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Yogita Dhas, PhD

Content writer – Clinical

Easy-to-find irAEs can be used as indicators to predict neoadjuvant chemo-immunotherapy response.

Published on: August 16, 2023

Original author: Ye Tao, et al. (2023) (DOI: 10.3389/fonc.2023.1135140)

Lung cancer is the prominent cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) patients are diagnosed with early-stage disease in only 25% of cases, making them amenable to surgery with a curative goal. The development of neoadjuvant therapy made it possible for locally advanced patients to accept surgical resection, and the addition of immunotherapy further improve the pathological outcomes of these patients. Locally advanced patients might now accept surgical resection due to the development of neoadjuvant therapy, and the addition of immunotherapy significantly improves the pathological results in these patients. Patients with PD-L1-expressing locally progressed or metastatic NSCLC, as well as those with locally advanced disease following radical resection or concomitant chemoradiotherapy, have benefited greatly from the immunotherapy. It has been hypothesized that immune-related adverse events (irAEs) are linked to therapy effectiveness. In this prospective trial, the author explained how the early onset of irAEs was linked to better clinical outcomes. Methodology: This study was a prospective study performed on patients with NSCLC those received neoadjuvant Toripalimab (240mg, every 3 weeks) plus double platinum-based chemotherapy. This study was conducted between December 2020 to March 2022 at Peking University Cancer Hospital. This study (the Renaissance study, NCT04606303) received approval from the Peking University Ethic board (2020YJZ58). Patients who had resectable IIB-IIIB NSCLC without an EGFR/ALK mutation were included in the study. The authors have investigated the association between clinical outcomes and irAEs following neoadjuvant therapy. According to the clinical manifestation, an interdisciplinary team of doctors, surgeons, and radiologists confirmed the irAEs. Analysis was done on the relationship between irAEs and pathological outcomes. Results: A total of 55 patients were enrolled in this study, with a male-to-female ratio of 10:1 and a median age of 62 years old. Out of 55 patients, 44 were diagnosed with squamous cell carcinoma. With a median preoperative waiting period of 67 days (IQR 39-113 days), 48 of 55 patients eventually had thoracic surgery. According to the pathological findings, 24 patients (50%) and 31 patients (64.6%), respectively, had complete pathological responses and major pathological responses. Among the 48 patients who underwent R0 resection, immunotherapy-related thyroid dysfunction, rash/pruritus, and enteritis occurred in 11 patients (22.9%), 7 patients (14.6%), and 1 patient (2.1%), respectively. The median time to commencement of thyroid dysfunction was 45 days (IQR 21-91 days), and six patients (54.5%) with thyroid dysfunction obtained a major pathological response and five (45.5%) achieved a pathological complete response. The median time of onset was 8 days (IQR 6-29 days), six patients (85.7%) with rash or pruritus attained major pathological response and five patients (71.4%) achieved a pathological complete response. In addition, irAEs did not significantly affect preoperative waiting time (93 days vs 97 days, P=0.630), intraoperative blood loss (67.4 mL vs 64.3 mL, p=0.831), or operation duration (170.6 min vs 165.7 min, p=0.775). Impact of research: This clinical trial showed that the immunotherapy-related rash may be associated with pathological outcomes, demonstrating that basic irAEs like rash can be used as indicators to predict response to neoadjuvant chemo-immunotherapy. For patients with resectable NSCLC, this might result in a favorable therapeutic outcome as suggested by some irAEs. Given the potentially favorable signal on treatment-associated effects, this study underlined the significance of appropriately identifying irAEs that may benefit from neoadjuvant immunotherapy.

Phase 2 study of pembrolizumab in patients with recurrent and residual high-grade meningiomas.

Published on: April 12, 2023

Original author: Brastianos, P.K., Kim, A.E., et al. (2022) (DOI: 10.1038/s41467-022-29052-7)

Meningiomas are the most prevalent primary central nervous system tumor, with a prevalence of 170,000 cases in the United States. Maximal safe resection is the cornerstone of meningioma treatment, and adjuvant radiation may be necessary in some cases. Due to lack of effective systemic therapies, there are limited options for additional therapies, especially for recurrent or higher-grade meningiomas. Recent studies suggest, targeting the immunological microenvironment may be a promising meningioma treatment. The authors consequently proposed that pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, would have antitumor activity for high-grade meningiomas. The authors have designed a prospective phase-2 study investigating pembrolizumab in patients with progressive high-grade meningiomas using a dosage schedule that has proven effective in systemic cancers. Methodology A total of 26 patients were enrolled, who had grade 2 or 3 meningiomas that were histologically determined to be progressive, residual, or intracranial. This study was conducted from November 2017 to January 2021. A 200 mg dose of pembrolizumab was injected intravenously every 3 weeks, until the time of disease progression, death, or intolerable toxicity. While dose interruptions for adverse events (AEs) for up to 12 weeks were authorized, dose reductions were not. Every 6 weeks, a brain MRI was taken for restaging. Intracranial and extra cranial responses were assessed. Results Out of a total of 26 patients, 1 patient withdrew consent before receiving pembrolizumab. Hence, 25 individuals served as the sample size for efficacy and safety evaluations of pembrolizumab, a PD-1 inhibitor. The primary endpoint of the study was the proportion of patients alive and progression-free at 6 months (PFS-6). Secondary endpoints comprise progression-free and overall survival, best intracranial response, and toxicity. With a PFS-6 rate of 0.48 and a median PFS of 7.6 months, this study has successfully achieved its primary goal. One (or more) grade-3 or higher treatment-related adverse events have been seen in 20%. Conclusion According to these findings, pembrolizumab shows promising efficacy against a subset of malignant cancers. To determine the biological characteristics of the meningioma tumor microenvironment that may influence the effectiveness of immune-based treatments, additional research is required.

Grading of IDH‑mutant astrocytoma using diffusion, susceptibility, and perfusion‑weighted imaging.

Published on: January 17, 2023

Original author: Yang X, Xing Z, She D, et al. (2022) (DOI: 10.1186/s12880-022-00832-3)

The accurate grading of IDH-mutant astrocytoma is essential to develop therapeutic strategies and evaluating the prognosis of patients. A preoperative classification of these entities could be beneficial for the treatments of patients, particularly in those who have a contraindication to surgery or in cases where the lesions are unresectable. With the aid of apparent diffusion coefficient (ADC) measurements, diffusion-weighted imaging (DWI) can noninvasively evaluate the Brownian motion of water molecules in vivo. The grading of gliomas may benefit from using dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI), which can offer hemodynamic parameters with tumor angiogenesis. Susceptibility-weighted imaging (SWI), a more improved approach, may semi-quantitatively evaluate tumor micro-hemorrhages and vasculature via intratumoral susceptibility signal intensity (ITSS). These techniques have all been used to distinguish between different glioma grades. IDH-mutant astrocytic glioma grading is a topic that is rarely covered in studies. The combination of DWI, DSC-PWI, and SWI may help to increase the accuracy of diagnosis in IDH-mutant astrocytic gliomas. Therefore, the researchers in the present study investigated the usefulness of DWI, SWI, and DSC-PWI in grading IDH-mutant astrocytoma. Methodology In the present study, 107 patients with IDH-mutant astrocytoma who underwent DWI, SWI, and DSC-PWI were retrospectively evaluated. Values for the minimum apparent diffusion coefficient (ADCmin), maximum relative cerebral blood volume (rCBVmax), and intratumoral susceptibility signal intensity (ITSS) were evaluated. ADCmin, ITSS, and rCBVmax values were studied between grade 2 vs. grade 3, grade 3 vs. grade 4, and grade 2 + 3 vs. grade 4 tumors. To rate their diagnostic abilities, receiver operating characteristic (ROC) curve analysis, tenfold cross-validation, and logistic regression were performed. Results The results of the present investigation showed that, in comparison to grade 3 tumors, Grade 4 IDH-mutant astrocytoma’s displayed considerably lower ADCmin and greater rCBVmax (adjusted p <0.001). When compared to grade 4 tumors, grade 3 IDH-mutant astrocytomas had considerably reduced ITSS levels (adjusted p <0.001). Grade 2 and grade 3 IDH-mutant astrocytomas had significantly different ITSS levels (adjusted p = 0.002). The highest AUC for differentiating grade 2 and grade 3 cancers from grade 4 tumors was obtained when the ADCmin, ITSS, and rCBVmax were combined. Impact of research This study demonstrated that DWI, SWI, and DSC-PWI are useful for assessing the tumor grade in IDH-mutant astrocytomas. The diagnostic precision of grading IDH mutant astrocytomas may be enhanced by the combination of ADCmin, ITSS, and rCBVmax. This study proposed that the combination of these advanced techniques could improve the diagnostic efficacy in grading IDH-mutant astrocytic gliomas.

A six-metabolite panel as potential blood-based biomarkers for Parkinson’s disease.

Published on: October 18, 2022

Original author: Stephan Klatt, et al. (2021) (DOI: 10.1038/s41531-021-00239-x)

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD) and affects around five million people worldwide. People with PD typically exhibit symptoms when 50% or more dopaminergic neurons of the substantia nigra are demolished. Therefore, the early introduction of disease-modifying treatments would result in maximum effectiveness. Ideally, this would be before major neuronal death and, hence, long before clinical symptoms become apparent. Currently, there aren't any disease-modifying treatments for PD, thus early and precise diagnosis of PD might help researchers find such treatments. Research into the understanding of the early pathophysiological event in PD would be supported by pre-symptomatic detection. Presently, there is no trustworthy biomarker for pre-symptomatic idiopathic PD (iPD) detection. This emphasizes the significance of the development of a new diagnostic marker to enable early diagnosis and evaluation of new potential treatments. Methodology In this study, 38 iPD-relevant metabolites were extracted from the blood serum of 231 individuals, and the concentration of these metabolites was quantified by using a targeted triple quadrupole liquid chromatography-mass spectrometry (QQQ LC/MS) method, to uncover changes solely based on the disease. This cohort is presently one of the largest metabolomic studies including iPD patients, drug-naive iPD, healthy controls, and patients with Alzheimer’s disease as a disease-specific control group. All the experiments were conducted under The University of Melbourne human ethics committee approval ID1136882. All participants provided written informed consent before their inclusion in the study. They examined the impact of L-DOPA on the tested metabolites along with the impact of age and sex before and after confounder adjustment. Additionally, they examined changes in the ratios and interactions of all targeted metabolites and used this to recognize potential biomarkers. Results The study found six metabolites (3-hydroxykynurenine, aspartate, beta-alanine, homoserine, ornithine, and tyrosine) that were significantly different between iPD patients and control participants. There were no substantial interactions between either age and control/iPD or between gender and control/iPD associated with metabolites. They also investigated all possible ratios and interactions. Comparing the mean ratio/interaction levels between the control and iPD groups, they identified 11 ratios and 23 significantly different interactions (p < 0.00009) between the two groups. In addition, they performed a multivariate analysis including both individual analytes and ratios/ interactions to examine if a panel of markers collectively could provide better discrimination between control and disease groups. Using a combination of feature selection (LASSO) and model selection via Akaike information criterion (AIC) reduction, seven markers including Cys, 2-aminobutyric acid, Tyr, L-KYN, a ratio of Arg/3-AA, a ratio of Asp/L-KYN, and product of β-ala*Orn were selected in a linear model to separate control from iPD participants. These seven metabolites resulted in an AUC value of 0.905 with an accuracy of 86.2%. Using the same method, a set of six markers were selected in a linear model to separate control from AD participants (Asp, Cys, Tryp, Homoserine/N-Acetyl-phenylalanine, Pro/3-HK, and Gln*Typtamine). A multivariate model to predict AD from controls had an area under the curve (AUC) of 0.884, with an accuracy of 79.3%. Impact of research The study measured the concentration of relevant metabolites extracted from the blood serum of 231 individuals to uncover changes solely based on the disease. This study also identified potential biomarkers to distinguish between control and disease (PD and AD). Presently, various tissue- and fluid-based biomarkers are being explored to enhance PD diagnosis, monitor disease progression, assess treatment responses, or categorize PD subtypes. Therefore, a panel of biomarkers could aid to increase the accuracy of iPD diagnosis and treatment outcomes and they have a great potential for utilization in clinical practice. Conclusion iPD and its progression appear to cause global metabolic alterations in peripheral body fluids as well as the brain. This study adds to the evidence that amino acids and metabolites of the kynurenine pathway are changed in patients with iPD. The present study suggested that the panel of metabolites might be used as a potential prognostic or diagnostic assay for clinical trial prescreening, or for assisting in diagnosing pathological diseases in clinics.

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