Autonomy in old Age” (AiA) research group for “LiLife” Project (Project ID: ZS/2018/11/95324). We would like to thank the team of the Data Integration Center of University Medicine Magdeburg for local data-analysis solutions; they are supported by MIRACUM and funded by the German Federal Ministry of Education and Research (BMBF) within the “Medical Informatics Funding Scheme” (FKZ 01ZZ1801H). | PMC9938059 |
Data availability | The datasets generated during the current study are available from the corresponding author upon reasonable request. | PMC9938059 | ||
Declarations | PMC9938059 | |||
Conflict of interest | The authors have no conflicts of interest. | PMC9938059 | ||
Research involving human participants and/or animals | The study protocol and the written informed consent were performed in accordance with the Declaration of Helsinki, as revised in 2013, and were approved by the Human Research Ethics Committee of the University of Granada (n°924) and the “Servicio Andaluz de Salud” (Centro de Granada, CEI-Granada). | PMC9938059 | ||
Informed consent | Informed consent was obtained from all individual participants included in the study. | PMC9938059 | ||
References | PMC9938059 | |||
Background | Lung cancer | DISEASE, ADVERSE EFFECTS, LUNG CANCER | Lung cancer (LC) is associated with high mortality and poor quality of life (QoL). The disease as well as oncological treatments such as radiation and chemotherapy with adverse effects can impair the QoL of patients. Add-on treatment with extracts of | PMC9990362 |
Methods | REGRESSION | A real-world data study was conducted using registry data. Self-reported QoL was assessed by the evaluation of the European Organization of Research and Treatment Health-Related Quality of Life Core Questionnaire scale (EORTC QLQ-C30). Adjusted multivariate linear regression analyses were performed to analyze factors associated with changes in QoL at 12 months. | PMC9990362 | |
Results | pain, non-small-cell lung cancer | A total of 112 primary LC patients (all stages, 92% non-small-cell lung cancer, median age 70 (ICR: 63–75)), answered the questionnaires at first diagnosis and 12 months later. Assessment of 12 months changes in QoL revealed significant improvement of 27 points for pain (p = 0.006) and 17 points for nausea/vomiting (p = 0.005) in patients who received combined radiation and VA. In addition, significant improvements of 15 to 21 points for role (p = 0.03), physical (p = 0.02), cognitive (p = 0.04), and social functioning (p = 0.04) were observed in guideline treated patients receiving no radiation but add-on VA. | PMC9990362 | |
Keywords | PMC9990362 | |||
Introduction | cancer deaths, Lung cancer | LUNG CANCER | Lung cancer (LC) remains the leading cause of cancer deaths worldwide [ | PMC9990362 |
Methods | PMC9990362 | |||
Study design and patients | ONCOLOGY | We conducted a longitudinal monocentric RWD study by extracting and analyzing demographic data, information on diagnosis, histology, integrative oncological treatment data as well as QoL data from the oncological registry Network Oncology (NO) [ | PMC9990362 | |
Objective | The objective of this study was to analyze the self-reported QoL in guideline-treated LC patients in a LC center and the association with additional VA therapy applied alone or in combination with radiation. | PMC9990362 | ||
Data collection | As described in detail previously [ | PMC9990362 | ||
Analyses of self-reported QoL | For the explorative evaluation of self-reported QoL the EORTC QLQ-C30 questionnaire was utilized and analyzed which includes evaluations of global health, functioning and symptom scales [ | PMC9990362 | ||
Statistical analysis | REGRESSION | Demographic and diagnostic variables were collected at T0. Continuous variables were described as median with interquartile range (IQR); categorical variables were summarized as frequencies and percentages. Student´s t-tests were applied, to detect differences; p-values < 0.05 were considered to be significant. Multivariable linear regression analyses were performed to identify influencing factors and to address potential sources of bias and confounders. In order to yield reliable model results, stepwise regression selections were performed and models with high adjusted | PMC9990362 | |
Results | PMC9990362 | |||
Discussion | breast cancer, cancer, Cancer-related pain, pain, lung cancer | BREAST CANCER, CANCER, ADVANCED CANCER, LUNG CANCER, REGRESSION | The findings of the present RWD study reveal significant improvements of self-reported QoL in LC patients receiving VA therapy alone or in addition to radiotherapy.Regarding QoL, it has been shown in clinical trials that VA treatment reduces chemotherapy-related side effects and improve tolerability, which then in turn may have a positive impact on QoL [In breast cancer patients it was previously described that several EORTC QLQ-C30 functioning as well as symptoms scales improved in association with concomitant VA therapy [In the present RWD study, marked, although not significant, reductions ranging from 10 to 18 points were observed for all the symptom scales except financial difficulties in patients receiving VA treatment without radiation (Table Cancer-related pain is multifactorial, and for that optimal pain relief multimodal treatments including anticancer therapies and analgesics should be implemented to achieve the best possible QoL. According to WHO recommendations, radiotherapy is used to reduce the need for analgesics and improve QoL [Even though patients in the combined RadVA group had more advanced cancer stages than the other groups (Table Limitations of our study include the non-randomized, non-controlled, and unblinded nature of the study design which is prone to various biases including selection bias. A possible bias arises from the fact that the observation period was 12 months and therefore no conclusions can be drawn about the QoL of patients who were unable or unwilling to respond after 12 months, or who were already deceased. However, we tried to reduce confounding bias by conducting adjusted multivariate linear regression analyses. Nevertheless, this RWD study provides implications for the clinical efficacy of concomitant VA treatment for LC patients being consistent with published data in LC patients and for other cancer entities. The strengths of our study include the presentation of real-world care of LC patients in a German certified lung cancer center. | PMC9990362 |
Conclusions | lung cancer, nausea, vomiting, pain | LUNG CANCER | Our results suggest that self-reported QoL has been improved 12 months after diagnosis in lung cancer patients receiving VA therapy. A remarkable benefit on self-reported pain, nausea and vomiting appears to be associated with combined radiation and VA treatment in this cohort. This stresses the importance of considering and evaluating combined oncological treatments with VA in future concepts for the improvement of QoL in lung cancer patients. | PMC9990362 |
Acknowledgements | We would like to thank all medical documentation officers of the NO consortium involved in the present work. | PMC9990362 | ||
Author contributions | Study conception and design: FS, DS, SLO, AT, CG; Project administration and resources: FS; Methodology: FS, DS, SLO, AT, CG; Provision of patients FS, CG; Supervision: FS, DS; Data curation and formal analysis: SLO, AT. Writing-original draft preparation: SLO. Writing—review and editing: FS, DS, AT, CG; All authors have read and agreed to the published version of the manuscript. | PMC9990362 | ||
Funding | The NO was partially funded by Iscador AG Arlesheim, Switzerland, Abnoba GmbH Pforzheim, Germany, and Helixor Heilmittel GmbH Rosenfels, Germany. By contract, researchers were independent from the funder. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. | PMC9990362 | ||
Availability of data and materials | The anonymized data that support the findings of this study are openly available in the repository figshare.com ( | PMC9990362 | ||
Declarations | PMC9990362 |
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